JML Transcription

AR07231
1 three affiants?
2 A. Yes, pardon, pardon me. Yes, yes, yes.
3 11 Q. Okay. And to clarify, I believe you referred to Dr.
4 Phillips, I think it’s just Mr. Owen Phillips.
5 A. Okay.
6 12 Q. Is that accurate?
7 A. Yes, I had a look at that as well, yes. That’s
8 accurate.
9 13 Q. Okay, thank you. And, Dr. Schabas, where are you
10 located today?
11 A. I’m in Toronto.
12 14 Q. Okay. Are you in your residence?
13 A. Yes.
14 15 Q. Okay. And do you have a copy of your affidavit and
15 exhibits before you?
16 A. I, I have - yes, I believe I do. I’ve got them - I’ve
17 got the affidavit, I can probably find the exhibits if
18 need be. I’m not - no, I don’t have the exhibits in
19 front of me.
20 16 Q. The exhibits including your expert report?
21 A. No, I have my expert report. I have my, my expert
22 report and I have my CV, I think. Yes, I have, I have
23 those, yes. So I have those...
24 17 Q. Okay.
25 A. I don’t have all the footnotes for my, my affidavit.
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1 That’s all.
2 18 Q. So when you say your footnotes you mean the
3 authorities on which you relied in your expert report?
4 A. That’s what I meant, yes.
5 19 Q. Okay. But you do - I wanted to clarify, you have your
6 exhibit - your, I’m sorry, your affidavit and the main
7 exhibits to it which include your CV and your expert
8 report.
9 A. Correct.
10 20 Q. Okay. Do you have anything else before you?
11 A. I have on, just looking at my computer screen, what I
12 have open, I have opened a copy of the Federal/
13 Provincial/ Territorial document that you circulated
14 to me a few hours ago. I think that’s all I have open
15 on my screen.
16 21 Q. Okay. Okay, thank you. Other than those documents we
17 just discussed, you can confirm you do not have any
18 notes or any other materials before you?
19 A. I do not, no. No.
20 22 Q. Thank you. And you agree you will not access anything
21 else unless it is shared with you?
22 A. If that’s - I mean I don’t know the rules here, but
23 I’m quite happy not to access anything else unless
24 it’s okay with you. No problem.
25 23 Q. Okay. All right, thank you. And just one more thing,
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1 and can you confirm that you will not discuss any
2 aspect of this cross examination in any matter -
3 manner with any other person until it is concluded
4 including during any breaks we may take with the
5 exception of discussion with counsel on questions to
6 which he has raised an objection.
7 A. That’s fine.
8 24 Q. Okay. And just a few other small housekeeping

9 matters, I don’t expect to keep you too long today,
10 but you can expect we’ll likely take a break at about
11 90 minutes in if we are not then concluded or close to
12 being concluded.
13 A. Okay.
14 25 Q. However, if you consider you otherwise need a break,
15 please let me know and we will try to accommodate you.
16 A. Okay, thank you.
17 26 Q. And my - and of course also, almost all my questions
18 will be in respect of your expert report which you’ve
19 attached as an exhibit to your affidavit. I will
20 always try to be accurate and identify the document on
21 which I’m asking questions. However, if I’m silent on
22 this point, you should expect my questions to be in
23 respect of your report.
24 A. Okay.
25 27 Q. Is that a fair approach and will you understand if I
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1 do that?
2 A. Seems fine to me, yeah.
3 28 Q. Thank you. All right, one last question before we
4 proceed, are there any corrections you need to make to
5 your affidavit and attachments since it was sworn,
6 served, and filed?
7 A. I’m not aware of any. There are a couple of
8 grammatical errors, but I think you’ll probably

9 forgive me on, on those. But other than that, I don’t
10 think so.
11 29 Q. Okay. Small typographical errors of and of things of
12 that nature is what you’re referring to.
13 A. Well I think I put an apostrophe on an its when I
14 shouldn’t have, but my Grade 6 teacher will have to
15 forgive me.
16 30 Q. Well, Dr. Schabas, my father was a professor of
17 English, so I know full well what that’s like. All
18 right, thank you. Dr. Schabas, I note from your
19 report, and it’s supported by your CV, that you are a
20 retired physician, that’s correct?
21 A. That’s correct.
22 31 Q. And you retired in 2016.
23 A. The end of 2016, yes.
24 32 Q. Okay. And are you - do you currently practice as a
25 physician in any capacity?
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1 A. I do not. I don’t do any clinical medicine. The
2 extent of my practice, I guess, has been, has been
3 things like this affidavit with relation to, well
4 almost exclusively, Covid-19, yes.
5 33 Q. Okay. And just going to clarify a few things, you do
6 not currently have any hospital privileges?
7 A. I don’t have a medical license. I’m, I’m, I’m an
8 Emeritus Fellow of the Royal College of Physicians,

9 but I have no medical licenses, no hospital
10 appointments, no university appointments anymore.
11 34 Q. Okay. I was going to ask about university
12 appointments, thank you for clarifying that. And you
13 are not currently engaged in any active medical
14 experimental research?
15 A. No.
16 35 Q. I read your CV and it indicates you have not published
17 any peer reviewed papers since 2012, is that still
18 accurate?
19 A. I, I, yes, I think that’s true, yes.
20 36 Q. All right. So to - I read your CV, of course, and I
21 note you were the Chief Medical Officer of Health for
22 the province of Ontario in 1997 - sorry, ’87 to ’97,
23 and that’s accurate. And you were also a Medical
24 Officer of Health for one of the regional health units
25 in Ontario, is that - that’s correct?
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1 A. Twice. I was a Medical Officer of Health for the
2 bureau of East York Health Unity from, I think, it was
3 ’83 to ’87 before I became the Chief Medical Officer
4 of Health and then I was the Medical Officer of Health
5 for the Hastings, Prince Edward County Health Unit
6 from, I’m going from memory here, but I think it was
7 sort of 2005 to 2016, yes.
8 37 Q. And if I use the shorthand Hastings Public Health

9 Unit, you’ll understand that I’m referring to...
10 A. Prince Edward County may forgive you, yes.
11 38 Q. Yes, thank you. Now I understand that, with the
12 Ontario system, that as you described, each regional
13 health unit has a Medical Officer of Health and that’s
14 correct? And...
15 A. Yeah, they’re not, they’re not actually technically
16 regional health units, they’re - a health unit is a
17 geographic area defined by law. Each, each, each
18 health unit has a Board of Health or in some cases the
19 regional counsel, if there is a regional counsel,
20 serves as the Board of Health.
21 39 Q. Okay. I’ve also seen the term a public health unit,
22 is that...
23 A. Yeah, that, that actually has a, well, public health
24 unit, has a legal meaning and it, it refers to it in
25 the - under the Health Protection and Promotion Act,
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1 it refers to a geographic area. But the term has
2 often been used to describe the organization itself,
3 so it’s, it’s the, the, the, the organization that
4 provides public health is often referred to not quite
5 correctly as a public health unit.
6 40 Q. No, that’s fair. So as Chief Medical Officer of
7 Health for Ontario for those ten years, 1987 through
8 1997, what I understand - and this may be more the

9 current obligation on the Chief Medical Officer of
10 Health, but would you agree that it’s to ensure that
11 appropriate actions are taken to respond to urgent and
12 emergency situations?
13 A. I, I’m, I’m not sure that that was ever articulated
14 specifically, but I think there was an understanding
15 that, that there were - the Chief Medical Officer of
16 Health, I always felt, had the responsibility to
17 provide the leadership, the provincial level, level
18 leadership. The - you should probably know, the
19 Medical Officers of Health actually don’t report to
20 the Chief Medical Officer of Health in, in a direct
21 way. But the Chief Medical Officer of Health, I
22 always felt, had an overarching responsibility for the
23 province and indeed, even then, had powers that if it
24 was necessary to assume the authority over a local
25 Medical Officer of Health, there was a mechanism for
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1 doing that. It never happened in my - that was never
2 necessary in my ten years as Chief MOH, but I always
3 felt the responsibility was there and, and, and the
4 authority was there if needed.
5 41 Q. Okay. So that was going to be my question, the Chief
6 Medical Officer of Health has the authority to direct
7 local jurisdictions to implement Public Health actions
8 in response to a Public Health risk or emergency.

9 A. The law, and again, I’m, I’m thinking back to when I
10 was the Chief Medical Officer of Health and when I was
11 more famil - I was - I don’t know with - how to the
12 extent the law has been amended, but I was very
13 familiar with it then, the, the Chief Medical - the,
14 the Minister of Health could direct the Chief Medical
15 Officer of Health to assume the authority of a board
16 of health. And that meant – in it that was a
17 mechanism by which the Chief Medical Officer of Health
18 could essentially take over a local board of health if
19 necessary.
20 42 Q. Okay. And in acting through your roles as the Chief
21 Medical Officer of Health, you would receive
22 information from the Ministry of Health in respect of
23 Public Health issues.
24 A. Yes.
25 43 Q. Yeah. And information that would not necessarily be
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1 immediately publicly available.
2 A. I’m, I’m not sure that was ever an issue. I’m not -
3 with related to Public Health matters, we, we, I mean,
4 we, we receive reports of infectious diseases which
5 are confidential. But they came up through the local
6 Medical Officers of Health through the Ministry of
7 Health, but to that extent, yes.
8 44 Q. Okay. So you would receive information from the local

9 Medical Officers of Health is what you said, correct?
10 A. They, they had, they, they have - had a legal
11 responsibility to report some information about some
12 communicable diseases, yes.
13 45 Q. Thank you. Right. I’m just going to go through a few
14 sources in your expert report. Taking you to
15 paragraph 16 of your report, if you have it available.
16 A. Hang on just a second. Yeah, okay.
17 46 Q. Okay. There’s a sentence there and I think it reads,
18 “While influenza is not the same as SARS Covid-19,
19 these diseases share many similarities particularly
20 related to the dynamics of transmission and, by
21 analogy, the presumed effectiveness of control
22 measures.” Do you see that sentence?
23 A. Yeah. I do, yes.
24 47 Q. And at footnotes nine and ten within that sentence,
25 you cite two Wikipedia entries for influenza and
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1 Covid-19.
2 A. Yeah, Mm-hmm.
3 48 Q. Is...
4 A. Those are good summaries of, of, of those aspects,
5 yes.
6 49 Q. So you consider it to be a good summary?
7 A. Yes. Of - to the extent that I cite it there, yes.
8 The, the diseases are similar and particularly the,

9 the dynamics of transmission are similar, yeah.
10 50 Q. Do you consider Wikipedia to be an authoritative
11 source for medical information?
12 A. I think in so - I, I think it varies on the article
13 and on the, on the - it’s like, it’s like, it’s like
14 articles in peer-reviewed journals. Some of them are
15 authoritative and some of them, I’m afraid, are junk.
16 But I was, again, it’s been a few months since I
17 looked at this, but I think I was reasonably
18 satisfied. The, the - there’s, there’s nothing,
19 there’s nothing very controversial about, about, I
20 don’t think, about the, the statement that the
21 dynamics of transmission of these two diseases are
22 similar.
23 51 Q. Okay, but do you consider Wikipedia to be equivalent
24 to a medical encyclopedia?
25 A. I don’t think anybody uses medical encyclopedias
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1 anymore, so I can’t comment on that.
2 52 Q. Okay. Do you consider it to be equivalent to a
3 medical textbook?
4 A. I think in some cases, in some articles, it will be
5 better than medical textbooks because it will be more
6 up to date than medical textbooks. I don’t think
7 you’ll find much about Covid-19 in, in medical
8 textbooks, not in published medical textbooks. I

9 think it was reliable enough for the purposes for
10 which I used it.
11 53 Q. Okay, thank you, Dr. Schabas. In paragraph 35 of your
12 report...
13 A. Okay. Hang on, just give me a second. Let me get...
14 54 Q. Absolutely.
15 A. Okay.
16 55 Q. Sorry. In paragraph 35 of your report, there’s a
17 sentence there, you say the risk of contracting SARS
18 Covid-19 during air travel is probably very low and
19 then you have a quotation mark...
20 A. Yeah.
21 56 Q. Lower than from an office building, classroom,
22 supermarket, or commuter train, end quote.
23 A. Yeah.
24 57 Q. So I notice there you footnote to - you have a
25 footnote number 17...
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1 A. Yeah.
2 58 Q. And it takes you to the landing page of
3 jamanetwork.com. Now do you agree that JAMA Network
4 is an open access medical journal published...
5 A. Yeah.
6 59 Q. By the American Medical Association?
7 A. Yes, Mm-hmm.
8 60 Q. And would you agree that the landing page is not an

9 article?
10 A. And I apologize, the - when I clicked the link, it
11 took me to the article on this subject. So if, if
12 that’s not - if that doesn’t land where I thought it
13 did, I, I guess I’m not as, as, as, as, as adept with
14 some of these things as I thought. I apologize for
15 that. There, there was related to a - there was a, a
16 summary article from which I drew this quote in, in
17 JAMA which is what I was relating to. So I apologize
18 if the link doesn’t connect there.
19 61 Q. Okay. Mr. Presvelos, it’s not my practice to ask for
20 undertakings.
21 MR. PRESVELOS: I’ll give it to you anyway.
22 MR. DRUMMOND: During cross...
23 MR. PRESVELOS: Yeah.
24 MR. DRUMMOND: Examination, but I’m going to ask if you could
25 undertake to provide the site to the article that...
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2 MR. DRUMMOND: Dr. Schabas took that summary from.
3 UNDERTAKING 1: Provide the specific link to the JAMA
4 Network website that brings you to the article
5 mentioned in footnote 17 of Dr. Schabas’ expert
6 report.
8 MR. DRUMMOND:
9 62 Q. Okay. And one more question about sources, Dr.
10 Schabas,...
11 A. Mm-hmm.
12 63 Q. Footnote 18 of your report, you provide a link to a
13 paper, it’s on a medRxiv...
14 A. Yeah.
15 64 Q. Org...
16 A. Yeah.
17 65 Q. Link. And it’s a paper from Buchan and I’m hoping I’m
18 pronouncing that name right.
19 A. Yeah.
20 66 Q. Entitled Effectiveness of Covid-19 Vaccines Against
21 Omicron or Delta Symptomatic Infection and Severe
22 Outcomes.
23 A. Okay, yeah. That’s...
24 67 Q. Now, do you acknowledge that this document is a pre-
25 print?
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1 A. I do. I’m just looking at - that’s the wrong
2 reference. I don’t - there, there’s an error there.
3 The, the, the Buchan article relates to Ontario,
4 that’s the test negative, it’s the paper you shared
5 with me. And I apologize, that’s not the correct
6 reference. There is another reference, and I don’t
7 know how that happened, that, that reflected that. So
8 the, yeah, the Buchan paper is a pre-print. It was in

9 fact subsequently published that analysis was
10 subsequently published later as a peer-reviewed paper,
11 but it was a pre-print. But it’s the wrong reference
12 for that statement anyway.
13 68 Q. Okay. Mr. Presvelos, I’m going to ask for another
14 undertaking for Dr. Schabas to correct...
15 UNDERTAKING 2: Correct any footnotes in Dr. Schabas’
16 expert report including the incorrect reference in
17 footnote 18.
18 MR. PRESVELOS: I was already going to do it, yeah.
19 MR. DRUMMOND: Yeah, and any references in his footnotes that are
20 inaccurate.
21 MR. PRESVELOS: Okay.
22 MR. DRUMMOND: All right, may I proceed, Mr. Presvelos? I don’t
23 want...
25 MR. DRUMMOND: Okay, thank you. All right, Dr. Schabas, can you
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1 - I noticed that it’s in your list of documents and
2 earlier in this examination you mentioned that you had
3 before you the Canadian Pandemic Influenza
4 Preparedness Planning Guidance for the Health Sector?
5 A. No, I didn’t say I had it before me. The one I had
6 before me is the FTP report.
7 69 Q. Okay. I am, okay, I’m going to share my screen again.
8 If you’ll bear with me one second.

9 A. Sure.
10 70 Q. Are you, oh sorry, are you able to see that document?
11 Dr. Schabas, is it visible to you?
12 MR. PRESVELOS: I think he’s frozen.
13 MR. DRUMMOND: Okay.
14 MR. PRESVELOS: At least I don’t see - I can’t see any movement
15 on my end. I don’t know if you can see him move at
16 all on your end.
17 MR. DRUMMOND: I cannot. His screen is blank.
18
19 OFF RECORD TECHNICAL ISSUES
20
21 MR. DRUMMOND:
22 71 Q. Okay, Dr. Schabas, we had a small technical problem.
23 Can you, just for clarity, can you confirm what you
24 last heard before you - we lost connection with you?
25 A. Well you were talking about sharing the, the Pandemic,
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1 the, the National Pandemic Influenza Plan with me.
2 72 Q. Okay. All right, I’m going to try that again.
3 A. Okay.
4 73 Q. Okay. Dr. Schabas, can you see this document that
5 says at the top Canadian Pandemic Influenza
6 Preparedness Planning Guidance for the Health Sector?
7 A. Yes, I can.
8 74 Q. Okay. Dr. Schabas, for short forms, will you

9 understand me if I use the acronym CPIP...
10 A. Sure.
11 75 Q. To refer to this document?
12 A. Sure, no problem.
13 76 Q. Okay. And I under - I note that this document is
14 cited in your list of materials used in the
15 preparation of your expert report. That’s accurate?
16 A. That’s accurate, yes.
17 77 Q. And so you have reviewed this document?
18 A. I did, yes.
19 78 Q. Okay. And you are aware that this document, this
20 version of the document, was published in 2018?
21 A. Yes.
22 79 Q. Okay, thank you. Were you involved in the writing of
23 the 2018 version of CPIP?
24 A. No.
25 80 Q. Okay. Were you or are you a member of the CPIP task
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1 group?
2 A. No.
3 81 Q. Okay. Okay and do you recognize that CPIP is not a
4 response plan to an influenza pandemic?
5 A. I’m not quite sure what you mean by that.
6 82 Q. All right. I’m going to take you to section 1.2...
7 A. Okay.
8 83 Q. Of the CPIP. I’m going to actually shrink this

9 slightly. Is it still visible to you?
10 A. Yeah, that’s fine.
11 84 Q. This is on, it would be at the bottom of the page,
12 page seven of this document. Do you note that in that
13 last paragraph in section 1.2, it states it is
14 important to note that CPIP is not an actual response
15 plan rather it is a guidance document for pandemic
16 influenza that can be used to support an FPT? And I
17 take it you understand FPT means Federal, Provincial,
18 Territorial.
19 A. Yes, that’s fine. Yeah.
20 85 Q. All hazards, health emergency response approach. So
21 I’ll just ask again, do you recognize that CPIP is not
22 an actual response plan?
23 A. Yes. And I note also it says while CPIP is specific
24 to pandemic influenza, much of its guidance is also
25 appl - applicable to other Public Health emergencies.
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1 Yes, I do note that.
2 86 Q. Yes, thank you. Yes, that’s an accurate statement of
3 what follows. Dr. Schabas, as a general proposition,
4 do you agree that any Public Health response to a
5 public health emergency, including a pandemic, should
6 be based on best available information?
7 A. Yes.
8 87 Q. And do you agree that the best available information

9 about a Public Health emergency or the effectiveness
10 of measures in response may change through the course
11 of the emergency?
12 A. Yes.
13 88 Q. And so do you agree that Public Health measures in
14 response to a Public Health emergency may change in
15 response to changing information?
16 A. I would hope they would change in response to changing
17 information.
18 89 Q. Okay. And do you agree that CPIP contemplates that
19 decisions on appropriate health measures may change
20 based on available evidence?
21 A. That’s my recollection, yes.
22 90 Q. Okay. Do you agree also that CPIP endorses a
23 precautionary approach in periods of uncertainty in a
24 pandemic?
25 A. Yes.
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1 91 Q. Okay, thank you. And finally, do you agree that CPIP
2 contemplates that travel restrictions may be used in
3 certain situations?
4 A. Yes.
5 92 Q. Thank you. I’m going to stop sharing my screen. Mr.
6 Presvelos, I’d like to just enter this as an exhibit,
7 please.
8 EXHIBIT 1: Canadian Pandemic Influenza Preparedness

9 Planning Guidance for the Health Sector.
10 MR. PRESVELOS: Go ahead.
11 MR. DRUMMOND: Madame Reporter, I think that would be - I don’t
12 know if you use Exhibit 1 or Exhibit A, but it would
13 be the first.
14 COURT REPORTER: Okay, we’ll use numbers because the other ones
15 we use numbers. So Exhibit 1.
16 MR. DRUMMOND: That’s fine, thank you. Dr. Schabas, have you -
17 are you aware of the Federal, Provincial, Territorial
18 Public Health response for ongoing management of
19 Covid-19?
20 A. Yes, I’m aware of it.
21 93 Q. Okay. Have you reviewed it before today?
22 A. Not in any detail. I’ve had a l - I, I, I, the answer
23 is I have reviewed it, yeah, but not in any detail.
24 Yes, but I have been aware of it, yes. We’re talking
25 about the most recent version, I hope, the March 25,
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1 2022 version or...
2 94 Q. Yes...
3 A. Yeah, that’s fine. Yes. So sure.
4 95 Q. Again, I’m just going to share my screen for that
5 purpose. And do you recognize this document? You
6 said you would have had - it would’ve been provided to
7 you earlier this morning?
8 A. Yes, that’s right.

9 96 Q. And this is the Federal/ Provincial/ Territorial
10 Public Health Response Plan for Ongoing Management of
11 Covid-19. And just to be clear, this is the third
12 edition dated March 25, 2022.
13 A. Correct, yeah. Yes.
14 97 Q. And I, and Dr. Schabas, I appreciate that this was
15 issued after your affidavit was sworn. Did you review
16 the second edition issued in April 2021?
17 A. No, I have not seen any of the earlier versions.
18 98 Q. Okay. Just - and so just to confirm, you did not see
19 or review the first edition issued in August 2020?
20 A. No.
21 99 Q. Okay. I’m just going to take you to a section of this
22 document. And again, I’m going to make it smaller.
23 And this, for clarity, this is on page six of the
24 document. There are pages at the bottom there in blue
25 and I’m taking you to a provision on page six. And do
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1 you under - are you aware of the purpose of this
2 management plan? I’m sorry, is my screen no longer
3 visible?
4 A. No, I, I see, I see you on your screen. Yes, there
5 you are. But, but I, I don’t see the document on the
6 screen.
7 100 Q. Okay. I am going to try again. Visible. Okay, I’m
8 going to close this and try again. I hope you’ll bear

9 with me. Dr. Schabas, do you see on your screen at
10 the top it says 1. Introduction?
11 A. Yes, I do.
12 101 Q. Okay. Are you aware of the purpose of this document?
13 A. Yeah, the purpose is stated in the first paragraph.
14 It’s basically a high level planning document.
15 102 Q. Okay. And you agree that it’s a forward planning
16 approach for ongoing management of Covid-19 in Canada?
17 A. Well I’m not sure what the difference is between a
18 forward planning and a planning approach since all
19 planning is forward, but yes, I think that’s what it
20 is. Yeah.
21 103 Q. Okay. I take your point that all planning is forward.
22 We don’t want to get caught in odd time issues. Now
23 I’m just - given the purpose of this document, I’m
24 going to ask you about a statement in your affidavit
25 at paragraph 22.
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1 A. Okay.
2 104 Q. I’m just going to stop sharing for a moment.
3 A. Paragraph 22, now let me just find my paragraph 22.
4 Okay.
5 105 Q. Okay. In that paragraph, you state, “Since it was
6 very clear from” - I’m sorry, I don’t want to misread
7 it, let me start again, “Since it was clear from very
8 early days that the dynamics of transmission of SARS

9 Covid-19 were fundamentally like those expected of
10 pandemic influenza, Public Health should’ve relied on
11 these plans as a basis for its response to Covid-19.”
12 A. Yes.
13 106 Q. And do - so do you stand by that statement given this
14 subsequent planning document from Federal/ Provincial/
15 Territorial authorities?
16 MR. PRESVELOS: Sorry, counsel, sorry, if I may, counsel, have
17 you established when the very first Federal/
18 Provincial/ Territorial Public Health Response Plan
19 was actually published? So the version that’s in
20 front of the doctor is May 25, 2022. I understand
21 they may have been one around a year earlier in 2021
22 at, I mean, have we established when the very first
23 FPT Response Plan was actually published? I think
24 that’s an appropriate context in asking this question.
25 MR. DRUMMOND: I did say it was – it was in, the date, I’m sorry,
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1 it was August 2020.
2 MR. PRESVELOS: I didn’t hear that, sorry. So you said August
3 2020 was the first version of this plan.
4 MR. DRUMMOND: The first edition, yes.
5 MR. PRESVELOS: Sorry, the first edition of this plan.
6 A. So just to be clear, what that sentence refers to is
7 it refers to the, the initiation of the response to
8 Covid-19. That’s the intent of the sentence is that

9 it’s all in, it’s all in the past tense, should have
10 relied on those plans as a basis for the response to
11 SARS Covid-19. So that, that’s what that sentence
12 means.
13 MR. DRUMMOND:
14 107 Q. That - in that, you would include CPIP as a document
15 that should’ve been relied on for planning?
16 A. Yes.
17 108 Q. Okay.
18 A. Among other documents, but certainly CPIP was one of
19 them, yes.
20 109 Q. Okay. And you would agree that it’s appropriate to
21 update these plans?
22 A. Absolutely, yes.
23 110 Q. Thank you. Just a moment, please. Sorry, one second.
24 Thank you for your patience, Dr. Schabas. I’m going
25 to take you to another page in the same document I
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1 referred to earlier. I’m going to share my screen.
2 And for identification purposes, this is at page, I
3 believe, it’s 64 of the document. And at appendix ten
4 it refers to international border...
5 A. I’m, I’m not looking, I’m not, I’m not, I’m not
6 looking at the document, I’m looking at you.
7 111 Q. I’m terribly sorry.
8 A. There we go. Now, here we go, okay.

9 112 Q. You would think after two years I’d know how to use
10 this technology better but thank you. In the first
11 paragraph under appendix ten, you - the second
12 sentence there it says in reference to border and
13 travel health programs, I’m sorry. These measures
14 together - actually, I’m just going to read the two
15 sentences. “Since the onset of the pandemic, the
16 Public Health Agency of Canada”, I’m going to use the
17 acronym PHAC, P-H-A-C, “has significantly shifted and
18 expanded its border and travel health programs to
19 focus primarily on mitigating the risk of Covid-19
20 importation. These measures together with other FPT
21 responses help to protect the capacity of provinces
22 and territories and to provide health services to
23 Canadians. Prior to Covid-19, it was not envisioned
24 that Canada would implement extent to border closures
25 as a pandemic response measure.” You agree that
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1 before Covid-19 and in part based on CPIP, there was
2 no contemplation of border measures in most cases?
3 A. Oh, as I point out in my affidavit, this issue was
4 discussed by the WHO document on non-pharmaceutical
5 interventions in an influenza pandemic. And they, I
6 believe, I’m, I’m going from memory, but I believe
7 they specifically recommended against border closures
8 as a control measure.
9 113 Q. In respect of an influenza pandemic?
10 A. Yes. And, and as we noted when we looked at the
11 Canadian plan, that those sorts of lessons in fact
12 should also be applied more broadly to Public Health
13 emergencies as CPIP suggested.
14 114 Q. And you would agree that Covid-19 is a different
15 pandemic from previously seen influenza pandemics?
16 A. Well as I explain in my affidavit, they are different
17 viruses. I don’t think that’s a surprise to anyone.
18 But, I guess, the point I make in my, in my affidavit
19 and which I, I very much stand by, is that when at the
20 beginning of the, of the Covid-19 pandemic, decisions
21 had to be made and they had to be made with imperfect
22 knowledge and I fully, I fully understand, I get that
23 and, and there was a profound sense of urgency. I
24 understand that. But the, the right way to make
25 decisions and, and we go to some of the WHO documents
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1 which talk about evidence advised decisions, is to
2 make those decisions to be, to be advised by the best
3 evidence available. Now it, it’s, it’s my, my, my
4 opinion that the similarities between influenza and,
5 and Covid-19, and I would say particularly as it was
6 understood in the spring of, of, of 2020 were, were,
7 were very similar. And therefore, influenza planning
8 was in fact a very good foundation for, for decision

9 making about Covid and should’ve been used as, as - so
10 that’s number one, but the other, the other aspect is
11 that, again, in the state of, of, of, of imperfect
12 knowledge or as, as we were in 2020, you have to rely
13 on the best available information. So even if you
14 don’t think influenza is a pretty - a great model for,
15 for Covid, now I think it was, but you don’t think it
16 was and I think reading Dr. Galanis’s affidavit,
17 perhaps she doesn’t think it was, but the, the onus is
18 still to rely on the best available. So unless
19 someone has a better data set, a better source of
20 evidence, to rely on than influenza, and I’ve never
21 heard anyone propose that, so we’d either use
22 influenza or we just fly blind and make decisions
23 baked (sic) on - based on intuition which frankly I
24 think is largely what happened.
25 115 Q. Thank you, Dr. Schabas. Just a small - one small
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1 thing that I’m going to, I’m sorry, can you still see
2 my screen?
3 A. I can, yes.
4 116 Q. Okay. At the bottom of paragraph, I’m sorry, page 64,
5 under the heading Planning Variables or Signals, the
6 emer, it reads, “The emergence of the Omicron variant
7 underscored the need for ongoing surveillance and
8 operational readiness for resurgence. Moving forward,

9 PHAC will continue to maintain a high level of
10 readiness to respond to Covid-19 through a combination
11 of border and travel measures.” And not - I don’t
12 want to inaccurate, there’s a list of the intentions
13 behind them, but this is different from the guidance
14 in CPIP, isn’t it?
15 A. The - there are many aspects to Canada’s response
16 particularly and relevant to this discussion to issues
17 of border that are different from what was in CPIP.
18 I, I think that’s my point is that we should have
19 relied - we should have been evidence advised. Many
20 of the measures they refer to here were not evidence
21 advised and really are still not evidence advised
22 because no one’s - we’ve not made the effort or put
23 aside the resources to do the kind of evaluation that
24 would give us evidence. The, the, the information on
25 influenza, again, is not, is not intuitive. The WHO
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1 did a very careful review in 2019, their expert
2 committee did, on the actual evidence and looking at
3 the quality of the evidence and not only identifying
4 what measures could be used, but what the quality of
5 the evidence was to support them. That’s very
6 important because, in fact, for many of these measures
7 or at least some of these measures here, there is no
8 quality of evidence to support it because there really

9 isn’t anything other than intuition and expert opinion
10 which in the hierarchy of medical evidence is, is, is,
11 is, I’m, I’m afraid is the lowest quality.
12 117 Q. Just a moment, Dr. Schabas. All right, Dr. Schabas,
13 just one more question about this. And I don’t think
14 you’ll disagree with this, but, well you may, that’s
15 for you. I don’t mean to...
16 A. Thank you.
17 118 Q. I don’t mean to tell you what you should or shouldn’t
18 do. Did - and I’m taking you to the mid page of page
19 65 or so, and it’s a paragraph beginning, “As
20 international and domestic border shift, border and
21 travel measures need to be adapted accordingly.” And
22 I think you’d agree with that principle? Though
23 you’re free not to.
24 A. Well, well yes, I, I, I agree they need to be adapted
25 according to changing circumstances and changing
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1 evidence. But as I said before, I think many of the
2 measures that we adopted from the beginning had no
3 evidentiary basis, in fact, were contrary to the
4 evidence.
5 119 Q. And just one more question, in the bottom of that
6 paragraph there’s a statement that says, “There is a
7 variety of possible approaches that could be explored
8 and implemented in any combination as the current

9 Omicron driven wave subsides.” And I’m taking you
10 actually to the last of these bullets here.
11 A. Mm-hmm.
12 120 Q. It says, “Testing or vaccination certificate continue
13 to ease or impose measures according to travellers’
14 test results and are proof of vaccination in a way
15 that is justified by available scientific evidence and
16 is sensitive to legal and ethical issues including
17 around equity and accessibility.” Do you see that?
18 A. Yes.
19 121. Q. And do you agree that measures could be eased or
20 imposed based on available scientific evidence?
21 A. Well governments have shown they have the authority to
22 ease or impose measures at their well, so I could
23 hardly argue with the statement that they may continue
24 to ease or impose measures. The basis on which they
25 do that is often mysterious to me, but, but it, it
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1 could include those things, yes.
2 122 Q. Okay. Dr. Schabas, would you acknowledge that PHAC
3 has access to evidence that would be considered by the
4 Chief Public Officer of Health of Canada?
5 A. I, I, I presume so, yes.
6 123 Q. And it would be evidence that you would not have
7 access to?
8 A. Oh, I see, you think proprietary information of some

9 sort. I have no idea, I, I have no idea.
10 124 Q. Okay. I didn’t use the word...
11 A. I mean...
12 125 Q. ...proprietary.
13 A. Okay, the, the, the, the sort of information that, I,
14 I could only relate to my time as, as Chief Medical
15 Officer of Health, and my time working in Public
16 Health, the only information that we would have access
17 to that the general public would not have access to
18 would be issues that involve medical confidentiality.
19 So they would involve, they would involve people’s
20 names and conf - personal medical information around
21 individual cases which in, in theory was shared with,
22 with the Chief Medical Officer of Health although, of
23 course, I never saw it. I don’t believe that’s
24 relevant to planning, so the sort of summary
25 information, the epidemiological information that
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1 would be the basis for a response should be available,
2 not just to the Chief Public Health Officer, but to
3 everyone. I’d be quite shocked if it wasn’t.
4 126 Q. Okay. All right, thank you, Dr. Schabas. I’m just
5 going back to the first page of this document. Mr.
6 Presvelos, I’d like to enter this as an exhibit,
7 please.
8 A. I, I wonder if I could comment on something else that

9 you asked before. Is that, is that all right just to
10 advise the court? I’ve got something I thought I
11 would have more time to expand on.
12 127 Q. Well, it - I’m the one who asks the questions.
13 A. No, no.
14 128 Q. But I’ll...
15 A. Will you allow me to do that? I’d appreciate that,
16 yeah. You made the respon - the statement before, and
17 again, I thought I - I thought it was the beginning of
18 a line of questioning that I’d have an opportunity to
19 respond to. You said that, that CPIP envisioned a
20 precautionary approach. And I acknowledged that was
21 true, but what, what I should’ve done and would like
22 to do is to, is to, is to analyze or expand on that a
23 little bit because the, the so called precautionary
24 approach is based fundamentally on the precautionary
25 principle which is, is a, is a statement of principle
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1 that comes out of the environmental movement. And,
2 and basically it says that when you are going to
3 intervene with the natural order of things that you
4 need some - you need strong evidence. In fact, some
5 iterations of the precautionary principle talk about
6 scientific certainty which is kind of an oxymoron and
7 I’m not going to - not endorsing that. But the notion
8 of, of the precautionary principle, first of all, it,

9 it, it has to be evidence-based. It’s not a blank
10 cheque to do whatever you feel you should do in, in,
11 in a, in a, in a situation. It doesn’t - it’s not a,
12 it’s not a - whatever, whatever you do has to be, has
13 to be clearly evidence-based and you need to be able -
14 you need - and the, and the more, the more intrusive
15 the intervention, the higher degree of evidence you
16 need. I think that’s what the precautionary principle
17 says. It also, I think, is, is a matter of
18 perspective. And I think that’s particularly relevant
19 to Covid-19 because if you view the world through
20 simply the prison, that the only thing we need to be
21 precautionary about is Covid-19 cases. Then that can
22 lead the whole series of interventions that in fact
23 are not really precautionary at all, because they have
24 unintended or, or an - but anticipatable side effects
25 or, or effects on, on people’s lives, on education, on
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1 fundamental human rights and all kinds of things like
2 that that are in fact profou, profoundly damaging. So
3 a, a precautionary approach to Covid would first of
4 all require that it be evidence-based and second of
5 all it would, it would require a holistic view of, of,
6 of the, of the, the, the implications of the
7 interventions because, because what, what, what, what
8 may appear to be precautionary in terms of controlling

9 Covid-19 may be profoundly reckless in terms of what
10 it does to education, right to travel, people’s
11 employment, people’s social interaction, and things of
12 that sort.
13 MR. PRESVELOS: And with that, counsel, and with that counsel, I,
14 I consent to you tendering this document as an exhibit
15 on the record. And I would also appreciate your
16 indulgence for a three minute nature break, if that’s
17 acceptable.
18 EXHIBIT 2: Federal/ Provincial/ Territorial Public
19 Health Response Plan for Ongoing Management of Covid-
20 19.
21 MR. DRUMMOND: That’s perfectly fine, thank you. I will stop
22 sharing and we can go off the record.
23
24 OFF RECORD
25
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1 MR. DRUMMOND:
2 129 Q. Dr. Schabas, I’m, I’m going to take you back to one
3 provision of CPIP which we looked at earlier. And if
4 you bear with me just one second. Okay. Dr. Schabas,
5 I’m just going to share my screen one last time. Dr.
6 Schabas, can you see this?
7 A. I can. Well yeah, yes, Guiding Principles and
8 Approaches, yes.
9 130 Q. Yes. And you understand that this is within the
10 document we’ve previously entered as an exhibit to
11 this cross examination?
12 A. Yes.
13 131 Q. Just under Guiding Principles and Approaches and the
14 heading says the following, “principles underpin
15 Canadian pandemic preparedness and response activities
16 and decision making.”
17 A. Yes.
18 132 Q. And I’m taking you to the next page where it says, “In
19 addition to these main guiding principles, Canadian
20 pandemic planning and response activities are also
21 guided by.” And I’m just going to ask you about this
22 first one which says, this first bullet which says, “A
23 precautionary/protective approach - this approach is
24 particularly applicable in the early stages of a
25 pandemic when evidence-informed decision-making is not
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1 possible due to lack of data and the uncertainty of an
2 evolving event. This means taking timely and
3 reasonable preventive action proportional to the
4 threat and evidence-informed,” a hyphenated word, “to
5 the extent possible. This does not mean that in the
6 absence of evidence, all actions must be taken.
7 Rather, it means that as emerging evidence reduces
8 uncertainty, evidence-informed actions may supersede

9 those precautionary measures taken at the outset.” Do
10 you note that, Dr. Schabas?
11 A. I, I, I read it there, yes.
12 133 Q. And is that, is that a fair, sorry, let me put that
13 another way, is that what you understand to be an
14 expression of a precautionary approach in Public
15 Health measures?
16 A. I think, let me just, just let me pause and read it
17 again before I comment.
18 134 Q. Absolutely.
19 A. Okay, so what I would, I would say is that, that, that
20 the, the emphasis that I would put on this is, is, is,
21 is the need for evidence-informed decision making. So
22 precaut - even when you respond in a precautionary
23 way, it’s like I said before, it’s not a blank cheque
24 in - if, if there is reasonable evidence to inform
25 your decision making, that’s what you should rely on.
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1 And I believe there was reasonable evidence in, in, in
2 Ap - in February, March, April of 2020 regarding the
3 roots of transmission of Covid-19, knowledge which has
4 evolved over time, but it’s fundamentally robust
5 related to how its spread gave us - in fact, we’ve, we
6 had evidence, we had evidence-informed decision making
7 based on our handling of other respiratory viruses and
8 our knowledge of other respiratory viruses for which

9 there was in fact a very substantial body of
10 scientific knowledge that, that, that we should’ve
11 relied on. The other, the other aspect that, again, I
12 would emphasize is when we talk about precautionary
13 measures, it’s not simply limited to the impact on the
14 spread of the respiratory virus. It’s related to the
15 other, other effects, the, the kinds of measures that
16 were undertaken in, in March of 2020. Things like
17 closing our borders, things like closing our schools,
18 things like in, in Ontario and, and at least some
19 other provinces shutting down all non-emergency
20 healthcare. Those - those are measures that had a
21 profound dangers attached to them and particularly
22 since at the time there was no reason to think this
23 was going to be a short-lived problem. So that, in
24 fact, again, I would say that those kinds of measures
25 which were taken on the basis, which were not
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1 evidence-informed measures, in fact, many of them were
2 contrary to the evidence, were not precautionary, they
3 were reckless.
4 135 Q. All right, Dr. Schabas, I’m just going to stop sharing
5 the screen.
6 A. Oh, just - sorry, could you go back to that just for
7 one second? Just I want to make sure I commented on
8 that appropriately.
9 136 Q. Okay. Just a second, please.
10 A. Yeah, I just can’t help but notice that the next
11 bullet point was use of established practices and symp
12 - systems to the extent possible which, again, touches
13 on a point that I made in my affidavit which is, I
14 think, a very important principle, not just of Public
15 Health but of all of medicine is that when you are
16 uncertain of what to do, then you rely on the, on the
17 fundamental basics of, of those things that you know
18 have, have been effective in the past which is why it
19 was so important that we looked at the body of
20 evidence that already existed for, for, for pandemic
21 respiratory viruses most of which, in fact virtually
22 all of which, came from influenza.
23 137 Q. All right. Thank you, Dr. Schabas. I’m going to stop
24 sharing the screen now, if that’s all right. Okay, I
25 think I’m almost done, Dr. Schabas. Just give me a
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1 moment. Okay, at the outset of this cross
2 examination, you confirmed that you reviewed the
3 affidavit of Owen Phillips in preparing for this.
4 A. Yes, yeah, yeah, yeah.
5 138 Q. Okay. And now in Mr. Phillips’s affidavit, it’s to
6 the effect that there have been significantly more
7 deaths from Covid than from influenza.
8 A. Yes.
9 139 Q. Did you note that in his affidavit?
10 A. Yes, there have been.
11 140 Q. Okay. And, okay, just one second. Okay. All right,
12 Dr. Schabas, if you give me just one minute I think
13 you’re probably done, but I’m just going to check my
14 notes.
15 MR. PRESVELOS: Sorry, counsel, did you want to get off the
16 record?
17 MR. DRUMMOND: If - just for a minute, please, yes.
18 A. If, if I could just say if, if we’re going to leave
19 Mr. Phillips’s affidavit, now you did make a statement
20 that I’d, I’d like to maybe inform the court a little
21 bit more about if, if I could regarding the statement
22 you made about influenza deaths. Because it, it’s,
23 it’s generally acknowledged in, in Canada, it’s quite
24 a robust literature that we can expect up to 6,000
25 influenza attributable deaths in an influenza year.
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1 And indeed, the, the cumulative total of roughly
2 30,000 deaths from, from, from Covid over two years
3 is, is more than two severe influenza seasons, but,
4 but in, in balancing that, the, the reason for that is
5 that we’ve had, in effect, six waves of, of, of Covid.
6 And each of those waves has caused a, a mortality
7 that’s, that’s, that’s, that’s similar to influenza.
8 So yes, the burden has been greater than influenza,

9 but many of the analogies still stand. And, and the
10 key difference with Covid is that it has evolved much
11 faster. Influenza tends to evolve on a year to year
12 basis, Covid, because it’s a novel virus and something
13 which I don’t think we properly anticipated in the
14 beginning has evolved much faster. But each
15 individual Covid waves, in terms of mortality, has
16 been roughly comparable to a severe influenza season
17 in Canada.
18 141 Q. All right, thank you, Dr. Schabas. I’m just going to
19 - I think I’m going to take one moment if we could go
20 off the record.
21
22 OFF RECORD
23
24 MR. DRUMMOND:
25 142 Q. Thank you, Dr. Schabas. Those are all my questions
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1 today. I hope you have a pleasant May afternoon.
2 A. Thank you very much.
3 143 Q. I leave it to your counsel to ask anything he may have
4 in redirect.
5 MR. PRESVELOS: Thank you. I have nothing to ask in redirect.
7 CROSS-EXAMINATION ENDS
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CERTIFICATE OF COURT TRANSCRIBER
I, Anna Dass, hereby certify the foregoing to be a true and
accurate transcription of the evidence given in the matter,
taken by way of electronic tape recording to the best of my
skill, ability and understanding.
Court Transcriber
ACT ID: 2887221650
May 20th, 2022
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CANADIAN PANDEMIC
INFLUENZA PREPAREDNESS:
Planning Guidance for the
Health Sector
AR07273
Également disponible en français sous le titre :

PRÉPARATION DU CANADA EN CAS DE GRIPPE PANDÉMIQUE
Guide de planification pour le secteur de la santé
© Her Majesty the Queen in Right of Canada, as represented by the Minister of Health, 2018
HP40-144/2018E-PDF
ISBN: 978-0-660-26617-6
Pub.: 180093
AR07274
TABLE OF CONTENTS
PREFACE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.0 INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.1 Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.2 Purpose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.3 Audience and Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.4 Changes in This Version. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.0 CONTEXT FOR PLANNING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

2.1 Understanding Pandemic Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.1.1 Influenza and the Origin of Pandemics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.1.2 Typical Pandemic Characteristics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.1.3 Pandemic Impact. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.2 Uncertainties and Unpredictability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.3 Lessons Learned from the 2009 Pandemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.4 Understanding Canada’s Diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.5 Ethical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.6 Legal Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2.6.1 International Requirements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.6.2 Federal Legislation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.6.3 Provincial/Territorial Legislation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.0 CANADA’S APPROACH TO PANDEMIC INFLUENZA. . . . . . . . . . . . . . . . . . . . . . . . . 20

3.1 Goals and Objectives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.2 Guiding Principles and Approaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.3 Coordination of National Preparedness and Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
3.3.1 Emergency Management Frameworks and Plans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3.3.2 Pan-Canadian Coordination of the Pandemic Health Sector Response . . . . . . . . . . . . . . .23
3.3.3 North American Plan for Animal and Pandemic Influenza . . . . . . . . . . . . . . . . . . . . . . . . . 23
3.4 Pandemic Roles and Responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
3.4.1 World Health Organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
3.4.2 Canada – FPT Governments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
3.5 Risk Management Approach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.5.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.5.2 Risk Management Considerations in Pandemic Planning and Response. . . . . . . . . . . . . . 30
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3.6 Planning Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

3.6.1 Origin and Timing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.6.2 Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.6.3 Pandemic Epidemiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.6.4 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.6.5 Impact and Interventions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.7 Pandemic Planning Scenarios. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3.8 Pandemic Phases and Triggers for Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
3.8.1 WHO Pandemic Phases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
3.8.2 Canada’s Approach to Pandemic Phases and Triggers for Action. . . . . . . . . . . . . . . . . . . . . 37
4.0 KEY COMPONENTS OF PANDEMIC INFLUENZA

PREPAREDNESS AND RESPONSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
4.1 Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4.2 Laboratory Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4.3 Public Health Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
4.4 Vaccine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
4.5 Antiviral Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
4.6 Infection Prevention and Control and Occupational Health . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.7 Health Care Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
4.8 Clinical Care Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
4.9 Communications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
4.10 Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
5.0 ASSESSMENT AND EVALUATION OF PANDEMIC

PREPAREDNESS AND RESPONSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
5.1 Assessing Preparedness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
5.2 Evaluating the Pandemic Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
APPENDIX A – FACTORS AFFECTING PANDEMIC IMPACT . . . . . . . . . . . . . . . . . . . . . . . 57
APPENDIX B – PANDEMIC RISK ASSESSMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
4 CANADIAN PANDEMIC INFLUENZA PREPAREDNESS: Planning Guidance for the Health Sector
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PREFACE
Canadian Pandemic Influenza Preparedness: Planning Guidance for the Health Sector (CPIP) is a
federal, provincial, and territorial (FPT) guidance document that outlines how jurisdictions will work
together to ensure a coordinated and consistent health sector approach to pandemic preparedness and
response. CPIP consists of a main body, which outlines overarching principles, concepts, and shared
objectives, as well as a series of technical annexes that provide operational advice and technical
guidance, along with tools and checklists on specific elements of pandemic planning. The CPIP main
body and its annexes are intended to be used together.
CPIP was first published in 2004. In 2006, the Pan-Canadian Public Health Network (PHN) Council
approved an updated version of CPIP as an evergreen document to be updated as required. In 2009,
Canada’s pandemic preparedness planning efforts were tested for the first time, with the emergence of
the H1N1 influenza pandemic. In 2012, a CPIP renewal process was initiated by the PHN Council. This
latest version of CPIP was approved by FPT Deputy Ministers of Health in 2014, with further updates in
2018. It incorporates evidence from H1N1 lessons learned reviews conducted at the FPT and international
levels and by various stakeholder groups, and scientific advances. As an evergreen document, the CPIP
main body and each annex will be reviewed every 5 years, with updates made between review cycles,
if necessary.
Since 2012, the CPIP Task Group (CPIP TG) has overseen the CPIP renewal process. The CPIP TG
consists of members with expertise in the areas of pandemic and seasonal influenza, pandemic
preparedness planning and response, emergency management, epidemiology, public health, virology,
bioethics, immunization, surveillance, and laboratory diagnosis.
The updated CPIP allows for a more flexible and adaptable response to future pandemics, providing
scope for provinces and territories (PT) to adapt their own plans and responses to local and regional
circumstances. The title of the document also has changed, from Canadian Pandemic Influenza Plan for
the Health Sector to Canadian Pandemic Influenza Preparedness: Planning Guidance for the Health
Sector, to more accurately reflect its role and intended use as a guidance document.
CPIP now supports a risk management approach and includes new concepts such as pandemic impact
assessment, descriptions of pandemic scenarios of varying impact, and identification of triggers for a
Canadian response. It also better reflects Canada’s geographic, demographic, cultural, and socio-
economic diversity and the imperative for planners to take this diversity into account. CPIP has been
subject to extensive FPT government review and targeted stakeholder consultations. Stakeholders
included national level organizations representing health professionals, emergency preparedness and
first responders, community services, the private sector, and Indigenous peoples.
CANADIAN PANDEMIC INFLUENZA PREPAREDNESS: Planning Guidance for the Health Sector 5
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1.0 INTRODUCTION
1.1 Background
Canadian Pandemic Influenza Preparedness: Planning Guidance for the Health Sector (CPIP) provides
planning guidance to prepare for and respond to an influenza pandemic. Influenza pandemics
(subsequently referred to as pandemics) are unpredictable but recurring events that occur when a novel
influenza virus strain emerges, spreads widely and causes a worldwide epidemic. Unfortunately, it is not
possible to predict the anticipated impact of the next pandemic or when it will occur.
Planning for a prolonged and widespread health emergency of unpredictable impact is challenging but
essential. It requires a “whole of society” response and the coordinated efforts of all levels of government
in collaboration with their stakeholders.
Pandemic planning activities within the health sector in Canada began in 1983. The first Canadian
pandemic plan was completed in 1988 and was followed by several updates. In 2004, the Canadian
Pandemic Influenza Plan for the Health Sector was published as the result of extensive collaboration
among FPT and other stakeholders. Before this version, the last major update to the CPIP and its
annexes occurred in 2006.
The 2009 influenza A (H1N1) pandemic (subsequently referred to as the 2009 pandemic) provided the
first real test of Canada’s pandemic preparedness planning efforts. Collaboration among all levels of
government and stakeholders was unprecedented compared with previous events like the Severe Acute
Respiratory Syndrome (SARS) outbreak in 2003. The public health and health care systems were stressed
but in most instances were able to cope. Antiviral stockpiles were deployed and pandemic vaccine
was administered to millions of Canadians. There were, however, many challenges identified in
this experience.
Canada’s pandemic planning continues to evolve on the basis of research, emerging evidence and the
lessons learned from the 2009 pandemic. The value of building on seasonal influenza surveillance
systems and control measures is well recognized. Making these systems and measures as robust as
possible in the interpandemic period will help prepare for a strong pandemic response.
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1.2 Purpose
CPIP’s overall purpose is to provide planning guidance for the health sector for pan-Canadian
preparedness and response, in order to achieve Canada’s pandemic goals:
First, to minimize serious illness and overall deaths, and second to minimize societal
disruption among Canadians as a result of an influenza pandemic.
The main body of CPIP provides strategic guidance and a framework for pandemic preparedness and
response, whereas the CPIP annexes provide operational advice and technical guidance, along with
tools and checklists. As an evergreen document, CPIP will be updated as required to reflect new
evidence and best practices.
It is important to note that CPIP is not an actual response plan. Rather, it is a guidance document for
pandemic influenza that can be used to support an FPT all-hazards health emergency response approach.
While CPIP is specific to pandemic influenza, much of its guidance is also applicable to other public
health emergencies.
1.3 Audience and Scope

CPIP is pan-Canadian pandemic planning guidance for the health sector developed under the guidance
of a group of Canadian experts. The primary audiences are the FPT ministries of health together with
other ministries that have health responsibilities. While it is anticipated that CPIP’s strategic direction
and guidance will inform FPT planning in order to support a consistent and coordinated response across
jurisdictions, PTs have ultimate responsibility for planning and decision-making within their respective
jurisdictions. CPIP also serves as a reference document for other government departments, non-
governmental organizations (NGOs) engaged in health issues, and other stakeholders.
While CPIP provides pandemic planning guidance, it does not address business continuity preparedness
or overall management of a health emergency. These activities are critical for an effective pandemic
response; however they are more appropriately addressed in the emergency plans of individual
jurisdictions and organizations. Neither does CPIP address pandemic preparedness and response
in the non-health sectors (e.g., community and social services, public safety), although some of its
content may be a useful reference.
1.4 Changes in This Version

There have been considerable changes to CPIP since the 2006 version in both format and content. The
strategic nature of the information in the main body of the planning guidance has been strengthened
and lessons learned from the 2009 pandemic have been incorporated. While the overall pandemic
goals remain the same, new objectives have been added along with a set of principles to support the
response. These are accompanied by a discussion of ethical considerations pertaining to pandemic
preparedness and response, and consideration of the implications of Canada’s diversity and the needs
of vulnerable persons. Roles and responsibilities for each level of government have been described
more explicitly.
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The new CPIP outlines a risk management approach to support a flexible and proportionate response.
Risk management involves setting the best course of action in an uncertain environment by identifying,
assessing, acting on and communicating risks. Information has been added about what is known and
what is uncertain about pandemic influenza. The planning assumptions have been updated, and four
hypothetical planning scenarios have been developed to illustrate the importance of developing plans
and response strategies that are flexible and can be adapted as circumstances require. CPIP also
provides triggers for action that are based on novel virus emergence and pandemic activity in Canada
rather than the global World Health Organization (WHO) phases. Finally, content has been updated
in each of the specific response areas.
The CPIP technical annexes are being renamed according to their subject (e.g., Surveillance, Vaccine)
instead of being named alphabetically. As part of the CPIP renewal process, it is intended that each
of the technical annexes will be revised.
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2.0 CONTEXT FOR PLANNING

2.1 Understanding Pandemic Influenza
2.1.1 INFLUENZA AND THE ORIGIN OF PANDEMICS
While there are four types of influenza virus (A, B, C and D), only influenza A and B viruses cause
seasonal outbreaks in humans, and only influenza A viruses have been known to cause pandemics.
Aquatic birds are the natural hosts for influenza A viruses, although a wide range of species can be
infected and significant disease outbreaks can occur in poultry, pigs and other species. Most of these
animal influenza virus strains do not cause disease in humans although occasional human (zoonotic)
infections occur, usually through close contact with infected poultry or animals.
Influenza pandemics or worldwide epidemics occur when an influenza A virus to which most humans
have little or no immunity acquires the ability to cause sustained human-to-human transmission leading
to community-wide outbreaks. Such a virus has the potential to spread rapidly worldwide, causing
a pandemic.1
These novel viruses may arise through genetic reassortment (a process in which animal and human
influenza genes mix together) or genetic mutation (when genes in an animal virus change, allowing the
virus to easily infect humans). Pigs can become infected with influenza viruses from different species and
act as a “mixing vessel” to facilitate the reassortment of genes from different viruses.
Not all novel influenza viruses evolve into pandemic viruses. Some novel subtypes, like the avian A
(H5N1) virus, have caused sporadic human cases on an ongoing basis since 1997 but have not gained
the ability to spread easily in humans. As the overall human case fatality rate for A (H5N1) infections has
been over 50%,2 there are concerns about the potential of a high impact human pandemic if this virus
gains the capacity to spread easily between people.
1
World Health Organization. Pandemic influenza risk management – WHO Pandemic Influenza Risk Management May 2017.
Available from: www.who.int/influenza/preparedness/pandemic/influenza_risk_management_update2017/en/
2
World Health Organization. Influenza at the human-animal interface. 4 July 2013. Available from:
www.who.int/influenza/human_animal_interface/Influenza_Summary_IRA_HA_interface_03July13.pdf.
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2.1.2 TYPICAL PANDEMIC CHARACTERISTICS

Historical evidence suggests that influenza pandemics occur three to four times per century. In the last
100 years there were four pandemics separated by intervals of 11 to 41 years. They varied greatly in
their impact, as measured by illness and deaths. The 1918–1919 pandemic had a high impact, killing an
estimated 30,000 to 50,000 people in Canada and 20 to 50 million people worldwide. The impact of the
1957 and 1968 pandemics was considered moderate, whereas the 2009 pandemic had a lower impact.
Pandemics of the Last 100 Years, subtypes and common names:

1918–1919: H1N1 “Spanish flu”
1957–1958: H2N2 “Asian flu”
1968–1969: H3N2 “Hong Kong flu”
2009: H1N1 Influenza A (H1N1) 2009
While every pandemic is different, some common characteristics can be recognized:

• The pattern of disease is different in pandemics than in seasonal influenza.
• Pandemics may arrive outside of the usual influenza season and typically have more than one wave
of illness.
• The total duration of a pandemic is likely to be 12 to 18 months.
• During a pandemic, the new pandemic virus replaces other circulating influenza strains. Afterwards,
the pandemic strain becomes part of (and may dominate) the mix of seasonal influenza A viruses.
• During seasonal influenza, most hospitalizations and deaths occur in the elderly and persons with
underlying health conditions, whereas, in a pandemic, disproportionately more severe disease and
death is seen in young people and in persons without underlying health conditions.3
• There is a gradual reversion back to the typical seasonal morbidity and mortality pattern over the
decade following the pandemic.
During the 1918–1919 pandemic, 99% of influenza-associated deaths in the United States (US) were in
persons under 65 years of age and nearly half of these among previously healthy adults 20–40 years of
age. In subsequent pandemics, the proportion of influenza-associated deaths in the US in persons
under 65 years of age was 36% (1957–58), and 48% (1968–69).4 In the 2009 pandemic 70% of reported
deaths in Canada were in persons under 65 years of age.5
3
Simonsen L, Clarke MJ, Schonberger LB, et al. Pandemic versus epidemic mortality: a pattern of changing age distribution.
J Infect Dis 1998;178:53–60.
4
Ibid.
5
Helferty M, Vachon J, Tarasuk J et al. Incidence of hospital admissions and severe outcomes during the first and second
waves of pandemic (H1N1) 2009. Can Med Assoc J 2010;182:1981−7.
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2.1.3 PANDEMIC IMPACT

The term “severity” is often used to describe both severity of disease in individuals (clinical severity) and
the overall “severity” of a pandemic in a population. In CPIP, the term severity is used to describe clinical
severity of disease in individuals and impact is used to describe the effects of a pandemic on the
population. For planning and response purposes, describing the impact of a pandemic on the population
is a more meaningful approach than talking about its “severity”. It is acknowledged that this usage may
vary from the approach of some other authorities. For example, the WHO uses the term “pandemic
severity” for what CPIP terms “impact” but the concepts are the same.6
Severity refers to clinical severity of disease in an individual (e.g., mild, moderate or severe disease)
Impact refers to the effects of a pandemic on a population (e.g., low, moderate, or high impact)
Pandemics vary in their impact, as do seasonal influenza outbreaks, although usually on a higher scale of
magnitude. A low impact pandemic might resemble moderate to severe seasonal influenza outbreaks,
although its epidemiological profile would be different in important ways as previously described. In
contrast, pandemics of moderate to high impact could result in high rates of illness and death across the
country and would severely challenge the health care sector. They could also disrupt the normal functioning
of society and put people with limited resources and support systems into a more vulnerable state.
Numerous factors can affect pandemic impact. These are outlined below and described in more detail
in Appendix A:
• Viral factors are perhaps the most important. These characteristics of the virus itself are usually
described as transmissibility (ability to spread) and virulence or clinical severity (the ability to cause
severe disease). Transmissibility can be defined in terms of both the extent and the speed of spread
and it can vary by season and setting.
• Factors affecting population vulnerability include pre-existing population immunity, the presence
of underlying health conditions, or unexpected new risk factors for severe disease. Impact may be
increased in vulnerable populations, including among Indigenous peoples or settings such as remote
communities, homeless shelters and overcrowded housing.
• Response factors include the effectiveness of interventions (e.g., public health measures, vaccine,
and antiviral medications), the health care system response (e.g., access, surge capacity), and
risk communications, along with the extent of public adoption of desired behaviours and
social mobilization.
The impacts of a pandemic in psychosocial terms may be acute in the short term but can also undermine
the long-term psychological well-being of the population. Psychosocial issues are not only experienced by
those who become ill; distress permeates through the family and the community (e.g. financial stress due
to economic downturns, caregiver burnout, occupational stresses, stigma/social exclusion).
The range of issues associated with psychosocial planning is broad involving all levels of government
and multiple planning partners, including humanitarian actors such as community-based organizations,
government authorities and NGOs and are closely aligned with the practice of risk communication.7
6
World Health Organization. Pandemic influenza risk management—WHO interim guidance. 2013. Available from:
www.who.int/influenza/preparedness/pandemic/influenza_risk_management/en/index.html
7
Inter-Agency Standing Committee (IASC) Guidelines on Mental Health and Psychosocial Support in Emergency Settings (2007).
Available from: www.who.int/mental_health/emergencies/guidelines_iasc_mental_health_psychosocial_june_2007.pdf
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2.2 Uncertainties and Unpredictability

Influenza is unpredictable – every influenza season and every pandemic is different. These uncertainties
make pandemic planning challenging and highlight the need for flexibility and adaptability. Some of the
major unknown areas about the next pandemic are the following:
• When the next pandemic will occur— although historically pandemics have occurred three to four
times per century, there is no predictable interval. It should not be assumed that the 2009 pandemic
has provided a respite during which preparedness efforts can be relaxed.
• Where it will emerge—while most seasonal influenza strains emerge in East/Southeast Asia,8 the
same is not true for pandemic influenza; the 2009 pandemic emerged in Mexico. An influenza
pandemic could emerge anywhere in the world, and there may be very little lead time before Canada
is extensively involved.
• What the nature of spread will be—pandemics often first arrive outside the usual influenza season (e.g.,
in late spring or summer) and typically have more than one wave of infection. However, this is not true
in all circumstances or in all areas. A small first wave is often followed by a larger second wave, but the
relative size of pandemic waves may vary. The speed of spread may also vary – pandemic waves can be
intense or more spread-out over time. An intense wave would put more stress on the health care system.
• What its characteristics will be—the basic characteristics of the next pandemic virus are unknown,
including its antigenic type (e.g., H2, H5, H7), its transmissibility and virulence, and the age groups
and clinical groups most affected.
• What its impact will be—the last four pandemics demonstrated that population impact can vary
from low to high and is not the same in all populations or settings. It is important to consider all
possibilities and make plans adaptable for different circumstances. This will help ensure that the
response is proportional to the evolution of the pandemic in any specific community.
• What effect interventions will have—typical seasonal influenza interventions are expected to be
effective during the pandemic. However, the novel virus could be resistant to antiviral medications
and/or pandemic vaccine production could be delayed or unsuccessful. The extent of vaccine uptake
and adoption of public health measures is also unknown. Furthermore, interventions could have
unintended consequences.
2.3 Lessons Learned from the 2009 Pandemic

There were many important epidemiological observations from the 2009 pandemic to take into account
in future planning and response. These include the speed with which cases and sporadic outbreaks
appeared in Canada after the novel virus was first detected and the early involvement of some remote
and isolated communities, with severe disease in some First Nations communities. There was considerable
variation in the timing and intensity of pandemic waves, especially the first wave, across the country.
Although the symptoms were similar, age groups affected and risk conditions varied from seasonal
influenza. Greater impact was seen in pregnant women and Indigenous peoples, and persons with
morbid obesity were newly recognized as being at high risk for complications. For the duration of the
pandemic, seasonal influenza strains were replaced by the pandemic strain and as with previous
pandemics, it was not certain whether this single A strain dominance would continue. In the 2010/2011
influenza season A (H3N2) and B strains began to re-circulate and the pandemic virus became the
seasonal A (H1N1) strain.
8
Russell CA, Jones TC, Barr IG et al. The global circulation of seasonal influenza A (H3N2) viruses. Science 2008;3210:340–6.
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A number of challenges were identified in the national response. Surveillance demands were very heavy
from the start, and were accentuated by the lack of linked information systems in some jurisdictions,
unclear protocols for sharing information, and limited capacity for epidemiological analysis. The process
for release of the National Antiviral Stockpile (NAS) was uncertain. There was high demand for critical
care and ventilators for affected children and adults. Preparation and timely approval of concise national
guidelines was difficult. The pandemic immunization program faced challenges with uncertain timelines
for vaccine delivery, prioritization of vaccine supply, logistics of local campaigns and communication of
changing recommendations.
On the positive side, previous planning processes and relationship-building led to unprecedented FPT
collaboration and many successful stakeholder engagement efforts. Existing surveillance systems, like
FluWatch, and ready-to-use hand hygiene and respiratory etiquette campaigns were valuable.
Mathematical modeling was successfully used to support decision-making in some areas (e.g.,
recommendations for vaccine prioritization) and it was recognized that a number of other areas would
benefit from modeling (e.g. predicting pandemic impact).
Following the pandemic, the Government of Canada (GC)9 and most PT governments conducted
lessons learned reviews. In addition, the Standing Senate Committee on Social Affairs, Science and
Technology held extensive hearings on the response.10 Some common themes emerging from these
reports and recommendations were identified to improve preparedness, such as:
• streamlined FPT governance structure and clarification of roles and responsibilities;
• improved scalability and adaptability of response, with triggers to activate and deactivate specific
responses while taking into account the variable impact and timing of the pandemic in different
geographic regions;
• development of integrated electronic information management systems;
• strengthened surveillance systems and epidemiological capacity;
• collaborative processes to develop and strengthen guidance documents for health care workers
(HCW) and other stakeholders to establish timely availability, accessibility, consistency and cultural
sensitivity of messages;
• strategies to communicate risk, uncertainty and changing information;
• active participation of all stakeholders in pandemic preparedness and response;
• strengthened linkages with primary care and other front-line service providers;
• development of mechanisms for rapid funding and research priority-setting, multi-jurisdictional
studies and centralized ethics approval for multi-centre studies;
• mechanisms to integrate new research findings into evidence-informed practice; and
• regular and rigorous testing of plans at all levels.
9
Public Health Agency of Canada. Lessons Learned Review: Public Health Agency of Canada and Health Canada Response to
the 2009 H1N1 Pandemic. November 2010. Available from:
www.phac-aspc.gc.ca/about_apropos/evaluation/reports-rapports/2010-2011/h1n1/index-eng.php
10
Standing Senate Committee on Social Affairs, Science and Technology. Canada’s Response to the 2009 H1N1 Pandemic.
December 2010. Available from:
www.parl.gc.ca/40/3/parlbus/commbus/senate/com-e/soci-e/rep-e/rep15dec10-e.pdf
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2.4 Understanding Canada’s Diversity

Canada’s geographic features and population diversity can create challenges in mounting an effective
response to a public health emergency. Canada is a huge country geographically with communities that
range in size from large cities to small rural and remote settlements. The proportion of people living in
rural areas in Canada (18.9%) is low in comparison to other developed countries and is steadily declining.
The proportion of the rural population, however, varies greatly (from 14% to 53%) from one province or
territory to another. It is lowest in British Columbia and Ontario and is highest in the Atlantic provinces
and the territories.11
Canada is diverse in terms of language, religious beliefs, ethnicity, culture and lifestyle. Indigenous
Peoples make up almost 4% of the population, the second highest percentage in the world after New
Zealand.12 While many Indigenous peoples live in remote and isolated communities in the North, about
half live in urban areas. The median age of Canada's Indigenous Peoples is considerably younger than
that of the non-Indigenous peoples (27 years compared with 40 years respectively). 13
The proportion of foreign-born people in Canada is one of the highest in the world at 20%,14 most of
whom settle in large cities. Toronto and Vancouver now have over 40% visible minority populations
and Montreal has 16%. In addition there are many temporary residents, such as foreign workers and
foreign students.15
The needs of remote and isolated communities may be greater than other communities because of
geographic isolation and health, social, environmental, economic and cultural considerations. These
may affect the baseline health status and thus increase the vulnerability of their residents. In addition,
some remote and isolated communities lack basic amenities, such as household access to running
water, that are assumed to be present when public guidance like hand hygiene is issued. It is important
to consider these factors, along with limited access to health care and transportation challenges, when
planning for all aspects of the pandemic response in remote and isolated communities. Similar concerns
may affect urban marginalized or vulnerable populations.
11
Statistics Canada. Canada’s rural population since 1851. 2012–02–09. Available from:www12.statcan.gc.ca/census-
recensement/2011/as-sa/98-310-x/98
12
Statistics Canada. 2006 Census: Aboriginal Persons in Canada in 2006: Inuit, Metis and First Nations, 2006 Census.
Available from: www12.statcan.ca/census-recensement/2006/as-sa/97-558/p2-eng.cfm
13
Statistics Canada. Canada Year Book 2011. Available from:
www.statcan.gc.ca/pub/11-402-x/2011000/pdf-eng.htm
14
OECD. Society at a Glance 2011: OECD Social Indicators. 4.5 Migration. Available from:
http://dx.doi.org/10.1787/soc_glance-2011-en
15
Statistics Canada. Canada Year Book 2011. Available from:
www.statcan.gc.ca/pub/11-402-x/2011000/pdf-eng.htm
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There are individuals within all jurisdictions whose needs are not fully addressed by traditional services
or who cannot comfortably or safely access and use standard resources. Examples of these vulnerable
persons include, but are not limited to, individuals who are:
• physically or mentally disabled (e.g., visually or hearing impaired, mobility limitations, cognitive
disorders);
• limited or non-English or French speaking;
• low literacy;
• geographically, culturally or socially isolated;
• low income;
• medically or chemically dependent;
• homeless or street-involved;
• housebound or frail seniors; and
• new immigrants and refugees.16
It may not be a single one of these conditions that determines the degree of vulnerability, but rather a
combination of them under certain circumstances.17
Studies indicate that there is a social gradient of risk during influenza pandemics, based on social
vulnerabilities that are likely to lead to increased exposure to infection, risk of basic human needs not
being met, insufficient support and/or inadequate treatment.18 Vulnerable populations might become
more marginalized if pandemic health services are streamlined into standard approaches to reach the
general population.
Within the nationally coordinated pandemic response it is important to allow sufficient local flexibility to
address the unique needs of vulnerable populations. Detailed influenza-specific planning guidance has
been developed for vulnerable populations in Canada.19,20 These referenced documents should be
useful for FPT and regional/local planners.
Responsibility for planning for vulnerable populations is often unclear and although public health is
typically involved, inclusion of all relevant stakeholders is important for comprehensive planning and
buy-in. It is important for planners to address the unique needs of their jurisdiction. This begins with
identifying populations and settings associated with increased risk of illness or severe outcomes from
pandemic influenza along with persons who might need tailored prevention and care services during a
pandemic. Specific planning considerations include information needs (e.g., language, cultural style
and methods of dissemination); access to assessment, treatment (including antiviral medications) and
convalescence support; access to vaccine; and need for support for activities of daily living.
16
International Centre for Infectious Diseases. Flu season and the most vulnerable people. Preparing your organization, staff,
volunteers and clients for seasonal and pandemic flu.
17
Pan American Health Organization. Protecting Mental Health During Epidemics. May 2009. Available from:
www.paho.org/hq/index.php?option=com_docman&task=doc_download&Itemid=270&gid=1433&lang=en
18
O’Sullivan T, Bourgoin M. Vulnerability in an influenza pandemic: looking beyond medical risk. Oct 2010.
19
International Centre for Infectious Diseases. Op cit.
20
International Centre for Infectious Diseases. Issues in pandemic influenza responses for marginalized urban populations;
key findings and recommendations from consultation meetings and key informant interviews. March 2010.
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2.5 Ethical Considerations

This section summarizes the more important ethical considerations in pandemic planning but is not
intended to be an actual ethical framework. Ethical considerations are also addressed more specifically
in various CPIP annexes with supporting tools and frameworks where available.
In Canada, ethical considerations are increasingly taken into account in the development of health
policy. Ethical analysis helps to identify the ethical issues and determine how to do the right thing in a
fair, just and transparent way. Many of the issues encountered in pandemic preparedness and response
involve balancing rights, interests and values. Examples include decisions over resource allocation;
prioritization guidelines for pandemic vaccine and antiviral medications; adoption of public health
measures that may restrict personal freedom; roles and obligations of HCWs and persons providing
medical first response, as well as their employers; the potential need for triage in the provision of critical
care; and responsibilities to the global community.21
The application of ethical reasoning to pandemic preparedness and response begins with identifying
and prioritizing the ethical questions in the issue under consideration. Analysis should include reflection
on the ethical considerations associated with the options, taking into account the societal versus
individual interests and values that are at stake. Ethical tensions are inevitable. When weighing the
options, it is important to be guided by the Canadian pandemic goals.
As pandemic planning initiatives fall within the domain of public health, they are guided by a code of
ethics that is distinct from traditional clinical ethics.22 Whereas clinical ethics focuses on the health and
interests of individuals, public health ethics focuses on the health and interests of a population. When a
health risk like a pandemic affects a population, public health ethics predominates, and a higher value
is placed on collective interests.
In practical terms, this means there should be an emphasis placed on trust and solidarity. Successful
public health activities require relationship-building and can contribute to creating and maintaining trust
between individuals, populations and health authorities. Solidarity is the notion that we are all part of a
greater whole, whether an organization, a community, nation or the globe. Another important
consideration is reciprocity, meaning that those who face disproportionate burdens in their duty to
protect the public (e.g., HCWs and other workers who are functioning in a health care capacity, for
example police or fire personnel who are providing medical first response) are supported by society,
and that to the extent possible those burdens are minimized.
The concept of stewardship is also closely related to trust. Stewardship refers to the responsible planning
and management of something entrusted to one’s care, along with making decisions responsibly and
acting with integrity and accountability. Trust, stewardship and the proper building of relationships also
mean that the power conferred to government and health authorities will not be abused. For example,
if restrictions are deemed essential for proper risk management, they must be effective and proportional
to the threat, meaning that they should be imposed only to the extent necessary to prevent foreseeable
harm. These restrictions should also be counterbalanced with supports to minimize the burden on those
individuals affected.
21
World Health Organization. Ethical considerations in developing a public health response to pandemic influenza. WHO/CDS/
EPR/GIP/2007.2. 2007. Available from: www.who.int/csr/resources/publications/WHO_CDS_EPR_GIP_2007_2c.pdf
22
Kenny NP, Sherwin SB, Baylis FE. Re-visioning public health ethics: a relational perspective. Can J Public Health. 2010;101:9-11.
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The concepts of equity and fairness are very important to Canadians. In a pandemic context, they lead
to a number of considerations. As much as possible, benefits and risks should be fairly distributed
through the population. This may be difficult, however, in some circumstances, such as a pandemic that
differentially affects certain populations or a very severe pandemic if resources are in short supply.
Decisions should take health inequities into account and try to minimize them, rather than make them
worse. Access to necessary health care may be restricted in a health crisis; however, available resources
(e.g., vaccine and antiviral medications) should be distributed in a fair and equitable way. What will
constitute fair and equitable distribution will be context dependent. Therefore the transparency and
reasonableness of decision-making processes are important.
Good decision-making processes are also essential for ethical decision-making. They involve
the following:23,24
• openness and transparency—the process is open for scrutiny, and information about the basis for
decisions and when and by whom they were made is publicly accessible;
• accountability—being answerable for decisions;
• inclusiveness—stakeholders are consulted, views are taken into account, and any disproportionate
impact on particular groups is considered; and
• reasonableness—decisions should not be arbitrary but rather be rational, proportional to the threat,
evidence-informed and practical.
2.6 Legal Considerations

The legal considerations that arise in the context of pandemic preparedness and response are varied
and complex. International laws as well as FPT legislation will be relied upon during both the preparedness
and responses phases of a pandemic.
2.6.1 INTERNATIONAL REQUIREMENTS
International Health Regulations (2005)

The current International Health Regulations (2005) [IHR (2005)] came into force in 2007. They provide
a framework for monitoring and enhancing global public health capacity and international communication
regarding potential public health emergencies of international concern (PHEIC). The aim of the IHR
(2005) is to prevent the international spread of disease while limiting interference with international
traffic and trade. The IHR (2005) also establish a more effective and transparent process for WHO and
its Member States (including Canada) who are States Parties to the Regulations, to follow when
determining and responding to a PHEIC. Most importantly, they broaden the scope of international
collaboration to include any existing, re-emerging or new disease that could represent an international
threat. The IHR (2005) are available at: www.who.int/ihr/en/.
23
University of Toronto Joint Centre for Bioethics Pandemic Influenza Working Group. Stand on Guard for Thee: Ethical
considerations in preparedness planning for pandemic influenza. 2005. Available from: www.jcb.utoronto.ca/people/
documents/upshur_stand_guard.pdf
24
UK Cabinet Office and Department of Health. Responding to pandemic influenza. The ethical framework for policy and
planning. 2007. Available from:
www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_080751
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The IHR (2005) include obligations for States Parties to:

• develop core capacity for surveillance and response;
• establish a national focal point (NFP) as the contact point for WHO on all IHR matters; and
• notify WHO of all potential PHEIC within specified time frames.
In order for Canada to meet the IHR (2005) requirements, all levels of government must collaborate. In
Canada, PTs use established protocols to report influenza infections of international concern to the
Public Health Agency of Canada (PHAC), which is Canada’s NFP. After an initial assessment if notification
is required, PHAC communicates with the WHO. Reportable influenza-related events include cases of
human influenza caused by a new subtype as well as cases having potential international public health
implications that meet the notification criteria established under Annex 2 of the IHR (2005). WHO then
re-assesses the event to determine whether the event constitutes an actual PHEIC. The first PHEIC
declared by the WHO under the IHR (2005) was the influenza A (H1N1) pandemic in 2009.
Pandemic Influenza Preparedness Framework

The Pandemic Influenza Preparedness Framework (PIP Framework) for the sharing of influenza viruses
and access to vaccines and other benefits was adopted by the World Health Assembly in 2011. The PIP
Framework aims to improve the sharing of influenza viruses with pandemic potential and to achieve
more predictable, efficient and equitable access for countries in need of life-saving vaccines and
medicines during future pandemics. The PIP Framework is available at:
www.who.int/influenza/pip/en/.
Under the Framework, Member States, including Canada, are responsible for:
• ensuring the timely sharing of influenza viruses with human pandemic potential with the Global
Influenza Surveillance and Response System (GISRS);
• contributing to the pandemic influenza benefit-sharing system; and
• continuing to support the GISRS.
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2.6.2 FEDERAL LEGISLATION

The Emergency Management Act (2007), section 6(1), makes each minister accountable to Parliament
for a government institution responsible to identify the risks that are within or related to his or her area
of responsibility and prepare emergency management and response plans with respect to those risks;
to maintain, test and implement those plans; and to conduct exercises and training in relation to them.
In accordance with responsibilities under the Act, the federal Minister of Health is primarily responsible
for developing, testing and maintaining mandate-specific emergency plans for the federal Health
Portfolio, which includes Health Canada (HC) and PHAC. These emergency plans outline the federal
response to national public health threats or events such as major disease outbreaks (including an
influenza pandemic), and to the health effects of natural disasters or major chemical, biological,
radiological, nuclear and explosive (CBRNE) events.
Furthermore, the Quarantine Act (2005) strives to prevent the introduction and spread of communicable
diseases into and out of Canada by providing the Minister of Health with the authority, including
enforcement mechanisms, to take public health measures as required. Pandemic Influenza Type A is
listed in the Act’s Schedule of Diseases.
2.6.3 PROVINCIAL/TERRITORIAL LEGISLATION

Health emergency management in the PTs in Canada is governed by legislation specific to each
jurisdiction. This legislation requires the PT governments to have comprehensive emergency plans
respecting preparation for, response to and recovery from emergencies and disasters, including those
with potential impact on critical infrastructure. Important health emergency management powers are
also found in public health legislation.
The 2009 pandemic provided an opportunity to identify problems or gaps in existing legislation
(including public health legislation) that should be addressed in order to respond more effectively to a
future pandemic. An effective response requires an authority to establish appropriate leadership for a
coordinated response, along with authority for PT and local public health officials to implement
appropriate control measures. Planners should ensure that they will have authority to mount an effective
response whether or not an emergency is officially declared.
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3.0 CANADA’S APPROACH TO PANDEMIC INFLUENZA

3.1 Goals and Objectives
Goals serve an important purpose in guiding preparedness and response, and in prioritizing the use of
resources if necessary. Canada’s goals for pandemic preparedness and response are:
First, to minimize serious illness and overall deaths, and second to minimize societal
disruption among Canadians as a result of an influenza pandemic.
These national goals were originally presented in the Canadian Pandemic Influenza Plan for the Health
Sector, which was endorsed by FPT Ministers of Health in 2004. The goals, and their sequence, had
undergone extensive deliberation by FPT pandemic planners and other stakeholders. A survey carried
out as part of the Canadian Program of Research on Ethics in a Pandemic (CanPREP) found that over
90% of participants agreed that the most important goal of pandemic influenza preparations was
saving lives.25 During the 2009 pandemic, the pandemic goals were invaluable in guiding aspects of
the response.
Ritvo P, Wilson K, Gibson JL, et al. Canadian survey on pandemic flu preparations. BMC Public Health 2010;10;125.
25
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The supporting objectives for the health sector are as follows:
A. MINIMIZE SERIOUS ILLNESS AND OVERALL DEATHS BY

• reducing the spread of infection through promotion of individual and community actions;
• protecting the population through provision of pandemic vaccine and implementation of
other public health measures; and
• providing treatment and support for large numbers of persons while maintaining other
essential health care.
B. MINIMIZE SOCIETAL DISRUPTION BY
• supporting the continuity of health care and other essential services;
• supporting the continuation of day-to-day activities as much as possible and promoting a
return to normal community functioning as soon as possible;
• maintaining trust and confidence through
–– support of evidence-informed decision-making by collection, analysis and sharing of
communication of appropriate and timely advice to decision-makers, health professionals
and the public; and supporting a coordinated response by working collaboratively with all
levels of government and stakeholders.
3.2 Guiding Principles and Approaches
The following principles underpin Canadian pandemic preparedness and response activities and
decision-making:
• Collaboration—all levels of government and health care stakeholders need to work in partnership to
produce an effective and coordinated response. This implies adopting consistent and collaborative
approaches to planning, response and recovery, and having an effective FPT decision-making
process. It also implies involvement of stakeholders in these steps.
• Evidence-informed decision-making—decisions should be based on the best available evidence to
the extent possible. It is recognized that other factors also enter into decision-making, such as legal
and institutional constraints, values, costs and availability of resources.26
• Proportionality—the response to a pandemic should be appropriate to the level of the threat.
• Flexibility—actions taken should be tailored to the situation and subject to change as new information
becomes available. The pan-Canadian approach should be consistent, although patterns of spread
may mean that regional and local jurisdictions will require flexibility in terms of the scale and timing
of their response.
Oxman AD, Lavis JN, Lewin S et al. SUPPORT Tools for evidence-informed health Policymaking (STP) 1: What is evidence-
26
informed policymaking? Health Res Policy Syst 2009;7(Suppl 1):S1
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In addition to these main guiding principles, Canadian pandemic planning and response activities are
also guided by:
• A precautionary/protective approach – this approach is particularly applicable in the early stages
of a pandemic when evidence-informed decision-making is not possible due to lack of data and
the uncertainty of an evolving event. This means taking timely and reasonable preventive action,
proportional to the threat and evidence-informed to the extent possible. This does not mean that
in the absence of evidence, all actions must be taken; rather, it means that as emerging evidence
reduces uncertainty, evidence-informed actions may supersede those precautionary measures taken
at the outset.
• Use of established practices and systems to the extent possible – it is extremely difficult to implement
new ways to do things during an emergency. Effective seasonal influenza responses support a strong
pandemic response, as well-practised strategies and processes can be rapidly ramped up to manage
the pandemic.
• Ethical decision-making – ethical principles and societal values should be explicit and embedded
in all decision-making, including the processes used to reach decisions. It is especially important
to ensure that all actions respect ethical guidelines tailored to the concerns of public health, while
respecting the rights of individuals as much as possible.
3.3 Coordination of National Preparedness and Response

The global nature of a pandemic requires a response that differs from many other types of emergency.
Traditionally, the responsibility to deal with an emergency is placed first on the individual/household to
manage the effects of the emergency as it affects them, and then on successive levels of government as
the resources and expertise of each are needed. Public Safety Canada is responsible for coordinating
the whole of government response when the federal government is involved in the response to an
emergency. Within the PTs a similar function is performed by the appropriate ministry or emergency
measures organization.
In a pandemic situation, a pan-Canadian whole-of-government response is required so that all potential
resources can be applied to minimizing the pandemic’s negative health, social and economic impacts.
Pandemic plans should be aligned across jurisdictions to facilitate successful FPT collaboration during
a pandemic.
The following sections provide a high-level overview of FPT health emergency planning and response
relevant to pandemics.
3.3.1 EMERGENCY MANAGEMENT FRAMEWORKS AND PLANS

The GC has in place a coordinated system of federal emergency management frameworks, systems and
emergency response plans, many of which can be accessed at Public Safety Canada’s website. These
plans are based on the four components of the emergency management continuum (prevention and
mitigation, preparedness, response and recovery) and they use an all-hazards approach. Emergency
response plans for the federal Health Portfolio are part of this GC system.
The FPT health sector also has a system of frameworks and emergency response plans parallel to those
of the federal health sector, that are comprehensive and flexible enough to address any type of national
health emergency. The development and maintenance of some of these documents, including CPIP, is
overseen by the PHN.
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The federal and FPT emergency management plans are supported by various operational annexes and
guidance documents. These are nested under the generic all-hazards emergency response plans and
deal with more specific threats.
3.3.2 PAN-CANADIAN COORDINATION OF THE PANDEMIC HEALTH SECTOR RESPONSE

Because a pandemic is a significant health event, the FPT ministries of health have the primary mandate
for the health sector response in their respective jurisdiction and act as advisor for other sectors on
health issues.
At the federal level, the Centre for Emergency Preparedness and Response (CEPR) at PHAC is the
Health Portfolio’s focal point for coordinating and providing a wide range of emergency management
services with other federal departments, PT governments, NGOs and the private sector. CEPR is
responsible for the Health Portfolio Operations Centre (HPOC) in Ottawa and its linkages to other
operational centres at the FPT level.
Coordination of the FPT health sector response to a pandemic will follow the governance structure
outlined in the FPT Public Health Response Plan for Biological Events (FPT-PHRPBE). The FPT-PHRPBE
is complementary in nature and used in conjunction with existing jurisdictional planning and response
systems.
The FPT-PHRPBE is intended to bridge the gap between PT public health response plans and federal
health response plans by providing a single, common overarching governance framework for the FPT
health sector that can be applied, in full or in part, during a significant public health event requiring a
coordinated FPT response, such as an influenza pandemic.
The FPT-PHRPBE defines a flexible FPT governance mechanism that identifies escalation considerations
and response levels for a scalable response, and to improve effective engagement amongst public
health, health care delivery and health emergency management authorities during a coordinated FPT
response. This will ensure that at the time of a response, notification processes and inter-jurisdictional
information-sharing will be enhanced; public and professional communication will be addressed; and
advance planning and decision-making between and amongst multiple jurisdictions will be facilitated.
Finally, as the effects of a pandemic are not exclusive to the health system, it is critical for FPT governments
and emergency management partners to use a common approach in responding to a pandemic.
Emergency social services (e.g. non-medical services considered essential for the immediate physical
and social well-being of people affected by disasters) should be coordinated within the broader PT
response and aligned with health system activities.
3.3.3 NORTH AMERICAN PLAN FOR ANIMAL AND PANDEMIC INFLUENZA

The North American Plan for Animal and Pandemic Influenza (NAPAPI) outlines how Canada, Mexico
and the US intend to work together to combat an outbreak of animal influenza or an influenza pandemic
in North America. The NAPAPI addresses both animal and public health issues, including early notification
and surveillance, joint outbreak investigation, epidemiology, laboratory practices, medical
countermeasures (e.g., vaccine and antiviral medications), personnel sharing and public health measures.
It also addresses border and transportation issues. While the NAPAPI is not legally binding, it reflects
strong commitments by the countries involved to work collaboratively.
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3.4 Pandemic Roles and Responsibilities

Collaboration in pandemic planning and response is strengthened by having clearly defined and well-
understood roles and responsibilities. While this section focuses on government responsibilities, it is
acknowledged that other partners also have important roles and responsibilities in a pandemic. These
partners include the non-health sector, private sector, NGOs, municipalities and local/regional health
authorities, and international organizations. Similarly, members of the general public bear responsibility
for keeping themselves informed and for cooperating with measures to reduce the spread of illness.
3.4.1 WORLD HEALTH ORGANIZATION

WHO’s pandemic roles and responsibilities are outlined in the WHO pandemic influenza risk management
guidance document and include:27
• coordination of the international response under the IHR (2005), including conducting global
risk assessments;
• communication of the global situation using the global pandemic phases;
• declaration of a PHEIC and pandemic as required under the IHR;
• provision of information and support to affected States Parties;
• selection of the pandemic vaccine strain and determination of when to move from seasonal to
pandemic vaccine production; and
• provision of oversight and support for implementation of the PIP Framework.
3.4.2 CANADA—FPT GOVERNMENTS

Responsibility for health services in Canada is shared across all levels of government. High-level roles
and responsibilities for FPT governments are outlined below; more detailed information about roles and
responsibilities for specific response components can be found in the CPIP annexes. It is recognized
that responsibilities for federal populations, which are summarized at the end of this section, are complex
and evolving.
A. INTERNATIONAL ASPECTS
International aspects of influenza management and liaison are a federal responsibility.
The federal government is responsible for:
• acting as the national focal point for the WHO on all IHR (2005) matters and managing all international
aspects of pandemic preparedness and response;
• providing travel health notices and other health related information relevant to international travel; and
• exercising powers under the Quarantine Act to protect public health by taking comprehensive
measures to help prevent the introduction and spread of communicable diseases in Canada. Such
measures may include, but are not limited to, the screening, examining and detaining of arriving
and departing international travellers, conveyances (e.g., airplanes and cruise ships) and their goods
and cargo.
27
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B. COLLABORATION, COMMUNICATION, INFORMATION SHARING

AND POLICY RECOMMENDATIONS
While PT governments are responsible for communications plans and messaging within their jurisdictions,
a coordinated pan-Canadian pandemic response requires collective infrastructures, response capacities
and coordinated activities.
• ensuring that risk assessments for novel and pandemic viruses are prepared and communicated as
required; and
• facilitating the coordination of the overall pan-Canadian response to a pandemic.
FPT governments will work collaboratively to:

• coordinate and support the process required for development and periodic updating of CPIP and its
annexes, for which PHAC acts as the custodian;
• assess capacity gaps for a pan-Canadian response and address gaps as necessary;
• align federal pandemic plans for federal populations, (see Section F for federal populations), with PT
plans, where relevant;
• assess surveillance capacity, standards and protocols and modify as necessary;
• assess laboratory capacity, standards and protocols and modify as necessary;
• establish and support pan-Canadian policies and recommendations on the use of antiviral medications
and vaccine during a pandemic;develop and implement public health guidance;
• ensure development and dissemination of clinical care guidance;
• develop a pan-Canadian communication strategy that reflects Canadian linguistic, literacy and cultural
characteristics and allows for the alignment of messaging by FPT jurisdictions where appropriate;
• establish protocols for the sharing of relevant information, including but not limited to FPT plans
and drafts; surveillance information; jurisdictional communications, strategies and messaging; and
pandemic response interventions and impacts; and
• identify and address rapid research response priorities and leverage their respective research
undertakings.
C. ANTIVIRAL MEDICATIONS AND INFLUENZA VACCINE

• providing regulatory authorization to market antiviral medications and influenza vaccines;
• acting as the focal point for vaccine manufacturers and international regulatory collaboration;
• providing regulatory authorization to conduct clinical trials;
• negotiating with manufacturers and establishing contracts for the FPT purchase of antiviral medications
and vaccine for pandemic purposes;
• national monitoring of adverse reactions to antiviral medications and vaccines; and
• providing antiviral medications and vaccine to those federal populations not covered by arrangements
for PT provision.
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PT governments are responsible for maintenance, monitoring, distribution and administration of antiviral
medications and vaccine in their respective jurisdictions. They will work collaboratively to:
• provide antiviral medications and, when available, vaccine to recommended populations;
• share information regarding the distribution and use of antiviral medications and vaccines in their
respective jurisdictions; and
• monitor and report adverse vaccine reactions.
The PT governments are also responsible for the distribution of vaccines and antiviral medications to
most federal populations, but this varies by federal population and jurisdiction (see section F on
federal populations).
FPT governments will work collaboratively to develop strategies to mitigate the effects of insufficient or
delayed antiviral drug and/or vaccine supply, should such a situation arise.
D. HEALTH SECTOR PREPAREDNESS AND RESPONSE

Health sector preparedness and response remains the responsibility of each jurisdiction. In some
jurisdictions responsibility for emergency social services also falls to the health sector.
PT governments are responsible for:
• ensuring that PT pandemic plans (or all-hazards plans depending on the jurisdiction) are developed,
tested and periodically updated;
• considering the content and intent of CPIP in the development of their PT jurisdictional plans;
• communicating and engaging with the general public, media and stakeholder groups about
their respective plans; and
• activating PT pandemic or all-hazards plans.
The federal government has similar responsibilities for federal departments within the health sector and
for federal populations in collaboration with the PTs (see section F on federal populations).
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E. HEALTH CARE PROVISION

The provision of health care is an essential component of pandemic response and is primarily a
PT responsibility.
PT governments are responsible for:
• developing plans to increase surge capacity in order to care for affected persons in their jurisdiction;
• providing health care services for persons within their jurisdiction, including for federal populations
while leveraging agreements that are in place. (federal populations and federal responsibility are
covered in the next section);
• developing and maintaining memoranda of understanding and protocols as needed, preferably
before the pandemic, to facilitate interprovincial/territorial movement of patients and licensed health
care professionals during a pandemic and other aspects of mutual aid;
• developing, as necessary, a strategy for collecting and monitoring data on health care service use;
• ensuring the provision of medications, supplies and equipment required for provision of pandemic
health care services; and
• working collaboratively to establish protocols and guidelines for prioritizing health care services
during times of high service demand and staff or supply shortages in the respective jurisdiction.

• ensuring the provision of health services, medications, supplies and equipment for specified federal
populations/employees who normally access federally operated health care services;
• facilitating access to surge capacity, including from federal programs, employees and resources, to
support PT responses if required;
• mobilizing medical supplies in the National Emergency Strategic Stockpile (NESS) as surge capacity
to support PT responses; and
• facilitating the acquisition of extra medical supplies through Public Services and Procurement Canada
and other federal agencies as appropriate.
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F. FEDERAL POPULATIONS
Federal populations are those populations for which the federal government either provides health care
and benefits, goods and/or services or reimburses the cost of providing health care and benefits. With
the exception of the Canadian Forces which has its own distinct health care system for active members,
the needs of federal populations must be integrated into PT pandemic planning activities in order to
establish a comprehensive and coordinated pandemic response.
Federal populations include the following:
• First Nations on-reserve, inclusive of First Nations who have assumed responsibility for health services
under a transfer agreement;
• active members of Canadian Forces;
• federal offenders or inmates of federal penitentiaries;
• refugee claimants, protected persons, detainees under the Immigration and Refugee Protection Act,
rejected refugee claimants, and other specified populations; and
• Canada-based staff at missions abroad.

• supporting the provision and distribution of medications, supplies and equipment to federal
populations, as noted in the list above, through existing FPT distribution and administration systems.
The federal government will work collaboratively with PT governments to:

• ensure that access to pandemic health services for all federal populations is available on the same
basis as is provided to other residents of Canada, while leveraging agreements that are in place. This
involves but is not limited to access to antiviral medications, influenza vaccines and supplies needed
for provision of pandemic health care services; and
• facilitate the coordination of federal planning for federal populations with PT pandemic plans.
3.5 Risk Management Approach

3.5.1 OVERVIEW
Risk management is a systematic approach to setting the best course of action in an uncertain
environment by identifying, assessing, acting on and communicating risks. A risk management approach
provides a useful framework for addressing the uncertainties inherent in pandemic planning and
response. Risk management supports the CPIP planning principles of evidence-informed decision-
making, proportionality, and flexibility; and a precautionary/protective approach when there is uncertainty
early in an event.
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Figure 1 provides a graphic overview of the risk management process as outlined in ISO 31000, the
international standard for risk management. The individual steps involved in risk management are then
briefly described.
FIGURE 1—ISO 31000 RISK MANAGEMENT PROCESS28
Establishing the context
Risk Assessment
Communication Risk Identification Monitoring

and and
Consultation Risk Analysis Review
Risk Evaluation
Risk Treatment
Risk assessment is a central component of risk management. Its purpose is to provide evidence-informed
information and analyses for making informed decisions on how to treat particular risks and select
between options. There are three parts to risk assessment:
• Risk identification involves identifying what might happen, or what situations might exist that could
affect achievement of the objectives of the organization or system.
• Risk analysis involves analysing the risks in terms of their probability and potential impact (who is
affected and to what extent). This analysis helps identify the planning considerations and options
for each component of the response. The analysis should also assess the public’s perception of risk
and how it could influence the risk management response, so that communications strategies and
messaging can be tailored appropriately.
• Risk evaluation involves determining the significance of the level and type of risk in order to make
decisions about future actions. Ethical, legal, financial and other considerations are also inputs to the
decisions. Decisions may include the need and priorities for treatment, whether an activity should be
undertaken or which of a number of paths should be followed.
Risk treatment follows risk assessment and involves identifying and recommending risk treatment
options, i.e. options for management or control. Risk treatment options should include steps that need
to be taken in advance, as well as potential actions at the time of the pandemic.
Communication and consultation are also integral parts of the risk management process. Effective
communication with stakeholders should facilitate adequate understanding of the risk management
decision-making process, ensure that the process is transparent and help people to make informed
decisions. A risk communications plan should be developed at an early stage.
Canadian Standards Association. CAN/CSA-ISO 31000-10. Risk management—Principles and guidelines (Adopted ISO
28
31000:2009, first edition 2009-11-15). 2010.
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Monitoring and review are important for assessing factors that could change over time and for
documenting effectiveness of interventions. Such reviews should lead to periodic updates of the
risk assessment.
3.5.2 RISK MANAGEMENT CONSIDERATIONS IN PANDEMIC PLANNING AND RESPONSE

Given the large number of variables that are involved in influenza pandemic planning, comprehensive
risk management is challenging. The four pandemic planning scenarios described in section 3.7 can
assist with risk identification by providing a starting point to think through the risks that would be
associated with pandemics of varying impact and their implications.
It is also worthwhile to anticipate key decisions that will need to be taken during the pandemic to help
guide the development and analysis of options. It is also worthwhile to clarify ahead of time and to the
extent possible what level(s) of government should be involved with which types of decision when the
time comes. Examples of these key decisions are as follows:
• what is the scale of the response;
• whether (and when) to escalate or de-escalate the response;
• when, what and how to communicate with the public;
• what amount of vaccine and the formulation(s) to order;
• how vaccine use should be prioritized;
• what public health interventions should be used, when and within which populations, and whether
they need to be adjusted over time;
• what influenza testing and treatment strategies to recommend and whether they need to be adjusted
over time; and
• what supplementary assessment and treatment services might be needed and, if necessary, when
they should be started and stopped.
Anticipating key decisions should be accompanied by identification of the types and sources of
information required for decision-making. Establishing robust surveillance for seasonal influenza
establishes baselines, develops capacity and provides a platform for escalation during the pandemic.
Anticipating key decisions should also lead to development of relevant options for risk treatment. From
a pandemic preparedness perspective, examples of risk treatment include continuity of operations
planning; establishment of stockpiles for antiviral medications and other key supplies; development of
advance contracts for pandemic vaccine; strengthening influenza surveillance systems, diagnostic and
analytical capacity; establishment of protocols for pandemic research; and establishment of
communications networks to plan effective and coordinated risk communications strategies.
When a pandemic occurs, planning scenarios are replaced by a real event and response activities will be
guided by the available evidence. During the initial stages, little may be known about the likely pandemic
impact or the populations most at risk. Many decisions will have to be made before solid information is
available and then adjusted, if necessary, as more becomes known, keeping in mind that it is often
difficult to scale back a response. As the evidence emerges over time, understanding of the situation will
continue to change as new information becomes available and will always be incomplete. A risk
management approach will be used throughout the response by all responders. Risk assessments will
provide key input into FPT decision-making by identifying what is known at that point in time, what
might occur and when, and the major areas of uncertainty.
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PHAC will facilitate development of timely and credible risk assessments to support FPT decision-
making. These formal risk assessments will be conducted at the start of the pandemic to inform the
initial response and then periodically as new information emerges (e.g., at the end of a pandemic wave).
Risk assessments will address key information needs, including viral characteristics, the anticipated or
experienced impact on the health care system and community, age and risk groups most affected,
occurrence of antiviral resistance and estimated effectiveness of control measures. As the pandemic
progresses, there will be questions about likely occurrence of more pandemic waves, whether new risk
factors are emerging and whether the response should be escalated or de-escalated. Appendix B
identifies relevant considerations for initial and ongoing pandemic risk assessments and identifies
potential sources for the supporting information.
3.6 Planning Assumptions

This section on planning assumptions and section 3.7 on pandemic planning scenarios describe two
important tools for pandemic planning. These tools provide distinct but complementary approaches.
Identifying planning assumptions is a way to deal with uncertainty. Assumptions provide a useful
framework for planning but should not be regarded as predictions. While planning assumptions are
rooted in evidence to the extent possible, 29,30 they are basically educated guesses. As the pandemic
unfolds, emerging evidence is used to guide the response. Informing the planning assumptions
identified below is the WHO’s Pandemic influenza risk management interim guidance (2013), the UK’s
Scientific summary of pandemic influenza & its mitigation (2011) and discussions from the Canadian
Pandemic Influenza Preparedness Planning Assumptions Workshop held in 2011.
3.6.1 ORIGIN AND TIMING

• The next pandemic could emerge anywhere in the world and at any time of year.
• There may be no lead time before the novel virus reaches Canada.
• The first peak of illness in a geographic area within Canada could occur within weeks of first detection
of the novel virus in that area. The first peak in mortality is expected to be several weeks after the
peak in illness.
29
30
Department of Health. Scientific summary of pandemic influenza & its mitigation. 2011. Available from:
www.dh.gov.uk/en/Publicationsandstatistics/DH_125318
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3.6.2 TRANSMISSION
• The pandemic virus will behave like seasonal influenza viruses in significant ways:
–– incubation period—is expected to last from one to three days;
–– period of communicability—adults are infectious from 24 hours before and up to five days from
the onset of symptoms, and children may be infectious for up to seven days. Longer periods have
been found, especially in persons with immune compromising conditions;
–– methods of transmission—mainly by large droplet and contact (direct and indirect) routes; the role
of airborne transmission is unclear.
• Transmission is expected to be relatively lower in spring and summer than in fall and winter (the
general pattern of transmission in temperate countries).
• Transmission is possible from asymptomatic persons but is greater when symptoms, such as coughing,
are present and viral shedding is high (i.e., early in the symptomatic period).
3.6.3 PANDEMIC EPIDEMIOLOGY

• Most communities will experience two or more pandemic waves of different magnitudes. In any
locality, the length of each wave will be from several weeks to a few months but may vary by community.
• There will be geographic variability with regard to the timing and intensity of waves, although multiple
jurisdictions will be affected simultaneously.
• The pandemic is expected to last 12 to 18 months.
• The novel virus is expected to displace other circulating seasonal strains during the pandemic. After
the pandemic, the pandemic virus will continue to circulate as a seasonal strain. It may completely
replace previously circulating seasonal influenza A subtypes or continue as one of several circulating
seasonal A subtypes.
• Relatively more severe disease and mortality is expected to occur in the young and in persons without
underlying health conditions compared to seasonal influenza.
3.6.4 CLINICAL FEATURES

• Population clinical attack rates (averaged across all age groups) are expected to be 25% to 45% over
the course of the pandemic.
• Clinical symptoms are expected to develop in about two-thirds of people who are infected with the
pandemic influenza virus.
• The general, uncomplicated clinical picture is expected to be the same as for seasonal influenza:
respiratory symptoms, fever and abrupt onset of muscle ache, fatigue and headache or backache.
• Persons at high risk for complications from seasonal influenza31 are expected to also be at increased
risk of severe disease and complications from pandemic influenza infection, although additional risk
groups may emerge.
National Advisory Committee on Immunization. Statement on seasonal influenza vaccine for 2013–2014. Can Commun Dis
31
Rep 2013; 39 (ACS-4):1–37. Available from: www.phac-aspc.gc.ca/publicat/ccdr-rmtc/13vol39/acs-dcc-4/index-eng.php
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3.6.5 IMPACT AND INTERVENTIONS

• Impact will vary across communities, and vulnerable populations are expected to be affected
more severely.
• Workplace absenteeism may be higher than the estimated clinical attack rate because of caregiving
or concern about personal safety in the workplace in addition to worker illness.
• Vaccine is expected to be available in time to have an impact on the overall pandemic but will not
be available for the first wave.
• Personal hygiene measures are expected to help to reduce transmission between individuals and
within households and other settings.
3.7 Pandemic Planning Scenarios

This section discusses another important tool for pandemic planning. The use of multiple planning
scenarios is specifically intended to support the planning principles of evidence-informed decision-
making, proportionality, and flexibility; and a precautionary/protective approach.
Planning scenarios provide a starting point to think through the implications and risks that would be
associated with pandemics of varying population impact. Scenarios can also be used for exercises and
training in support of pandemic plans. To help with risk identification, four pandemic planning scenarios
have been developed that describe potential pandemic impacts varying from low to high. Figure 2
displays the four scenarios in a two-by-two table and estimates where the past four pandemics might be
placed, according to an analysis conducted by the US Centers for Disease Control and Prevention (CDC).32
FIGURE 2—FRAMEWORK FOR THE PLANNING SCENARIOS, WITH PREVIOUS

PANDEMICS PLACED AS PER CDC ANALYSIS33
HIGH
1918
B 1968 1957
D
Transmission
2009
A C
LOW
LOW Clinical Severity HIGH
32
Reed C, Biggerstaff M, Finelli L et al. Novel framework for assessing epidemiological effects of influenza epidemics and
pandemics. Emerg Infect Dis. 2013;19:85-91.
33
Ibid
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Scenario A (low impact)—this scenario involves an influenza virus with low transmissibility (ability to
spread) and low virulence (clinical severity). Its impact is comparable to that of moderate to severe
seasonal influenza outbreaks or the 2009 pandemic. It might be expected to stress health care services.
Scenario B (moderate impact)—this scenario involves an influenza virus with high transmissibility and
low virulence. Its impact is worse than seasonal influenza in terms of numbers ill, which would be
expected to stress health care services through sheer volume. High absenteeism would put all sectors
and services under pressure.
Scenario C (moderate impact)—this scenario involves an influenza virus with low transmissibility and
high virulence. Its impact is worse than seasonal influenza outbreaks in terms of severe clinical illness,
which would be expected to stress critical care health services. The high virulence could cause significant
public concern and may lead to people staying home from school and work.
Scenario D (high impact)—this scenario involves an influenza virus with high transmissibility and high
virulence, and its anticipated impact is much worse than that of seasonal influenza outbreaks. It would
cause severe stress on health care services, and high absenteeism would put all sectors and services
under extreme pressure.
There are several important points to note about the scenarios:

• Whatever the pandemic impact, the epidemiological picture is expected to be significantly different
from that of seasonal influenza, in that relatively more severe disease and mortality will occur in the
young and in persons without underlying health conditions compared to seasonal influenza.34
• The four basic scenarios do not incorporate all of the potential factors (or “what-ifs”) that can affect
the impact of a pandemic and should be considered in risk assessment. Some of these factors are
population-wide and could affect all scenarios (such as seasonality, pre-existing immunity or antiviral
resistance), whereas others might be setting-specific (such as planning for a remote community). See
Appendix A for more details about these additional factors and their potential impact. Additional
risks may also be identified as planners consider all stages of the pandemic and components of the
proposed response.
Table 1 provides some added description to the scenarios for planning purposes, along with potential
impact considerations associated with each scenario.
TABLE 1 – DESCRIPTION AND POTENTIAL IMPACT OF THE FOUR PANDEMIC PLANNING SCENARIOS
PANDEMIC SCENARIO
NATURE
A B C D
OF IMPACT
(LOW IMPACT) (MODERATE (MODERATE (HIGH IMPACT)
IMPACT) IMPACT)
BASIC VIRUS Low High Low High

CHARACTERISTICS transmissibility/ transmissibility/ transmissibility/ transmissibility/
low virulence low virulence high virulence high virulence
Simonsen L, Clarke MJ, Schonberger LB, et al. Pandemic versus epidemic mortality: a pattern of changing age distribution.
34
J Infect Dis 1998;178:53-60.
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PANDEMIC SCENARIO
NATURE
A B C D
OF IMPACT
IMPACT) IMPACT)
NATURE AND • Similar numbers • Higher number of • Similar number of • Large numbers
SCALE OF ILLNESS as in moderate or cases than large cases as with large of people ill
severe seasonal seasonal outbreak seasonal outbreak • High proportion
influenza outbreaks but similar clinical but illness is more with severe
• Mild to moderate severity severe disease
clinical features • Overall increased • Overall increased
(in most cases) numbers needing numbers needing
medical care and medical care and
with severe with severe
disease disease
IMPACT ON • Ambulatory and • Ambulatory • Ambulatory and • Health care

HEALTH CARE acute-care and acute-care acute-care services may be
SERVICES services stressed services very services very overwhelmed
but able to cope stressed stressed • Ambulatory
• ICUs at capacity • Health care • Health care services fully
• Public health and services no longer services no longer stretched
laboratory services able to continue able to continue • Hospitals able
stressed all activities all activities to provide only
• Long-term care • ICUs under severe • ICUs under severe emergency
may or may not pressure pressure services
be affected • Long-term care • Long-term care • Triaging necessary
(depending on may or may not be may or may not be for critical care
pre-existing affected affected services
immunity) • Settings with • Settings with • Collapse of
limited surge limited surge services could
capacity (e.g., capacity e.g., lead to higher
nursing stations) nursing stations) mortality than
may be even more may be even more expected
stressed stressed • Settings with
limited surge
capacity (e.g.,
nursing stations)
may be highly
stressed
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PANDEMIC SCENARIO
NATURE
A B C D
OF IMPACT
IMPACT) IMPACT)
BROADER • Limited workplace • High workplace • Potential • High absenteeism

SOCIETAL IMPACT disruption absenteeism workplace • Services and
• Some school • Some services absenteeism and businesses under
disruption experience school disruption extreme pressure
pressures from fear of
• Elevated public • Potentially severe
exposure
concern • Schools likely supply chain
disrupted • Considerable problems
public concern
• Some supply chain • Could disrupt
over occurrence
problems provision of basic
of very severe
• Elevated public services
disease
concern • Extreme public
• Surges in need for concern and
health care psychosocial
services. distress
• Mass fatalities may
overwhelm death
care services (e.g.
funeral homes,
mortuaries)
ECONOMIC Minimal if any Productivity may Productivity may Very high

IMPACT be affected be affected
Initial period when impact is unknown—A formal scenario has not been proposed for the initial period
when the pandemic has not yet been characterized in terms of its potential impact. However, some of
the possible observations for this preliminary period are as follows:
• sporadic cases and limited outbreaks may be occurring;
• there will likely be elevated demand on telephone information lines, ambulatory care and laboratory
services;
• public health services may be stressed;
• elevated media and public concern can be anticipated;
• international travel and trade could be disrupted; and
• there could be increased demand and shortages of publicly available supplies, e.g., infection control
and basic emergency supplies, antivirals.
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3.8 Pandemic Phases and Triggers for Action

3.8.1 WHO PANDEMIC PHASES
Pandemic phases were introduced into pandemic plans to assist planning and serve as triggers for
action, thus supporting the principles of flexibility and proportionate response. Previous Canadian
pandemic plans incorporated the WHO pandemic phases, with additional designations proposed to
identify activity levels within Canada.
After the 2009 pandemic, the IHR Review Committee35 recognized that the WHO pandemic phases had
presented challenges in interpretation and were used in different ways – as a planning tool, as a method
to describe the global situation and/or as an operational tool to trigger action. The Committee
recommended simplifying the WHO phase structure and separating operational considerations at
country level from the WHO global preparedness plan and its phases.
WHO’s 2013 pandemic guidance36 describes the four phases that WHO will use to communicate a high-
level global view of the evolving picture. The phases reflect WHO’s risk assessment of the global situation
regarding each influenza virus with pandemic potential that is infecting humans. The four global phases are:
• Interpandemic phase—the period between influenza pandemics;
• Alert phase—when influenza caused by a new subtype has been identified in humans. This phase is
characterized by extra vigilance and careful risk assessment;
• Pandemic phase—the period of global spread of human influenza caused by a new subtype.
Movement between the interpandemic, alert and pandemic phases may occur quickly or gradually;
• Transition phase—reduction of the assessed risk resulting in de-escalation of global actions.
The global phases and their application in risk management are distinct from (1) the determination of a
PHEIC under the IHR (2005) and (2) the declaration of a pandemic. These are based upon specific
assessments and can be used for communication of the need for collective global action, or by regulatory
bodies and/or for legal or contractual agreements, should they be based on a determination of a PHEIC
or on a pandemic declaration.37
As pandemic viruses emerge, countries face different risks at different times and should therefore rely
on their own risk assessments, informed by the global phases, to guide their actions. The uncoupling of
national actions from global phases is necessary since the global risk assessment, by definition, will not
represent the situation in each country.
35
World Health Organization. Implementation of the International Health Regulations (2005). Report of the Review Committee
on the Functioning of the International Health Regulations (2005) in relation to Pandemic (H1N1) 2009. A64/10. 5 May 2011.
Available from: http://apps.who.int/gb/ebwha/pdf_files/WHA64/A64_10-en.pdf
36
World Health Organization. Pandemic influenza risk management – WHO interim guidance. 2013. Available from:
37
Ibid.
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3.8.2 CANADA’S APPROACH TO PANDEMIC PHASES AND TRIGGERS FOR ACTION

Canada’s response to the novel/pandemic virus will relate to its presence and activity levels in this
country, which may not coincide with the global picture. Therefore, the WHO global phases will not be
used to describe the situation in Canada or be used as triggers for action in Canadian jurisdictions.
While the triggers for action described below may parallel some of the global WHO phases, it is not
expected that they will line up exactly. For example, Canada might be well into the first pandemic wave
before WHO announces the global pandemic phase (as happened in the 2009 pandemic) or conversely
Canada might be still anticipating the first domestic outbreaks when the pandemic phase announcement
is made.In the 2009 pandemic, there was considerable variation in pandemic wave activity across
Canada and even within PTs, in terms of both timing and intensity. This was particularly apparent in the
first wave making blanket descriptions, triggers or responses inappropriate.
DESCRIBING PANDEMIC ACTIVITY

Descriptive terms such as the start, peak and end of a pandemic wave, will be used instead of phase
terminology to describe pandemic activity in the country or in a jurisdiction within Canada. Pandemic
wave activity can be further characterized for jurisdictions of any size using FluWatch definitions for no
activity, sporadic activity, localized activity and widespread activity.38
TRIGGERS FOR ACTION

Triggers for action provide guidance for initiation of FPT activities and for their modification and
cessation. Pandemic response should be appropriate to the local situation, so it is important that triggers
and related actions be applied at PT or regional/local level as appropriate to the situation. Potential
triggers for action in Canadian jurisdictions during the initial alert stages and the pandemic itself are
identified in Table 2. The typical actions listed are at a high level; more detailed triggers for individual
response components can be found in the annexes. Note that the triggers are not necessarily linear; for
example, not all jurisdictions may find their capacity exceeded and therefore some may not need to
invoke that particular trigger.
TABLE 2 – PANDEMIC TRIGGERS AND TYPICAL ACCOMPANYING ACTION
TRIGGER TYPICAL ACTIONS FOR CONSIDERATION COMMENTS
NOVEL VIRUS • Preparations to enhance surveillance • Tailored communications

CAUSING HUMAN within Canada to health sector and
CASES DETECTED • Intelligence gathering from affected areas general public continue
SOMEWHERE throughout the response
• Relevant public and health sector communications
IN THE WORLD
(NO OR LIMITED
TRANSMISSION)
Public Health Agency of Canada. FluWatch. Definitions & calendar for the current season. Available from:
38
www.phac-aspc.gc.ca/fluwatch/index-eng.php
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NOVEL VIRUS WITH • Enhanced surveillance by PTs within Canada • Pandemic may be imminent
SUSTAINED HUMAN • Intelligence gathering from affected areas; or have already started
TRANSMISSION preliminary risk assessment
DETECTED
• Development of specific laboratory diagnostics
SOMEWHERE
IN THE WORLD • Enhancement of illness prevention messages and
other public health measures (e.g., hand hygiene,
respiratory etiquette) as appropriate
• Confirmation of pandemic vaccine arrangements
with manufacturer
NOVEL/PANDEMIC • Continuation of above activities • Depending on

VIRUS (WITH • Activation of health emergency response protocols circumstances, activation
SUSTAINED HUMAN of health emergency
• Detailed investigations of early cases to determine
TRANSMISSION) protocols might already
epidemiological and clinical characteristics and
FIRST DETECTED have occurred
inform risk assessment
IN CANADA
• Arrangements for antiviral access/strategic
deployment of NAS
• Provision of clinical guidelines and public
health advice
NOVEL/PANDEMIC • Treatment of cases • Escalation of activities as

VIRUS DETECTED • Ramping up health sector capacity to deal with pandemic activity moves
IN PT OR LOCAL increasing number of cases from sporadic cases into
JURISDICTION full pandemic wave,
• Additional public health measures (e.g., school
followed by de-escalation
closures) as appropriate
as it wanes
• Preparation for vaccine distribution, administration
and monitoring
• Ongoing surveillance to monitor influenza activity
and epidemiological analysis to characterize
pandemic
• Relevant public and health sector communications
• Assess need for supportive emergency and social
services (e.g. reception centres, volunteers,
faith-based organizations
DEMANDS FOR • Further escalation of surge capacity • May not reach this level
SERVICE START TO • Prioritization or triage of services as needed in any or all jurisdictions
EXCEED AVAILABLE
• Implementation of broader public health measures
CAPACITY
(e.g., banning of large gatherings)
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THE PANDEMIC • Preparation for a resurgence of influenza

WAVE WANES • Replenishing of supplies as needed in anticipation
AND DEMAND FOR of another wave
SERVICE FALLS TO
• Evaluation of response and revision of plans
MORE NORMAL
as required
LEVELS
• Preparation for immunization program
• Ongoing surveillance to detect resurgence
• Assessment of the psychosocial impact on the
population (e.g. workforce resiliency, mental
health, social cohesion) of the first wave
PANDEMIC VACCINE • Administration of vaccine as quickly as possible

IS AVAILABLE FOR • Monitoring of vaccine uptake, safety
ADMINISTRATION and effectiveness
SECOND OR • Treatment of cases

SUBSEQUENT • Continuation of immunization if already started
PANDEMIC WAVE
• Ongoing surveillance to monitor influenza activity,
ARRIVES
antiviral resistance and strain changes
PANDEMIC IS OVER • Completion of pandemic studies and reports • Identification of lessons

AND NORMAL • Evaluation of response and revision of plans as learned and their
ACTIVITIES RESUME required incorporation into
pandemic planning are
• Return to more normal operations
critical activities in the
• Preparation for post-pandemic seasonal influenza recovery from a pandemic
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4.0 KEY COMPONENTS OF PANDEMIC INFLUENZA PREPAREDNESS

AND RESPONSE
This chapter provides a high-level overview of the major components of influenza preparedness and
response. Each section of the chapter describes the purpose and strategic approach of one of the
response components and demonstrates how it supports the overall pandemic goals. Detailed
operational guidance and tools for each component can be found in the respective CPIP annex.
All parts of the health sector, including public health, will be under stress during a pandemic. Advance
planning, training and exercises will greatly assist in handling this increased demand on health services,
staffing, resources and supplies and in providing the best possible clinical outcomes for persons ill with
influenza. Continuity of operations and surge capacity planning are key components of health sector
preparation, together with strong infection prevention and control and occupational health programs
within each organization that provides health services.
Public health authorities play a leadership role in their jurisdiction in pandemic preparedness, response
and recovery. They are responsible for communication to the public, the health sector and other
stakeholders. The public health response to a pandemic also includes surveillance (both epidemiological
and laboratory), the provision of pandemic vaccine and antiviral medications, and the application of
public health measures such as promotion of personal and social distancing measures to reduce spread
in households and the community.
In planning for the delivery of health services, it is important to encompass the entire continuum of care
from medical first response to critical care, and to include community health partners. Planning for the
provision of health care needs to be linked with public health and community-wide partners so that
interdependencies can be identified and addressed.
The health care system includes workers of many disciplines, who will be at varying levels of risk during
an influenza pandemic. HCWs are defined broadly as individuals who provide health care or support
services in the health care setting, such as nurses, physicians, dentists, nurse practitioners, paramedics,
medical laboratory workers, other health professionals, temporary workers from agencies, unregulated
health care providers, students, volunteers and workers who provide support services (e.g., food,
laundry, housekeeping). The concepts and advice that are provided for HCWs also apply to other
workers who are functioning in a health care capacity, for example police or fire personnel who are
providing medical first response.
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4.1 Surveillance
The purpose of pandemic surveillance is to provide decision-makers with the timely information they
need for an effective response. Pandemic surveillance uses data obtained through routine and enhanced
surveillance activities (e.g., data from sources such as laboratories, PT partners, hospital networks and
sentinel practitioners) together with information from special studies to obtain a comprehensive and
timely epidemiological picture of the pandemic.
These pandemic surveillance programs will monitor parameters such as:
• the geographic spread of the novel/pandemic virus across Canada;
• the trend of disease occurrence as it rises and falls within each PT and across the country;
• the intensity and impact of the pandemic (e.g., clinical cases, hospitalizations and deaths; severe
clinical syndromes and associated risk groups; and demands on the health system); and
• changes in the antigenicity and antiviral sensitivity of the virus.
STRATEGIC APPROACH
A risk management approach to an influenza pandemic requires access to timely information, analysed
and presented in a way that is useful to decision-makers. Epidemiological and laboratory surveillance
data are key components of the formal risk assessments that will be produced to inform the response.
One of the most critical needs is an early assessment of the potential impact of the pandemic so as to
prepare the health care system and to plan interventions that are proportional to the situation. Systems
or studies to produce the early impact assessment and other required information need to be in place
before the pandemic.
Pandemic surveillance should be built on existing surveillance systems for seasonal influenza, which
involve an extensive network of surveillance partners and are practised every year.
During a pandemic, collection of additional surveillance elements may be required to identify risk factors
for severe disease and populations at increased risk. Targeted surveillance activities may be required for
remote and isolated communities, including many Indigenous communities, to describe outbreaks
appropriately in these regions. Other special studies (e.g., seroprevalence surveys) will be needed to
inform decision-making.
Surveillance activities will need to be adapted in response to rapidly evolving situations; they may be
streamlined, expanded or scaled down depending on information needs at particular times within the
evolving pandemic. The scope of the pandemic and the urgency of information needs will require
expedited and secure electronic data transfer and enhanced capacity for data analysis and interpretation.
More details about pandemic surveillance strategies and activities can be found in the Surveillance Annex.
4.2 Laboratory Services

Laboratory-based surveillance is an integral part of monitoring influenza activity. Because the signs and
symptoms of influenza are similar to those caused by other respiratory pathogens, laboratory testing
must be conducted to diagnose influenza definitively. Rapid identification of a novel influenza virus and
timely tracking of virus activity throughout the duration of the pandemic are critical to the success of a
pandemic response. In the early stages of a pandemic, laboratory services also contribute to appropriate
clinical treatment.
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The purpose of laboratory services during a pandemic is to:

• identify the first cases of a novel influenza strain occurring in Canada;
• support public health surveillance by monitoring the geographic spread of disease and the impact
of interventions;
• facilitate clinical management by distinguishing patients infected with the pandemic influenza virus
from those with other respiratory diseases;
• monitor circulating influenza viruses for antiviral resistance and strain characteristics; and
• assess influenza vaccine match and support vaccine effectiveness studies.
STRATEGIC APPROACH
The pandemic laboratory response is built on the principles of collaboration, flexibility and use of
established practices and systems. As part of annual influenza surveillance, all public health laboratories
and other laboratories that routinely test for influenza submit aggregate data weekly during the influenza
season to the National Microbiology Laboratory (NML). These data are collated and disseminated by
PHAC through the Respiratory Virus Detection Surveillance System and FluWatch. In addition, public
health laboratories and other designated laboratories across the country submit isolates to the NML to
monitor for antigenic changes within the circulating viruses. This information is shared with international
partners through GISRS. Sustaining these relationships and strengthening capacity within the laboratory
system during the interpandemic period will support a timely and effective pandemic response.
During a pandemic, influenza testing laboratories will support epidemiological efforts to track the
spread and trends of the pandemic, monitor antiviral resistance and support clinical management. The
Canadian Public Health Laboratory Network (CPHLN) will support public health and diagnostic
laboratories by providing recommendations and best practices for specimen collection and testing for
the novel influenza virus. The NML will share protocols, reagents and proficiency panels to ensure that
test methods are capable of detecting the new virus. Molecular testing is the primary method used for
the diagnosis of influenza.
Antiviral resistance will be monitored and outcomes will inform clinical management of patients. Antiviral
resistance testing is conducted primarily at the NML, as well as some provincial laboratories.
The laboratory response will be adjusted as the pandemic progresses. Initially the NML will be heavily
engaged in characterization of the novel virus and development of diagnostic reagents. All laboratories
should anticipate high test volumes initially as the novel virus spreads across the country. During peak
periods, laboratories will need to prioritize specimen collection to prevent overload. At this point,
diagnosis of influenza in the community will be made primarily by clinical assessment; however, testing
to support the management of certain patients (e.g., those requiring admission to hospital) will be
expected to continue together with identification of outbreaks and surveillance. If ongoing monitoring
shows increasing levels of antiviral resistance, more testing may be necessary to support clinical
management of severely ill patients, especially those not responding to treatment.
Throughout the pandemic, public health, diagnostic and research laboratories, including those involved
in the Canadian Immunization Research Network (CIRN), will also play an important role in supporting
studies to better understand the novel pandemic virus and its impact.
More details about pandemic laboratory strategies and activities can be found in the Laboratory Annex.
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4.3 Public Health Measures

Public health measures are non-pharmaceutical interventions that can be taken by individuals and
communities to help prevent, control or mitigate pandemic influenza. Public health measures range
from actions taken by individuals (e.g., hand hygiene, self-isolation) to actions taken in community
settings and workplaces (e.g., increased cleaning of common surfaces) to those that require extensive
community preparation (e.g., pro-active school closures). The purpose of public health measures is to
• reduce transmission of the novel/pandemic virus, thereby helping to reduce the overall size of the
outbreak and the number of severely ill cases and deaths; and
• slow the rate of transmission in order to reduce the peak burden on the health care system and buy
time in anticipation of vaccine.
STRATEGIC APPROACH
Public health measures are typically implemented at the community level. The responsibility and
legislative authority for implementing public health measures belong to the relevant PT and local public
health authorities, with the exception of international border and travel related issues for which the
federal government is responsible. In addition, the Canadian Forces Health Services is responsible for
implementing public health measures on all Canadian Forces establishments/bases/wings/stations
across Canada and for Canadian Forces personnel deployed abroad.
There are important concepts to consider when planning and implementing public health measures.
The measures should be used in combination to provide “multi-layered protection”, as the effectiveness
of each measure on its own may be limited. Actions should be tailored to the anticipated pandemic
impact and the local situation, supporting the principles of flexibility and proportionality. Some measures,
like hand hygiene and respiratory etiquette, are applicable in all pandemics. Other measures (e.g.,
proactive school closures and travel restrictions) might be used only in moderate- to high-impact
situations, as they can be associated with significant societal and economic costs.
A risk management approach will help weigh the potential advantages of particular interventions against
their disadvantages and unintended consequences. Decisions about which measures to deploy also
raise fundamental ethical challenges. For example, when considering restrictive measures, it is important
to balance respect for autonomy against protection of overall population health. In such situations, the
principles of proportionality, reciprocity and flexibility are involved, with a view to safeguarding individual
freedom to the extent possible while promoting protection against the health and societal consequences
of influenza infection.
There are several types of public health measures for jurisdictions to consider during an influenza pandemic:
• Individual measures—Public health advice will be provided to protect well individuals against
influenza and prevent ill individuals from spreading infection, e.g., through hand hygiene, cough
etiquette, staying home while sick. These measures should already be familiar through annual public
health campaigns.
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• Community-based measures—Guidance will be produced and disseminated to minimize illness and

transmission of infection within settings such as workplaces, schools, post-secondary institutions,
childcare centres, communal living facilities, remote and isolated communities, camps and cruise
ships. Social distancing measures or strategies may be used to minimize close contact among persons
in public places, e.g., pro-active school closures; cancellation or modification of public gatherings;
and alternative workplace approaches, such as teleconferences and working from home. Because
of their potential societal impact, social distancing measures are most applicable in pandemics of
moderate to high impact.
• Border and travel measures—These interventions include provision of travel health advice, screening
of travellers and travel restrictions. Evidence for their effectiveness is limited and their implementation
would depend on the risk assessment and resultant risk/benefit analysis of the actions being
considered.
• Case and contact measures—Some circumstances involving novel/pandemic viruses may warrant
case and contact management by public health authorities. These might include an individual human
case or cluster involving a novel virus, suspected human infections associated with an animal influenza
outbreak, or initial cases of the pandemic virus in the country or area. The extent of the investigation
and recommended measures should be feasible and relevant to the situation.
While aggressive measures (e.g., widespread antiviral use and restriction of movement) to attempt to
contain or slow an emerging pandemic in its earliest stages were previously considered possible on the
basis of modeling, experience from the 2009 pandemic has resulted in general agreement that such
attempts are impractical, if not impossible.
Additional details about public health measures can be found in the Public Health Measures Annex.
4.4 Vaccine
Immunization of susceptible individuals is the most effective way to prevent disease and death from
influenza. The purpose of Canada’s pandemic vaccine strategy is to
• provide a safe and effective vaccine for all Canadians as quickly as possible;
• allocate, distribute and administer vaccine as efficiently as possible; and
• monitor the safety and effectiveness of pandemic vaccine.
The phrase “vaccine for all Canadians” is intended to be interpreted broadly. It refers to all persons in
Canada (whether or not they are citizens) as well as Canada-Based Staff (CBS), their dependents and
Locally Engaged Staff (LES) at Canadian missions abroad and Canadian active duty personnel (Canadian
Forces) abroad.
An effective pandemic vaccine strategy is built on strong seasonal influenza immunization programs.
The overall impact of the pandemic vaccine strategy will depend on vaccine efficacy and uptake, as well
as the timing of vaccine availability in relation to pandemic activity. Using current egg-based vaccine
production technology, pandemic vaccine production is expected to take from four to six months, so it
is not likely to be available by the time the first pandemic wave reaches Canada. Furthermore, it will
become available in stages, which may require prioritization of initial vaccine doses.
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STRATEGIC APPROACH
In 2011, Canada entered into a new ten-year contract for pandemic influenza vaccine supply to ensure
that there is rapid and priority access to a supply of adjuvanted pandemic influenza vaccine produced
in Canada. Canada’s pandemic vaccine strategy also includes contracting for a secondary supply of a
pandemic vaccine.
Health Canada has developed a regulatory strategy to review and authorize a safe and efficacious
pandemic vaccine for use in Canada within the shortest time frame possible. A pan-Canadian approach
to pandemic immunization, including prioritization of populations during initial roll-out of the vaccine,
will help optimize equitable access and desirable outcomes. Pan-Canadian guidance will include an
allocation plan for equitable vaccine distribution, recommendations for pandemic vaccine use and
recommendations for prioritization of initial supplies.
Other key elements of the national vaccine strategy include the monitoring of vaccine uptake, adverse
events and vaccine effectiveness, building on existing systems such as the Canadian Adverse Events
Following Immunization Surveillance System (CAEFISS). Rapid studies will be carried out to confirm or
refute vaccine safety concerns.
PTs, Canadian Forces Health Services, and federal departments with the responsibility for immunization
should have plans for efficient and timely vaccine administration, including the ability to target key
population groups and collect information on vaccine uptake and adverse events. Lessons learned from
the 2009 pandemic indicate that vaccine registries and electronic information systems to capture and
transmit data are essential tools to support the vaccine program.
More details about the pandemic vaccine program can be found in the Vaccine Annex, including a
prioritization framework to guide decision-making if vaccine is expected to be in short supply.
4.5 Antiviral Medications

Antiviral medications can be used to treat influenza cases or to prevent influenza in exposed persons
(prophylaxis). Antiviral medications are the only specific anti-influenza intervention available that can be
used from the start of the pandemic, when vaccine is not yet available.
Canada’s antiviral strategy supports FPT stockpiles of antiviral medications for use in the event of an
influenza pandemic, primarily for early treatment and for outbreak control in closed facilities. Early
treatment of influenza cases, as early as possible within 48 hours of symptom onset, is recommended in
order to reduce the severity and duration of illness, particularly the occurrence of influenza-related
complications, hospitalization and death. Early treatment may also help mitigate societal disruption by
reducing the duration and severity of illness experienced by workers in the health care and other critical
infrastructure sectors.
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STRATEGIC APPROACH
There are two national stockpiles in Canada:
• The NAS is a stockpile that is held and managed by the PTs. The NAS is composed of the antiviral
medications oseltamivir and zanamivir, with oseltamivir dosage formulations that are appropriate for
both adults and children.
• The NESS is a federally owned stockpile of emergency supplies. The NESS is held and managed by
PHAC and includes a stockpile of oseltamivir and zanamivir. NESS antivirals are intended to provide
surge capacity in support of the PT response during a pandemic.
Federal government departments, such as the Canadian Forces (for active duty personnel) and Global
Affairs Canada (for mission staff overseas), hold stockpiles of antiviral medications to meet the anticipated
needs of their staff.
Jurisdictions need strategies to facilitate timely access to antiviral medications, particularly for high-risk
persons including pregnant women, children (who need special formulations), vulnerable populations,
and residents of remote and isolated communities. Pre-positioning of antiviral medications should be
considered for some communities to facilitate rapid access (e.g., remote northern communities).
Clinical guidelines have been developed for antiviral use for seasonal influenza.39 Virus-specific clinical
guidance and treatment protocols will need to be developed at the onset of the pandemic, based on
pandemic epidemiology and available scientific evidence. Pandemic use will focus primarily on early
treatment of influenza cases, particularly persons with severe disease or with risk factors for complications
or severe disease. There are limited indications for the use of antiviral medications for prophylaxis
during a pandemic, primarily for control of laboratory-confirmed influenza outbreaks in closed health
care facilities or settings where persons at high-risk of complications reside.
Distribution and uptake of antiviral medications should be monitored in real time to optimize appropriate
use, identify the need for additional purchases during the pandemic, and support post-pandemic
utilization and effectiveness studies. Monitoring adverse reactions and antiviral resistance helps inform
decision-makers as to whether changes in the recommendations regarding antiviral use are required.
Adverse reaction reports are collected and assessed through the Canada Vigilance Program of the
Marketed Health Products Directorate (MHPD) of Health Canada. Ongoing monitoring of antiviral
resistance is conducted by the public health laboratory system and reported as part of FluWatch.
More details about antiviral medications and their use in a pandemic can be found in the Antiviral
Annex, including a prioritization framework to guide decision-making if antiviral medications are
expected to be in short supply.
Aoki FY, Allen UD, Stiver HG, Evans GA. The use of antiviral drugs for influenza: A foundation document for practitioners.
39
Can J Infect Dis Med Microbiol. 2013;24 Suppl C:1C-15C.
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4.6 Infection Prevention and Control and Occupational Health

A major influenza outbreak may have a substantial impact on the ability of health care organizations to
keep those providing or receiving health care services safe. Infection prevention and control (IPC) and
occupational health (OH) programs should work together to prevent exposure to and transmission of
pandemic influenza during the provision of health care. Working jointly with occupational health and
safety committees is essential in meeting these goals. The application of appropriate IPC and OH
processes by HCWs and organizations is important in all health care settings along the continuum of
care, including but not limited to medical first response, practitioners’ offices and other ambulatory care
settings, acute care, long-term care and home care settings.
STRATEGIC APPROACH
A timely pandemic response is only possible when an organization and its personnel are experienced in
IPC and OH protocols and practices, supported by strong programs. Well-functioning IPC programs
should prevent, limit or control the acquisition of health care associated infections for everyone in the
health care setting, including patients, HCWs, visitors and contractors. Well-functioning OH programs
should identify workplace hazards and support appropriate processes and training to ensure that
employees can perform their duties in an environment that minimizes exposure to environmental
hazards.
Important elements of IPC and OH programs for pandemic preparedness and response in the health
care setting include the following:
• adequate staffing of IPC and OH professionals in the health care organization to conduct education
and training for front line staff;
• organizational risk assessments, best carried out in the interpandemic period, to identify engineering,
administrative and personal protective equipment (PPE) controls that will best protect patients, HCWs
and visitors in the health care setting;
• comprehensive education and training for HCWs in the organization on influenza IPC and OH issues;
• point-of-care risk assessments that are carried out by individual HCWs before they enter a patient’s
environment or initiate patient care to determine the appropriate PPE, isolation and cohorting
strategies for a given patient, during a given intervention, in a specific room, area or facility;
• provision of influenza vaccine to persons working for or being cared for by the organization;
• ongoing surveillance for health care associated infections, including respiratory infections;
• respiratory protection programs to ensure that HCWs who may need to wear a respirator (including
N95 respirators) are trained, fit-tested and prepared;
• a wide range of “source control” policies, including a 2-metre spatial separation between infected
sources (e.g., patients) and uninfected hosts (e.g., other patients); admission screening; screening of
visitors; and expanded respiratory and hand hygiene programs for HCWs, patients and visitors; and
• systematic administrative practices to enable rapid identification and segregation of patients, HCWs
and visitors with symptoms of influenza-like illness (ILI).
For detailed guidance about IPC and OH activities during a pandemic, see the annex on Prevention and
Control of Influenza during a Pandemic for all Healthcare Settings.
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4.7 Health Care Services

The effective provision of health care provides patients with the right level of care in the right place, at
the right time. In a pandemic this means managing an influx of patients with influenza, while maintaining
care required for patients with urgent non-influenza conditions. It is necessary for any organization that
provides health care to plan for a range of scenarios, including those with very high patient load and
potential high staff absenteeism, as demand for health care services may exceed the capacity of the
existing system. At the start of a pandemic, early assessment of its anticipated impact will help the
health care sector to implement plans to manage the anticipated workload.
STRATEGIC APPROACH
Planning for the delivery of health care in a pandemic is a particular challenge as there is little excess
capacity in the Canadian health care system, particularly in remote and isolated communities.
Nonetheless surge capacity planning is an essential component of pandemic preparedness for all levels
of care, including telephone information lines, primary and ambulatory care practitioners, emergency
medical services, hospital and critical care, long-term and palliative care, home care and other community
care including death care services (funeral homes, medical examiners, coroners). Surge capacity planning
involves development of strategies for enhancing levels of staff and volunteers, equipment and supplies
and, potentially, space to accommodate more patients. It also includes consideration of novel approaches
to enhancing assessment and care. Surge capacity plans should include regional or even province-wide
components.
The 2009 pandemic highlighted the importance of improving integration and coordination so that the
health care response functions as a system during an emergency. This involves integration across the
continuum of care within a health region and across and among PTs. Integration is facilitated by involving
stakeholders from all levels of care in planning and exercises, including emergency medical services,
community service providers, volunteer organizations and public health. Electronic information
management systems are essential tools for monitoring service delivery and resource utilization across
the health care system and transferring information among organizations.
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The collection of health care delivery data is an important aspect of seasonal and pandemic influenza
surveillance. Monitoring hospital and ICU admissions and ventilator use were added surveillance
components in the 2009 pandemic, contributing valuable information on the epidemiology of severe
disease and its risk factors. Surveillance of emergency department utilization can indicate when
community health services are at or reaching capacity so that other measures can be considered.
Best practices and lessons learned advise that health care organizations and practitioners carry out
business continuity planning and maintain strategic reserves of critical equipment and supplies. Detailed
plans to store, distribute and track use of stockpiled items should be developed and exercised.
Pandemic-specific issues for health care provision include the following:
• Self-care instructions—self-care instructions can empower individuals and families, improve care and
optimize the use of the health system; they are useful for dealing with seasonal as well as pandemic
influenza. During the 2009 pandemic, many jurisdictions used the media, public announcements and
credible websites to promote tools to assist the public on conducting an influenza self-assessment,
self care and when to seek medical attention or go to the hospital.
• Telephone advice lines—these were extensively used in the 2009 pandemic to provide information
and advice, and to triage people with suspected influenza from those with other respiratory infections.
Trained operators directed people to appropriate clinical assessment and care if needed, and helped
avoid unnecessary visits to physicians and emergency departments by providing advice on self-
care at home. Heavy, and sometimes overwhelming, demand reinforced the necessity for business
continuity planning and for operation on a 24/7 basis during a pandemic.
• Primary care—the primary care sector will be responsible for the assessment and treatment of
ambulatory influenza patients. PTs often face challenges in engaging primary care practitioners, who
may not be well linked to the rest of the system. PTs should work with professional associations to
develop communications strategies, protocols and guidelines, e.g., for office business continuity
planning and IPC. At the time of the pandemic, PTs should anticipate providing primary care
practitioners with situation updates, guidance on laboratory testing and clinical management of
influenza patients, information on pandemic vaccine (with clear direction on their role in its provision)
and access to additional or pre-positioned PPE and supplies. Primary care surge capacity can be
enhanced by PT strategies such as new fee codes for telephone advice and prescribing, temporarily
allowing practice expansion to patients who are not registered with the practice (when this is not
normally permitted), and expanding the role of other health professionals and non-traditional
workers (e.g., allowing prescribing of antiviral medications by pharmacists). Influenza assessment
centres and alternate care sites may be needed in some communities, particularly in high-impact
situations. Responsibility for their establishment is best determined in advance so that appropriate
planning can take place.
• Hospital-based care—the impact on the acute care sector and the demand for critical care will be
influenced by the epidemiology of the pandemic, i.e., the overall numbers with severe disease,
the age and risk groups most at risk of severe disease and the dynamics of the pandemic wave
(compacted or prolonged), as well as the extent of early antiviral treatment in the community. Critical
care planning and preparation for high demand for ventilators or other specialized equipment (e.g,
extracorporeal membrane oxygenation) needs special attention. Critical care surge capacity plans
should include triage tools that contain both ethical guidance and processes to address bed flow
and ventilator utilization. Service needs for paediatric patients (including critical care) and pregnant
women should be specifically addressed.
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• Health care in remote and isolated communities—There may be limited capacity to provide acute
care and/or a lack of appropriate medical equipment and services (e.g., ventilators, oxygen therapy)
for treating critically ill patients in remote and isolated communities. Under normal circumstances,
these needs are met through medical evacuations to acute care facilities in larger centres. However,
an increase in medical evacuations could overwhelm the receiving jurisdictions, making it essential to
coordinate with receiving jurisdictions and to do everything possible to detect ILI as early as possible
and to treat and keep affected persons in the community.
• Other health care services—services such as mental health, home care, palliative and hospice
care, long-term care and other community health and social services may not be well linked to
regional and local pandemic planning processes. Though often overlooked in pandemic planning,
their functioning is critical to achieving the pandemic objectives by providing early and appropriate
treatment outside of hospitals to those who do not need acute hospital care. These organizations
must be involved in pandemic planning and encouraged to have business continuity plans in place
so that they can continue to provide their services to some of the most vulnerable patients in the
community with minimal interruption during a pandemic.
During a severe pandemic, death care services may be overwhelmed and local planners may need to
consider alternate systems and resources than those that normally manage deaths, such as setting up
temporary morgues and delaying funerals/burials. This may cause increased stress or complications in
the grieving process for families, particularly when certain religious and/or cultural practices have specific
directives about how bodies are managed after death. Planning guidance is available from the WHO,
Pan American Health Organization and the International Red Cross on the effective management of
mass fatalities during a disaster.40
4.8 Clinical Care Guidelines

Clinical care involves the assessment and treatment of persons with suspected or confirmed pandemic
influenza. The spectrum of illness seen with influenza is broad and ranges from asymptomatic infection
to severe illness causing death, which is frequently due to exacerbation of an underlying chronic
condition or secondary bacterial pneumonia. Certain aspects of pandemic influenza management may
be unfamiliar to some practitioners, and new risk factors and presentations may emerge. Critically ill
patients may require extraordinary support measures, some of which may not be universally available in
a high-impact pandemic.
STRATEGIC APPROACH
During a pandemic, health care practitioners will need clinical guidelines for assessment, laboratory
testing, treatment (including antiviral medications), and management of secondary infections and
critically ill patients. Service needs for specific populations (e.g., paediatrics, pregnant women) should
be specifically addressed. Guidelines specific to the clinical management of patients in remote and
isolated communities should also be available, as there are unique considerations in these settings.
Clinical care guidelines must be timely and user-friendly, and be produced by sources that practitioners
consider reliable. Establishing and testing agreed upon approaches for the development of clinical
guidelines during the interpandemic period will help to ensure that the necessary processes are in place
to support the pandemic response.
Pan American Health Association; World Health Association; International Committee of the Red Cross:
40
Management of Dead Bodies after Disasters: A field Manual for First Responders. 2016. Available from: http://iris.paho.org/
xmlui/handle/123456789/31295
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4.9 Communications
Communication of information and advice is often the first and most important public health intervention
during an emergency. This is especially true for an emerging pandemic, where behaviour change is a
central part of risk management. Providing clear and consistent information about the disease, who it
affects, how it spreads and ways to reduce risk is an effective way to help reduce the spread of infection
before other interventions like vaccine are available. Open and honest public communication also
reinforces trust in public health authorities and helps to minimize societal and economic disruption.
Communications planning for an influenza pandemic uses a risk communications approach.41 It
integrates a broad range of communication capacity and expertise, including social marketing,
stakeholder consultation and use of social media. It involves collaboration of all partners involved in the
pandemic response to deliver consistent, complementary, and effective communications that meet the
needs of the public and stakeholders.
STRATEGIC APPROACH
Pandemic risk communications incorporate the principles of collaboration, proportionality, flexibility
and use of established practices and systems. Research conducted during and after the 2009 pandemic
reinforced the importance of core risk communication principles such as transparency and stakeholder
collaboration in achieving pandemic response objectives.42
It is essential to be proactive about communication throughout the pandemic, with information and
updates for the media, the public, and other stakeholders. Information may be limited initially and will
change as the science evolves and more is learned. The post-2009 pandemic reviews identified
difficulties in communicating uncertainty and dealing with changing information, particularly for
pandemic vaccine. Therefore, strategies to communicate risk, uncertainty and changing information
are critical.
Communicating in ways that demonstrate transparency, cultural sensitivity and use of plain language is
essential in building and maintaining public trust. Consistent messaging and “speaking with one voice”
will also foster trust and understanding and help avoid confusion.
While communication and messaging within jurisdictions is ultimately a PT responsibility, pandemic
communications planning should involve all health partners. The FPT communication response will be
coordinated through the PHN Communications Network. Collaboration with nongovernmental, private
sector and international organizations is also important. The media should be seen as a key partner and
engaged in the interpandemic period as well as during the pandemic.
41
Health Canada. Strategic risk communication framework. 2005. Available from:
www.hc-sc.gc.ca/ahc-asc/pubs/_ris-comm/framework-cadre/index-eng.php
42
Risk Sciences International. Risk communication for H1N1 pandemic influenza. 2012. Report to the Public Health Agency of
Canada (unpublished)
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Communication with the public—Research has demonstrated that risk perception is the strongest
indicator of willingness to change behaviour during a public health event, and that it is largely shaped
by the public’s emotional response to the event.43 Monitoring of public perception, information needs
and concerns is an important role in the pandemic response and should be planned for. Effective
stakeholder identification and engagement will also play a large part in this work. Building relationships
with stakeholders in the interpandemic period will help facilitate productive interactions during the
pandemic. Federal and PT pandemic communications plans should pay particular attention to reaching
vulnerable populations and persons who may have limited access to mainstream media. These groups
may require a tailored communications approach, using a variety of formats and delivery mechanisms
(e.g., using ethnic media outlets as a conduit to ethno-cultural communities).44
Communication with the health care sector—Communications with HCWs and organizations deserves
special attention in the planning process. These stakeholders should be engaged in two-way dialogue
to help ensure that products and messages meet their needs for timely, clear, concise and relevant
communications. Resources should be developed in the interpandemic period so they can be quickly
adapted when a pandemic occurs.
For details on the pandemic risk communication approach, see the Communications and Stakeholder
Liaison Annex.
4.10 Research
Research plays a key role in addressing knowledge gaps about the influenza virus and effective influenza
prevention, treatment and control for both seasonal and pandemic influenza. Much of this research can
be carried out in the interpandemic period, but some can only be conducted during a pandemic. Given
the potentially long interval between pandemics, it is important not to miss these infrequent but
invaluable opportunities and to plan for a rapid research response.
STRATEGIC APPROACH
Key components of a successful pandemic influenza research strategy include identification of research
needs, development and ongoing support of partnerships and research networks, identification of
sustained funding sources, and advance establishment of protocols and rapid ethics review processes
for pandemic research. Knowledge translation strategies to bring significant findings to decision-makers
in a useful and timely way are other key components.
Ibid
43
Greenberg J. Emergency-risk communication for vulnerable populations in Canada. April 2012. Report to the Public Health
44
agency of Canada (unpublished)
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Identification of research needs—It is important that influenza research needs are periodically reviewed
and prioritized. This information is helpful to funding agencies like the Canadian Institutes of Health
Research (CIHR) and PHAC, and feeds into similar international initiatives by WHO and others. The
annexes to this document identify existing research needs in specific areas of the response, such as
vaccines and antiviral medications.
Research networks—Networks that are created to conduct research in the interpandemic period are
well placed to facilitate pandemic research. Provincial public health agencies and PHAC are increasingly
collaborating on epidemiological and other public health studies. The Canadian Immunization Research
Network (CIRN), a national network of key vaccine researchers, is active in ongoing influenza vaccine
research projects. The mathematical modeling community has developed several networks and is
collaborating more closely with public health. Canadian intensive care researchers have developed
international clinical networks, such as the International Forum for Acute Care Trialists (InFACT) that will
establish open access protocols, data-sharing processes and ethical frameworks to streamline the
response to a new emerging disease or pandemic. These existing networks need ongoing support. As
they may not be sufficient to address all of the pandemic research needs, ongoing focus on this aspect
is required to ensure readiness for the research response.
Rapid research response—Special research studies, such as seroprevalence studies and the role of
bacterial pathogens in serious outcomes, will be needed to inform pandemic decision-making. As these
studies must be mounted quickly, advance planning is critical for their success and timeliness. Leveraging
existing partnerships among PHAC, Health Canada, provincial public health agencies, clinical and
academic institutions and networks together with populations of research interest such as CIRN and
CIHR and engaging them in planning for a rapid research response is essential. Advance plans should
include preliminary agreements with potential researchers and development of research protocols and
strategies for rapid ethics approval and funding arrangements.
Knowledge translation —Many important decisions must be made quickly during a pandemic. Evidence-
informed decision-making requires strong knowledge translation strategies to ensure that existing and
new research findings are taken into account. Enabling strategies include compiling research findings
from the 2009 pandemic and maintaining up-to-date literature reviews in key areas, such as the
effectiveness of public health measures, relevant vaccine studies, and antiviral treatment and resistance.
Processes for critical appraisal and dissemination of new research findings should be established in the
interpandemic period. Strategies should also be developed to help decision-makers understand and
make optimal use of evidence and research.
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5.0 ASSESSMENT AND EVALUATION OF PANDEMIC PREPAREDNESS

AND RESPONSE
Preparing for and responding to a pandemic is a complex process that requires the coordinated efforts
of all orders of government in collaboration with their stakeholders. To ensure that pandemic plans (or
all-hazards plans according to the jurisdiction) are comprehensive and effective, jurisdictions should
assess their level of preparedness, test their plans regularly and evaluate their pandemic response.
5.1 Assessing Preparedness

Preparedness is a responsibility of individuals, organizations and jurisdictions at all levels. PTs are
responsible for preparedness activities that will take place at the PT level and they may also provide
advice and/or support to regional and local areas. Assessing the level of pandemic preparedness
enables jurisdictions to monitor the progress of their pandemic planning, identify gaps and prioritize
future planning efforts. Use of checklists, perhaps coupled with site visits, are potential tools for
monitoring progress and levels of preparedness.
It is also important to determine whether responses can be implemented effectively so as to achieve the
intended results. Training and exercises should be conducted on a regular basis to maintain preparedness
levels as part of a cycle of continuous improvement. Training should also be made a priority for new
workers. Exercises can take many forms, ranging from discussion-based activities such as seminars and
workshops to larger more complex activities such as activating plans and simulating response activities.
It is best for organizations to work their way up to larger exercises. This progression allows organizations
to understand their plans better and identify interdependencies, and to make changes and adjustments
before attempting a larger, more complicated activity. Following an exercise a formal After Action Report
should be prepared, along with an implementation plan to address the gaps identified. Problem areas or
weaknesses should be corrected through additional training and/or changes or additions to plans.
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In addition to specially designed exercises, seasonal influenza provides annual opportunities for all
jurisdictions to test specific components of a plan. For example, seasonal influenza immunization
campaigns allow PTs to test rapid distribution of vaccine and supplies while local jurisdictions can
practise mass clinic strategies and use of their health emergency management mechanisms to organize
the clinic rollout. Other emergencies also provide opportunities to practise and refine components of
an effective pandemic response, like command and control and communications.
5.2 Evaluating the Pandemic Response

For future reference, it is important to document completely the processes and activities used and
decisions made during the response to the pandemic, along with the outcomes achieved. The response
should be evaluated to see if it was carried out as intended and that it led to the desired outcomes. This
evaluation helps ensure that lessons learned from the real life event are captured and remain available
to inform pandemic plan revisions. The evaluation involves assessment through an After Incident or
Lessons Learned report following the pandemic, accompanied by an implementation plan to address
the identified gaps. A critical opportunity to evaluate and adjust the response also comes at the end of
the first pandemic wave.
In addition to gleaning lessons learned from the pandemic response, it is important to ascertain how
well the pandemic response met the goals and objectives of pandemic preparedness and response in
Canada. Lessons learned would focus on the assessment of the strategic approach for the key
components outlined in this document as a measurement of how well the response met the identified
purposes of each of the key components. This higher level and formal evaluation of the pandemic
response would involve FPT partners and consider various aspects of the pandemic response. A
comprehensive, harmonized approach to pandemic evaluation across jurisdictions should be developed
in the interpandemic period so that the main findings and best practices can be identified.
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APPENDIX A – FACTORS AFFECTING PANDEMIC IMPACT

The table lists a series of factors that could affect the impact of a pandemic and describes their potential
impact. Consideration of these factors and their potential mitigation will supplement use of the basic
planning scenarios and help planners prepare a more adaptable response.
TABLE—FACTORS THAT AFFECT PANDEMIC IMPACT AND THEIR POTENTIAL IMPACT
CATEGORY FACTOR POTENTIAL IMPACT
VIRUS CHARACTERISTICS
TRANSMIS- Degree of High infectivity means that a large number of people will
SIBILITY transmission become ill. This would affect absenteeism in schools and
workplaces, including health care settings. Health care services
would face increased demand. Disruptions in basic services
could occur if absenteeism affects critical infrastructure.
Speed of spread A concentrated wave with many people ill over a short period
would have higher impact on absenteeism and demand for
health care than the same number of cases spread over a longer
period.
Season of arrival Transmission is lower in spring and summer so pandemic waves

in that period might be smaller. Higher impact would also be
expected with late fall/winter waves due to juxtaposition of usual
winter pressures from other viruses and co-circulating bacteria.
VIRULENCE Clinical severity High virulence means a high proportion of severe cases among
the ill, placing strain on acute and critical care services. The
typical pandemic mortality age shift to younger age groups
could also increase public concern. Unexpected clinical features
could affect provision of acute and critical care.
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POPULATION VULNERABILITY
POPULATION Pre-existing population Pre-existing population immunity might be present in persons

VULNERABILITY immunity above a certain age due to previous circulation of related strains.
This could reduce their risk of infection (although their age might
increase their risk of severe disease if they did become ill).
Sparing of older persons would significantly reduce overall
impact on hospitals and long term care facilities. Higher impact
would be anticipated if all age groups are involved.
Unexpected risk factors New risk factors for severe disease could mean that more people
need health care services. They could also affect vaccine
prioritization.
Special groups and Impact may be increased in high-risk populations or settings

settings (e.g. remote communities, homeless shelters and overcrowded
housing). Risk could be elevated because of age, underlying
health conditions, poor access to health care, poor
socioeconomic conditions, etc.
RESPONSE FACTORS
PUBLIC HEALTH Vaccine availability, Timing of vaccine availability in relation to pandemic activity
INTERVENTIONS timing, effectiveness could influence vaccine prioritization and affect uptake. Vaccine
impact would be reduced if most people experience illness
before vaccine is available.
Antiviral availability Antiviral supply might be insufficient in a very large pandemic.

and resistance Antiviral drug resistance would reduce supply of effective
antiviral medications, thus resulting in need to prioritize use.
Supply issues could lead to increased numbers of
hospitalizations, severe illness and death.
Public health measures In some circumstances (e.g. virus with lower transmissibility),
wide adoption of public health measures could lead to
significant reduction in transmission.
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HEALTH CARE Access to care Good access to primary care and early antiviral treatment would
SYSTEM reduce rates of complications and hospitalizations. Lack of
RESPONSE access to critical care could increase mortality in seriously ill
patients.
Surge capacity Lack of surge capacity could affect outcomes if demand for
services outstrips supply. Triaging of critical care services would
be needed as surge capacity is exceeded. As services become
overwhelmed, mortality might increase in both influenza and
non-influenza emergency patients.
Availability of Drug supply problems or antibiotic resistance could affect

antibiotics and other clinical outcomes. Shortages of infection control supplies could
drugs, supplies affect viral transmission and increase staff concern.
RISK Behavioural response Levels of public awareness and understanding and risk
COMMUNICA- perception, along with level of trust in health authorities, could
TIONS affect degree of adoption (and therefore potential effectiveness)
of preventive behaviours such as infection prevention
behaviours, social distancing, and uptake of vaccine and antiviral
medications.
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APPENDIX B—PANDEMIC RISK ASSESSMENTS

The table identifies relevant considerations for initial and ongoing pandemic risk assessments and
identifies potential sources of data to generate the information needed. In a pandemic, the Public
Health Agency of Canada will prepare or arrange for the risk assessments to be prepared
and disseminated.
TABLE - PANDEMIC RISK ASSESSMENTS
WHAT INFORMATION IS NEEDED?

HOW WILL THIS BE
CATEGORY
INITIAL RISK ONGOING RISK LEARNED?
ASSESSMENT ASSESSMENTS
OVERALL RESPONSE
NATURE OF RESPONSE What will be the overall Is the impact changing? Estimates/predictions
impact? How are we coping? of impact (see sections
below)
CHARACTERISTICS OF THE VIRUS
TRANSMISSIBILITY How fast will it spread? Will there be more than Molecular and genetic
one pandemic wave? studies
Is transmissibility Incubation period and
changing? generation time
Reproductive number
(R0)
Real-time modeling
How many will be Will follow-up waves be As above

affected? larger or smaller? Serological attack rate
See also population When will the next wave Clinical attack rates in
vulnerability begin, peak, end? various settings
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HOW WILL THIS BE
CATEGORY
VIRULENCE (CLINICAL How severe is the Is disease severity Molecular and genetic
SEVERITY) disease? changing? studies
What proportion of ill Rates of hospitalization,
people will have intensive care unit (ICU)
complications, need admission, ventilator
hospitalization, die? use
Are there unusual Case fatality rate/ratio
clinical presentations? Clinical case series of
persons with severe
disease
Outbreak reports
POPULATION VULNERABILITY
POPULATION Will all age groups be How is population Levels of pre-existing

VULNERABILITY affected and to what immunity changing as population immunity
extent? the outbreak Periodic seroprevalence
progresses? surveys
What are the risk factors Are new risk factors/ Epidemiological studies
for severe disease? groups emerging? Clinical case series
Outbreak reports
Are there settings and Are there additional Epidemiological studies

populations at settings and PT/NGO feedback
increased risk? populations at
Socioeconomic data
increased risk?
Are we effectively
targeting our
interventions?
Any unintended
consequences from
our interventions?
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HOW WILL THIS BE
CATEGORY
PUBLIC HEALTH INTERVENTIONS
ANTIVIRAL Is there antiviral Are antiviral resistance Antiviral susceptibility

MEDICATIONS resistance? patterns changing? and resistance testing
Will antivirals be safe? Are the antivirals safe? Antiviral distribution
Will antivirals be Are the antivirals and uptake
effective? effective? Adverse reaction
Are we able to Are the right patients reports
effectively mobilize the receiving them in a Effectiveness studies
NAS? timely way? Distribution reports
and special studies
VACCINE Will vaccine be safe? When will vaccine Early epidemiological

Will vaccine be be available? studies (re: high-risk
effective? Are there changes groups)
When will it be to the usual high-risk PT monitoring and
available? groups? feedback
Is there adequate Vaccine uptake and
capacity for rapid effectiveness
immunization? AEFI reports
How can vulnerable
groups be reached?
Is pandemic vaccine
safe?
Is it effective?
PUBLIC HEALTH What is the anticipated Are the interventions Measures of

MEASURES impact, including on acceptable? transmissibility and
transmission? Are they effective? virulence
Mathematical modeling
Public opinion research
Community surveys
INFECTION PREVENTION Will the usual IPC Are the usual IPC Information on
AND CONTROL (IPC) measures be effective? measures effective? incubation period,
If not or unsure, what If not or unsure, what infectivity, routes of
additional precautions additional precautions transmission, etc.
should be taken? should be taken?
Are there unintended
consequences?
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HOW WILL THIS BE
CATEGORY
SYSTEM RESPONSE
PUBLIC HEALTH What will be the What is the impact on Measures of

potential impact? public health services transmissibility and
and health human virulence
resources (HHR)? Surveillance and clinical
Are they able to cope? studies
PT feedback
COMMUNITY What will be the What is the impact on Measures of

HEALTH CARE potential impact? community health care transmissibility and
services and HHR? virulence
Are they able to cope? Surveillance and clinical
studies
Information on antiviral
resistance
PT feedback
Media monitoring
ACUTE CARE SERVICES What will be the What is the impact on Measures of
potential impact? acute care services and transmissibility and
HHR? virulence
Are they able to cope? Surveillance and clinical
What bacterial studies
complications are Information on antiviral
occurring? and antibiotic resistance
Are the treatment Clinical studies
strategies effective? PT monitoring and
feedback
Media monitoring
LONG-TERM CARE AND Will long-term care or What is the impact on Information on pre-
OTHER COMMUNITY other residential these facilities, their existing immunity
RESIDENTIAL CARE facilities for the elderly services and HHR? Surveillance and
or disadvantaged be at outbreak investigations
significant risk of
PT feedback
outbreaks?
Media monitoring
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HOW WILL THIS BE
CATEGORY
SOCIETAL IMPACT Will there be significant What is the impact on Measures of

workplace or school schools, businesses, transmissibility and
absenteeism? critical infrastructure virulence
Will community services and other community School and workplace
be affected? services? absenteeism
What is the impact on surveillance
vulnerable populations? PT feedback
What is the psychosocial Media monitoring and
impact on the public surveys
population?"
Clinician surveys
What is the economic
Qualitative studies
impact?
RISK What will be the level What are the levels of Traditional and social
COMMUNICATIONS of public concern? public concern? media monitoring
What issues will be What issues are of most Tracking of public
of most concern? concern and are we inquiries
addressing them Public opinion research
effectively?
Stakeholder feedback
What is the level of (PTs and NGOs)
public awareness and
understanding of the
situation?
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FEDERAL/PROVINCIAL/
TERRITORIAL PUBLIC
HEALTH RESPONSE
PLAN
FOR ONGOING
MANAGEMENT OF
COVID-19
3rd Edition
March 25, 2022
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F/P/T PUBLIC HEALTH RESPONSE PLAN FOR ONGOING MANAGEMENT OF COVID-19
Table of Contents
List of Acronyms and Abbreviations ............................................................................................................. 3
Executive Summary....................................................................................................................................... 4
1. Introduction .......................................................................................................................................... 6
2. Context .................................................................................................................................................. 7
2.1 Omicron........................................................................................................................................... 7
2.2 Disproportionate impacts and societal consequences ................................................................... 8
2.3 Societal disruption .......................................................................................................................... 8
2.4 Risk framework ............................................................................................................................... 9
2.5 Response governance and concept of operations ........................................................................ 10
2.6 Previous waves.............................................................................................................................. 10
3. COVID-19 Response Goal and Objectives ........................................................................................... 11
3.1 Goal ............................................................................................................................................... 11
3.2 Objectives...................................................................................................................................... 12
4. Forward Planning ................................................................................................................................ 15
4.1 Planning Assumptions and Areas of Uncertainty.......................................................................... 15
4.2 Planning for ongoing COVID-19 risks, response and readiness needs.......................................... 18
4.3 Planning for recovery .................................................................................................................... 25
4.4 Planning with Indigenous Communities ....................................................................................... 27
5. Addressing the consequences of pandemic response ........................................................................ 30
6. COVID-19 F/P/T Response Components ............................................................................................. 33
7. Assessment and Evaluation ................................................................................................................ 34
Appendix 1: Modelling Support for Forward Planning ............................................................................... 35
Appendix 2: Epidemiological Drivers .......................................................................................................... 37
Appendix 3: Planning for the reasonable worst case scenario ................................................................... 39
Appendix 4: COVID-19 Response Planning with Indigenous Communities ................................................ 44
Appendix 5: Surveillance ............................................................................................................................. 49
Appendix 6: Laboratory Response Activities .............................................................................................. 52
Appendix 7: Public Health Measures .......................................................................................................... 55
Appendix 8: Infection Prevention and Control ........................................................................................... 57
Appendix 9: Vaccination ............................................................................................................................. 58
Appendix 10: International Border and Travel Health Measures ............................................................... 64
Appendix 11: Health Care Systems Infrastructure ...................................................................................... 66
Appendix 12: Communications and Outreach ............................................................................................ 69
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Appendix 13: Research ............................................................................................................................... 72

References .................................................................................................................................................. 76
List of Acronyms and Abbreviations
AEFI Adverse events following immunization

CIC Canadian Immunization Committee
CPIP Canadian Pandemic Influenza Preparedness: Planning
Guidance for the Health Sector
F/P/T Federal/Provincial/Territorial
F/P/T PHRPBE Federal/Provincial/Territorial Public Health Response Plan for
Biological Events
IPC Infection prevention and control
ISC Indigenous Services Canada
LAC Logistics Advisory Committee
NACI National Advisory Committee on Immunization
PHA(s) Public health authority/authorities
PHAC Public Health Agency of Canada
PHM(s) Public health measure(s)
P/T Provincial/Territorial
PT Province, Territory
SAC Special Advisory Committee
TAC Technical Advisory Committee
VOC(s) Variant(s) of concern
WHO World Health Organization
2SLGBTQI+ Two-Spirit, lesbian, gay, bisexual, transgender, queer (or
questioning), intersexed plus
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Executive Summary
This document is the third edition of the Federal/Provincial/Territorial (F/P/T) plan which was developed
in collaboration with federal, provincial and territorial public health officials via the F/P/T Special
Advisory Committee (SAC) on COVID-19, First Nations, Inuit and Métis partners, and health system
partners, for these and other stakeholders. It is an evergreen document that is intended to provide a
Pan-Canadian forward planning approach for ongoing management of COVID-19 in Canada and facilitate
awareness and coordination both within and beyond the public health sector.
This edition focuses on the transition from the acute response to waves of COVID-19 activity occurring in
a largely susceptible Canadian population, towards a more sustainable long-term response to the
ongoing presence of COVID-19 in the context of increased population immunity and other public health
priorities. This is referred to as the Transition phase, and while acute response needs may be reduced
during this time, there is a need to maintain readiness to respond to any new COVID-19 risks while
addressing ongoing response and recovery needs. Much like other technical guidance, this document
may require updating as our scientific knowledge of the SARS-CoV-2 pathogen and duration of immunity
due to the COVID-19 vaccines and previous infections increases, and the epidemiological picture evolves
in Canada and globally.
The plan acknowledges jurisdictional roles and responsibilities, and therefore provincial/territorial (P/T)
flexibility and customization are expected. The autonomy of provinces and territories with respect to
management of their respective health systems is acknowledged; this document is not intended to
convey any requirements or obligations. First Nations, Inuit and Métis communities may choose to
adapt approaches to the specific needs and contexts of their communities, as highlighted in the sections
focusing on planning with Indigenous Communities.
Key elements of this edition of the plan include:
public health objectives for the Transition phase;

forward planning assumptions;
planning for ongoing response, recovery and readiness;
a section on addressing the consequences of pandemic response; and
Appendices with updated summaries of each main component of the public health response (i.e.,
Surveillance, Laboratory Response Activities, Public Health Measures, Infection Prevention and
Control and Clinical Care Guidance, Vaccination, International Border and Travel Health Measures,
Health Care Systems Infrastructure, Risk Communications and Outreach, and Research).
The pandemic response goal, to minimize serious illness and overall deaths while minimizing societal
disruption as a result of the COVID-19 pandemic, highlights the need to balance the impact of COVID-19
in terms of both severe outcomes and societal disruption. The ability to achieve this balance has been
challenging during the response and is likely to be one of the key lessons learned for future pandemic
responses.
Vaccination and public health measures (PHMs) have been successful in reducing the number of cases of
COVID-19 and associated serious illness and deaths in Canada, however, the Omicron-driven wave
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necessitated the re-implementation of restrictive measures in many jurisdictions in order to ensure

health care systems did not become overwhelmed. The COVID-19 response has been unprecedented
with the swift implementation and public adoption of response measures. However, use of these
measures now needs to be de-escalated or adapted in the context of: decreasing incidence of infection,
circulation of a less virulent variant, high vaccination coverage, infection-acquired immunity, public
fatigue with the pandemic response1 2 3 4 5, and the unintended physical and mental health
consequences of the pandemic response6 7 8. At the same time there is a need to plan ahead for the
potential for repeated emergence of new variants of concern (VOCs) that may be more transmissible,
severe, and/or immune-evasive. This will involve evaluating the menu of options for public health
measure (i.e., pharmaceutical and non-pharmaceutical) with consideration of the triggers and timing of
each. It is expected that jurisdictions may not enact broad, restrictive measures unless absolutely
necessary (e.g., if there is high observed severity).
The World Health Organization (WHO) promotes use of a risk-based approach across the continuum of
pandemic phases, including the Alert phase, Pandemic phase, Transition phase and Interpandemic
phase.9 This edition of the plan promotes a risk management approach, which involves considering the
likelihood and impacts of potential threats like new VOCs, while also mitigating the impact of realized
risks.
As jurisdictions move out of the acute response phase and start to focus on recovery and preparedness
for the routine management of COVID-19 in the Canadian population, there is a need to monitor, assess
and revisit COVID-19 risks in the context of other public health priorities. This is reflected in the updated
ongoing management objectives for the Transition phase. In particular, recovery activities need to
address health consequences and risks, backlogs within health care systems and the impact of
interrupted public health program delivery, that have occurred over the course of the pandemic
response.
The disproportionate impact of both health outcomes and response measures, on some groups within
Canada10 11 has been another key observation over the course of the pandemic to date. The restrictive
nature of many of the response measures have had some negative health, well-being and societal
consequences for groups such as: older adults, essential workers, children and youth, racialized
populations, Indigenous Peoples, people living with disabilities, women, Two-Spirit, lesbian, gay,
bisexual, transgender, queer (or questioning), intersexed plus, (2SLGBTQI+) communities, people who
use drugs, people living on low incomes, newcomers to Canada, and people who are experiencing
homelessness and/or under-housed.12 13 14
An overall lack of public health and health care capacity, in particular surge capacity, in Canada, both in
terms of human resources and infrastructure, has been clearly illustrated clearly during this pandemic
but particularly with the Omicron-driven wave.
The deleterious impact the COVID-19 pandemic response has had on the mental and physical health of
responders, given its duration and intensity, and how this might affect recovery efforts and future
response capacity, also requires consideration.
think broadly about system-wide improvements. How lessons learned will be addressed by current
-makers, the next cohort of responders (e.g., students
in health disciplines) and society at large, needs to be a part of this multi-faceted process.
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1. Introduction
The purpose of the Federal/Provincial/Territorial Public Health Response Plan for Ongoing Management
of COVID-19, is to provide federal, provincial and territorial public health officials, First Nations, Inuit and
Métis partners, health system partners and other stakeholders with a Pan-Canadian forward planning
approach for ongoing management of COVID-19 in Canada. This plan promotes a long-term risk
management approach.
The first edition covered immediate planning imperatives for the fall/winter 2020 period and the second
edition focused largely on preparedness for variants of concern (VOCs). This third edition focuses on the
transition from the acute response to waves of COVID-19 activity occurring in a largely susceptible
Canadian population, towards a more sustainable long-term response to the ongoing presence of
COVID-19 in the context of increased population immunity and other public health priorities.
As an evergreen document this third edition reflects that scientific knowledge of the SARS-CoV-2
pathogen has increased, the epidemiological picture has further evolved in Canada and globally, the
understanding of the disproportionate impact the pandemic has had on marginalized population groups
has grown15 16, risk mitigation strategies have shifted, and new medical countermeasures have become
available (i.e., vaccines, therapeutics and diagnostics). It recognizes the need to balance the strategies
and measures necessary to minimize COVID-19 risks against the need to address the public health and
societal impacts of the sustained pandemic and the unintended consequences of the measures that
have been required to mitigate risks to date.
(WHO) previously
developed for pandemic influenza preparedness, response and recovery; this document focuses on
federal/provincial/territorial (F/P/T) public health activities that are needed for the Transition phase .
This is the phase between the acute pandemic response and the phase where COVID-19 is able to be
managed like other common infectious diseases in Canada. While acute response needs may be reduced
during this time, there is a need to maintain readiness to respond to any new COVID-19 risks while
addressing ongoing response and recovery needs. The Transition phase may occur over years, not
months, and the emergence of new VOCs and/or impact of waning immunity that may be associated
with increased disease activity and possibly increased severity, could necessitate a return to more acute
response type activities during this time frame.
The timing of the transition may be varied across Canada due to differences in epidemiology, availability
of health care resources, and risk tolerance. This edition of the Plan is informed by the current context,
and experience and evidence gained over the course of the pandemic response. As with previous
editions, this third edition also draws on existing intergovernmental pandemic preparedness, public
health emergency planning and data, information and resource sharing agreements, arrangements and
protocols in addition to the Canadian Pandemic Influenza Preparedness: Planning Guidance for the
Health Sector (CPIP). It is assumed that an ongoing (but appropriately scaled) F/P/T coordinated
response structure and activities as outlined in the F/P/T Public Health Response Plan for Biological
Events (F/P/T PHRPBE), will be needed to support the ongoing response, recovery and readiness
requirements during the Transition phase.
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As with other F/P/T plans, this document outlines overarching objectives, acknowledges jurisdictional
roles and responsibilities, identifies when cohesive F/P/T approaches are anticipated and when
provincial/territorial (P/T) flexibility and customization are expected. The autonomy of provinces and
territories with respect to management of their respective health systems is acknowledged; this
document is not intended to convey any requirements or obligations. This document has been
developed to facilitate planning for the management of COVID-19 that is not only flexible and adaptive
but driven by the assessment of COVID-19 risks in the Canadian population going forward.
2. Context
COVID-19 continues to represent an unprecedented challenge to the health, social and economic well-
being of Canadians, and the global community. More than two years into the pandemic, the Canadian
response has been strengthened by the availability of vaccines, testing, and therapeutics but further
challenged by the emergence of highly transmissible and immune evasive VOCs.
The availability of vaccines and rollout of population-based vaccine programs that prioritized reducing
the health impact in people at higher risk for poor health outcomes first, had a significant impact on
COVID-19 associated serious illness and overall deaths experienced in Canada. A high level of adherence
to the recommended public health measures (PHMs) remained essential, especially when the Omicron
variant of concern (VOC), which was associated with increased transmission and decreased vaccine
effectiveness (primarily effectiveness against transmission) and some therapeutics, emerged.
Mitigating the impact of COVID-19 in Canada continues to require a comprehensive, integrated and
cross- -of- -of- our
span of control while trying to reduce the risk and impact of what is not. The context of our planning,
therefore, is primarily Canadian-centric but recognizes that the global situation has a significant effect
on our response activities, the risk of resurgence, and the duration of the Transition phase in Canada.
2.1 Omicron
The Omicron-driven wave highlighted the need for ongoing adjustments and tailoring of the response as
the risk profile changes. The Omicron variant, although causing less severe disease among infected
individuals, still threatened to exceed health care delivery capacity limits due to the sheer number of
people infected with this highly transmissible, immune evasive VOC. Omicron arrived prior to the winter
holiday season while considerable Delta VOC activity was ongoing and when a pandemic fatigued
Canadian population was spending more time indoors, and gathering in large numbers. This increased
the risk of transmission at a time when vaccine-induced protection had started to wane and booster
dose programs had not yet been broadly implemented. To mitigate the risks associated with Omicron,
booster dose programs were quickly expanded across the country and restrictive PHMs were re-
instated, but were unsustained in many jurisdictions. Rapid antigen test use was expanded as
overloaded public health systems largely shifted surveillance and testing strategies away from individual
case and contact identification and management. Focusing on outbreak response in high-risk settings,
and measures to reduce overload of health care systems due to community circulation of Omicron,
became the priority in many jurisdictions.
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2.2 Disproportionate impacts and societal consequences
From the start of the pandemic, Canada implemented extraordinary broad and restrictive community-
based PHMs (e.g., school closure, restrictions on gatherings, workplace/ business restrictions).
Restrictive community-based PHMs were maintained or re-implemented in many jurisdictions in
response to Omicron. Many of these measures have had unintended negative health, well-being and
societal consequences,17 18 19 despite implementation of a significant level of societal support measures
(e.g., income support, housing support, and expansion of social services such as mental health and food
assistance).
The unintended, yet largely foreseeable, societal consequences of the pandemic response, have
affected virtually the entire population. However, diverse groups within Canada have been
disproportionately impacted by the pandemic, in part due to pre-existing inequities that were
exacerbated by the pandemic.20 21 These groups include but are not limited to: older adults , essential
workers, children and youth, racialized populations, Indigenous populations, people living with
disabilities, women, 2SLGBTQI+ communities, people who use drugs, people living on low incomes ,
newcomers to Canada and people who are experiencing homelessness and/or under-housed. 22 23 24 As a
result, their recovery as well as preparedness for future pandemics may require a more intensive and
expansive approach that focuses on reducing inequities and building resilience.
2.3 Societal disruption
Societal disruption was associated not only with high levels of disease activity, but also the restrictive
measures implemented to reduce transmission during these periods. The closure or reduced access to
workplaces, businesses, schools and daycares, and recreational facilities, disrupted normal routines, and
often created confusion as recommendations and requirements changed over time and differed
between jurisdictions. Paradoxically, many of those experiencing these disruptions were those least at
risk of severe disease (e.g., school aged children, healthy young adults). 25
Health care worker absenteeism from the workplace, due to the need to isolate or quarantine, further
compromised already reduced health care capacity even in well resourced jurisdictions. Similarly,
absenteeism amongst other essential service providers led to business continuity challenges.
The initial acceptance of necessary but disruptive response measures was impressive and beneficial as
Canadians were learning about the impact of SARS-CoV-2 in our population and how best to reduce it.
However, it is uncertain if the same level of personal sacrifice and societal disruption will be widely
acceptable in the future. It is important that forward plans revisit the triggers and timing of measures
implemented to reduce serious illness that also carry broader societal consequences. Even with the
availability of economic and other supports, there is a limit to the public tolerance of these measures
that are known to disrupt societal routines and functioning.
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2.4 Risk framework
The , encourages a risk-based approach to

planning across a continuum of pandemic phases. The WHO phases (Figure 1) are intended to represent
how the global incidence of cases (with all waves of pandemic activity collapsed into one pandemic
phase) progresses over time and consequently provides a framework for the WHO's risk assessment of
the global situation. This terminology, developed as part of influenza pandemic planning, has been less
prominent during the COVID-19 pandemic, but still provides a useful context for transition planning.
Specifically, this terminology and risk framework can be utilized at F/P/T tables to foster a Pan-Canadian
approach to describing the current situation and planning by phase based on the level of pandemic,
epidemic and ongoing level of disease activity in Canada.
Figure 1: The continuum of pandemic phases26
The Transition phase is the phase between the acute pandemic response and the phase where COVID-
19 is able to be managed like other common infectious diseases in Canada; the latter being the
Interpandemic phase. The Interpandemic phase is not intended to represent the period between waves
of pandemic activity; rather, it is the time between new pandemics which has ranged from 10-40 years
for influenza but has not been established for SARS-CoV-2 since this is the first documented pandemic
caused by a coronavirus. The WHO characterizes the Transition phase as the time as the
assessed global risk reduces, de-escalation of global actions may occur, and reduction in response
activities or movement towards recovery actions by countries may be appropriate, according to their
own risk assessments .
Within Canada, federal and P/T risk assessments can now be informed by a substantial evidence base
that when combined with local/regional epidemiological data, response experience and impact analysis,
will help determine a risk-based approach for recovery and ongoing preparedness activities through the
transition and interpandemic phases. However, uncertainty will continue to factor into risk assessments
going forward since the emergence of VOCs with varied epidemiological characteristics need to be
considered and the incidence and impact of COVID-19 during the Transition and Interpandemic phases
will not be known until it is observed over a number of months to years. Given these caveats and
recognizing that risk tolerance will likely vary between jurisdictions and over time, this document
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proposes planning based on achieving F/P/T objectives, using risk-based approaches for the use of
measures and the communication of public health recommendations.
2.5 Response governance and concept of operations
Throughout the response the F/P/T Public Health Response Plan for Biological Events, has provided the
framework for our F/P/T governance and concept of operations. This governance structure, which
includes the Special Advisory Committee, Technical Advisory Committee (TAC), Logistics Advisory
Committee (LAC) and Public Health Network Communications Group and associated secretariats has
facilitated the coordination of the public health response. The frequent meeting of these groups have
enabled real-time discussion of evidence, risk and strategic planning which has led to a robust response.
These forums for developing broad recommendations, approving response related products (e.g.,
guidance, risk communications, operational protocols), assessing risk and information sharing, have
Level 4 F/P/T response level throughout the pandemic. As
expected, provinces and territories (PTs) have adapted the F/P/T products and PHAC guidance products
approved in these forums for use as needed in their jurisdictions. This has resulted in variations in the
level of application and differences in timing of use of these products but nevertheless the structure has
ensured thorough consideration and discussion of all aspects of the public health response.
As many PTs have now shifted into the Transition phase based on assessed risks and observed
transmission levels, it will be important to consider whether (and when) the level of F/P/T response can
be scaled back from a Level 4 - Emergency response to a Level 3 - Escalated response as part of forward
planning. The concept of operations, supports ongoing review of the required F/P/T response level in
the form of a feedback loop that includes ongoing monitoring of risks and necessary risk mitigation
activities.
2.6 Previous waves
Before looking forward, it is important to think about the epidemiological characteristics and key drivers
of previous waves, as these essentially are different scenarios that we have already faced and can
potentially learn from the response to each. Specifically, there is a need to examine the triggers and
timing of response measures implemented in each previous wave and subsequently, the impact these
had on reducing serious illness, but also the societal consequences of the measures.
Figure 2 depicts the number of cases and prevalence of hospitalization due to COVID-19 in the Canada
over time. Although influenced by testing capacity and policies, the data is sufficient to summarize the
national trends in incidence and severity, recognizing that the impact of the waves varied between PTs.
Each significant wave was driven by a change in variant and/or contact rates (i.e., degree of interaction
between people outside of households). The impact of vaccination, which has included a relative
reduction in severe disease (i.e., requiring hospitalization), is not clearly evident in the figure due to the
underestimate of Omicron incidence. Also, testing in hospitals may have identified those with Omicron
who were admitted for another reason which could affect the death data.
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Figure 2: Pandemic waves and key drivers of COVID-19 impact
3. COVID-19 Response Goal and Objectives

3.1 Goal
responding to the COVID-19 pandemic is based on that established for pandemic

influenza in the Canadian Pandemic Influenza Preparedness: Planning Guidance for the Health Sector
document (last updated August 2018). The goal is:
To minimize serious illness and overall deaths while minimizing societal disruption as a result of
the COVID-19 pandemic.
This goal has guided F/P/T public health response actions during the pandemic phase in Canada, with an
emphasis on minimization of serious illness and death. Measures and strategies implemented with this
goal in mind have helped reduce the incidence of COVID-19 in Canada and associated serious illness and
deaths.
Reducing the health impact of COVID-19 while minimizing societal disruption has been extremely
27 28
challenging has increased and led to related challenges with
respect to public adherence to recommended measures. Recognizing that some groups of Canadians
face disproportionate barriers in their ability to adhere to these measures, has influenced the way local
response measures have been implemented (e.g., off hour vaccination clinics for shift workers, mobile
or pop-up clinics). Strategies to address these barriers will be an important lesson to carry forward for
future responses and planning documents.
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The goal statement, which highlights the need to balance the impact of COVID-19 in terms of both
health outcomes and societal disruption, will lead to shifts in emphasis during the Transition phase.
During periods of lower disease activity, the amount of serious illness should be manageable within our
existing health care systems and with the use of therapeutics. Therefore, the use of measures that are
known to have disruptive impacts in our society (i.e., restrictive measures) should be limited. However,
given the ongoing risk of a virulent VOC with immune escape properties, there may be a need to re-shift
the emphasis back to a focus on minimizing serious illness and death.
3.2 Objectives
As jurisdictions move out of the acute response phase and start to focus on recovery and preparedness
for managing COVID-19 as a routine infectious disease in Canada, there is a need to revisit ongoing
management objectives in the context of other public health priorities many of which have not
received adequate resources during the pandemic response phase.
3.2.1 Transition Phase

The Transition phase is a challenging time. The risk of resurgence will remain uncertain, but must be
planned for as the level of protection provided by vaccination and/or previous infection decreases over
time in the Canadian population and while pandemic activity continues globally. There will be a need for
multiple concurrent public health activities, all dependent on a largely exhausted public health work
force, all in the context of ongoing uncertainties regarding new variants.
Reducing COVID-19 associated serious illness to a locally manageable level (i.e., that can be managed
without disruption of other public health and health care services and programs), while maintaining
surveillance and readiness for any resurgence, and strengthening risk assessment capacity, are key
objectives during the Transition phase. However, during this phase there is also the need to
concurrently address recovery activities, documenti , and
starting to resume public health programs that were inadequately resourced due to the need to re-
direct resources towards COVID-19 pandemic response and may have large unmet needs. This also
includes starting to address ongoing health system capacity and data collection challenges. Any reliance
on State of Emergency status to achieve the necessary support for the pandemic response should be
considered and accounted for prior to discontinuing this declared State in order to ensure Transition
phase objectives will be met.
The following public health objectives aim to mitigate risks during the Transition phase.
Approach:
To take risk and evidence based public health action to reduce the morbidity and mortality of
COVID-19 to a locally low, manageable and tolerable level, while minimizing or mitigating the
negative physical and mental health consequences of these actions especially amongst
populations in situations of vulnerability; and,
To work collaboratively with the international community to support response and recovery in
other countries.
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Tools/Measures/Resources:
To identify and address, with dedicated health resources, the unintended mental and physical
health consequences and risks that have occurred over the course of the pandemic response, as
part of current response and recovery activities.
To continue delivering COVID-19 vaccination programs as recommended, in an efficient,
equitable manner;
To support the administration of therapeutics in an efficient, equitable manner;
To use testing strategies and genomic surveillance to optimize the management of ongoing risks
(e.g., to facilitate early treatment of those at high-risk of severe disease; to prevent introduction
into congregate living settings; to detect potential VOCs; to assess wastewater as an indicator of
community disease activity; to support targeted test, trace and isolate interventions, should a
future variant have characteristics that justify doing so);
To replenish and support access to vaccines, personal protective equipment, testing, and COVID-
19 therapeutics as needed;
To examine COVID-19 related risks in the context of other public health risks and re-balance
resources as needed to identify and address priorities;
To bolster positive individual health behaviours and facilitate incorporation of individual,
business and institutional changes into everyday practices; and,
To use mathematical modeling to help inform preparations for different epidemiological
patterns that may occur during the Interpandemic phase in Canada.
Readiness:
To ensure ongoing surveillance to facilitate early detection of resurgence signals and to inform
risk assessments; and,
To ensure readiness and capacity to respond appropriately to new risks (e.g., emergence of new
VOCs) and manage ongoing residual risks.
Recovery and Evaluation:
To support recovery and physical and mental health of pandemic responders;

To foster public understanding of ongoing risks while managing expectations for the recovery
period (e.g., duration and potential need to re-implement pandemic response measures) and
changes to improve resilience as COVID-19 transitions to an ongoing, more predictable,
infectious disease in Canada; and,
To document lessons learned and start forward planning aimed at improving future response
capacity, efficiency and addressing response elements identified as gaps or weaknesses in after
action evaluative reports/activities.
Within health care systems there will be a need to focus on clearing

was interrupted or delayed due to the need to re-allocate resources for treatment of COVID-19 cases
and increasing future surge capacity. borating centres,
public health agencies, health care and laboratory systems will continue to provide necessary supports
during the Transition phase.
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3.2.2 Interpandemic Phase

The onset of the Interpandemic phase will likely be identifiable only with retrospective data analysis.
While coronaviruses routinely circulate and cause illness in the Canadian population, COVID-19 has
newly emerged and therefore what the ongoing/stabilized epidemiology will be in the future is not yet
known. For planning purposes it is important to consider different epidemiological patterns that may
occur during the Interpandemic phase in Canada. Mathematical modeling and scenario based planning
can help inform these preparations, however it is clear that monitoring the epidemiology of COVID-19 in
the context of other diseases and ensuring a readiness to respond to signals of concern will be necessary
on an ongoing basis.
Pandemic recovery activities may still be occurring during this phase, however, the focus should shift
towards achieving preparedness-oriented objectives. During this phase it will be important to examine
and implement broad improvements in public health and health care systems; particularly those that
increase surge capacity and resilience. System-wide improvements that aim to reduce the
disproportionate impact experienced by several diverse populations during the COVID-19 pandemic
phase should also be prioritized as these improvements have the potential for immediate (non-COVID
specific) benefits to health status. Furthermore, public health objectives in this phase should include
addressing post- and measures that not only improve
capacity but also efficiency and timeliness of response components. Robust situational awareness and
linkages across the health sector will also improve preparedness during this phase.
Upon reaching the Interpandemic phase, our public health objectives will shift to mitigate risks and
improve preparedness for a broad range of risks. Anticipated objectives for the Interpandemic phase
include:
To ensure an ongoing state of readiness to identify risk signals;
To prepare to mitigate risks to the extent possible through a cycle of timely, informed risk
assessment, capacity assessment and preparedness activities;
To build capacity and improve efficiency within the public health and health care systems to
ensure ongoing health priorities are sufficiently resourced and surge capacity is available to
address response needs for future epidemics and pandemics;
To examine ongoing acquisition and stockpiling needs;
To improve linkages (e.g., data, professional networks, research community) and connectivity
across health sector to foster real-time data analysis and rapid scale-up during response periods;
To modernize and improve efficiency of data management and risk assessment processes;
To update pandemic guidance products aimed at preparedness, response and recovery with a
focus on addressing elements identified as gaps or weaknesses in after action evaluative
reports/activities (i.e., integrate lessons learned for the COVID-19 response); and,
To work with other sectors to strengthen the social and economic services and policies that
promote and protect health, prevent disease and build resilience (e.g., adequate housing,
employment and income supports).
While not within the scope of public health planning, it should be noted that health care settings should
also consider actions during the Interpandemic phase that will increase preparedness for infectious
disease management in their settings. This could include revising and/or increasing training in infection
prevention and control practices to be better protect health care workers and patients/residents from
disease transmission and addressing infrastructure needs (including space and ventilation components).
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4. Forward Planning
Transition phase activities must simultaneously address: ongoing response, recovery and readiness
needs in order to achieve the numerous objectives for this phase. Therefore, forward planning must be
comprehensive with recognition that flexibility and nimbleness are critical since some needs may
become higher priority than others at different points during the phase. Prioritization may also be
necessary during this potentially long transition period, due to reliance on an exhausted and/or reduced
public health workforce.
4.1 Planning Assumptions and Areas of Uncertainty
This third edition of the plan aims to support consistent but flexible public health planning at all levels of
government in order to support long-term COVID-19 response, recovery and readiness activities. Plans
should reflect a combination of cohesive F/P/T approaches and objectives with regionally and locally
adaptable actions; taking into account the needs of diverse groups within Canada on the basis of health
status, age, gender, race/ethnicity, culture, ability status, and other socio-economic and demographic
factors.
Table 1 identifies forward planning assumptions that aim to provide a basis for planning in the Canadian
context following the Omicron-driven wave. The areas of uncertainty, listed in Table 2, help identify
current unknowns and areas where the evidence base is rapidly expanding but is not at the point where
it can support a planning assumption. Given these areas of evolving evidence and knowledge,
operational plans need to include flexible elements or placeholders that can be updated over time and
as knowledge and experience increase. Both planning assumptions and areas of uncertainty require
validation and/or updating and may be triggers for re-visiting and modifying plans.
Table 1: Summary of planning assumptions
Forward planning assumptions

Epidemiology and Risk:
Transmission of COVID-19 will be ongoing, however the baseline level of transmission, as well
as the impact, frequency or timing of resurgences are as yet unknown.
COVID-19 adds a continuous net burden on health care.
Epidemiology of the Transition phase could include surges in disease activity (due to outbreaks
and/or new variants).
Viral evolution is to be expected.
Timing of phases (progression through and duration of) may vary between PTs and may not be
a linear progression from response to transition to interpandemic.
The proportion of infected individuals experiencing asymptomatic, symptomatic or severe
disease could vary significantly based on the infecting variant. Transmission by asymptomatic
and pre-symptomatic cases will continue to occur.
The risk factors for severe disease will not change significantly over time (i.e., including with
the emergence of new variants).
There will be ongoing risk of internationally-imported COVID-19 cases that will vary with the
global epidemic risk (e.g. the risk in neighboring countries, the level of global immunity etc.).
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Impact and Interventions:
Public health management during the Transition phase will shift from a focus on requirements
to recommendations and support for individual evidence and risk-based decision-making.
A strong surveillance system is needed during the Transition phase.
The vaccination strategy will continue to evolve based on new evidence, availability of new
vaccines and related supply, and the epidemiological situation in Canada.
Vaccination can reduce the incidence and impact of long-COVID.
Recovery activities include addressing unintended consequences and risks, backlogs with
health care systems and the impact of interrupted public health program delivery that have
occurred over the course of the pandemic response.
There is ongoing potential for emergence of new variants that may require a shift of focus
from recovery actions back to response actions. This shift will be risk-based with consideration
of other public health priorities.
There will continue to be a Pan-Canadian approach to prioritization/targeting of any limited
resource which will be based on an ethics framework. Policy development around prioritizing
limited resources will also be informed by other logistical, epidemiological and societal
considerations, for example the Declaration of the Rights of Indigenous Peoples.
Response and recovery measures implemented in one jurisdiction could have an impact on
neighbouring jurisdictions, even if they themselves do not implement that measure.
Initiatives to address human resource and infrastructure needs will be required to build health
care and public health system capacity.
Ongoing/long term management of COVID-19 will require public health programs to mitigate
surges in the demand for hospital resources.
Determining an acceptable level of risk together with ongoing assessment of the global
epidemic risk will inform ongoing management activities at international borders.
Immunity:
A significant level of population immunity, together with PHMs and other measures will be
required to reduce COVID-19 transmission to levels that are manageable without disruption to
health systems and broader societal function.
A variant that has significant genotypic and/or phenotypic changes (i.e., through mutation,
recombination, or evolution from an earlier ancestor) compared to previously circulating SARS-
CoV-2 variants, increases the risk of immune escape.
Circulation of a variant with immune escape properties means that the proportion of the
population that is susceptible to infection with this new variant will be increased.
The level of immunity in the population (achieved through prior vaccination or infection) will
wane over time.
Circulating neutralizing antibodies and cellular immunity are key to providing protection
against infection and severe disease, respectively, with other immune mechanisms
contributing to each as well. Both are generally effectively induced by intramuscular
vaccination, but vaccine-induced protection against variants may vary and protection,
particularly against infection and also somewhat against severe disease, is expected to
decrease over time.
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The level of protection received from vaccination will correlate in the short term with the
number of appropriately spaced doses received and time from receipt of their last dose. This
level may be affected by the immune competence of the individual, the intervals between the
doses they received, the products received and the time since last dose.
Infection stimulates the immune response (i.e., production of antibodies and cellular immune
response), and is likely to induce mucosal as well as systemic immunity in immunocompetent
individuals.
Infection-induced immunity varies by a host of factors (age, severity of the illness, underlying
medical conditions, vaccination status). .
Infection-induced immunity may offer good level of protection but compared to vaccination it
is less consistent and predictable.
Infection in addition to being vaccinated confers better protection than infection alone.
Population immunity is function of the combination of individuals with varied levels of
protection achieved through vaccination (with various products and/or combinations of
products with varying effectiveness) and differing histories of prior infection.
Table 2: Summary of areas of uncertainty
Areas of uncertainty
The epidemiology of COVID-19 endemicity in Canada- meaning the baseline level of transmission, as well
as the impact, frequency or timing of resurgences (e.g., whether and when COVID-19 will eventually
have a seasonal pattern similar to other respiratory infections).
How ongoing circulation of SARS-CoV-2 will interact with other respiratory viruses (e.g., influenza, RSV),
and the impact this will have on health care service demand during seasonal peaks and on population
immunity.
The epidemiology of other respiratory viruses after 2 years of limited circulation.
The prevalence of Post-COVID Condition/Long-COVID in our population and the impact this sustained
manifestation of COVID sequelae will have on morbidity, mortality, future health system resources, the
workforce/economy and society in general.
The level of COVID-19 morbidity and mortality considered acceptable/tolerable by the Canadian
population.
The level of PHMs that Canadians will tolerate and use of PHMs in the absence of mandates.
The degree to which new variants will require adjustments to the response, recovery and ongoing
preparedness activities in order to achieve objectives.
The effectiveness of mucosal vaccines and whether they elicit better protection against infection and
elicit immune protection against illness.
There may be a limit to the protection received from repeated vaccination.
Immune correlates of protection against infection or severe disease.
How effective different current and new vaccines and therapeutics will be in response to new VOCs.
The deleterious impact the COVID-19 pandemic response has had on the mental and physical health of
Canadians, including those disproportionately impacted.
How the deleterious impact the COVID-19 pandemic has had on responders might impact recovery
efforts and future response capacity.
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Whether the lessons (i.e., not yet learned ) can be addressed by current responders and
decision makers, the next cohort of responders, (e.g., students in health
disciplines) and society at large.
The extent of provincial and territorial formal review and inquiry processes.
The extent to which the pandemic will catalyze change in various sectors to address social determinants
of health and conditions for marginalized, racialized, Indigenous or harder to reach communities.
The degree to which public trust in public health leaders, approaches and science in general has been
negatively and positively impacted, and the duration of these impacts.
4.2 Planning for ongoing COVID-19 risks, response and readiness needs
Ongoing COVID-19 response activities and readiness for detection and response to resurgences of
COVID-19, must continue to be addressed during the Transition phase. Throughout this period of
transition towards more predictable COVID-19 disease activity in Canada it is important to consider that:
the timing/specific characteristics of potential new variants is unpredictable, therefore
transition to a relatively stable pattern of disease will likely take years, not months;
immune escape variants can be expected to emerge over time this may be a key driver of any
increased spread, although increased intrinsic transmissibility is also possible;
variants with higher severity remain possible and whether the intrinsic virulence of the variant
causes an increase in observed severity in our population, will be determined by a number of
factors (i.e., who is getting infected, residual protection from vaccination and past infections,
and the effectiveness of tools and measures implemented);
genetically-divergent variants could suddenly emerge (e.g., from zoonotic sources, evolution in
immune compromised hosts); and,
determining the epidemiology of a new variants will require time and will therefore challenge
our ability to make timely risk-based decisions without a high level of uncertainty.
4.2.1 Population immunity

Population immunity will be considered significant when it is sufficient to decrease and sustain COVID-
19 activity in Canada at a level where it can be managed concomitantly with other public health issues
and without straining public health and health care resources. However, population immunity is a
product of the combined immunity of all individuals in a population and to some degree the protective
herd immunity effect when a high proportion of individuals are well protected at the same time (and
mixing with unprotected individuals). Individuals will have varied levels of protection achieved through:
vaccination - with products/combinations of products, with varying effectiveness, and in people
with varied immune competence, and
prior infection(s).
The protection achieved through vaccination or infection will wane over time and may be insufficient to
prevent infection with a new VOC, as was seen with Omicron. For these reasons, there are multiple
scenarios for the future of COVID-19 in Canada, and at this point it is not possible to predict with any
certainty which scenario or combination of scenarios we will experience. This is not unique to Canada
and similar conclusions have been reached by other countries.29
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4.2.2 Ongoing transmission

Given the shifts in the level of population immunity that can be expected to occur over time, ongoing
transmission, due to imported cases, outbreaks and changes in contact rates amongst susceptible
populations, is anticipated. It is also expected that waves of infection may continue to occur
predominantly due to the introduction and spread of new variants. The frequency and amplitude of
these waves of infection will depend on:
the characteristics of the variant; in particular the degree of immune evasion will impact the size
of the susceptible population and together with intrinsic transmissibility, the subsequent degree
of spread, and
the timing of, triggers for, and effectiveness of tools/measures implemented to reduce
transmission and prevent serious illness and deaths.
Mathematical modelling supports planning our response to epidemics and outbreaks, and the COVID-19
pandemic has demonstrated the important role and need for the full range of modelling tools required
to support decision-making during a complex public heath crisis. This role and the types of models
currently in use are described in Appendix 1: Modelling Support for Forward Planning.
For forward planning purposes, it is helpful to think about a range of possible scenarios and the key
drivers/characteristics of each; keeping in mind how the characteristics of the circulating variant (or
variants) may manifest in Canada based on our level of population immunity at the time. Figure 3,
depicts possible patterns of incidence, hospitalizations and the level of population immunity. The
otted orange line for case incidence
and a corresponding dotted blue line for hospitalization prevalence.
Figure 3: Possible patterns of incidence, hospitalizations and population immunity
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In Appendix 2: Epidemiological Drivers, the epidemiological drivers that influence: 1) the number and
timing of new cases and, 2) health related impacts of cases, is presented for reference. (Note: this
content has been retained from the 2nd edition of this Plan)
4.2.3 Observed severity

The number of hospitalized cases is one of the key variables used to represent observed severity in the
population over time. This will be driven by the level of ongoing transmission in the population and the
intrinsic transmissibility of the circulating variant(s). The observed severity of a new variant in the
Canadian population will be a function of:
the intrinsic virulence of the variant;
who is getting infected (i.e., individuals with high-risk medical conditions, the elderly or low-risk,
younger individuals) and who is not (i.e., due to residual protection from prior vaccination
and/or infection; and
the effectiveness of measures aimed at reducing severity and infection particularly amongst
high-risk groups (e.g., evasion of therapeutics).
There is a role for the effective use of therapeutics, especially those that can be accessed and taken in
the community early in course of infection, which subsequently will impact the amplitude
of the wave of COVID-19 related hospitalizations (see Figure 3). Pre-exposure prophylaxis with
monoclonal antibodies for very high risk group who may not make good responses to vaccinations will
also be available in the near future. Figure 4 identifies the 3 main drivers of observed severity in a
population and highlights where public health action has the most influence.
Figure 4: Drivers of observed severity in a population
Serious outcomes of SARS-CoV-2 infection beyond the acute hospitalization period, specifically the Post-
COVID Condition Long-COVID , also requires attention in forward plans. Public health
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authorities (PHAs) could play a leadership role in highlighting the need for, and facilitating funding of,
research aimed at increasing the understanding of the epidemiology, including risk factors, for this
syndrome. As more people experience this post-virus syndrome, necessary physical/rehabilitative and
mental supports must be identified, quantified and used to plan for resources required for new
programs and long-term management strategies. Collaboration across the health sector would facilitate
a coordinated approach.
4.2.4 Risk management

Planning for the Transition phase, requires a risk management approach. As the epidemiology of COVID-
19 in Canada becomes more stable and predictable, COVID-19 specific actions need to be transitioned
into sustainable public health activities. Critical to this transition is ensuring that public health has the
capacity to: provide informed, timely risk assessments on an ongoing basis that include but are not
limited to COVID-19, and to response rapidly to signals of increased risk (e.g., severe VOCs). This risk
management approach will help determine where to allocate and prioritize public health resources. It
will also inform the need for system wide enhancements that will increase readiness and resilience for
future pandemics.
While supporting and recognizing the interrelatedness of public health and health care delivery within
our health care systems, the optimal public health response will be contingent on the ability to:
rapidly assess new risks (e.g., new variants) - which includes monitoring the level of
susceptibility and vulnerability in the population,
mitigate the risk by prioritizing and appropriately timing the use of highly effective, lower
consequence measures, and implementing measures that are commensurate to the risk,
minimize residual risk and response-associated consequences which includes considering
additional tools and measures that can lower residual risk as well as minimizing foreseeable,
unintended, societal consequences of our responses
evaluate impact of measures to inform what worked well and what could be improved upon,
scale up and down the response - based on the epidemiology of COVID-19 and related risks,
with consideration of timing, triggers, effectiveness and risk tolerance
increase the resilience in population and our health care systems through addressing
inequities in the social determinants of health, encouraging investment to improve surge
capacity in both human resources and infrastructure, bolstering positive individual health
behaviours and facilitating incorporation of individual, business and institutional changes into
everyday practices.
Ongoing management of COVID-19 during the Transition phase includes ensuring the capacity to detect
signals of resurgence, and the readiness to ramp up a response that is proportionate to the risk. Risk
assessment is an important first step but the data needed to confidently inform the risk level is usually
inadequate at the time the new signal is detected, especially if the signal is the emergence of a new
variant. If the signal arises in another country, even if data is available on observed severity, the
generalizability to the Canadian population and challenges with inferring intrinsic virulence from early
population-level impact will remain30. Genetic analysis of the variant may be helpful if there are
mutations that are common to previously circulated variants but the ability to extrapolate population
impact from these data will also be highly uncertain.
To facilitate readiness to respond in a manner proportionate to the risk, consideration of the viral
characteristics and observed severity together with risk factors, can help inform which tools or measures
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to employ in the response. Content regarding planning for a reasonable worst case scenario has been
retained from the second edition of this plan in Appendix 3: Planning for the reasonable worst case
scenario, as it is still relevant and potentially applicable during the Transition phase.
Table 3 links these considerations with potential measures. Most non-restrictive measures will likely
become recommended as opposed to mandated during the Transition phase. Therefore the role of
public health will focus on empowering individuals to increase their resiliency by adopting individual
health behaviours and make well-informed, risk-based decisions regarding what measures and
protections to use and when, based on up-to-date evidence. This will involve doing: 1) a risk analysis as
soon as possible after detection of a signal of concern, and 2) ongoing assessment of the risk factors
identified in Table 3 in order to track the level of vulnerability in the Canadian population (e.g., due to
waning immunity) over time, and 3) then providing credible advice to the public through risk
communication activities. The list of tools/measures to mitigate the risks in Table 3 is intended to be
illustrative not exhaustive.
Essential roles of public health and other government officials beyond encouraging individuals to
conduct risk assessments and improve their protective behaviours is to strengthen societal structures
through legislation and regulation so that there can be adequate testing, data collection, analysis and
reporting, as well as enforcement of comprehensive border and travel health measures and
opportunities for children, students, workers and other populations to have access to proper protective
equipment and avoid exposure to coronaviruses.
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Table 3: Considerations for use of public health tools and measures
Viral Risk factors Tools/Measures to mitigate

Characteristic (level/degree of each affects risk
and Impact level)
Transmissibility inherent transmissibility of the virus Surveillance sufficient for early detection
how much it will viral growth potential/growth rate Test, trace and isolate / quarantine (increased access to rapid
spread in Canada population immunity tests)
vaccine effectiveness against infection Restrictive measures (capacity limits, school closures, vaccine
contact rates mandates)
indoor vs outdoor exposure PHMs (community and personal measures e.g. masks)
Correct use of, and adherence to, Measures to prevent reverse zoonotic transmission and
recommended PHMs secondary zoonosis,31 i.e., decreasing high-risk human-animal
interactions
Immune escape size of susceptible population Vaccine boosters
who will be effectiveness and availability of Rapid assessment of vaccine effectiveness in different
vulnerable to vaccines and therapeutics (e.g., populations
infection effectiveness of monoclonal antibodies) Enhanced lab genetic sequencing capacity
Monitoring for resistance to therapeutics
Monitoring of treatment effectiveness in immunocompromised
populations (to mitigate risk of mutated variants developing)
Measures to prevent reverse zoonotic transmission and
secondary zoonosis i.e., indirectly reducing risk of viral
evolution in animals32
Virulence viral attachment and replication site Availability of effective therapeutics and treatment
potential for Speed of viral replication and resulting Pre-positioning of therapeutics in community
severe disease viral load Research (e.g., identification of animal models for early severity
due to viral immune evasion estimates/projections)
properties and host ability to cause lung injury
response ability to cause hyperinflammation and
immune dysregulation33
Observed Size and clustering of high-risk Early implementation of targeted protective measures for
severity group(s) i.e., those that are: individuals at high risk of severe disease especially for those in
how much severe o elderly congregate settings (e.g., active screening, visitor restrictions,
disease is o immunocompromised use of masks)
experienced or o experiencing chronic medical Prioritized access to vaccines and therapeutics
could be expected conditions Increase health care capacity/surge capacity (infrastructure and
(Note: this is o pregnant human resources)
influenced by the o obese
viral characteristics vaccination status and time since last
previously listed in dose
this table) history of prior infection
how effective PH measures are at
protecting high risk groups
vaccine effectiveness and vaccine
coverage in high risk groups
Treatment access & capacity
Effectiveness of therapeutics
The risks of a variant with high intrinsic virulence, health care systems becoming overwhelmed, and the
need to implement restrictive measures (which have known negative societal consequences and
increase the risk of public backlash and lack of adherence to public health recommendations), are all
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connected. Forward planning needs to focus on the timing of, triggers for, and effectiveness of
tools/measures implemented to reduce transmission of variants expected to have high observed
severity in the Canadian population.
4.2.5 Timing
The timing of when to implement a measure, is usually based on an imminent risk or observed impact
and the level of risk tolerance amongst decision makers and the public. In response to Omicron,
measures were initiated before the impact of Omicron in our population was well understood. During
the Transition phase we are now seeing pandemic fatigue, public risk perception and risk tolerance
playing a greater role in the expeditious lifting of response measures.
Since most public health measures are preventive in nature, the effectiveness is usually affected by the
timing of implementation. In short, the earlier after detection of a risk, the better. However, given the
duration of the pandemic and the now known societal consequences of restrictive measures, there may
be more reluctance to implement these types of measures early and broadly without strong evidence of
observed severity in the Canadian, or a comparable, population. Individuals, equipped with public health
recommendations, will likely take precautions when the risk is real to them or their friends and family.
This will be too late for optimal population-based effectiveness.
Assuming there is no significant change in the population sub-groups at highest risk for severe outcome,
it is likely that early implementation of restrictive measures will only be widely acceptable if they are
targeted at, and known to be effective in, those at highest risk of severe disease and death. For example,
targeting measures at settings where risk is likely to be greatest (e.g., long term care homes and other
congregate living for older adults, as well as other high risk congregate living settings).
4.2.6 Triggers
The triggers for risk mitigation tools and measures will require consideration of how likely it is that the
risk will be realized, what the potential severity of impact will be and the expected effectiveness of risk
mitigation measures. Moving forward into the Transition phase it can be expected that decisions
regarding the timing and triggers for action will include an element of risk tolerance, especially if
expected severity is uncertain.
Triggers for public health action during the Transition phase will be based on the current epidemiology
and subsequently, the demand on response resources and objectives of the response. Any significant
change in response needs and requirements, which may or may not be able to be met with the existing
capacity, may require adjustments in the public health response. Changes on demands for laboratory
diagnosis, hospital treatment, or vaccines, could trigger an increase or decrease in response activity. For
example, availability of vaccine for children triggered an increase in the number of clinics occurring in
the community settings; whereas a decrease in laboratory capacity triggered a need for an increase in
rapid test use and recommendations for self-care.
Similarly a change in emphasis of the response, for example to focus less on reducing transmission in the
general population and more on protecting those at risk of severe disease, will also trigger a change in
public health approach.
From an advanced planning perspective, the triggers for use of tools and measures should be based on a
risk analysis that includes a focus on the risk of observed short-term and long-term severity, the risk of
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health care systems becoming overwhelmed, and the risk of societal disruption due to both disease and
response measures implemented to reduce transmission.
4.2.7 Effectiveness
The effectiveness of any measure is highly variable and depends on the intrinsic properties (e.g.,
filtration capacity in a mask), whether it is consistently used properly (e.g., fit of mask) and at the
population level, the uptake/adherence amongst the at risk proportion of the population (e.g.,
consistent mask use whenever in a public indoor setting). The relative effectiveness will vary between
populations and over time, which is why timing and triggers are linked to effectiveness.
Recognizing that there are consequences of every measure both at an individual and population level,
our experience to date has highlighted the need to balance the expected effectiveness of the measure
against the possible negative consequences. Ideally, we all want highly effective measures with low
negative consequences. Vaccination is one of the few measures that might be considered in this
category. Therefore, forward planning for the public health response need to include:
vaccine research and domestic production of vaccines,
ongoing monitoring of the evidence base for the effectiveness of tools and measures,
conducting research in the Canadian context to contribute to the evidence base,
survey of knowledge, attitudes and behavior regarding measures to inform potential
acceptance/uptake/adherence of recommended and mandated measures,
evaluation the effectiveness of measures used during the pandemic, and
examination of how to best to support adoption of effective behaviours at a population level.
4.3 Planning for recovery
In addition to ongoing response activities, the implementation of recovery-oriented activities is essential

during the Transition phase. Planning for recovery in society includes addressing the broad
consequences, backlogs within health care systems and the impact of interrupted public health program
delivery, that have occurred over the course of the pandemic response. From a risk perspective, this
involves examining COVID-19 related risks in the context of other public health risks, and re-balancing
resources as needed to identify and address priorities. Recovery activities should include dedicating
public health resources to address the broad, unintended mental and physical health consequences and
risks that have occurred over the course of the pandemic response (See section 8).
4.3.1 Societal recovery

Given the uncertainties imbedded in the Transition phase, this will be an important time to foster public
understanding of the ongoing risk environment while managing expectations for the recovery period
(e.g., duration and potential need to re-implement pandemic response measures) and changes to
improve resilience and mental wellbeing as COVID-19 becomes a persistent infectious disease in
Canada. A part of this involves recognizing varying levels of risk tolerance in our population and the
impact the information public health officials have provided to the public has had on how individuals
accept and manage risk.
Many people have become more risk averse over the course of the pandemic and recovery for them
iding reminders of what was tolerated previously and putting
COVID-19 in the context of other daily risks. For those at higher-risk of severe disease (e.g.,
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immunocompromised) the addition of SARS-CoV-2 as another pathogen that they need to beware of can
be fear-provoking and overwhelming and therefore is likely best managed on an individual basis. At the
other end of the spectrum, we now have people who feel confident in their understanding of COVID-19
risks to undertake, and make behavioral decisions, based on their own personal risk assessments. This
type of empowerment is positive and public health facilitation of well-informed individual decision-
making will be needed throughout the Transition phase.
Part of this transition back to more individual health decision-making and self-care, involves recognizing
and respecting that people may make decisions that deviate from public health recommendations and
that are not foremost in the interest of public health. Therefore, fostering recovery will include
contextualizing risk and risk reduction measures for the population, while respecting individual
differences.
Effective risk communication, in addition to ongoing knowledge translation and transparency, will be
important to managing public expectations, facilitating evidence-based individual decision-making and
maintaining public trust. Replenishing and supporting equitable access to effective vaccines, personal
protective equipment and COVID-19 therapeutics as needed during this phase, will also mitigate the risk
of future shortfalls and loss of public trust in our health care systems.
Societal recovery will require broad consideration and implementation of recovery activities adapted for
population sub-groups and settings, for example: public health systems, health care systems, racialized
communities, critical infrastructure, workplaces, schools, and congregate living settings.
4.3.2 Responder recovery

Planning activities are also needed to address the fact that the COVID-19 pandemic response has had a
deleterious impact on the mental health of many responders (which include but is not limited to: public
health workers, health care workers and social service providers). How this might impact recovery
efforts and future response capacity is a major concern. Decreases in the available workforce have
occurred due to burnout, early retirement, extended health/stress leaves and use of short-term
solutions to supplement the workforce. There is also a need for the remaining responders to take time
off work to recover, decompress and regain the energy required to continue to work in a stressful, often
challenging, environment. Recovery efforts need to start with measures to improve the physical and
mental health of pandemic responders, recognizing that this may be a prolonged need. This is necessary
as some mental health conditions, such as post-traumatic stress disorder, may take months or even
years to develop. Consideration should be given to increasing access to employee assistance programs
(e.g., to all, not just full-time employees), and expanding the coverage available for counselling and
other mental health services.
The period following an acute response often includes a series of inquiries, external evaluations and
even legal challenges that require the same exhausted responders, expecting a reprieve, to continue
work under potentially stressful conditions. It is important to recognize and prepare responders for this
disheartening and challenging reality as this is difficult to avoid. Strategic planning for how to lessen the
load on any one individual or team and be more efficient in terms of meeting these ongoing demands is
needed.
This is also a time where changes to the workplace would be beneficial to ensure access to proper
ventilation and protective equipment in the event of continued transmission of variants. Many workers,
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who were working virtually/remotely, may be anxious about returning to their designated office in
person while those who routinely work virtually from a remote location may feel more disconnected
and less well supported than they did when the majority were working virtually.
4.4 Planning with Indigenous Communities
In response to the COVID-19 pandemic, Indigenous Services Canada (ISC) has provided or supported
primary health care and public health services in First Nations and Inuit communities (see Appendix 4).
For example, ISC provided access to personal protective equipment (PPE), supported communities in
acquiring temporary assessment, screening, and isolation structures, assessed and supported re-
opening of schools and other public facilities, provided surge capacity to address additional mental
wellness needs, testing and contact tracing, and worked alongside provinces and territories, and
Indigenous organizations, to prioritize access to vaccines for Indigenous people across Canada.
While First Nations living on reserve and Inuit living in land claim regions originally experienced lower
rates of COVID-19 than the general Canadian population, First Nations, Inuit, and Métis had higher
infection rates during the latest wave dominated by the Omicron variant. Urban First Nations, Inuit, and
Métis have also been overrepresented in COVID-19 case counts throughout the pandemic.
Currently the most recent wave dominated by the Omicron variant is subsiding across the Indigenous
population. Decisions made by Indigenous communities, regarding the lifting of health restrictions at
the same time as many of their provincial and territorial counterparts, vary according to the local
context and case rates. The vaccine rollout across Canada continues to prioritize access and allocation
for Indigenous Peoples, and the uptake of vaccines has been largely successful, especially in light of
vaccine hesitancy as a result of mistrust in the government due to colonial practices. As of February 15,
2022, 87.6% of First Nations living on reserve aged 12 years and older have received at least two doses
of the vaccine.
While a full evaluation of the pandemic and response is a vital task to be undertaken during or following
the Transition phase of the pandemic, some lessons learned have already become apparent. These
include:
the need to continue to work with Indigenous partners to prioritize Indigenous knowledge,
lived experiences, priorities, and concerns around health and healthcare;
the need to continue to work to gain trust from Indigenous Peoples and communities in
order to effectively provide both primary and public health care services;
significant discrepancies in social determinants of health is an increased risk for Indigenous
Peoples with respect to both incidence and severity of communicable disease, particularly
for respiratory illnesses; and,
preparedness for health emergencies and pandemics and the ability to move quickly and
flexibly allows a response to meet the distinct needs of First Nations, Inuit and Métis. This
preparedness includes funding flexibility, access to PPE and medical supplies, timely
knowledge translation, timely Indigenous (and non-Indigenous) language translation
services, and health care personnel surge capacity.
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4.4.1 Focus for Transition Phase

As Canada moves into the Transition phase of the COVID-19 pandemic, First Nations, Inuit, and Métis
will have specific needs and considerations to be addressed in addition to those of the general Canadian
population. Health equity gaps for First Nations, Inuit, and Métis populations are the result of colonial,
historical, political, societal, and economic factors that have long influenced Indigenous health and
Indigenous social determinants of health. Vaccination in the context of COVID-19 has shown, in several
communities, the positive spin-offs of P/T collaboration with health and social services institutions as
well as the added value of the cultural safety approach adopted by these institutions as part of their
public health responsibilities towards communities and Indigenous Peoples. However, inequalities
persist in part due to systemic racism experienced in the healthcare system and increased access to
culturally safe services, as defined by Indigenous Peoples themselves, are required to support these
populations. Important risk factors, such as higher rates of overcrowding and major repairs in homes,
and inadequate resources to improve built environments, have the potential to contribute to
transmission. Additionally, the waves of increased cases across Canada have not necessarily occurred in
the Indigenous population at the same time as the general population; this has increased the
comparative difference in risk between Indigenous Peoples and the general Canadian population. The
impacts of the pandemic were exacerbated by overcrowded housing and other deficiencies in their built
environment. As a result, it is important to recognize that First Nations, Inuit, and Métis, may have
distinct needs and objectives that could differ from the general Canadian population, and from each
other. Nonetheless, key priorities are expected to include:
continuing to prioritize access to vaccines and therapeutics (particularly those designed to

mitigate severe disease and hospitalization) in order to reduce the greater burden of risk
experienced by Indigenous Peoples;
taking public health action to reduce the incidence, morbidity, and mortality of COVID-19
among First Nations, Inuit, and Métis populations to low levels, as determined by each
community, in a way that minimizes the negative physical health and well-being impacts and
;
assessing and addressing the impacts of the redirection of resources (financial, personnel,
and expertise) toward COVID-19 to the possible detriment of other public health services
and primary health care delivery;
addressing and catching up with the back-log of public health activities, particularly TB
screening and testing, childhood immunizations, and STBBI screening that have been
delayed during the pandemic;
dedicating public health resources and providing community support to address the
unintended physical health and well-being impacts of the pandemic and consequences of
pandemic response that have in particular impacted First Nations, Inuit, and Métis given
their historical and colonial experiences;
remaining in a state of readiness in order to swiftly address the potential threat that
possible new variants may pose to Indigenous communities;
Providing access to trauma-informed and cultural competency training to public health
surge staff and responders to ensure culturally safe and appropriate care is provided to First
Nations, Inuit, and Métis;
Supporting the assessment, investigation and identification of risks and hazards in the built
environment (e.g. restaurants, schools, and long-term care facilities) so as to reduce
transmission and supporting communities in mitigating and preventing those risks;
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ensuring ongoing surveillance to facilitate early detection of resurgence signals and to

inform risk assessments;
provide access to First Nations, Inuit, and Métis to COVID-10 surveillance data that is
distinctions-based for decision-making by Indigenous leadership;
supporting the recovery and well-being of Indigenous pandemic responders and pandemic
responders supporting Indigenous people and communities;
in partnership with Indigenous communities and organizations, developing future strategy
and approaches for managing and responding to COVID-19 in the long-term, as it becomes a
more predictable ongoing infectious disease in Canada;
support the education of clinicians to be able to respond adeptly to future variants of
COVID-19, and other novel pathogens as they arise;
assessing and articulating the additional burden of risk placed on First Nations, Inuit, and
Métis by ongoing COVID-19 as a result of colonial, historic, political, societal, and economic
factors that impact social determinants of health;
reflecting, analyzing, learning, and documenting lessons learned and developing a plan
aimed at improving future response capacity and efficiency; it will also address response
elements identified as gaps or weaknesses in evaluation reports/activities in partnership
with Indigenous communities and organizations;
fostering understanding of the ongoing risk environment while managing expectations for
the recovery period (e.g., duration and potential need to re-implement pandemic response
measures) and changes to improve resilience as COVID-19 becomes an ongoing, predictable
infectious disease, in a sustainable way; and,
evaluating community based testing capacity that has been established over the pandemic
and plan for transition to testing for other pathogens and maintain readiness for future
emerging diseases concern.
4.4.2 Planning Variables and Signals

There are several unknown variables as well as currently held assumptions that will change the course of
actions that will be taken during the Transition phase. The assumptions are:
COVID-19 will become an ongoing, predictable infectious disease in Canada; and,
the ongoing evolution of the virus is assumed, and therefore additional variants of concern are
considered likely, including those which may prove to be more transmissible or virulent.
Unknown Variables include:

The degree to which the relaxation of restrictive public health measures will increase the
risk for resurgent secondary wave of Omicron cases or other variants of concern, and the
degree to which that risk may be disproportionally borne by Indigenous communities.
It is unknown if COVID-19 will eventually become seasonal in nature, as with other
respiratory viral illnesses.
not available
to First Nations, Inuit and Métis individuals and communities during the height of the
pandemic, and the resources required to address it is unknown, but can be assumed to be
quite significant based on information from regions, communities, and care providers.
The scale of the additional physical and well-being impacts caused by the pandemic and the
pandemic response for First Nations, Inuit, and Métis and the resources required to address
it is unknown but should be assumed to be quite high.
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The waning protection of vaccines over time, and their efficacy when novel variants of
concern may arise.
The Indigenous community self-determined acceptable level of COVID-19 incidence,
morbidity, and mortality among First Nations, Inuit, and Métis, and the degree to which that
tolerance may differ from the general Canadian population.
The future response capacity available to support future needs during resurgences of
COVID-19, and other illnesses to the trauma, moral injury, fatigue, and burnout faced by
healthcare providers and other responders.
The future response capacity of Indigenous communities given the collective trauma caused
by COVID- - physical health and well-being.
The degree of trust First Nations, Inuit, and Métis may have in the federal government,
provincial and territorial governments, and local public health providers, as well as public
health, in general, has been improved or damaged during the ongoing response to COVID-
19.
4.4.3 Transition Planning and Recovery

While it is understandable that the during the transition phase significant resources are directed
towards planning, learning, and reassessing best practises for managing COVID-19 on an ongoing basis,
as well as planning for potential other novel pathogens, it is critical to ensure that these important
exercises do not draw resources away from the recovery period required within First Nations, Inuit, and
Métis communities. Indigenous communities will face considerable challenges in addressing the backlog
of primary care and public health services and will require additional resources in order to do so. There
is a risk that inadequate support for Indigenous communities in addressing this backlog will further
widen the gap of health inequities between First Nations, Inuit, and Métis and non-Indigenous
Canadians. There is, however, an opportunity that appropriate support in addressing this backlog will
both serve to decrease those inequities, and act to make steps toward decolonizing health services, as
Indigenous leaders and organizations are invited to partner in this work.
5. Addressing the consequences of pandemic response

The response to COVID-19 over the last 2 years has yielded multiple diverse impacts aside from the
successful reduction in serious illness and deaths experienced in Canada due to COVID-19. On the
positive side, the need for strong public health capacity as part of the health care continuum is now
more fully recognized and decision-makers, the media, and the public are now highly aware of the role
and responsibilities of public health in pandemic response. Connectivity across the health system has
also improved, but still requires more work in particular to support timely, evidence-based decision
making for the Canadian context. There has also been an increase in public understanding of scientific
concepts, particularly regarding immunology and epidemiology, and the use and trust in science as a
basis for decision making. Similarly, public health literacy and understanding, as evidenced by
widespread uptake of recommended public health measures, has increased in the population.
Furthermore, changes in workforce surge capacity (e.g., employment of foreign-trained health

professionals), domestic manufacturing and infrastructure, and increased capacity and flexibility to work
virtually from home, may prove to be positive long-term consequences of the pandemic response.
Strengthened stakeholder collaboration and relationships were also noted across multiple levels. The
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accelerated development of online technology, tools and platforms such as schedulers for public to self
schedule lab testing, vaccine scheduling, public access to lab results and apps which can be used for
other health care needs in the future were also positive outcomes.
Some of the positive consequences, however, were also temporary or diminished over time. For
example, initially there was an increased public trust in governmental decision-making and sense of
unity as evidenced by large turnouts to mass testing, support for health care workers, and high
adherence to recommended measures. However, as the pandemic progressed this seemed to decline as
public trust began to erode and community divisiveness increased especially in certain populations
whose employment and economic prospects were diminished. 34
Unfortunately, there are also many negative consequences, many of which affected specific segments of
the Canadian population. These groups include but are not limited to: older adults, essential workers,
children and youth, racialized populations, Indigenous populations, people living with disabilities,
women, 2SLGBTQI+ communities, people who use drugs, people living on low incomes, newcomers to
Canada and people who are experiencing homelessness and/or under-housed. These consequences of
the response include impacts on childhood development, access to health services, mental health,
family and gender-based violence, and social isolation and exclusion. 35 36
Many of the negative unintended consequences of the pandemic response were the result of existing
baseline inequities in Canadian society. Table 4 provides examples of some of the negative
consequences, contributing factors and potential sources of data or evidence that could help inform the
magnitude of the impact.
Table 4: Negative consequences of the COVID-19 public health pandemic response
Negative consequence Contributing factors Data/evidence sources (examples)
Delayed diagnosis of Office/clinic closures Hospital booking data

treatable medical conditions Restricted access to health care facilities Laboratory requisition volumes
Prioritization of health service delivery Comparison of annual trends in incidence
Isolation and quarantine requirements requiring of chronic diseases (e.g., cancer) between
appointment postponement pre-pandemic and pandemic years,
Reallocation of health care workers to COVID-19 controlling for changes to screening
focused areas practices etc.
Laboratory capacity for other diagnostics limited due
to COVID-19 laboratory demands
Delayed surgical and Office/clinic closures Hospital admission and length of stay data
medical treatment Restricted access to health care facilities Comparison of annual trends in hospital
Prioritization of health service delivery services usage (e.g., number of surgeries)
Isolation and quarantine requirements resulting in between pre-pandemic and pandemic
postponement of treatment/surgery years
Reallocation of health care workers to COVID-19 Surveys
focused areas
Reallocation of hospital beds for COVID-19
treatment
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Domestic abuse, child Isolation and quarantine requirements, stay at home Police reports
safety orders, and work from home recommendations Hotline / Support service usage
(increasing stress level and time in close contact in Emergency room data
the home) Referrals to community services (e.g.,
Lack of access to supports
Delayed child School, daycare, camp and recreational service School based data (e.g., progress reports,
development/education closures or restrictions standardized testing results)
Isolation and quarantine requirements Hotline / Support service usage
Recommendations for physical distancing, gathering Surveys of parents, child care providers
limits and other public health measures Speech and language service referrals
Increased substance use Isolation and quarantine requirements, stay at home Alcohol and cannabis sales data
and related harms, such as orders, and work from home recommendations Paramedic call data
overdoses (increasing stress level and time in close contact in Public health and community service
the home) provider data re. overdose calls, harm
Reallocation of public health and health care reduction materials use, safe injection site
workers and services (e.g., safe injection sites, usage
paramedics) to COVID-19 focused areas so
decreased access to harm reduction and support
services
Changes in toxicity of drug supply
Increased levels of anxiety Isolation and quarantine requirements, stay at home Hotline / Support service usage
and depression orders, and work from home recommendations Trends in prescriptions for anti-anxiety
(increasing stress level and time without in person and anti-depressant medication
social contact) Referrals for counselling, psychological
Isolation and quarantine requirements limiting services
workforce participation and income (leading to Emergency room data (e.g., for incidents
feelings of lack of purpose, lack of control, etc.) of self-harm, psychiatric holds)
Uncertain nature of pandemic progression (and Mental health facility admissions
occurrence of resurgences after period of low Social/Behavioural science publications
transmission), disease severity, need to take Population surveys
precautions
Limitations on social gatherings and recreational
service closures or restrictions (i.e., normal outlets
for stress/anxiety/depression relief)
Increased personal and Isolation and quarantine requirements limiting Internal tracking at food banks and other
societal economic burden workforce participation and income community service organizations (e.g.,
PH restrictions limiting number of customers shelters)
PH messaging urging caution with certain activities Uptake of relief benefits
(e.g., business travel) Data from Affordable Housing
Price increases with/without supply chain Associations
interruption Unemployment insurance claims
Bankruptcy claims/number of business
closures
Inflation rates
Interruption of routine Isolation/quarantine requirements and public health Analysis of: disease rates and preventable
preventative health and measures limiting ability to hold and participate in health outcomes, usually mitigated by
public health services public health administered programs (e.g., prenatal public health programs
classes) Immunization registry data / routine
vaccine coverage data
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Reallocation of public health workers and services Data on use of preventative services (e.g.,
(e.g., surveillance and outbreak response for other mammograms, PAP smears, colon cancer
diseases) to COVID-19 focused areas screening)
Virtual appointments with health care providers Data on health workforce changes (e.g.,
reduced opportunities for in person health services Human resource data base, Professional
(e.g., administration of routine childhood College membership renewals)
vaccinations at well baby visits)
Health care and public health worker absenteeism
(e.g., due to burnout)
Health authorities and health care institutions need to identify priorities for immediate action like the
resumption of elective surgeries, non-COVID public health programs and full capacity operation of
diagnostic services and community services and clinics, and allocate resources accordingly.
Public health planning going forward needs to ensure capacity to detect, assess and mitigate negative
impacts that arose during the Pandemic phase; in particular, the consequences of the response that
may be ongoing but not currently substantiated by robust data. The prerequisites for this capacity need
to be identified (e.g., increase access and timeliness of data/evidence, cross-sector collaboration) and
tangible deliverables need to be incorporated into work plans that extend well beyond the Transition
phase. PTs have identified this as a priority; for immediate public health attention, for after action
reviews, and for incorporation in future pandemic plans. Specific public reports on the various pandemic
response consequences are now being produced in some jurisdictions.37
The pandemic response g

-COVID-19 serious illness
and deaths, due in part to the consequences of the response itself, was unavoidable. The onus is now on
PHAs to incorporate measures to address these consequences as a response component in pandemic
preparedness guidance and response plans. PHAs also have a role in communicating to decision-makers,
stakeholders and the public, the impact the social determinants of health have on population health and
resilience. With the pandemic in the forefront of the public consciousness, now is the time to connect
these dots using the measurable disproportionate impacts of the COVID-19 pandemic on the Canadian
population to prevent increasing health inequities for higher risk populations.
The diversity and magnitude of the consequences observed over the course of the acute pandemic
hallenges will require a cross-sector,
all of society approach. Furthermore, it is important that the multi-sectoral, multi-departmental
response to COVID-19 continues during the Transition phase in order to address these broad societal
consequences effectively.
6. COVID-19 F/P/T Response Components

Forward plans and current actions will also be informed by ongoing reflection regarding what has
worked well, what we have learned and what can be adjusted based on evidence and experience. The
response components identified in the CPIP have been used in the COVID-19 response structure. In this
edition of the plan each of the following components are addressed in dedicated appendices, to
facilitate rapid access to the specific content.
Surveillance (Appendix 5)
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Laboratory Response Activities (Appendix 6)

Public Health Measures (Appendix 7)
Infection Prevention and Control and Clinical Care Guidance (Appendix 8)
Vaccination (Appendix 9)
International Border and Travel Health Measures (Appendix 10)
Health Care Systems Infrastructure (Appendix 11)
Risk Communications and Outreach (Appendix 12)
Research (Appendix 13)
With a focus on those actions requiring F/P/T public health leadership and consultation, these
appendices provide details on the current status of F/P/T activities that are planned or already
underway that will assist and expedite complementary planning in each federal government
department, province and territory.
7. Assessment and Evaluation

One of the objectives of the Transition phase is to document lessons learned and start forward planning
aimed at improving future response capacity, efficiency and addressing response elements identified as
gaps or weaknesses in after action evaluative reports/activities. How lessons learned will be addressed
by current responders decision-makers, the next cohort of responders
(e.g., students in health disciplines) and society at large, needs to be a part of this multi-faceted process.
Assessing and evaluating pandemic response efforts during the Transition phase, while recent and
outstanding challenges are still front of mind, will help identify areas of improvement and prioritize
future planning efforts. It is also vital, on an ongoing basis, to determine whether response activities
have been effective and implemented efficiently and balanced appropriately to minimize societal
disruption and negative consequences in addition to minimizing serious illness and overall deaths.
The F/P/T COVID-19 response governance structure, which includes the SAC, TAC and LAC, provides
multiple fora for these discussions and opportunities for sharing of experience, lessons learned and
identified best practices. More structured processes for assessment and evaluation, including in-action
and after-action reviews should be considered at all levels of government and diverse sectors to inform
forward planning and future pandemic preparations. Findings from formal audits undertaken by F/P/T
governments will also be taken into consideration in future planning processes.
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Appendix 1: Modelling Support for Forward Planning

Modelling facilitates planning and informs ongoing readiness needs by exploring how possible ranges of
parameters relevant to these issues affect the extent and impact of the pandemic in Canada. Modelling
inputs require epidemiological data from surveillance and other sources, while outputs largely depend
on the underlying assumptions. Forecasting models are best suited to inform what may occur in the
coming 2-3 months, while modelling of scenarios provides additional information to decision makers for
long-term planning regarding the potential impact of control measures.
Modelling recreates the essential components of pathogen transmission cycles from our understanding
of the biology of the pathogens and their interactions with their hosts. Models help to predict where
and when infectious diseases may emerge or re-emerge, and they can be used to explore the best
methods or combinations of methods to control disease outbreaks or epidemics and protect the health
of Canadians. Models can take into account new events during the course of the pandemic such as
vaccination or emergence of new variants of concern.
For response to COVID-19, there are three broad types of model being used:
1. Deterministic compartment models. These are Susceptible-Exposed-Infectious-Recovered
in a population
move from one state to the next. This basic structure includes elements to model SARS-CoV-2
and impacts of public health measures, with more realism. These elements include
from which onward
transmission to susceptible people is limited or absent, compartments for asymptomatic cases
different levels of public health

effort. These models are used to inform broad policies at F/P/T tables, including i) estimating
numbers of cases, hospitalisations and deaths; ii) estimating the effects of non-pharmaceutical
interventions (NPIs), (physical distancing, case detection and isolation, and contact tracing and
v) estimating the
effect of the emergence of new variants of concern on the disease transmission.
2. Agent-based models. These are also SEIR models, and they can also be used to inform
development of Pan-Canadian strategies. However, because they can simulate disease
transmission with some detail in and amongst homes, work places leisure spaces etc., they are
particularly useful for decision-making at an individual community level regarding effects of
vaccination, needs for NPIs, and strategies for relaxing restrictive closures.
3. Branching models. These simply assess what factors cause single chains of transmission to
expand or become extinct. They are often used to assess the needs for controlling transmission
in work places or importation of cases.
The PHAC has developed models that can be shared, and are constantly undertaking modelling to
support decisions. The PHAC External COVID-19 Modelling Expert Group was formed in February 2020,
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and currently comprises 37 members from 21 universities across Canada, as well as 74 members from
other Federal departments/organisations provincial/territorial public health organisations. The group
comprises the majority of infectious disease modelling group leads in Canadian universities, and is
capable of supporting modelling needs for decision-making.
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Appendix 2: Epidemiological Drivers

This content has been retained from the 2nd edition of this plan as it may serve as a good reference,
particularly for new responders.
An epidemic curve pattern is one part of a planning scenario as it reflects the potential changes in the
number of new cases occurring over a period of time (see Figure A2-1). To ensure optimal planning, it is
important to consider not only the number of cases but variables that may shift the health and societal
impacts of those new cases and subsequently possible surges that exceed current health care and
public health capacity thresholds.
Figure A2-1: Epidemiological Drivers: Incidence
Figure A2-2 describes epidemiological drivers of health impact in terms of variables that may increase or
decrease the occurrence of severe illness and deaths due to COVID-19. These variables include but are
not limited to: changes in severity of illness experienced by the majority of cases due to increased
virulence, changes in high-risk groups (i.e., both the demographic characteristics of who is getting
severely ill and identification of new risk factors for severe illness), the impact of variants of concern,
availability of effective therapeutics and hospital care, and vaccine coverage. The manifestation of these
variables will also influence public risk perception and therefore, in a somewhat circular manner,
epidemiological drivers like adherence to recommended PHMs.
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Figure A2-2: Epidemiologic Drivers: COVID-19 Related Health Impact
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Appendix 3: Planning for the reasonable worst case scenario

This content has been retained from the 2nd edition of this plan. Minor edits (e.g., removal of dates)
have been made to make this a more generic reasonable worst-case scenario.
Reasonable worst-case scenario characteristics
A large wave with a peak of prolonged duration followed by ongoing peaks of decreasing amplitude but
several exceeding health care delivery, laboratory and public health capacity thresholds.
Peak is similar or higher than the incidence experienced at the peak of the Omicron wave.
Relatively high seasonal peak in winter occurs concurrently with severe influenza/other respiratory
pathogens season.
Similar timing of peaks across the country (each jurisdiction experiences peaks at same time).
New VOC with high transmissibility, increased severity and immune escape properties becomes the
dominant strain.
VOC with immune escape properties reduce vaccine effectiveness.
There is reluctance to take the licensed vaccines (or specific vaccines) or vaccine supply is insufficient or
delayed, reducing vaccine coverage.
Available vaccines do not significantly reduce transmission and do not confer long-term immunity.
Available treatment/therapeutics are less effective against dominant variant.
Weak/non-sustained post-infection immunity (recovered cases become susceptible again).
Demand for health care resources (hospitalizations, ICU beds, ventilators, personal protective equipment
(PPE), Long-term care spaces, etc.) exceeds system capacity (during wave peaks).
Shortage of health care providers (e.g., due to illness, burnout, work refusal, international competition).
Demands on both laboratory and public health resources exceed capacity (during all wave peaks).
Low level of compliance with public health measures.
Permeation of mis /disinformation in Canadian society and/or loss of public trust/confidence.
The generic reasonable worst-case scenario can be used to identify any new or outstanding
preparedness and response needs or issues that would require, or benefit from, a coordinated F/P/T
effort should Canada be faced with this scenario. It is provid -
intended to stimulate thinking concerning our current response efforts, capacity thresholds and
resiliency.
More specifically, the scenario presents a set of potential risks, each requiring mitigation strategies
based on an assessment of capacity requirements and our capability to manage the risks. Figure A3-1
identifies high-level capabilities that need to be in place for this scenario and Table A3-1 identifies
associated requirements that should be considered at all levels of government.
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Figure A3-1: Capabilities for management of the reasonable worst-case scenario
Table A3-1: Reasonable worst-case scenario risk management requirements
Capability Risk Management Requirements

DETECT signals timely surveillance data (local, P/T, national and international)
indicating a analysis of international data for the same or similar strain
significant surge laboratory resources to rapidly distinguish between COVID-19 strains (including VOCs)
in cases may and other respiratory viruses and to identify mutations associated with immune
escape and/or increased transmissibility
occur
rapid analysis/investigation to assess risk of large peak based on international,
national, P/T and precise/granular local level data (to assess risk of change in
dominant strain, risk of importation into and within Canada, and risk of exceeding
local health care and public health response capacity)
screening activities including targeted use of point of care screening tests
health system-wide early warning for increased demand on resources and response
activities
communication/education/sensitization regarding what constitutes a signal and how
to ensure appropriate timely notification of potential signal
ongoing vigilance/commitment to COVID-19 response
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PREVENT large continued use of restrictive community-based measures until key locally-adapted
prolonged peak indicators for relaxation of measures have been achieved
and surges, public health resources to ensure ongoing response measures are adequate to control
especially those spread of highly transmissible and virulent variants and prevent new cases of severe
disease (e.g., use of highly conservative assumptions for defining exposure, household
that exceed
quarantine approach)
capacity to
capacity for rapid detection (through screening and testing) and isolation of cases,
respond and rapid identification and quarantine of high exposure risk contacts
public cooperation with surveillance and case and contact management activities and
tools (i.e., to facilitate timely identification and isolation/quarantine, optimize use of
alerting apps)
use of suitable isolation and quarantine sites and high adherence to recommended
measures in place in these locations
gradual, controlled "re-opening" of settings and gradual resumption of activities (with
modifications) that are known to be associated with increased risk
high adherence to ongoing modifications/controls put in place especially as restrictive
PHMs are lifted
modified restrictions for essential workers
screening strategies that aim to prevent and/or rapidly detect introduction of the
virus into a susceptible high-risk population or setting
consistent, clear localized indicators for implementation or re-implementation of
restrictive PHMs
rapid deployment of targeted outbreak control/containment resources (including
high compliance with personal protective measures

proactive international border control measures (i.e., including quarantine, testing
requirements, travel restrictions)
increased messaging and public education regarding personal protective measures,
effectiveness of vaccines and requirement for PHMs following vaccination
evidence-based results from vaccine hesitancy efforts and work with diverse
populations to support vaccine trust, interest in getting informed, and in being
vaccinated
increased health care system capacity (especially in high-risk settings such as long-
term care) and consideration of how to deliver needed health care (e.g., at alternate
sites, using retired workers or students or alternate care providers)
REDUCE surges rapid implementation and maximizing efficiency of vaccine administration programs
in incidence and use of vaccine strategies that prioritize immunization of high-risk individuals, groups
hospitalizations and settings
adequate public health resources to ensure ongoing response measures to control
current spread and prevent new cases, hospitalizations and deaths
focus on rapid detection and isolation of cases, and rapid identification and
quarantine of contacts
rapid detection of outbreaks in high-risk settings and deployment of outbreak
control/containment resources
consideration of how to re-implement restrictive community PHMs and which PHMs
to re-implement based on clear local-level triggers
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increased use of/compliance with, personal protective measures

ongoing international border control measures with possible re-introduction of
restrictions
INCREASE laboratory surge capacity to: ensure rapid diagnosis and case notification, identify
health care and new VOCs, and lab-epi linkage to characterize and learn from current variants
public health sufficient resources to facilitate optimal delivery of the vaccine program (including
capacity clinic staff; immunizers; security; schedulers; local, accessible and appropriate
facilities; clear communication on who, when and how; tracking programs/registries
etc.)
availability of public health resources for surges in case and contact management
requirements in the community (including isolation of cases and quarantine of
contacts at home/alternative designated sites), development of new guidance
products and provision of expert advice based on evolving scientific literature
resources (i.e., human and equipment/supplies), planning and training for outbreak
control activities in high-risk settings, including clear emergency back-up contact
points
surge capacity to ensure availability/access to health care resources including
equipment (e.g., ventilators, PPE) during peaks
availability of sufficient health care providers to meet surge in demand
ability to access and distribute effective therapeutics
ongoing monitoring of scientific literature, networks and expert advice to inform best
practices for treatment and identification of effective therapeutics that reduce
hospitalization requirements and/or duration of hospitalization
recovery policies and measures (e.g., discharge for recovery at home or alternate site)
to avert potential backlogs in the hospital system
MONITOR surveillance for early indicators that other illnesses that may cause a surge in demand
demand for for health care resources (e.g., seasonal influenza, other respiratory pathogens)
health care strate i.e., re-scheduling of delayed treatments, procedures
resources and surgeries, in a way that demand is met without exceeding capacity thresholds
linkages between health care delivery and public health to ensure timely
establishment of alternative/over-flow care sites
enhanced monitoring of global supply chains that could trigger drug shortages and
identified alternatives and strategies to prioritize and conserve supply (e.g., critical
supply reserve etc.)
FOSTER ongoing ongoing public trust in PHAs

public vigilance clear, effective, culturally safe and appropriately tailored communication and
and adherence to education products to support continued public adherence to personal protective
measures and measures, community-based public health measures and to support vaccine
confidence and uptake
recommendations
transparency and clarity regarding rationales for recommendations
ability to provide feedback on impact, progress and success of measures
public knowledge, attitudes and behavior research to inform sustainable effective
behavioral changes and to combat pandemic fatigue and vaccine hesitancy
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monitoring of risk tolerance and public opinion in order to maximize adherence while
adjusting measures to locally tolerable/sustainable levels
support for enabling policy changes (e.g., paid sick leave) that facilitate adherence to
public health measures and compensate affected sectors
addressing of equity issues especially those that affect access to needed resources
(e.g., availability of suitable isolation and quarantine settings), ensuring public
messaging is providing in multiple languages and formats etc., and ensuring these
resources are shared with various partners such as Indigenous partners
consideration of incentives for adherence or adoption of new practices
empowerment focused initiatives
involvement of community to ensure community needs and potential barriers to
adherence are considered in public health measures
transparent, clear, and equitable application of reasonable enforcement activities (if
necessary)
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Appendix 4: COVID-19 Response Planning with Indigenous Communities

Indigenous Services Canada (ISC), the Public Health Agency of Canada (PHAC) and the F/P/T response
partners have been involved in various activities to support the COVID-19 response in First Nations, Inuit
and Métis communities and partners, including the work of the SAC. These supportive activities are
summarized below.
Preparedness: Resources to support pandemic planning updates/activation; access to vaccines,

medical supplies and PPE; training; and, guidelines. In the context of transitioning from the
Pandemic phase of COVID-19 (to managing it as another infectious disease in Canada), all partners
will continue to work to provide Indigenous communities the tools and resources needed in order to
respond to ongoing clusters of outbreaks within communities.
Health Human Resources: Resources to support community hired nurses and other health workers
as well as to support surge capacity for health human resources, including nursing, medical and
paramedical supports; as well as, charter services to get health human resources into communities.
Indigenous Services Canada is currently working with its regional offices, F/P/T response partners
and Indigenous partners and communities on a project to develop a surge response team of
primary focus would be deployments out to regions and communities that identify needs and
capacity for public health response, surveillance, and mental health crisis support and response.
Additional resources are also needed to provide for the logistical needs of these teams or
community-hired personnel including infrastructure and housing.
Infrastructure: Resources to procure temporary shelter solutions and to support communities in
efforts to re-tool existing spaces to offer safe assessment and overflow space; and, additional surge
supports for food, water and other supply chain components; coordination of chartered flights to
ensure availability of critical infrastructure supplies and professionals.
Infection prevention and control (IPC): Ongoing sharing of information (i.e., guidance on public
health measures and promoting personal health measures for individuals and health providers),
training and increasing capacity to support community response, including public service
announcements in Indigenous languages. Provision of training of community workers and health
providers on IPC. Ongoing funding for communities and service providers to increase their capacity
for infection prevention and control, including First Nations-run schools, boarding homes, family
violence shelters and friendship centres.
Testing: Resources to develop capability and capacity to conduct COVID-19 testing including the
provision of testing swabs, and rapid molecular and antigen point-of-care tests. In March 2020, the
NML initiated the Northern, Remote and Isolated (NRI) initiative in collaboration with Indigenous
Services Canada to build community-based testing (CBT) capacity in Indigenous and remote
communities across Canada. This includes First Nation, Inuit, and Metis communities, organizations
and service centres that are located in community or nearby communities that provide health
services. This initiative was aimed at addressing the unacceptable turnaround time for diagnostic
results experienced by people living in NRI communities, during the early phase of the pandemic.
The NRI initiative is community-led, and enabled by the NML with the goal of ensuring that
Indigenous communities have access to testing equivalent or better services found in major urban
centres, with turnaround times to results available in under 1 hour. As of March 7, 2022, this
initiative has seen diagnostic testing implemented in or near more than 300 Indigenous
communities across Canada, with more than 2 million tests and devices for COVID19 distributed
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through the NRI initiative. The NRI will serve as a foundation for CBT for other infectious diseases
(Tuberculosis, Hepatitis C, and others) beyond the current pandemic. This resource serves as a
critical infrastructure for pandemic preparedness and outbreak response for Indigenous Peoples and
hard to reach populations living in NRI sites.
Public health advice and guidance: Have developed and are continuing to keep up to date advice
and guidance to health professionals and communities that take into consideration the unique
context of communities.
Public facility control and prevention: Supporting high risk public facilities such as schools, day care
centres, restaurants and long-term care facilities, in implementing of COVID-19 prevention
measures. This included targeted inspections and assessments, and the provision of guidance,
advice and training to community leadership, facility operators, and staff. Participation in technical
networks to develop and apply building related interventions, such as ventilation, and to guide
policy, program and funding opportunities. Indigenous Services Canada is continuing to seek
resources to address the pre-pandemic service delivery gap and resulting backlog created from
diverting resources.
Governance: Continue to work with First Nations, Inuit, and Métis partners, the Public Health
Agency of Canada (PHAC)
departments, as well as their provincial and territorial counterparts for a coordinated and consistent
Canadian approach to COVID-19 to protect the health and safety of all First Nations, Inuit and Métis,
regardless of where they live in Canada.
Communications: Continue to develop and broadly disseminate communication messaging through
COVID-19 Single Window to networks with public service
announcements in multiple Indigenous languages. Using digital media to further reach stakeholders
with communications such as public health measures and maintaining an online, publicly available
repository of COVID-19 resources relevant for Indigenous Peoples in multiple languages and
formats. Multilateral calls with partners at the national and regional levels continue.
Surveillance: Adaptation of -19 across First
Nations communities; and development of a tracking tool to inform dashboards on key indicators of
COVID-19. COVID-19 epidemiological and vaccination data is updated regularly on the ISC COVID-19
webpage. ISC continues to fund and facilitate partnerships with Indigenous-led, distinctions-based
data initiatives. PHAC is working with provinces and territories to support collection of COVID-19
case and vaccination information, including race/ethnicity and Indigeneity to support understanding
of the impacts of COVID-19 and inform response planning and actions.
Vaccine response planning: Collaborating with federal departments, provinces and territories, and
First Nations, Inuit and Métis partners to ensure that health facilities in Indigenous communities
have the necessary immunization supplies, PPE, testing kits, and health human resources to deliver
vaccines as needed. Facilitating a COVID-19 Vaccine Planning working group with representation
from federal, provincial and territorial, and First Nations, Inuit and Métis partners to co-develop
approaches to support the ongoing access to COVID-19 vaccines for Indigenous Peoples, including
those living in urban settings. The work on vaccine access and response planning for Indigenous
Peoples will continue from the Pandemic phase and into the Transition and Interpandemic phases,
as needs arise for further doses in underserved populations due to variants of concern, and waning
immunity, etc.
Based on knowledge and feedback learned to date, ongoing collaboration and funding is needed to
support First Nations, Inuit, and Métis partners and their communities to respond to any future
surges/resurgences. This includes continued access to timely testing supplies, P/T labs for processing,
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and results, including point of care testing for northern, remote and isolated communities and capacity
to detect VOCs.
Access to care to treat more severe symptoms of COVID-19 in remote and isolated communities also
requires that ongoing arrangements, or new ones, are in place to ensure an adequate number of beds in
hospitals south of 60, to support the treatment of Indigenous Peoples living in northern, remote and/or
isolated communities without this type of service. In communities where there are long-term care
facilities, or Elders residences, it is important to have access to adequate resources to support their
planning in keeping Elders safe and healthy, including funding for basic infection prevention control
measures (i.e., PPE, high dose flu vaccine, cleaning supplies, etc.), as well as, developed public health
measures.
Learning from H1N1 and now COVID-19, we know that long standing public health gaps and health
inequities between First Nations Inuit and Métis, and non-Indigenous Canadians increase the likelihood
and potential severity of a COVID-19 outbreak in Indigenous communities, and we have seen this
throughout the pandemic, as well as in many cases, urban Indigenous populations. These inequities are
exacerbated in remote or fly-in communities, where access to necessary supplies and health care
services is limited as compared to non-Indigenous communities. We also know that during H1N1, data
for First Nations, Inuit, and Métis were not captured in a consistent way, or a way that supported
communities in their preparedness and response efforts. A distinctions-based approach has been
adopted by the federal government to ensure that the unique rights, interests and circumstances of the
First Nations, Inuit, and Métis are acknowledged, affirmed, and implemented. In this context, it takes
into account the cultural and socio-economic realities of First Nations, Inuit, and Métis communities
involved. Distinctions-based, Indigenous-led analysis of COVID-19 data is necessary to advancing
culturally appropriate and evidence-based approaches, for First Nations, Inuit and Métis communities.
The strategy/approach, actions and deliverables for these preparations for the short, medium and long-
term are presented below.
Short term: In the short term, ongoing work to continue to ensure First Nations, Inuit, and Métis
communities and organizations have access to necessary supplies (e.g., PPE, vaccines and related
administration supplies), human resources, and funding to support the COVID-19 response and planning
for future waves. Vaccine planning is a priority in the short term and is being conducted through
collaborative efforts in working groups to facilitate culturally safe and equitable access to the COVID-19
vaccine for all Indigenous Peoples, regardless of where they live in Canada. Communications regarding
the vaccine are being developed and distributed in multiple Indigenous languages, in partnership with
Indigenous leaders and organizations, to build vaccine confidence. ISC and PHAC continue to work with
partners to advocate for the prioritization of Indigenous Peoples for access to the COVID-19 vaccine.
There is a need for continued work on COVID-19 surveillance and tracking of the COVID-19 vaccine
administration, which is underway in collaboration with federal departments, provinces and territories,
and Indigenous partners. Resources to support Indigenous-led data
collection/governance/infrastructure to support data optimization for the longer term in Canada are
essential. Resources to bolster community-led public health supports, culturally appropriate
communication and information, and work are required, as well as training and capacity building to
support these functions.
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Medium term: As COVID-19 vaccine programs continue and the supply of the vaccine increases, the
tracking and reporting of vaccine uptake and effectiveness will be critical. ISC will also continue to work
with Indigenous partners to increase vaccine confidence, building on lessons learned from the vaccine
rollout. Continued work is required to support access to patient care, as well as the work of community
based workers and nurses in northern, remote and/or isolated communities, and increased funding for
telemedicine and virtual health care providers is necessary. This work aims to reduce the anticipated
backlog of medical or specialist appointments after the acute COVID-19 response phase, and support
access to timely care supporting better health outcomes. Ongoing monitoring of forest fires and flood
for possible evacuations and planning in light of COVID-19 will be maintained over the summer and fall
months.
Longer term: During the Transition phase, ISC will work with partners to facilitate after action reviews
that will inform emergency management funding and planning for future pandemics. ISC will be
supporting health emergency management capacity in First Nations and Inuit communities through
sustained funding for community-driven and designed health emergency management preparedness
and mitigation activities. The department will also prioritize culturally-informed health emergency
management capacity development and training opportunities with First Nations and Inuit partners.
ISC will also address the ongoing management of COVID-19 as an ongoing infectious disease with a
possible seasonal pattern of increased incidence. Part of this management plan will include monitoring
the high level signals that would necessitate a change in timelines or strategies and approaches and
subsequent actions and deliverables. These include:
community spread of new VOCs;

ongoing and prolonged community outbreak scenario;
signals and risks of community spread, where communities may be at a higher risk due
to geographic location;
access to health care to treat more severe symptoms;
strain on system for medevacs;
shifts in hospitalization rate, ICU admission rate, case fatality rate;
Post-COVID Condition/Long COVID;
reproductive rate;
outbreaks in long-term care facilities or Elder lodges; and,
shift in age/sex distribution of cases.
This new continuum approach could cover the full spectrum of services from supports for people living
with disabilities, to aging in place approaches, improvements to facility-based care, and services like
must address anti-Indigenous racism within health service systems and seek, as a matter of core
principle, to eliminate health inequities for all Indigenous Peoples.
Finally, ISC will undertake a review, in collaboration with Indigenous communities, partners and
organizations. The review will cover actions taken during the pandemic to learn about the challenges, ,
successes, weaknesses, strengths and opportunities in the approach taken, as well as to learn about the
distinct ways in which pandemics may impact Indigenous communities differently than non-Indigenous
communities. It will be important to work with Indigenous communities, partners, and organizations
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from the conception of this undertaking all the way through to the course of the review; this is critical in
creating an opportunity to continue the effort to decolonize health care, and promote Indigenous self-
determination within the field of public health.
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Appendix 5: Surveillance
The purpose of surveillance is to provide decision makers with the timely epidemiological and risk
information they need to inform action. Similar to national influenza surveillance (FluWatch), COVID-19
surveillance is a pan-Canadian initiative that integrates numerous data streams including existing
surveillance systems with novel, non-traditional data sources. Ongoing COVID-related surveillance, is
expected throughout the Transition phase with connectivity across health sectors to foster real-time
data analysis to facilitate early detection of resurgence signals and examine COVID-19 related risks in
the context of other public health risks.
Current Status/Focus
Currently, the following data sources enable monitoring of COVID-19 epidemiology:
Case-level data reported by PTs: A national dataset including demographic, race/ethnicity,
occupation, symptoms, clinical course and outcomes, exposures, vaccine history and variant
lineage information for all confirmed and probable COVID-19 cases in Canada. This information
used to monitor and describe the distribution of COVID-19 across priority epidemiologic factors.
Aggregate laboratory result data reported by Provincial public health laboratories: numbers of
positive tests and the number of tests performed to detect SARS-CoV-2. This information is used
to measure the level of SARS-CoV-2 transmission in the community and to monitor the need for
changes in community testing practices.
Whole genome sequencing data reported by PTs: national genomic sequencing data detects
SARS-CoV-2 variants, including VOCs.
Aggregate sampling: Wastewater surveillance is underway and showing some promise as a
surveillance and alert component at the regional level.
Data on travellers and border testing: Used to identify new genomic variants and monitor trends
at the border; thus facilitating early detection, situational awareness, and together with
isolation and quarantine measures, the reduction of travel associated transmission in Canada.
Special surveys: Impact of COVID- 19 on specific populations (e.g., health care worker).
Sentinel Surveillance Networks:
o Hospital networks - Several hospital-based data streams measure the impact of COVID-
19 in Canadian hospitals and collect detailed case information on most severe cases.
o Canadian Pediatric Surveillance Program - occurrence of Multi Inflammatory System in
Children (MIS-C).
o Community-based systems/ networks - Assess the level of transmission in the
community and the epidemiologic characteristics of outpatient cases.
Publicly available data: supplementary data source to add situational awareness on COVID-19
transmission in jurisdictions and internationally.
The federal, provincial and territorial public health partners are leveraging existing mechanisms
and operating procedures to collaborate on multijurisdictional and complex COVID-19 outbreak
investigations. This allows sharing of capacity and resources toward the goal of better
understanding COVID-19 in our communities.
Outbreak surveillance: systematically collates COVID-19 outbreak events in Canada through
partnership with federal, provincial and territorial health authorities.
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Preparations/Forward Planning
Forward planning will
management goals as they evolve through the next phases of the pandemic. Key changes to the public
health management strategy with impacts on surveillance include: the withdrawal of population-level
PCR testing and the reduction or elimination of public health follow-up of cases, which impacts data
availability; and the relaxation of restrictive public health measures, which may have impacts on the
epidemiology of COVID-19. As a result of these changes, alternative surveillance approaches are
required to accurately inform timely public health policy and intervention decisions.
The surveillance strategy will focus on a multi-component/multi-pathogen surveillance model where

applicable, with improved linkages and efficiency of data management. The focus will be on: i)
monitoring, detecting and assessing signals of COVID-19, including the detection of variants of interest
/VOCs; ii) monitoring and describing the clinical and epidemiologic features of severe COVID-19 infection
(hospitalizations and deaths); iii) gaining a greater understanding of impacts of COVID and long COVID
and populations at high risk for poor health outcomes; and iv) understanding waning of vaccine
immunity. Multiple data streams are required to address these areas of focus: some existing; some
requiring modification; and some new initiatives requiring implementation.
The preparations and ongoing activities based on the anticipated short, mid or long-term timeframe are
identified below.
Short term:
Establish Pan-Canadian surveillance goals and objectives, updated surveillance system
framework (i.e., identification of data streams to retain, modify and develop), and revised
surveillance guidance for the transition period
Explore options for implementation or enhancement of sentinel or other community-based
surveillance data stream(s) (e.g., cohorts) to compensate for reductions in public health follow-
up of non-severe cases
Monitor vaccine performance, including coverage, safety and effectiveness, waning immunity
and vaccine escape.
Transition from Genome Canada/CanCOGeN support to sequencing laboratories, to PHAC
delivered support to integrated genomic surveillance and analysis
Support operationalization of genomic capacity and screening strategies and continue to
support mechanisms to facilitate linkages between epidemiological and laboratory data to
monitor on-going viral evolution including VOCs.
Further validation and integration, and use of wastewater testing as an early detection
mechanism.
Initiate planning for surveillance to identify broader impacts of COVID-19 and associated control
measures on health of Canadians.
Conduct scenario-based planning to identify signals that may arise, the surveillance information
required to detect and characterize the signals, and the associated public health actions
required to respond.
Support rapid epidemiologic investigations to characterise the transmission and impacts of new
variants and impact of vaccination in the context of outbreaks.
Provide federal surge capacity support.
Share timely information effectively with partners and publicly with Canadians.
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Medium to Long term:

Support rapid epidemiologic investigations if there is a concern that a new variant is driving
transmission (immune escape) and/or impacting severity outcomes.
Monitor vaccine performance, including coverage, safety and effectiveness, including issues
such as waning immunity and vaccine escape.
Conduct targeted surveillance on broader consequences of the response to inform public health
action.
Enhance data integration to evaluate evolving epidemiology in the context of increased
vaccination and immunity to support recovery.
Continue to build and maintain data and analytics capacity and knowledge transfer networks to
support on-going development and sharing of intelligence.
Consideration of surveillance strategies for Post-COVID Condition/Long COVID.
Integrate and operationalize wastewater genomic surveillance as a routine element of pathogen
detection and tracking.
Establish national reference center to enable monitoring for drug resistance for approved COVID
anti-virals.
Support the expansion of the current VirusSeq Data Portal for genomic data to support
controlled access for collaborative FPT and Academic investigation to lab data and associated
case data (pilot under Pan-Canadian Health Data Strategy).
Consideration of strategies that could detect zoonotic and reverse zoonotic (zooanthroponosis)
transmission. This could involve leveraging some of what has been established for human
testing/response and human genomic surveillance and new mechanisms beyond referrals from
wildlife agencies to National Centre for Foreign Animal
Disease (CFIA-NCFAD).
Planning Variables or Signals

It is possible that a new syndrome or rare event would require the development of a new, or
adjustments to, the surveillance strategy as has occurred for Multisystem Inflammatory Syndrome in
Children (MIS-C).
New settings or populations affected by outbreaks could emerge in outbreak surveillance (or via
outbreak intelligence gathering) which could precipitate new data needs, additional surveillance
activities or new variables to be collected to inform actions. For example, outbreaks among temporary
foreign workers have highlighted the need to be prepared to rapidly implement specific surveillance and
coordination mechanisms, as well as drawn attention to how social determinants of health (e.g.,
crowded housing, precarious work, access to medical services) can impact transmission and control of
COVID-19.
Surveillance strategy, capabilities and capacity, will focus on a multi-component/multi-pathogen

surveillance model as Canada transitions to the next phase of the COVID-19 pandemic. With the
expected withdrawal of population-level testing via PCR tests, alternative surveillance approaches are
needed to accurately inform timely public health policy and intervention decisions.
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Appendix 6: Laboratory Response Activities

Laboratory-based surveillance is an integral part of monitoring respiratory virus activity. Since the start
of the COVID-
leadership in regard to testing for COVID-19 and surge capacity for provincial and territorial public
health laboratories. The NML has also contributed to domestic and international efforts to better
understand COVID-19 virus characteristics that can inform the development of medical
countermeasures.
The NML, Indigenous Services Canada and CPHLN have worked closely and successfully with northern,
remote, and Indigenous communities to enable those communities to have greater access to laboratory
diagnostic tools (e.g., point-of-care, diagnostic platforms, reagents, training). Through collaboration with
the NML, the territories have been able to set up COVID-19 testing within each territory.
-19
outbreak. Provincial and territorial involvement in the sequencing efforts across Canada through the
Canadian COVID-19 Genomics Network (CanCOGeN) has greatly enhanced genomic sequencing
throughput. Ongoing communications with partners within industry, academia, and various government
levels have fostered a collaborative approach to sequencing and monitoring novel virus variants. The
National Microbiology Lab (NML) plays a lead role in supporting and guiding these efforts at all levels,
including through laboratory and bioinformatic analyses.
Wastewater-based surveillance of SARS-CoV-2 has emerged as an innovative tool to complement clinical

epidemiology and testing data and is a rapid and cost-effective approach for early detection of
outbreaks and surges as it monitors the circulation of variants of concern. The Public Health Agency of
Canada (PHAC), through the National Microbiology Laboratory (NML), developed a Pan-Canadian
Wastewater Surveillance Network with key partners and programs across different government levels
(federal/provincial/territorial/municipal) and academia to sample and test wastewater for COVID-19
from a large number of municipalities across Canada.
The Omicron-driven wave of the pandemic caused cases to surge, with testing demand exceeding
available laboratory capacity in most jurisdictions. In response, most P/T jurisdictions limited the use of
PCR testing to diagnose COVID-19 to specific target groups, including the unvaccinated,
immunocompromised, or those working or living in high-risk settings, with public health testing
guidance varying between jurisdictions.
Rapid antigen detection tests (RADT) are increasingly being used to support self-testing and case
detection. RADTs are comparatively less sensitive than RT-PCR-based testing, but may be appropriate
for screening purposes in higher prevalence settings where timely access to RT-PCR testing is limited.
The positive predictive value of RADTs will decrease as the true prevalence of infection in the target
population decreases.
The evolution of novel virus variants with altered characteristics has been observed, including increased
transmissibility and partial immune escape, posing new challenges to Canadians.
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laboratories, working through the CPHLN, are meeting this new challenge while continuing to address
other key COVID-19 and non-COVID-19 pressures through the following activities:
development and validation of diagnostic VOC screening assays;

updating of F/P/T screening and sequencing guidance for SARS-CoV-2 variants;
continued support for acceleration of whole genome sequencing and improvement of timeliness
of analysis and communication of variant information;
transition of support to PT sequencing laboratories from initial capacity building through
CanCOGeN to sustainable operation through NML support undertaking genomic surveillance
efforts to monitor the emergence and prevalence of VOCs within Canada, including through
border surveillance initiatives;
acquiring VOC samples to support Canadian diagnostic initiatives and research, including the
assessment of vaccine efficacy in the face of evolving variants;
continued work to evaluate serological testing kits as well as developing in-house serological
tools such as ELISA, neutralization assays and point of care tests (serological work is in support
of the broader Canadian Immunology Task Force), incorporating the ability to distinguish natural
infection from vaccine-derived antibodies;
collaboration with other partners, such as CIHR and academic, to undertake studies that help us
understand pathogen characteristics, including the differences brought on by virus variants;
continued readiness to tackle multiple respiratory virus outbreaks as needed, recognizing that
the PHMs in place have largely suppressed influenza and RSV activity but a resurgence might be
observed with the relaxation of PHMs;
continued growth of the Pan-Canadian Wastewater Surveillance network through various
federal, provincial, territorial and academic collaborations (currently almost 60% Canadian
population on sewage treatment systems is covered).
During the Omicron wave, access to molecular testing in most provinces and territories was constrained
due to very high case numbers. Many provinces and territories are continuing a shift to rapid testing
and individual responsibility for limiting the spread of COVID-19. This means reduced availability of
population-level surveillance testing with PCR tests that can then be used for genomic surveillance.
Efforts will be needed to transition to targeted surveillance (e.g., hospitals, primary care, and borders)
while also ensuring a minimum level of testing of a random selection of samples from communities.
The NML together with the CPHLN, is undertaking the following activities in order to continue to prepare
for potential surges/resurgences based on the reasonable worst-case scenario but also as part of the
laboratory preparedness long-term vision.
The Pan-Canadian Wastewater Surveillance network needs to be expanded further to cover more
Canadian population especially those in Northern, remote and isolated areas.
Short term:
Continuing
ensure laboratory response strategies are aligned and appropriate.
Continuing a strong collaborative approach toward developing and validating diagnostic testing.
Provide support for point of care testing.
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Work together to develop a robust collaborative research agenda into SARS-CoV-2 variants of
concern, their detection and public health impacts as vaccines are administered.
Mid term:
Continue optimizing various testing platforms and their uses to determine whether individuals
have been previously infected, especially for healthcare and other service providers such as
police, fire fighters, employees in long-term care facilities, etc.
Continue streamlining molecular and serological testing as well as variant screens and whole
genome sequencing, including stewardship of reagents so they are conserved as testing
demands increase.
Continue developing, validating, and enabling greater access to faster diagnostic tools such as
Point of Care tests and self tests (prioritizing northern, remote, isolated and Indigenous
communities).
Continue working with PTs and other stakeholders to inform the use of testing in specialized
settings (such as borders).
Create a sustainable wastewater-based epidemiology program.
Ongoing assessment of RADT performance characteristics and sample approaches; address gaps
in PH reporting of positive cases identified via RADTs; provide updated guidance regarding the
use of RADTs for the identification of SARS-CoV-2 infection.

Epidemiological data from January 2022 are beginning to demonstrate declines in case counts in most
Canadian jurisdictions, but with the combination of relaxation of public health measures, the very high
transmissibility of Omicron, and the expectation that additional high-transmissibility and immune
escape variants, effective genomic surveillance will be required. Early identification, detection and
tracking of additional variants will continue to be a priority as we move into the inter-pandemic phase.
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Appendix 7: Public Health Measures

PHMs are the range of non-pharmaceutical interventions implemented by individuals and PHAs at the
F/P/T and local level to reduce the risk of infectious disease transmission. PHM range from those applied
at the individual-level to community-based measures implemented in non-health care community
settings (e.g., schools, workplaces/businesses, gatherings and events).
Individual-level PHMs include actions that individuals can take to protect themselves and others,
including wearing masks, physical distancing, improving indoor ventilation, practising hand hygiene and
respiratory etiquette, self-monitoring for symptoms and staying home when sick.
Community-based measures range from public education campaigns, case and contact management
activities, and mask mandates; to restrictive measures to reduce interactions and prevent transmission
in population groups, settings and the community at large. R community-based measures
aim to reduce contacts by limiting movement, activities, or access to resources and public spaces.
Examples of such measures include: school closures, restrictions on gatherings, workplaces/businesses
restrictions or closures, inter- or intra-provincial or territorial travel restrictions, and curfews).
PHMs have been shown to be effective in controlling transmission of COVID-19 even where VOCs with
increased transmission are dominant.9,10 However, many of these measures have important
consequences that must be considered in public health decision-making. These consequences require
careful consideration and prioritization in relation to other determinants of health, such as impacts on
childhood development, access to health services, mental health, family and gender-based violence,
social isolation and exclusion, and at-risk communities. PHM effectiveness depends on the level of
adherence by the public, which is influenced by pandemic fatigue and factors such as living, working,
community conditions, and financial and social circumstances.
Since the start of the COVID-19 pandemic the F/P/T public health response has involved working closely
with multilateral partners, other government departments, and First Nations, Inuit and Métis partners
to develop, update and disseminate appropriate public health guidance for a range of target audiences
on how to detect, report, prevent and manage COVID-19 infection. One example of this is the formation
of the Public Health Working Group on Remote and Isolated Communities that adapts public health
measures guidance to the unique needs, context and considerations of these communities in the
response.
Currently, PHAs continue to adjust (re-instate, maintain, ease) PHMs in response to local circumstances
as the pandemic evolves, including the emergence of new COVID-19 variants that have the potential to
be more transmissible, cause more severe disease, or have known or potential for vaccine immune
escape. During the Transition phase it will be important to maintain readiness for new VOCs, seasonal
resurgence, decreased protection against infection over time, and community outbreaks among
populations at high risk of poor health outcomes. As part of readiness activities, effective public risk
communication regarding these possibilities will be needed in order to prepare the public for any
corresponding adjustments in the use of PHMs.
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Focus for Transition Phase

The focus during the Transition phase includes:
ongoing updates to existing or development of new F/P/T and/or PHAC guidance as evidence
evolves;
continuing to provide advice to the public on how to assess and mitigate COVID-19 risks, and
fostering public understanding of the on-going risk environment;
collaborating with F/P/T stakeholders on pandemic recovery and adjusting PHMs as required;
o highlighting current guidance for adjusting PHMs
normalizing individual-level PHMs so that they may become a part of everyday practices to help
reduce the risk of transmission of COVID-19 and other respiratory viruses (e.g., staying at home
when sick, improving indoor ventilation, hand hygiene, respiratory etiquette, cleaning and
disinfecting);
continuing to promote the use of additional layers of protection (e.g., wearing well-constructed
and well-fitted masks or respirators, physical distancing, avoiding or limiting time spent in closed
spaces and crowded places) across jurisdictions and normalize their use, particularly among
higher risk populations/settings. Individual use of these measures should be based on a personal
risk assessment which considers local COVID-19 activity and individual risk factors;
continuing to monitor the situation to identify triggers for reinstatement of certain PHMs (e.g.,
based on VOCs that are more transmissible, cause more severe disease, or have immune escape
properties);
identifying current gaps in knowledge and facilitating research activities to inform current and
future advice surrounding PHMs;
in alignment with scoping exercises and stakeholder consultations, as well as lessons learned
activities from the COVID-19 pandemic, evaluating the PHMs component of the COVID-19
pandemic response to incorporate outputs into PHMs planning for future pandemics; and
developing proactive, seasonal infectious illnesses prevention strategies/messaging for COVID-
19, similar to other respiratory illnesses (e.g., influenza, RSV).

Going forward, it will be important to consider uncertainties and challenges around:
the emergence of VOCs domestically and globally, particularly those associated with increased
transmissibility, more severe disease or immune escape;
decreased protection from vaccines over time;
community outbreaks in populations at high risk of poor health outcomes;
pandemic fatigue, as well as challenges related to public adherence and trust; and
managing risk for segments of the population that remain unvaccinated because they are either
not eligible (e.g., medical contraindications) or they choose not to be vaccinated.
Indicators such as COVID-19 epidemiology, health care and public health capacity, as well as risk
reduction measures in place for high-risk populations and settings should be considered when
determining if/when additional PHMs need to be implemented. If PHMs need to be re-instated, they
should be proportionate with the risk in the local community, balanced against the risk of unintended
consequences of the intervention, and responsive to the local circumstance (e.g., taking into
consideration key indicators and factors such as transmissibility and severity of a VOC.
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Appendix 8: Infection Prevention and Control

While impacting the F/P/T public health response, the provision of infection prevention and control (IPC)
and expert advice has predominantly been aimed at informing healthcare setting and infection
prevention and control professionals. Guidance for infection prevention and control will focus on
ongoing measures based on emerging IPC science for managing COVID-19 as an ongoing, predictable
infectious disease in Canada.
The current focus of response activities pertaining to IPC include:
ensuring that previously published COVID-19 Infection Prevention and Control documents
continue to provide up-to-date relevant and evidence-informed guidance; and,
preparing guidance for an ongoing COVID-19 activity in Canada particularly related to
routine practices, additional precautions, and other IPC guidance.
All COVID-19 Infection Prevention and Control guidance documents should be reviewed on an ongoing
basis to ensure they reflect the most up to date emerging science in IPC. This includes key infection
prevention and control findings in the literature, responding to new and/or changing science.

If additional infection prevention and control information emerges, (e.g., a change in mode of
transmission, dominance of VOCs with immune escape characteristics, or additional risk groups), there
may be a need to revise or develop additional IPC guidance documents.
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Appendix 9: Vaccination
In December 2020, Canada received its first shipments of COVID-19 vaccines and proceeded to
administer more than one million doses in the first two months of the national vaccination campaign.
Since then, the Government of Canada has been able to offer all people residing in Canada 5 years of
age and older a primary vaccine series, as well as booster doses to all those who are eligible.
To support the ongoing COVID-19 vaccination campaign, Canada has secured sufficient vaccine supply to
meet current and future needs including possible new vaccine formulations that may be variant specific.
The Government of Canada signed advance purchase agreements to secure access to several COVID-19
vaccine candidates, including Moderna, Pfizer-BioNTech, AstraZeneca, Janssen (Johnson & Johnson),
Novavax, Medicago, and Sanofi/GlaxoSmithKline. P/T governments, together with federal and
Indigenous partners, developed plans for the efficient, equitable and effective distribution and
administration of COVID-19 vaccines across Canada, including prioritizing key populations for early
vaccination based on risk of severe outcomes and risk of COVID-19 exposure, particularly in the context
of limited vaccine supply.
Much of this work was done in collaboration with the SAC and the Canadian Immunization Committee
(CIC) -19 pandemic response by fostering FPT
collaboration and vaccine rollout coordination. Most P/T immunization plans are informed by guidance
of experts
external to government who provide independent advice to the Public Health Agency of Canada and PTs
on the use of authorized vaccines in Canada. NACI continues to develop guidance on the optimal use of
COVID-19 vaccines, as new COVID-19 vaccines continue to be authorized and as new real world data and
evidence on COVID-19 and COVID-19 vaccines continue to emerge.
In addition to collaborative work with jurisdictions and Indigenous partners to purchase, allocate,
distribute and administer vaccines as efficiently, equitably and effectively as possible, work has also
been undertaken across Canada to monitor the safety, coverage and effectiveness of COVID-19 vaccines.
Vaccination will continue to be an important tool to prevent severe outcomes from COVID-19 and to
prevent healthcare system capacity from being overwhelmed, supporting continued access to health
care for both COVID-19 and non-COVID needs.
As of February 24, 2022 a total of six COVID-19 vaccines are authorized by Health Canada for use in
Canada including:
two mRNA vaccines (e.g. Pfizer-BioNTech Comirnaty, Moderna Spikevax),
two viral vector vaccines (e.g. AstraZeneca Vaxzevria and Janssen),
a protein subunit vaccine (e.g. Novavax Nuvaxovid), and
a virus like-particle-based vaccine (Medicago Covifenz).
Canada continues to be a world leader in COVID-19 vaccination coverage. With its robust vaccine supply
Canada is now focusing on providing booster and pediatric doses to all eligible people in Canada, guided
by scientific data and advice.
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F/P/T governments, First Nations, Inuit and Métis leadership and public health authorities continue to
collaborate38 to ensure that vaccination programs and vaccine delivery models are designed and
implemented in a manner that is equitable, accessible and sensitive to individual and community needs,
including robust, culturally a
Force has hosted over 50 bilateral and multilateral engagements with PTs, 1 Rehearsal of Concept, and 5
Federal, Provincial, Territorial and Indigenous summits (4 of which had international presenters) to
discuss various aspects of vaccine rollout and facilitate the sharing of best practices and lessons learned.
Implementation as documented in the Comprehensive Distribution Plan, and guided by the Vaccine
Annex of the CPIP is continu -19 immunization plan includes enhanced tracking
systems for monitoring adverse events following immunization (AEFI), the Vaccine Injury Support
Program, vaccine effectiveness, as well as assessment of vaccine uptake/coverage; allocation, storage
and handling; and vaccine delivery strategies. Instrumental to the FPT vaccine rollout is VaccineConnect,
a digital vaccine management platform, which has been designed to augment existing provincial and
territorial public health information technology systems to facilitate end-to-end vaccine and
therapeutics management. These enhanced tracking and monitoring systems have been critical for
alerting and signaling safety concerns, identifying supply challenges and for informing overall
immunization programming.
The National Operations Centre for COVID-19, is the federal logistical coordination entity and focal point
for managing vaccine delivery and collaboration with provinces and territories for distribution. The NOC
supports partners involved i -19 immunization roll out and continues to lead the
tracking of vaccine delivery and distribution across Canada.
PHAC has contracted logistics service providers who are supporting importation, storage and
distribution for several vaccine candidates. The logistic service providers complement provincial and
territorial supply chains, and align with the activities that provinces and territories and Indigenous,
remote and isolated communities have undertaken to strengthen supply chains within their jurisdiction.
Building upon the collaborative work to date to strengthen cold chains, continued F/P/T engagement
will facilitate advancement of this initiative throughout the supply chain.
A key component to the COVID-19 immunization roll out has been to ensure that health care providers
have the training, tools and resources they need to support public health practice for primary series,
booster and pediatric vaccination. The federal government continues to collaborate with PTs,
Indigenous partners, and other health system stakeholders and partners to facilitate the timely sharing
of scientific advice, provide educational webinars, immunization clinic guidance and evidence-based
information on vaccination decision supports to healthcare providers
Efforts to support COVID-19 immunization roll out also include emphasis on promoting vaccine
confidence and uptake. Through engagement with key partners, stakeholders and experts the
Government of Canada has taken a collaborative approach to better understand public opinion and
behaviour. This enhanced understanding informs the development of partnerships, educational tools,
vaccination projects, and communication strategies to further educate and build trust in COVID-19
vaccines, while addressing mis- and dis-information about vaccine safety and effectiveness. The
Immunization Partnership Fund (IPF) is a key funding tool in the federal toolbox to support public health
and non-traditional partners at community, regional and national levels to combat vaccine mis- and dis-
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information, address access barriers, and support culturally appropriate strategies to increase vaccine
confidence and uptake, and to reduce the incidence of vaccine preventable diseases including COVID-19.
Further, the Government of Canada has worked closely with P/ T governments and Indigenous partners
to develop a standardized Canadian COVID-19 proof of vaccination credential. This collaboration has
ensured Canadian citizens and residents had access to a trusted and secure way to demonstrate their
vaccination status internationally and domestically. The Government of Canada also engaged with
Indigenous communities and organizations to understand and respond to concerns associated with
proof of vaccination credentials, including gaps in reporting Indigenous vaccination data into P/T
systems.
-19 Vaccine Task Force, as well as the COVID-19 Joint

Biomanufacturing Subcommittee, helped identify areas for strategic investments in vaccine research,
development, and domestic bio-manufacturing. This has helped guide ongoing work by the Health
Portfolio, in partnership with Innovation, Science and Economic Development Canada, to facilitate
longer-term domestic production capacity and support future pandemic preparedness; In addition, a
COVID-19 Vaccine Clinical Trial Discussion Forum is convening academic, government, and industry
partners to discuss vaccine clinical trial challenges and optimal designs.
The Government of Canada continues to implement the Biomanufacturing and Life Sciences Strategy,
which was released in July 2021 and presents a long-
biomanufacturing sector and protecting individuals in Canada against pandemics and other health
emergencies in the future. Through strategic investments and partnerships, the Government of Canada
life saving medicines. This includes an agreement with leading COVID-19 vaccine developer Moderna to
build a state-of-the art mRNA vaccine production facility in Canada.
Through a variety of bilateral and multilateral mechanisms the Government of Canada will continue to
collaborate with provinces, territories, municipalities, Indigenous partners and other partners to
facilitate the rollout of COVID-19 vaccines. Guidance and tracking systems will continue to be updated as
vaccine supply changes. The National Emergency Strategic Stockpile procured sufficient supplies to
support F/P/T vaccine administration.
Timelines for activities that support -19 Immunization Plan are:

Short term
Immunization Readiness and Vaccine Rollout:
Ensure vaccines are deployed to all populations, as the result of detailed demand planning with
provinces and territories, to support subsequent doses as recommended, and for all eligible age
cohorts.
Developing a Vaccine Confidence Plan as Canada transitions to managing COVID-19 as an
ongoing infectious disease including: continue to integrate vaccine confidence messaging and
tactics into communications strategies for campaigns (e.g., COVID-19 boosters and pediatric
immunization).
Continue providing appropriate ancillary supplies to PTs for vaccine administration and explore
alternative technologies to optimize use.
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Work with provincial and territorial governments and Indigenous partners to ensure that COVID-
19 proof of vaccination credentials continue to be issued in a consistent and trusted manner,
and remain available to individuals in Canada for use internationally and domestically as
needed.
Work with partners to (1) harmonize eligibility, accessibility, security, and service support for
proof of vaccination credentials across the country; and (2) update the credential in response to
evolving needs both internationally and domestically.
Vaccine Surveillance:
Continue to collaborate with PTs to monitor vaccine safety and coverage and make information
available to Canadians to support vaccine confidence.
Monitor vaccine effectiveness to inform policy decisions, including the need for additional
booster doses.
Identification of vaccine strategies and vaccine-related research priorities to address changing
epidemiological context and emerging evidence (e.g., evidence on the duration of vaccine
protection).
Build additional functionality of VaccineConnect, the digital vaccine management system to
support jurisdiction vaccine program management and pan-Canadian reporting.
Vaccine Acquisition:
Manage existing and future supply arrangements, guided by scientific data and advice, to
-19 vaccination campaigns; considerations include ensuring appropriate mix
of mRNA and non-mRNA options as well as balancing current versus future supply needs in light
of new product vaccine technologies and formulations.
Continue to collaborate with manufacturers to obtain sufficient supportive guidance and
training to build the capacity and capability of provinces, territories, First Nations, Inuit and
Métis partners and federal department to manage anticipated supply and distribution of
vaccines.
Continue to work with FPT and international partners on the management of doses that are
.
Engagement:
Continue F/P/T and Indigenous collaboration to promote vaccines, confidence and uptake,
including booster and pediatric doses by reducing barriers to vaccination, including access to
convenient community vaccination sites and pop-up/mobile options.
Continue to -19 pandemic response via the F/P/T
Special Advisory Committee, Canadian Immunization Committee, and bilateral and multilateral
engagements.
In conjunction with Indigenous Services Canada and First Nations Inuit Health Branch, continue
to engage with Indigenous partners to support collaboration on vaccination programs and
vaccine delivery models that are equitable, accessible, and sensitive to needs and conditions of
communities
Ongoing F/P/T/I dialogues for sharing challenges and lessons learned, including strategies to
bolster vaccine roll-out capacity, target uptake in hard-to-reach populations and communities,
and to prepare for rapid roll-out of campaigns for new vaccine formulations for eligible age
cohorts and additional booster doses as needed.
Provide continuing support through the Immunization Partnership Fund regarding efforts by
partners at the community, regional and national levels to reach at-risk and underserved
populations, reduce access barriers and increase vaccine confidence and uptake through
evidence-based and culturally appropriate approaches.
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Continue bilateral and multilateral engagement with international partners

proof of vaccination credential is accepted internationally, and to seek mutual
verification/interoperability of credentials with other countries where possible and appropriate.
Mid term:
Work on vaccine confidence including public education and communication campaigns,
partnership project investments and tailored efforts targeted to the population as a whole and
priority subgroup in Canada as vaccine options, eligibility and COVID-19 epidemiology evolves
and to catch-up on uptake of routine immunization programs.
Prepare to address new challenges and the future vaccination needs of individuals in Canada by
building on best practices and lessons learned during COVID-19 through the renewal of the
National Immunization Strategy
Conduct/support data analysis to inform the need for new vaccine formulations to ensure
protection against emerging VOCs, booster doses, and/or seasonal vaccination programs.
Undertake causality assessments and support research to better understand specific safety
signals.
Explore new data collection methodologies, and partnerships to understand barriers to
vaccination
Manage vaccine supply arrangements, considering the possible recommendation for seasonal
booster campaigns, and the need to secure doses past 2023.
Continue to work with suppliers on availability of new product presentations, including single-
dose formats, in order to meet the evolving vaccine administration needs in Canada.
Engagement:
Build and maintain relationships, support community engagement and equip trusted community
leaders (e.g., faith-based leaders, newcomer support organizations, family/youth organizations)
with evidence-based information, resources and tools to support informed vaccination choices
and address mis- and dis-information.
Longer term:
Explore innovations/strategies to enhance the speed and scale of distribution and uptake of
vaccines and other medical counter measures to support planning for efficient and effective
response to pandemics and other infectious disease outbreaks.
Ongoing vaccine confidence, promotion and uptake support programming for COVID-19
vaccines, and to protect against other vaccine preventable diseases.
Adaptation of the contents of the CPIP Vaccine Annex for the COVID-19 context as necessary.
Explore options for leveraging VaccineConnect to support pan-Canadian medical counter
measure initiatives beyond COVID-19.
Ongoing monitoring of vaccine safety, coverage, and effectiveness in collaboration with
partners.
Evaluate current vaccine surveillance efforts to inform signal detection and the surveillance of
population risk or protection from vaccine preventable diseases.
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Capitalise on ongoing vaccine coverage surveillance to ensure necessary evidence is available to

assess the level of protection among different population.
Strategic planning for ongoing COVID-19 vaccine supply, including domestic bio-manufacturing
capacity, allocation and distribution models and logistics as needed.
Engagement
Maintain and enhance robust collaborative infrastructures with provincial, territorial and
Indigenous partners to support the evolution of COVID-19 vaccination campaigns and inform the
integration of lessons learned into routine immunization programming.
Work with key partners and stakeholders to explore how greater vaccine acceptance can be
fostered across Canada, taking into consideration lessons learned and best practice from COVID-
19, to allow for effective response to possible future pandemics and other infectious disease
outbreaks.
Application of lessons learned on COVID-19 vaccine confidence, promotion and uptake to
support and maintain partnerships and community outreach efforts for engagement and
equipping trusted community leaders with evidence-based information, resources and tools to
address mis-information and build long term vaccine confidence and support informed
vaccination choices to protect against vaccine preventable diseases.
In addition to COVID-19 vaccine planning, reducing hospitalizations due to seasonal influenza and
invasive pneumococcal disease through increased vaccine coverage can preserve both public health
resources (e.g., diagnostic/testing, outbreak response) and health care capacity (i.e., outpatient visits
and inpatient stays).
Routine immunization programs and Influenza vaccines

COVID-19 has required significant public health resources and has inadvertently led to temporary pauses
or disruption of routine immunization programs to prioritize pandemic response efforts. As provinces
and territories lift public health measures and as travel increases, the risk of vaccine preventable
diseases (VPDs) may also increase. Monitoring routine vaccination coverage and identifying and
addressing gaps in routine vaccinations will be important in preventing further spread of VPDs and
outbreaks, and in ensuring that the pandemic does not leave a long-lasting immunization gap in any
Canadian communities.
NACI will gradually resume activities to provide guidance on other VPDs as new vaccine products
emerge, and also to consider strategic use of existing products to prevent VPD resurgence and promote
health equity. Guidance from PHAC on managing VPD outbreaks (e.g., measles) will need to be updated
in order to prepare for a possible resurgence of VPDs in light of immunization gaps that have resulted
from the pandemic. CIC will also resume activity related to routine immunization to ensure that any
gaps in routine vaccinations as a result of the pandemic are addressed as well as any other issues
regarding immunization programs.

The evolving evidence on vaccine effectiveness and levels of vaccine confidence will be monitored to
support continued planning for education, outreach, and uptake supports for routine vaccination
programs and campaigns, including response to AEFI reports or signals. This requires continued AEFI
surveillance, health promotion and education, vaccine confidence monitoring, health care provider
supports, project partnerships, behavioural science and risk communication expertise.
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Appendix 10: International Border and Travel Health Measures

Since the onset of the pandemic, the Public Health Agency of Canada (PHAC) has significantly shifted and
expanded its border and travel health programs to focus primarily on mitigating the risk of COVID-19
importation. These measures, together with other F/P/T responses, help to protect the capacity of
provinces and territories to provide health services to Canadians. Prior to COVID-19, it was not
envisioned that Canada would implement extensive border closures as a pandemic response measure.
Successful implementation of border and travel health measures has required intensive and ongoing
multilateral engagement and cooperation with government and non-government stakeholders (e.g., the
air travel industry).
Focus for Transition Phase

Throughout the past two years, several border and travel health measures critical to the COVID-19
response have been developed and implemented. The following measures remain important during the
Transition phase, as F/P/T partners work to reduce COVID-19 incidence and associated serious illness to
a locally manageable level and kick starting recovery activities, while maintaining surveillance, risk
assessment capacity and readiness for any resurgence:
leveraging the provisions of the Quarantine Act and introducing 74 Emergency Orders as of January
31, 2022;
originally prohibiting entry of foreign nationals (unless exempt), followed by a limitation on entry
based on vaccination status;
restricting direct flights from countries of concern via a Notice to Airmen (NOTAM);
requiring that travellers obtain a negative pre-departure test from a third country when there are
issues with the quality of testing in a country of concern;
testing and quarantine/isolation requirements for incoming travellers to Canada, including a shift
from increased testing and quarantine in light of Omicron back to a surveillance testing model;
increasing the public health presence at the border (i.e., public health officers being assigned to 36
high volume points of entry) as well as enhanced PHAC capacity to conduct virtual health
assessments for COVID-19 via access to a 24/7 Central Notification System;
updated messaging and communication tools for the travelling public, including through travel
advisories, web presence, and travellers handouts;
linkages between federal and P/T guidance and oversight for the management of international and
domestic travellers;
ongoing cooperation and work with provincial and/or local law enforcement-related partners to
support compliance verification and enforcement activities, including ticketing travellers not
complying with federal quarantine and/or testing requirements; and,
enhanced partnerships with provincial and territorial health authorities and other key players to
support data-sharing, and compliance and enforcement of quarantine.

The emergence of the Omicron variant underscored the need for ongoing surveillance and operational
readiness for resurgence. Moving forward, PHAC will continue to maintain a high level of readiness to
respond to COVID-19 through a combination of border and travel measures that are intended to:
monitor the COVID-19 situation, most notably with the aim of quickly detecting VOCs at points
of entry (POEs) and limiting their importation;
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consider domestic epidemiological factors, including regionally-specific factors and provincial

and territorial public health measures;
track the progress of COVID-19 vaccine coverage both domestically and internationally and
ongoing scientific evidence on vaccine effectiveness;
monitor the availability and quality of COVID-19 testing both in Canada and abroad;
update modelling and risk analysis of other countries and international experiences to capture
lessons learned;
maintain operational capacity pre-, at- and post-border to handle anticipated incoming and
outbound travel volumes along with additional measures;
identify scalable border measure options in case of resurgence;
evaluate border measures including enhancing or easing measures in coordination and
alignment with F/P/T requirements (while factoring in whole of health system capacity);
consider the public health/health system capacity to manage potential increase in imported
cases (testing, provincial and territorial health care capacities, etc.); and,
monitor volumes into Canada by cohort (e.g., immigration status, purpose of travel, etc.) and
arrival mode.
As international and domestic contexts shift, border and travel measures need to be adapted
accordingly. PHAC is working towards a sustainable and adaptive border framework that mitigates
serious illness and severe outcomes while enabling economic recovery, enhances the surveillance
approach that is ready to respond if new threats are detected, and applies lessons learned from
Omicron in Canada and abroad. There is a variety of possible approaches that could be explored and
implemented in any combination, as the current Omicron-driven wave subsides.
Global restrictions: Reduce restrictions for travellers from all destinations, provide relevant
travel advice to Canadians, and continue surveillance at the borders.
Country-specific restrictions: Remove prohibition of entry for all foreign nationals, but
maintain/impose restrictions for high-risk countries by exception, based on risk of importation
Cohort restrictions: Modify exemptions to entry prohibitions and/or border measures based on
a sectoral analysis.
Testing and/or vaccination certification: Continue to ease or impose measures according to
evidence and is sensitive to legal and ethical issues, including around equity and accessibility.
The objective of this border framework will be to move towards an empowerment and surveillance
approach that is ready to respond if new threats are detected. Surveillance will continue to be the
partners will need to maintain the ability to ramp up measures in case of a resurgence of COVID-19 or
the emergence of new VOCs.
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Appendix 11: Health Care Systems Infrastructure

A significant resurgence of COVID-19 in any jurisdiction can have a substantial impact on health care
service capacity and the ability of health care organizations to provide optimum care to all patients.
Canadian businesses have stepped up to offer their solutions and expertise, or pivoted their
manufacturing facilities. Canada is now successfully producing: therapeutics (e.g., Molnupiravir) Made-
in-Canada PPE, medical equipment and supplies to address the urgent needs of frontline workers, and
the safety of Canadians at large. In addition, Innovation, Science and Economic Development Canada,
Health Canada, PHAC and PSPC Canada continue to work closely together to assess and monitor
ic manufacturing of medical equipment and supplies.
With respect to therapeutics, the Interim Order Respecting the Prevention and Alleviation of Shortages
of Drugs in Relation to COVID-19, made by the federal Minister of Health on October 16, 2020
introduced tools for the Minister to address drug shortages, or the risk of drug shortages, that may be
caused or exacerbated, directly or indirectly, by COVID-19.
The F/P/T public health response in terms of health care system infrastructure has involved linking with
those partners responsible for monitoring, anticipating and planning for surges in capacity within health
care systems in order to increase mutual knowledge and situational awareness, and support response
activities regarding the delivery of health care to COVID-19 cases in Canada. To support this work:
PTs have taken steps to support hospital surge capacity and ensure timely access to critical
equipment and supplies;
the Government of Canada continues to work with provinces and territories: to help ensure
health care systems are ready for future waves of the virus, to support populations in situations
of vulnerability and high-risk Canadians, including those in long-term care, home care, acute
care and palliative care, and to support people experiencing challenges related to mental
health, substance use, or housing;
PTs are working to develop, expand and launch virtual care and mental health tools, including
through the use of federal funding to support P/T services;
o The federal government is also committed to sustaining the Wellness Together Canada
portal, which is a free 24/7 bilingual online resource that all Canadians can access. The
portal serves to supplement any online mental health tools provided by PTs.
through the federal Safe Long-Term Care Fund, governments will work together to protect
people living and working in long-term care, including carrying out infection prevention and
control readiness assessments, making improvements to ventilation and hiring and training
additional staff or topping up wages to support workforce stability;
the federal government is supporting infection prevention and control measures in long-term
care, including funding for Healthcare Excellence Canada (formerly the Canadian Foundation for
Healthcare Improvement) to expand its LTC+ initiative and funding to engage with third parties
to help identify resources to conduct readiness assessments in long-term care facilities and
support training on infection prevention and control;
the federal government is also supporting PT testing programs in workplace and high risk
congregate settings through the procurement and distribution of free rapid tests;
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the Canadian Red Cross and other non-governmental organizations are being supported by the
federal government to build and maintain a humanitarian workforce to provide surge capacity
in response to COVID-19 outbreaks and other large-scale emergencies;
modelling has been used to project anticipated demands;
sharing of hospital-based data (on rates of admission, current capacity and
equipment/supplies/resources usage) has been included in surveillance products; and
the Logistics Advisory Committee (LAC) was convened in February 2020 to provide an F/P/T
forum for collaboration including identification of F/P/T PPE, equipment and supply needs,
informing procurement and facilitating allocation.
In terms of forward planning, the Government of Canada will continue to:
collaborate and work with PTs to better understand the rapid tests and PPE needs across the Pan
Canadian landscape;
explore opportunities to consider sustainable domestic production capacity for medical equipment
and supplies such as vaccines, therapeutics, rapid tests and PPE;
monitor for potential COVID-related drug shortages and work with PTs and stakeholders to
proactively develop and implement strategies to manage these risks;
Stockpile (NESS), provide medical equipment and supplies to First Nations, Inuit and Métis
communities to support the delivery of health care services;
consult regularly with PTs to identify need for federal COVID-19 surge capacity supports to
jurisdictions, including health human resources and mobile hospital units, as well as identify
initiatives over the medium-
encourage PTs to bolster their existing health human resources through the use of other sources
such as international medical graduates and foreign-credentialed health professionals;
facilitate sharing of best practices on alternate care facilities, triage and management of delivery of
non-COVID-19 health care services review the latest available scientific evidence to inform guidance
for health settings and develop tailored approaches for communities with specific health care needs,
such as remote, northern and isolated communities as well as Indigenous Peoples in urban settings;
work with PTs to support safe resumption of in-person primary care and mental health services
(where this were suspended/delayed or shifted to virtual care platforms);
work through the Health Standards Organization and the Canadian Standards Association (CSA)
group to set new national standards for long-term care so that older adults get the best support
possible, and work with PTs to use the standards to drive lasting change;
take more action to help people live longer at home;
work with PTs as well as other partners and stakeholders to develop national mental health and
substance use standards. (These standards will help ensure that Canadians receive high-quality
mental health and substance use services, no matter where they live or seek to access services); and
work with PTs to make sure that the entire Canadian population has access to high-quality care,
including ensuring access to a family doctor or primary care team, expanding capacity to deliver
virtual care, and increasing access to mental health services.
Provincial and territorial governments, along with health care facilities, many of which are already
working close to full capacity, continue to do further planning for how they have in some regions (and
could in the future) accommodate potentially large influxes of patients, including establishing triage
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protocols for the allocation of scarce resources such as ICU beds and specialized health human
resources. In remote, northern and isolated communities it is also critical to plan for further potential
supply-chain and medical evacuation interruptions due to weather.
The level and type of health care system resources needed to manage the Post-COVID Condition/Long-
COVID also requires coordinated planning, especially since its full impact remains to be determined.
Forward planning must also consider the broad health care system impacts and changes that have
occurred as a result of the COVID-19 pandemic in Canada; for example, the unanticipated reduction in
emergency room visits for serious conditions, the shift of primary care to virtual care, the unintended
but severe health and safety impacts of removing family caregivers from long-term care facilities,
increased incidence of opioid overdose, delayed/decreases in routine immunization, and the backlog of
elective procedures.
The implications of these impacts and changes include the need to plan for: more and different
supportive care for older adults -
ms more than is
necessary. In addition, understanding gaps that appeared, and lessons to be learned from how they
were addressed, in the intersection between PHMs, health care services and other social determinants
of health will be important to consider in a holistic way for future planning. For example, how to make
sure individuals experiencing homelessness receive adequate supports to be able to follow PHMs (e.g.,
isolation and quarantine protocols).

In the event health care institutions start to see an increase in the number or change in the
characteristics (e.g., demographics, underlying medical conditions) of patients being treated for COVID-
19, the Government of Canada will continue to work with PTs to monitor capacity and facilitate timely
access to medical equipment and supplies such as PPE, vaccine ancillary supplies, biomedical equipment
and intensive care unit (ICU) beds. The federal government continues to be ready to respond to PT
requests for assistance and surge support, (e.g., limited health human resource support, facilitation of
mobile health services capacity, safe voluntary isolation sites).
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Appendix 12: Communications and Outreach

Communication of information and advice in a public health emergency is a critical public health
intervention that helps to protect public health, save lives, and minimize the overall social and economic
impacts. To ensure this, information must be available in plain language and multiple formats and
languages so that it is accessible to all people in Canada, including those with low literacy. Using a risk
communications approach, the Public Health Agency of Canada, together with other government
departments and P/T counterparts and Indigenous partners, have worked hard to provide health care
providers, Canadians and key stakeholders with the timely, trusted, accessible, evidence-informed and
complete information they require to protect themselves, their families, their communities and
businesses. As Canada transitions to a more sustainable, long-term management of COVID-19, ongoing
proactive and targeted communications from trusted sources will continue to be important.
Focus for Transition phase

The focus remains on communicating clear, concise and timely information, within a constantly evolving
public environment, that will cut through mounting COVID-19 fatigue and mis- and dis-information. The
goal is to ensure people in Canada have the information they need to make informed decisions to help
protect themselves, their families and their communities from COVID-19.
As Canadians emerge from the latest wave, it is an opportune time to recognize all that we have
collectively accomplished, take a broad perspective and map out the path forward. While transitioning
out of the acute response phase, it is important to remain nimble and ready to respond to new risks in
an appropriate and proportionate manner. All levels of government need to communicate to Canadians
that progress may not be linear and continue to promote the various tools, including vaccines,
therapeutics, robust surveillance and individual public health measures, to avoid resurgences.
Communications, public education and advertising activities will:

encourage continued use of individual public health measures, including staying home when sick,
washing hands, wearing a mask, ventilation and rapid testing;
promote COVID-19 booster doses and pediatric vaccination, and possible seasonal immunization
programs, such as seasonal flu;
raise awareness of evolving border measures;
use credible/trusted sources to counter misinformation and address vaccine hesitancy;
communicate transitions to management of COVID-19 as an ongoing infectious disease in Canada
when prudent; and
communicate with empathy and honesty to recognize the efforts and sacrifices of Canadians have
saved lives; that we are now in a stronger position than ever before; and encourage everyone to
continue to use the various tools available.
These activities will be supported by F/P/T strategies, content and implementation plans that include:
sufficient public opinion research (POR) and behavioural insights (re. behaviours, vaccine, public
health measures, back to school) to identify , and capture
regional variations;
public education campaigns (COVID-19 vaccines, PHMs and mental health);
campaigns to ensure Canadians are aware of COVID-related travel requirements; and,
testing and contact tracing related communication activities.
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Effective communications will be achieved through a coordinated, strategic and scalable approach to
outreach and engagement. This includes communications by the Chief Public Health Officer (CPHO),
Deputy Chief Public Health Officer (DCPHO), Chief Medical Officers of Health (CCMOHs) across the
country and other P/T and local spokespersons, as appropriate; public education campaigns; traditional
and digital media outreach, social media, and website updates.
Significant outreach and engagement with a range of health and non-health stakeholders has been an
essential part of the national response to COVID-19. This outreach and engagement has evolved
throughout the pandemic from a focus on proactively sharing the latest public health developments and
resources to identifying stakeholder information needs and perspectives, to collaborating on guidance
development and joint communication initiatives, to transitioning towards a more sustainable approach
to long term management of COVID-19. A range of stakeholders have been engaged through regular
COVID-19 briefings, teleconferences and webinars including the following: CPHO Health Professionals
Forum (national health professional organizations), national allied health organizations, local public
health medical officers of health, critical infrastructure stakeholders, agriculture and agri-food
stakeholders, business groups, travel associations, airlines, and childcare and education stakeholders. A
range of community-level leaders have also been engaged including faith-based organizations,
organizations representing racialized communities, and engagement with national and community level
First Nations, Inuit and Métis organizations.
It has been and continues to be especially important to engage community leaders from Indigenous
communities, rural communities, racialized communities, groups representing newcomers to Canada,
and faith-based organizations to help deliver critical information39.
Challenges and Considerations:

Messages in the earliest phase of the pandemic were clear stay home; physical distance; wash your
hands; wear a mask. Now the environment is much more complex.
As populations and health care capacities differ across jurisdictions, there will be variability in
how each province, territory and community assesses risk and responds to the needs of their
respective jurisdictions. Messages and their delivery must be clear so as to avoid confusion and
assure Canadians that public health officials are aligned in their approach.
Canadians have gone through multiple waves across the country and there is a real balance that
needs to continue to be communicated as we transition away from the crisis phase: keeping
COVID-19 vaccinations up to date, being aware of personal and family risks, and maintaining
individual public health measures. This messaging can support individuals to make the right
choices for themselves and their family and can help mitigate the impact of pandemic fatigue.
COVID-19 is here for the foreseeable future and there will continue to be new and important
roles for public health to play. Messages must be designed to help manage expectations and
emphasize a risk-based approach.
The risk perception (and compliance) of Canadians will vary based on their individual
experiences and their unique reality. Canadians need to assess their activity, their risk tolerance,
their risk to others and the importance of their own behaviour in reducing risk. Our
communications efforts must arm them with the information to do so easily and accurately.
There is still much uncertainty that impacts how precise and definitive we can be in our
messaging, especially with the new VOCs. As science evolves and we learn more, advice to
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Canadians may change. It will be important to continue to communicate what is known and
what is not known.
There will continue to be an overwhelming amount of information on COVID-19 and some
Canadians may find it hard to distinguish misinformation or disinformation from information
from Governments and other credible health sources. Communications efforts must address
misinformation and provide everyone in Canada with evidence-based information to help them
make the decision to keep their COVID-19 vaccinations up to date.
Canadians expect timely and responsive communication using newer social media platforms
(e.g., TikTok, Instagram) and from leaders and influencers that are meaningful and trustworthy
within their communities and social media circles.
The pandemic has revealed and amplified deeply entrenched health, social, and economic
inequities that exist in Canada. The interaction of the social determinants of health in shaping
negative health outcomes and driving health inequities is more evident than ever before.
Communications efforts will need to acknowledge and address the broader health impacts of
this pandemic and consequences of the pandemic response.
Public opinion research has shown that public trust in messages from the medical and scientific
community is declining. Collaborative or complementary communications approaches, and
consistent messaging across jurisdictions can help to regain public trust.
public health measures, which can be leveraged in the ongoing fight against COVID-19 as well as
with other future public health events.

Surges in cases requiring adjustments to or re-instatement of community-based measures or
restrictions, along with any changes in science (e.g., new information about COVID-19 that requires a
th response or guidance to specific populations), changes to border
measures, emergence of VOCs, availability of boosters or pediatric vaccines, will all necessitate updating
of the current F/P/T communication strategy and products.
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Appendix 13: Research

The Government of Canada quickly
to the spread of the novel coronavirus (COVID-19). Early in the pandemic, research areas focused on
medical countermeasures (vaccines, therapeutics, and diagnostics), clinical management research,
predictive modelling, as well as social and policy research. Since then, the research focus has expanded
to areas such as mental health and substance use during the pandemic, safety in long-term care homes,
Indi -19, and variants of concern. Community engagement
is important to ensure culturally appropriate research approaches.
The Government of Canada established mechanisms for mobilizing rapid research responses for this
type of emergency, which have been activated to accelerate development of medical
countermeasures, to support priority research on the transmission and severity of COVID-19, and to
understand the potential benefits and potential limitations of medical, social and policy
countermeasures (e.g., the COVID Immunity Task Force).
Within the Canadian Institutes of Health Research (CIHR), the recently created Centre for Research
on Pandemic Preparedness and Health Emergencies, will build on
continues to grow its capacity to be a leader in preventing, preparing for, responding to, and
recovering from existing and future pandemics and public health emergencies.
The funding for the Centre for Research on Pandemic Preparedness and Health Emergencies
includes funds for studies on Post-COVID Condition/Long-COVID in Canada.
Health Canada established and continues to apply a number of temporary innovative and flexible
measures to help prioritize and expedite the regulatory review of COVID-19 health products without
compromising Canada's high standards for safety, efficacy and quality (these measures have been
put in place to facilitate safe and timely access to products Canadians and health care workers
need).
A wide array of Clinical Trials activities for therapeutics and vaccines are underway under the
Canadian Treatments for COVID-19 (CATCO) trial.
PHAC has established a pan-Canadian network for wastewater surveillance for SARS-CoV-2 in
collaboration with other federal departments, provincial, territorial and municipal governments and
academia across Canada that lays the foundation for timely detection and surveillance of COVID-19
across the country.
Several federal programs available aimed at mobilizing industry, innovation and research continue
to respond to COVID-19.
Networks such as CanCOVID, COVID-END and National Collaborating Centres, have been launched to
facilitate research effort and leverage transdisciplinary knowledge synthesis, translation and
expertise among Canada's scientific, policy, and health communities.
Capacity at federal research facilities is being leveraged, and federal granting agencies are
strategically aligned to support Canadian research capacity.
Knowledge on indoor air quality is being mobilized with federal, provincial, territorial and private
sector partners.
The Canadian private sector (R&D, manufacturing) is engaged in contributing to research and
development solutions.
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The Government of Canada is also supporting various strategies to bring significant findings arising
from these research efforts to decision-makers in a useful and timely way.
In an earlier version of this Plan, a number of needs had been identified in order to prepare against
surges/resurgences based on the reasonable worst-case scenario. In addition to the activities described
above, work has begun in earnest in several crucial areas.
i. Strengthening our capacity to deliver on relevant COVID-19 modelling work.

The COVID-19 pandemic has demonstrated the important role and need for greater and
ongoing capacity to implement the full range of modelling tools required to support
decision-making during a complex public heath crisis. Models help to predict where and
when COVID-19 infections may emerge or re-emerge, emergence of new variants of
concern, and they can be used to explore the best combinations of approaches to control
disease progression and protect the health of Canadians, including vaccination. Expert
groups continue their ongoing work on modelling the reproductive number (Rt) over the
course of the pandemic, and are working on modelling several scenarios for de-escalation
strategies, including border reopening and lifting travel restrictions.
ii. Examining and addressing the need to pursue research and surveillance studies aiming at better
understanding mechanisms of infections, transmission and immunity against the SARS-CoV-2 virus.
F/P/T governments are currently focusing on the investigation and tracking of the genetic
diversity of SARS-CoV-2, across Canada to better respond to its spread, particularly new
variants of concern. However, research is needed to examine the full potential of these
variants in their transmissibility, virulence and vaccine efficacy, and to monitor their
emergence and presence over time. The Government of Canada launched the COVID-19
Immunity Task Force, which engages universities, hospitals and public health officials to use
blood test (serologic) methods to track and study the immune status of various Canadian
populations, and will be used to support vaccine surveillance, safety and efficacy. The need
for research and research coordination with partners to understand transmission dynamics
and impact of non-medical measures (e.g., ventilation, portable air cleaners, etc.) is
beginning to take shape through early aerosol transmission studies in high-risk settings, such
as hospitals, prisons, and long-term care homes. Discussions and work continues with
domestic and international partners to develop COVID-19 animal models and medical
countermeasures.
iii. Strengthening our capacity to coordinate, perform, mobilize and utilize rigorous and rapid evidence
review.
More experts within and outside of government are being leveraged to generate and
disseminate evidence reviews and answer specific questions to provide the most up-to-date
scientific evidence for optimal decision-making.
iv. Exploring the epidemiological value of new, innovative methods to track community spread, such as
testing SARS-CoV-2 from sewage water.
Testing wastewater is providing early warning ability at the community level (municipality,
special settings such as Long-Term Care Facilities, prisons, hospitals and remote
communities). With its F/P/T partners, the federal wastewater surveillance program is
further strengthening the network throughout Canada for surveillance of public health
outcomes such as COVID-19.
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NML is conducting wastewater based metagenomics sequencing of COVID-19 virus for early
identification of VOCs/variants of interest.
v. Examining and addressing the need to pursue research and surveillance studies on COVID-19 at the
human-animal interface, and in particular to enhance our understanding of the possible impact of
new variants, the range of species that can get infected, and how different species may be affected,
carry and transmit the virus.
While there is limited information on the susceptibility of wildlife to SARS-CoV-2, the virus
has infected multiple animal species globally, including farmed mink, companion animals
(e.g., cats, dogs, ferrets, hamsters), and zoo animals (e.g., tigers, lions, gorillas, cougars,
otters, other).
Transmission from animals-to-humans has been reported from mink, and recently from
hamsters. Other instances of animal-to-human transmission have been suspected (e.g., big
cat-to-human in a zoo in the US); however, it has been difficult to clearly demonstrate
directionality, given the virus is transmitting so widely in people.
A collaborative team of scientists, and wildlife and public health experts from across Canada
has recently reported a unique lineage of SARS-CoV-2 in white-tailed deer that also includes
a viral genome from a human case from southwestern Ontario. According to the paper, the
human case had contact with deer prior to contracting COVID-19. This is the first report of
this new SARS-CoV-2 lineage and possible deer-to-human transmission of the virus.
There is currently no scientific evidence that animals play a large role in the current spread
of COVID-19. However, as the virus continues to evolve and change, the role of animals as a
source of new variants may also change.
Deer and other cervid species (such as elk and moose) are abundant across the provinces
and territories in Canada. More research is required to understand how widespread the new
lineage is in deer populations, how and if the virus is transmitted between species, and how
this virus differs from existing SARS-CoV-2 lineages in terms of transmission and potential to
cause disease.
vi. Strengthening laboratory capacity in the area of genomic innovation and bioinformatics.
The Government of Canada has begun to secure investments in this area.
NML is participating in Genome Canada funded consortium CanCOGen - for genomic
studies, both host and virus.
vii. Mobilizing knowledge from the social sciences.
There continues to be a need to invest in and mobilize knowledge relating to social sciences
such as sociology, anthropology and psychology. Specifically behavioural science and ethnic
research can guide future policy and regulatory actions.
Short to Mid term:

In the short to mid term, the approach to these preparations continues to be to:
work collaboratively with National partners, F/P/T, stakeholders groups, Indigenous partners
(including National Indigenous Organizations; Indigenous researchers and scholars; the National
Collaborating Centres for Public Health), and the Federal Science Community to support the
-19 response (Immunity Task
Force, the Vaccine Task Force, the Therapeutic Task Group) and Indigenous-led culturally
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grounded research (with appropriate community engagement and cultural safety in

approaches);
work collaboratively with federal science based departments and agencies with specific targeted
engagement with the CIHR and the Chief Science Advisor of Canada; and
continue engagement with the COVID-19 Governance Structure (via the Technical Advisory
Committee (TAC), LAC and SAC). Activities include sharing research, data and local experience
that will inform further planning in alignment with our stated public health pandemic goal and
objectives (e.g., quantifying the negative and positive consequences of the PHM that were uses
in the initial response to be better able to address the inequities that have arisen, evidence
generation in the effective and appropriate use of home rapid testing).

Similar to the other COVID-19 response components above, there are several factors that could
potentially impact preparations for the ongoing COVID-19 response, including: a significant shift in
genomic pattern of SARS-CoV2 (leading to examination of possible shift in virulence or infectivity),
significant increases in the mortality ratio, data from vaccine and therapeutic clinical trials, data on
immunological protection of Canadians, new/rigorous knowledge on the impact of COVID-19 specific
high-risk groups, and new/rigorous knowledge of the importance of a non-respiratory mode of
transmission.
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considerations for Member States in the WHO European Region," 2020. [Online]. Available:
https://apps.who.int/iris/handle/10665/335820. [Accessed March 4 2021].
28
https://doi.org/10.1186/s12879-021-06357-4
29
Scientific Advisory Group for Emergencies (SAGE) Academics: Viral evolution scenarios, 10 February 2022
[Online] Available:
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1054323/S15
13_Viral_Evolution_Scenarios.pdf
30
Bhattacharyya RP, Hanage WP. Challenges in inferring intrinsic severity of SARS-CoV-2 Omicron
variant from early population-level impact. HCPDS Working Paper Volume 21, Number 10. December 15, 2021.
[Online] Available: https://cdn1.sph.harvard.edu/wp-
content/uploads/sites/2623/2021/12/21_Hanage_Bhattacharyya_Challenges-in-assessing-Omicron-
severity_HCPDS-Working-Paper-Volume-21_No-10-1.pdf
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PMID: 32967592
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594747/
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Emerg Microbes Infect. 2020; 9(1): 2222 2235.
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PMCID: PMC7594747
PMID: 32967592
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594747/
33
-autoantibodies in severe COVID-19 also suggests
key component of severe COVID-

https://pubmed.ncbi.nlm.nih.gov/34264880/
34
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B.C. Centre for Disease Control. Societal Consequences of COVID-19. [Online] Available:
http://www.bccdc.ca/health-professionals/data-reports/societal-consequences-covid-19
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Canada -19 Immunization Plan: Saving Lives and Livelihoods. Available at:
https://www.canada.ca/en/public-health/services/diseases/2019-novel-coronavirus-infection/canadas-
reponse/canadas-covid-19-immunization-plan.html
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Krishnan, L., Ogunwole, S. M., & Cooper, L. A. (2020). Historical Insights on Coronavirus Disease 2019 (COVID-
19), the 1918 Influenza Pandemic, and Racial Disparities: Illuminating a Path Forward. Annals of Internal Medicine.
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79
AR07415
TAB 52
AR07416
Court File No. T-145-22

FEDERAL COURT
BETWEEN:
NABIL BEN NAOUM
Demandeur
et
LE PROCUREUR GÉNÉRAL DU CANADA
Défendeur

AND BETWEEN:
L’HONORABLE MAXIME BERNIER
Demandeur
et
Défendeur

AND BETWEEN:
THE HONOURABLE A. BRIAN PECKFORD, LEESHA NIKKANEN,
KEN BAIGENT, DREW BELOBABA, NATALIE GRCIC,
AND AEDAN MACDONALD
Applicants
and
ATTORNEY GENERAL OF CANADA
Respondent
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AND BETWEEN:
SHAUN RICKARD AND KARL HARRISON
Applicants
and
Respondent
_________________________________________________________________
CROSS-EXAMINATION OF DR. NEIL VIVEK RAU

May 18, 2022
_________________________________________________________________
Mahan Keramati For the Respondent

Sam Presvelos For Dr. Rau
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INDEX
PAGE
Exhibits ................................................... 4
Undertakings ............................................... 4
DR. NEIL VIVEK RAU
Cross-Examination by Ms. Keramati ..................... 5

Re-Examination by Mr. Presvelos ....................... 95
Proceedings Adjourned ................................. 102
Reporter’s Certification .............................. 103
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EXHIBITS
PAGE
1. Screenshot of the IPAC Canada website 37
2. Public Health Ontario definition of Antimicrobial
Stewardship 37
3. Article by Li et al., titled, “The Temporal Association 52
of Introducing and Lifting Non-Pharmaceutical
Interventions with the Time-Varying Reproduction
Number (R) of SARS-CoV-2: A Modelling Study Across 131
Countries.”
4. Epidemiology Summary of COVID-19 65
5. Early Impact of Ontario’s COVID-19 Vaccine Rollout 74
on Long-Term care Home Residents and Health Care Workers.
6. Effect of Covid-19 Vaccination on Transmission of Alpha 83
and Delta Variants.
7. Article titled, “Effectiveness of COVID-19 Vaccine 95
against Omicron or Delta Infection,” Version 1
8. Article titled, “Effectiveness of COVID-19 Vaccine 95
against Omicron or Delta Infection,” Version 2
UNDERTAKINGS
1. Provide recent publications relating to COVID-19 8
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DR. NEIL VIVEK RAU, Cross-Examination
1 MAY 18, 2022
2 CROSS-EXAMINATION COMMENCED
4 DR. NEIL VIVEK RAU, affirmed, testified:
6 COURT REPORTER: Can you just state and then spell
7 your full name for the record?
8 DR. RAU: It's Neil, N-E-I-L, Vivek, V-I-V-E-K, Rau, R-A-
9 U.
10 COURT REPORTER: Perfect. Thank you. Counsel, we’re
11 on the record. Whenever you’re ready.
12
13 CROSS_EXAMIANTION BY MS. KERAMATI
14
15 MS. KERAMATI:
16 MS. KERAMATI: Thank you. Good morning, Dr. Rau.
17 A. Good morning.
18 Q. Thank you for being with us today. My name is Mahan
19 Keramati. I'm counsel for the Attorney General of Canada, the
20 respondent in these applications. Can you state your full name
21 for the record, please? Dr. Rau, I believe you might be frozen.
22 Yes. Is it just me, or is he frozen?
23 MR. PRESVELOS: No. He’s frozen. I'm just saying, all that
24 setup and we lost him in the first minute. I'll text him.
25 MS. KERAMATI: Maybe we can go off the record.
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2 OFF RECORD
4 MS. KERAMATI: Okay. Dr. Rau, my - we left off with my
5 question. Can you please state your full name for the record?
6 A. Yes. Neil Vivek Rau. N-E-I-L, V-I-V-E-K, and then
7 R-A-U.
8 Q. Thank you.
9 DR. RAU: Just one technical thing. I'm gonna log into
10 ZOOM on my laptop, as well. Just in case we have a break. So,
11 we have it, but I’ll have it muted on one. Just that way, if
12 you need - if this happens again, we're going to be immune to
13 this. All right. I’ll be coming in like under another name.
14 Just a minute. So, I’m logging in twice. Oh, dear. It's not
15 letting me. I’m fine. Just proceed for now. Sorry about that.
16 Okay.
17 MS. KERAMATI: Well, I - I would rather you not trying to
18 - to get on ZOOM, while we're - while I'm answering my questions.
19 So, I'll give you a moment. If that's what you'd like to do.
20 DR. RAU: Okay. I just - I just want it as security, so,
21 that this - this doesn't happen to us again.
22 MR. PRESVELOS: Yeah. Let's deal with it, if it comes up,
23 because I don't think you can be in the same account
24 simultaneously on two different devices. It might sign you out
25 of one account.
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1 DR. RAU: That might be a problem. Okay. Fine. Just
2 forget it. Okay.
3 MS. KERAMATI: Okay. You're the doctor Neil Rau, who swore
4 an affidavit on March 11th, 2022 in these proceedings?
5 A. Yes, I am.
6 Q. And you've been sworn in today?
7 A. Yeah, yes. Just now, I guess.
8 Q. But for the benefit of the record, we're doing this
9 cross-examination by video conference, and I'm located in
10 Toronto. Dr. Rau, where are you located?
11 A. I'm in Toronto at my house.
12 Q. And would you please confirm that you're the only
13 person in the room?
14 A. Yes, I am. Only person in the house.
15 Q. Will you also confirm that during any breaks in this
16 cross-examination, you will not communicate with any party
17 outside of this virtual meeting, or take instructions from
18 anyone during examination, other than properly framed objections
19 by your legal counsel?
20 A. Yes, I affirm that. I - I will - just an extra caveat,
21 if there's a work-related call, unrelated to this, I may have
22 to take it, but I have tried to pause my work as well.
23 Q. Dr. Rau, do you have any printed or electronic
24 documents with you today?
25 A. Yes, I have my laptop here with my documents.
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1 Q. And - and what is on your laptop?
2 A. So, I currently have my affidavits. I have the
3 references that I used for my affidavit, in addition to some
4 additional ones, that have - additional publications that have
5 come up, since I swore my affidavit. And I also have the papers
6 that you have just sent me to - I downloaded those as well.
7 Q. Okay. The additional documents that you have, in
8 addition to your affidavit, the - the recent publications, you
9 said?
10 A. They are recent publications relating to COVID that
11 have relevance to what I have in my affidavit, but that I have
12 not cited necessarily.
13 Q. Okay. I will - can - can you provide the - these
14 documents? Just, Counsel, can undertake to provide?
15 MR. PRESVELOS: Yeah. Sure.
16 UNDERTAKING 1: Provide recent publications relating to
17 COVID-19.
18 A. Given that this is an emerging or rapidly moving
19 situation with COVID-19, there are new publications constantly
20 coming out, that's why this is happening.
21 Q. I understand.
22 A. Okay.
23 Q. As a final housekeeping matter, Dr. Rau, would you
24 please tell me what documents, you - you reviewed in preparing
25 for this cross-examination?
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1 A. Well, every document that I have cited in my report,
2 in essence...
3 Q. Okay.
4 A. ...um....
5 Q. I'm sorry, go ahead.
6 A. Yup. That’s - that’s in essence, what I did. Yeah.
7 Q. Did you review the Affidavit of Dawn Bowdish?
8 A. Yes, I have now done so. And I have also reviewed the
9 Affidavit of Dr. Jason Kindrachuk.
10 Q. Thank you. Dr. Rau, your affidavit attaches your CV
11 as Exhibit A, correct?
12 A. Yes.
13 Q. Your CV is complete and accurate as of March 11th,
14 2022?
15 A. Yes.
16 Q. And your affidavit attaches as Exhibit B, your Expert
17 Report, dated March 10th, 2022, that you wrote at the request of
18 counsel?
19 A. Yes.
20 Q. The report you prepared truthfully, reflects your
21 opinion?
22 A. Yes.
23 Q. And you have your affidavit and expert report with you
24 today, you said?
25 A. Yes, I do here. Yes.
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1 Q. Is it - is there anything you wish to change or correct
2 with your affidavit or report before we begin?
3 A. The Reference 29, Point 29, does not have an
4 associated reference with it. So, I submitted that to my counsel
5 this morning, to our counsel. It's protection against the
6 Omicron variant from previous SARS-CoV-2 infection, it’s quoted
7 in Qatar correspondence. So, I asked my counsel to provide that
8 to you, it was missing. And there was also one link that was
9 incorrect, that I think counsel’s already told you about.
10 MR. PRESVELOS: Yeah. We - I - I already - already
11 sent Sharlene an e-mail a couple days ago, or two days ago,
12 correcting that footnote. And, Counsel, I can send you the
13 document he's referring to. I can e-mail it to you, if you’d
14 like.
15 MS. KERAMATI: Yes, please.
16 MR. PRESVELOS: Just give me a second. All right. I just
17 e-mailed it to you.
18 MS. KERAMATI: Thank you. Okay.
19 Q. Dr. Rau, I'm going to ask you some questions about
20 your education and experience.
21 A. Yes.
22 Q. You're a medic. You're an internal medicine physician
23 with a specialization in infectious disease, correct?
24 A. That's correct.
25 Q. You completed your training in 1996?
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1 A. Correct.
2 Q. You were staff at the Department of Medicine at Credit
3 Valley Hospital from 1996 to 2006. Correct?
4 A. Correct.
5 Q. You were a member of the Pharmacy and Therapeutics
6 Committee for Credit Valley Hospital?
7 A. Yes, I was.
8 Q. This is a committee responsible for managing drug-
9 related issues. Correct?
10 A. It's a committee related to the appropriate use of
11 antivirals and antibacterial treatments, and treatment protocols
12 for disease.
13 Q. Thank you. It's not a committee related to vaccines?
14 A. No, it’s not.
15 Q. Since ...
16 A. Actually, it’s - correction. It was related to
17 influenza vaccination as well, at times, as well. That was the
18 main vaccination of relevance in health care workers and in
19 patients so, sometimes we've addressed issues related to that
20 as well.
21 Q. It was not related to the development of vaccines,
22 correct?
23 A. No, it was not.
24 Q. Since 1997, you've been the Medical Director of
25 Infection, Infection Prevention and Control at Halton
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1 Healthcare, correct?
3 Q. Halton Healthcare is the Regional Health Care
4 Organization.
5 A. Yeah. So, initially, it was just Oakville Trafalgar
6 Hospital in Oakville. And now it is a three site Regional Health
7 Hospital. So, it's Oakville, Milton, and Georgetown.
8 Q. And Milton District Hospital and Georgetown are
9 smaller hospitals?
10 A. That's correct. So, they have been largely expanded,
11 at least, the Milton one has been significantly expanded in the
12 last three years.
13 Q. They have about 180 beds combined?
14 A. That's correct, but the Milton Hospital might be
15 bigger than that. Put together, I don't want to split hairs,
16 the main big hospital is Oakville.
17 Q. Okay. Dr. Rau, going forward, I'm going to refer to
18 the term, “Infection Prevention and Control,” as IPAC, I-P-A-C.
19 A. Yes.
20 Q. IPAC practices can reduce the risk of transmission of
21 infection, correct?
22 A. I would have to agree and disagree with that comment.
23 Not every IPAC prevention measure is successful in reducing
24 infections. Sometimes we mitigate the effects of an infection
25 by our measures, but we can't actually reduce the incidence of
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1 infection. So, it depends on the disease in question.
2 Q. And the ....
3 A. It's - it’s not uniform. Sometimes it's control.
4 IPAC stands for Infection Prevention and Control. So, the
5 control part is mitigation, preventing the bad outcomes, which
6 you can't prevent. Ideally, you'd want to prevent and control,
7 but sometimes it's one, or the other, or both.
8 Q. But it - you would agree that it can reduce the risk
9 of transmission? Not necessarily prevent but reduce.
10 A. Correct. It can reduce. Yes.
11 Q. Yes.
12 A. It depends on the disease. I'll give an example,
13 Norovirus, Norwalk Virus outbreaks are constantly introduced to
14 the hospital. We can’t prevent that. Visitors and staff bring
15 it in. Sometimes we try to control the transmission or prevent
16 the transmission. Sometimes by the time we are realizing we
17 have an outbreak, it's already on the downside of the epidemic
18 curve and going away.
19 Q. When you say, you try to control the transmission, you
20 mean you try to reduce the transmission?
21 A. We try to, but in some cases, the transmission is
22 decreasing by the time we realize we have an outbreak that is
23 coming and going. Like, Norovirus, being the example.
24 Q. And IPAC practices can include hand hygiene?
25 A. Yes.
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1 Q. Use of personal protective equipment.
2 A. Yes.
3 Q. Masking?
4 A. Yes. That's personal protective equipment. That's
5 the same thing. Yeah.
6 Q. Physical distancing?
7 A. That is novel and that's only been implemented with
8 COVID-19. We've never done that before, but it's part of the
9 response for COVID-19 in hospitals.
10 Q. Including in the hospitals that you work at?
11 A. Yes, absolutely.
12 Q. And IPAC practices can include other nonpharmaceutical
13 interventions?
14 A. I'd like more detail on what you mean by other.
15 Q. Well, I suppose in other words, non-pharmaceutical
16 interventions fall under the category of IPAC. Do you agree
17 with that?
18 A. They may. Well, I guess, physical distancing could
19 be considered a non-pharmacological intervention.
20 Q. Yes.
21 A. And in the case of COVID, it’s being implemented. So,
22 yes, we are overseeing some of them, but most of the non-
23 pharmacological interventions are community interventions, as
24 you can see in the (Inaudible), that they do reduce - they’re
25 not so much hospital based. Hospital based is more of a personal
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1 protective equipment, and also the therapeutic side of COVID-
2 19, the treatment side, and the vaccination rollout side.
3 Q. And non-pharmaceutical interventions include things
4 like hand hygiene and personal protective equipment?
5 A. Yes.
6 Q. Outside of...
7 A. Yes. And masking, as well, would be considered that.
8 The term is non-pharmacologic, just to be....
9 Q. Pharm - non-pharmacological. Thank you.
10 A. Pharmacologic. The idea that a vaccine is a
11 pharmacological product, right, or pharmaceutical product.
12 Q. Thank you. Dr. Rau, I'm going to share my screen with
13 you.
14 A. Okay.
15 Q. It's a screenshot.
16 A. This is where I’m going to - I’m going to see if I can
17 get into - you don't think I can get into ZOOM another way, so,
18 I can look at it on my own computer here?
19 Q. Well, you actually have all of these documents that
20 I'll be taking.
21 A. Oh, good.
22 Q. And I’m share my screen as well.
23 A. Sure, sure.
24 Q. But this first document is a snapshot from the website
25 IPAC Canada.
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1 A. Yup. I saw that. Okay.
2 MR. PRESVELOS: Well, just - just wait a second, Doc. She’s
3 going to put it on the screen.
4 A. Mm-hmm. Mm-hmm.
5 Q. Do you see my screen, Dr. Rau?
6 A. Yes, I do.
7 Q. And do you see that this is the -a screenshot of the
8 website, IPAC Canada?
9 A. Yes.
10 Q. And IPAC Canada is the national professional body for
11 infection prevention?
12 A. It’s not a professional body. I want to be clear on
13 that. It's a national organization that is representing
14 infection control practitioners and some physicians who perform
15 my type of function.
16 Q. Right. I'm gonna read you....
17 A. It’s not a - it’s not a - it’s not a professional
18 regulatory body.
19 Q. Thank you. I'm gonna read an excerpt, describing the
20 role of IPAC professionals.
21 A. Yes.
22 Q. This paragraph:
23 Within hospital and other health care

24 facilities, Infection Control professionals, are
25 responsible for keeping abreast of all current
26 infection control standards and practices. They
27 must ensure that these practices are implemented
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1 and the standards maintained within their

2 institutions. This is done by orientation and
3 continuing education of health care workers,
4 consultation, surveillance, and coordination of
5 results. Infection Control professionals
6 maintain a strong liaison with public health
7 authorities.
8
9 Do you see that on your screen?
10 A. No, I don't.
11 MR. PRESVELOS: Sorry, I don’t see - I don’t see that
12 either.
13 A. Or could I go to the link, itself?
14 MS. KERAMATI: I’m sorry.
15 A. Cause all I have is the - I have a screenshot, I don’t
16 have the link.
17 MS. KERAMATI: One moment, please. Okay. I apologize.
18 I’m going to read that excerpt again. Okay. “An infection
19 prevention and control professional...” Do you see that on your
20 computer?
21 A. Yeah, yeah. I see that.
22 Q. “An individual who is employed with the primary
23 responsibility for development, implementation, evaluation, and
24 education related to policies, procedures, and practices, that
25 impact the prevention of infections. Integral competencies to
26 the role include knowledge of infectious disease processes,
27 microbiology, routine practices, and additional precautions,
28 surveillance, principles of epidemiology, resource utilization,
29 and education.”
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1 A. Yes.
2 Q. The purpose of these activities, and application,
3 competencies, will vary depending among the setting, which the
4 IPC functions.
5 A. Mm-hmm.
6 Q. Okay. Would you agree that this is an accurate
7 definition of your current role, as IPAC Medical Officer?
8 A. It's an accurate representation of what an infection
9 prevention control professional is, but I need to clarify here,
10 an infection prevention control professional is actually a
11 nurse, or a lab technologist, who is on the wards. It doesn't
12 describe my role, which is the medical director. I oversee a
13 numerous - a number of infection control practitioners, who are
14 not medically trained.
15 Q. I see.
16 A. Who are not trained as physicians, is what I mean to
17 say. They're medically trained, but not trained as physicians.
18 Q. So, your role would be....
19 A. So...
20 Q. I'm sorry. Go ahead.
21 A. So, my role is to develop all of these policies, or
22 implement, edit, revise, review these policies and decide how
23 we are going to roll these policies out. I provide the
24 leadership. I chair the Infection Control Committee every month
25 and we go over our surveillance results, and we talk about where
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1 we have a problem, and decide how we're going to try and make
2 an intervention or not, or whether we're going to watch it, or
3 what are the problems with the rolling response with COVID-19?
4 Where can we - where are we having challenges with maintaining
5 physical distancing, for example. You know, I’m just giving
6 examples. So, I'm giving the medical oversight to a number of
7 infection control prof - infection prevention control
8 professionals and we call them ICPs, in short.
9 Q. Thank you. Thank you. And related to your duties,
10 as Director of IPAC, is working in the field of antimicrobial
11 stewardship, correct?
12 A. Yes. Now we have a number of physicians in my practice
13 group. And so, some of us are doing more of it than others. I
14 don't do so much antibiotic stewardship now, because I have
15 another physician delegated to do that. I used to do it more
16 at Credit Valley Hospital, but now I focus on this, and the lab,
17 and microbiology as well.
18 Q. I'm going to share my screen with you again. This
19 time with the correct document. Do you see my screen, Dr. Rau?
20 A. Yes, I saw it. Yup.
21 Q. And this is a screenshot of the website Public Health
22 Ontario.
23 A. Yes.
24 Q. And you see the word, “Antimicrobial Stewardship?”
25 A. Yeah.
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1 Q. Okay. I'm gonna read a definition of Antimicrobial
2 Stewardship into the record, and I'd like you to tell me if it’s
3 - if you agree with this definition.
4 A. Mm-hmm.
5 Q. “Antimicrobial Stewardship, promotes the judicious
6 use of anti-microbials to limit the development of antimicrobial
7 resistant organism. Antimicrobial Stewardship programs support
8 coordinated interventions, designed to improve and measure the
9 appropriate use of anti-microbials, including selection, dosing,
10 duration of therapy, and route of administration.” Do you agree
11 with this definition?
12 A. I do, but I think it also has to be added to, now in
13 this era of COVID, because anti-microbials often describe
14 antibacterial agents. And now we have the era of antivirals,
15 more and more. And so, it's not just for COVID, there are other
16 viruses that we treat, post-transplant, HIV, and so on. There
17 are other medical diseases that we would still oversee, under
18 the rubric of antibiotic stewardship, or antimicrobial
19 stewardship, which is really antiviral stewardship. So, it's -
20 it's - this is correct, but there's more to it, than just this.
21 It’s not...
22 Q. Right. And anti-bac - antibacterial stewardship is a
23 major part of antimicrobial stewardship, and not the only part?
24 A. Correct. And it is now, for example, move towards
25 making sure we have available, the treatments for COVID-19, in
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1 hospital, that's just not an anti - antimicrobial, it's an
2 antiviral.
3 Q. And as you said, you have stepped away from - from
4 your role in antimicrobial stewardship. And so, when you were
5 immersed into the role, it was primarily dealing with antibiotic
6 stewardship?
7 A. It - it emerged - by 2004, it changed. We were
8 starting to consider the use of Acyclovir and ganciclovir, which
9 are antiviral agents, right. And even H1N1, by then, I was
10 doing less, but that was 2009. There was still the issue of the
11 vaccine rollout for H1N1, and therapeutics for flu. Also,
12 Tenofovir, which is an antiviral again. It's not purely
13 antibacterial. It's - it’s - even when I was doing it. And
14 also, the - the Antibiotic Stewardship Program, reports to our
15 Infection Prevention and Control Committee meetings every two
16 months. And we then submit the review of that to the Medical
17 Advisory Committee. So, I still have an administrative
18 oversight of this program.
19 Q. Dr. Rau, you're also a Medical Microbiologist,
20 correct?
22 Q. You've been in private practice, as a Medical
23 Microbiologist in two institutions?
24 A. Now, I have - that’s correct. So, I finished my
25 training in medical microbiology, 10 years after I started my
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1 practice as an Infectious Diseases Specialist. So, in 2007,
2 ’08, I went and finished one more year of training to get my
3 certification and medical microbiologist, which is completely
4 separate from infectious diseases from a world college
5 perspective. Then I started overseeing Medical Microbiology for
6 Halton Healthcare. And then during COVID, I had been seconded
7 to help part-time at Humber River Hospital in Toronto with their
8 microbiologist, microbiology response. So, I kind of part-timed
9 between both to make a full-time job, as a microbiologist, but
10 I'm also still administratively overseeing infection prevention
11 control. And I have another physician, who's dealing with that
12 as well. So, we have a group practice, where we delegate some
13 of the actions, just like a law firm might have a senior and
14 junior partner, kind of model.
15 Q. And you oversee the labs in Halton? Or you oversaw
16 the labs in Halton Healthcare and Humber River Hospital?
17 A. The Microbiology Lab. Microbiology Lab.
18 Q. Microbiology.
19 A. Yeah.
20 Q. And overseeing the labs means, supporting the
21 management of lab employees, for example?
22 A. Not so much that a little bit but more of its oversight
23 protocol. What testing is - what testing method are we going
24 to use? What target of the PCR, are we're going to use? When
25 are we going to use antigen tests instead of PCR tests? When
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1 are we going to repeat tests for PCR, after the first test comes
2 back negative? What if we run out of reagents for one system?
3 What are we going to then deploy? That's just on the COVID
4 side, and then there's the whole bacterial testing side,
5 protocols for that.
6 Q. And the decision on which test to use is based on
7 least partly on the cost, correct?
8 A. Sorry. You blocked out there. Is based partly on?
9 Q. The cost.
10 A. In part, and also availability. Right now, when it
11 comes to COVID, we've had huge issues with reagent shortage.
12 And there's been incredibly variable availability of testing.
13 At times, we had to restrict testing, as you may be aware,
14 because we were short of testing reagents. We had to be more
15 focused on who we were testing, especially early, but even more
16 recently during Omicron. So, I had to help make some of those
17 medical decisions, as to where we would cut back or not.
18 Q. You don't conduct research, as a microbiologist
19 though, correct?
20 A. No. Actually, I do. I participate in the Toronto
21 Invasive Bacterial Disease Network, Surveillance Projects with
22 Mount Sinai Hospital and Allison McGeer and I've actually
23 published some papers with them.
24 Q. I'm sorry, you said you - you - you participate in?
25 A. In surveillance research, surveillance research for
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1 bacterial resistance. So, I'm one of the sites submitting
2 specimens and checking perspect - so, you'll see on my resume,
3 there are some publications with Allison McGeer, that's through
4 the Toronto Invasive Bacterial Disease Network. And then more
5 recently, during COVID-19, I was participating in research,
6 helping to identify admitted patients with Omicron, to assess
7 severity disease with the Omicron versus Delta. We haven't
8 published the information because it turned out there wasn't
9 something worth publishing. But that's an example of how I
10 participated. It's not a large part of my job, but I would say
11 it's five to ten per cent of my job.
12 Q. And you said that you oversee the site. Is that
13 correct? Is that - that's - that's your contribution to the
14 research?
15 A. Correct. So, we - so, I would be submitting, helping
16 to – first of all Ethics Committee approval for a study where
17 we would decide what specimens, or as part of a protocol, we're
18 going to send to another lab for further testing, to look for
19 other resistance mechanisms, that may not be immediately
20 detectable in our own lab. But we would do the first line
21 screening to find such specimens.
22 Q. And when you say, “We...”
23 A. For...
24 Q. Right. When you say, “We,” is that specifically your
25 role in the - in....
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1 A. It's always a team effort. We have a whole
2 microbiology team of technologists. And the chief technologist
3 and the lab techs will find these specimens, but then I would
4 help set the protocol that in these circumstances, if you get a
5 specimen, freeze the isolate, put it in the deep freezer, and
6 then when we get a certain number of them, we send them to Mount
7 Sinai to be assessed further or to Public Health Ontario.
8 Q. Okay. What....
9 A. So I’m participating in whatever - called surveillance
10 lab projects.
11 Q. I understand. So, if I understand correctly, then you
12 are collecting - involved in collecting the specimens, but not
13 involved in analyzing the specimens, or the result?
14 A. Well, we have to - we have to do some analysis to
15 select the specimens. It's not just pack and ship, to actually
16 find the right kinds of specimens. So, there's the whole process
17 of setting up a protocol to detect a certain type of resistance.
18 But then there are other types of testing that we don't do. So,
19 many labs have tiered levels of what they do, like a reference
20 lab, might do something quite different from a community
21 hospital lab. And in a tertiary care hospital lab, might do
22 something different from a - a community hospital lab. And then
23 you have the national micro lab, that doesn't really handle
24 direct patient specimens, but they get isolates from another
25 reference lab for further testing.
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1 Q. Okay. I'm - I’m only....
2 A. There are different hierarchies.
3 Q. I’m only concerned with what your particular role has
4 been in assessing....
5 A. Yes.
6 Q. So, if I understand correctly, it has been in
7 collecting the specimens. And that might involve some
8 assessment and then sending it off for - for analysis, is that
9 correct?
10 A. Yes. But also - but that’s not the only form of
11 research I’ve done. There are other things on my resume that
12 are different. We're speaking only as in my medical microbiology
13 role, what I’ve done.
14 Q. Right.
15 A. If you look at my CV, there are other publications to
16 do with clinical issues, clinical cases, or, you know, use of
17 use of school transplant in C. difficile management. I published
18 that in a journal with other - a number of people in the Journal
19 of American Medical Association. We were doing - we had a huge
20 C. difficile outbreak problem. So, I was one of the
21 investigators looking at a different methodology.
22 Q. I understand. Dr. Rau, I - I - I don't recall if -
23 if I asked you this question. Are your hospitals, community
24 hospitals, the hospitals that you work at?
25 A. Yes, they are.
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1 Q. Okay. Thank you. Would it be fair to say that, in
2 your practice, as an Infectious Disease Specialist and Medical
3 Microbiologist, that your areas of focus throughout the years
4 have been on IPAC and antimicrobial resistance and stewardship?
5 A. That will be - the word focus is bothering me. It's
6 a major part of what I do, but a lot of what I do is also patient
7 care. I have a sizable clinical practice and clinical
8 experience.
9 Q. Okay. And....
10 A. And surveying, and also surveillance of hospital
11 infections, is under IPAC. So, we're doing surveillance of -
12 of trends of various community infections or non-community
13 infections in the hospital.
14 Q. At the hospitals in health and health healthcare?
15 A. Yes. Yes. Surveillance is huge. Yeah.
16 Q. And since the outset of the Pandemic, you've provided
17 consultation to staff at Halton Healthcare on the treatment of
18 COVID-19 patients, correct?
19 A. Yes. To other physicians who were taken care of first
20 line, because I’m the specialist.
21 Q. Yes. Prior to the Pandemic, you had no significant
22 involvement in respiratory viruses, correct?
23 A. That's not correct at all. Because there was - there
24 are numerous other respiratory viruses that we keep - we've seen
25 influenza, being the most noteworthy, respiratory syncytial
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1 virus, parainfluenza, other seasonal coronaviruses. Rarely,
2 adenovirus, there's a huge number of other viruses that we've
3 seen. This is not the first time. I've been in practice since
4 1996. We've had numerous bad flu years, good flu years.
5 Q. So, your involvement would have been as your role as
6 the IPAC Officer of these institutions?
7 A. Correct.
8 Q. You haven't conducted research or published widely in
9 this area?
10 A. Not widely. No. I am a clinician and administrator,
11 as a medical director, and then also in the lab, overseer.
12 Q. In your CV, you don't list any education publications
13 or research projects, and immunology, correct?
14 A. Yeah. That's correct.
15 Q. You're not an immunologist?
16 A. I'm not immunologist. No.
17 Q. In your CV, you don't list any training publication
18 or research projects in epidemiology, correct?
19 A. That's not correct. If you look at my CV, just a sec.
20 It depends how you define epidemiology. But to give an example,
21 go through here, back here. I have participated in - where is
22 it? On - take for example, the abstract by Stacy Works (ph),
23 Blue (ph), and myself. Clostridium difficile rates associated
24 with engineering controls in new hospital, rates of the disease.
25 That's epidemiology. It's hospital epidemiology.
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1 Q. Was this a - was this a peer-reviewed published work?
2 A. No, this was a - this was presented to the Infection
3 Prevention Control Canada Conference.
4 Q. I see. You have no publications in epidemiology
5 though would you agree?
6 A. I’m just going through my publications. Just a sec.
7 Let me go through, if I’ve done that.
8 Q. Take your time.
9 A. Actually, the third publication with Allison McGeer,
10 Invasive pneumococcal disease amongst (Inaudible), that’s
11 actually epidemiology. And that’s actually published in a peer-
12 reviewed journal.
13 Q. So, you're referring to your - the - your third
14 publication in your...
15 A. Yeah.
16 Q. CV, at page 3?
17 A. That’s - yeah. That’s part of the surveillance work
18 that I’m doing and that’s epidemiology. Yup.
19 Q. And you are not the first - the lead researcher in
20 this study, correct?
21 A. No, I’m not. No.
22 Q. Okay. You would not - you would agree, though, that
23 you're not an epidemiologist?
24 A. Well, I have a math degree from Waterloo.
25 Epidemiologist Math. So, I am not an epidemiologist with a math
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1 in epidemiology, for example, but I have a math degree.
2 Q. You have a math degree?
3 A. Math degree before I did medicine, and epidemiology
4 is easy math.
5 Q. It’s easy math?
6 A. I would think so.
7 Q. You would agree that you're not an expert in
8 epidemiology?
9 A. Yes. I'm not an expert at epidemiology.
10 Q. Okay. In your CV, you don't list any training
11 publications, or research projects in public health, correct?
13 Q. You're not a public health expert, correct?
14 A. Nope. I'm not an expert in that area.
15 Q. In your CV, you don't list any publications on in-
16 flight transmission or viruses, correct?
18 Q. You're not an expert on in-flight transmission of
19 COVID-19?
20 A. I don't agree with you on that, because as an
21 Infectious Diseases Specialist, we have to understand the
22 transmission and epidemiology of every single disease that we
23 manage or oversee. And a huge part of my job is understanding
24 the transmission of COVID-19 in my hospital environment, and
25 that being that it's the same virus, as you might encounter in
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1 a flight, that is highly relevant. So, I don't agree with that
2 comment.
3 Q. So, you - you are you are equating - all right. Let
4 me - let me reword my question. You - you agree that your
5 experience is on in-hospital transmission of COVID-19?
6 A. It's not just in hospital, even community. To
7 understand this disease, as an Infectious Diseases Specialist,
8 one has to be an expert on how this disease is transmitted in
9 general, where it's acquired, how it’s acquired, how long
10 should my patients isolate for, how do they acquire it at home?
11 It's just not a hospital-focused approach to the disease. So,
12 when it comes to transmission of this disease, I am fully
13 qualified to discuss this disease.
14 Q. You're qualified to discuss transmission of COVID in
15 any setting?
16 A. Yes, including long-term care and congregate settings
17 too.
18 Q. Dr. Rau, do you have expertise in aircraft, air flow,
19 and filtration systems?
20 A. No, I don’t.
21 Q. And you would agree that transmission varies with the
22 environment?
23 A. Yes, it does.
24 Q. In your CV, you've listed one publication on COVID-
25 19, correct?
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2 Q. And it was a review of the Canadian response to the
3 Pandemic up until August 2020, prior to Canada's vaccine
4 rollout, correct?
5 A. That is correct.
6 Q. The article was not related to COVID-19 vaccines?
7 A. Correct. It was prior to the availability of vaccine.
8 Q. In your CV, you don't list any specific education,
9 publication, or research project on vaccines, correct?
10 A. Except for pneumococcal vaccine. Number three.
11 Q. Thank you. You're not a vaccinologist correct?
12 A. I am not. No.
13 Q. From 2012 to 2019, you're a member of the committee
14 to evaluate drugs, correct?
16 Q. And the committee to evaluate drugs is an advisory
17 committee on drug-related issues?
18 A. Yeah. So, I was appointed to an order in council to
19 the Ministry of Health, to be an advisor on all aspects of anti-
20 viral and anti-bacterial therapeutics for the province, to
21 decide what drugs to put on the provincial formulary, and how
22 to reimburse drugs.
23 Q. It's not a committee on vaccines?
24 A. That is not a - no, it is not.
25 Q. You’re not an expert on vaccines?
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1 A. I don’t agree with that comment. I'm an expert, as
2 far as an infectious diseases specialist, would be, and a huge
3 part of the core competency of an infectious diseases specialist
4 through the World College certification, and even for medical
5 microbiology, but more so, efficiently, is to understand
6 vaccines, vaccine design, vaccine efficacy, which diseases are
7 vaccine preventable, waning immunity, even the immunology of
8 vaccines, different types of vaccines. That's a huge part of
9 the core training of an infectious disease specialist.
10 MS. KERAMATI: Counsel, can you confirm that Dr. Rau is not
11 being put forth as an expert on vaccines?
12 MR. PRESVELOS: Dr. Rau has expertise, particular
13 expertise, in vaccines as he's described to you, but he is acting
14 as an expert in this matter on infectious disease, and all the
15 other matters that you've already asked him about, as to whether
16 or not he has the requisite qualifications. And if there are
17 certain sub - if there are certain subject matters that fall
18 within that expertise, as Dr. Rau has already described to you,
19 I mean, it would be entirely appropriate to consider him an
20 expert in those areas as well. I don't think it's as linear,
21 as saying he's an expert in X, but not Y.
22 MS. KERAMATI: Would you agree that he - you're not putting
23 him forward as an expert on COVID-19 vaccines?
24 MR. PRESVELOS: I would have to consider that a bit, because
25 obviously his expert report does talk about waning immunity as
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1 it pertains to vaccination and waning immunity is something that
2 is properly qualified to opine on. So, again, I don't think,
3 you know, saying whether or not he's an expert on vaccines, is
4 a loaded - it's a loaded scope. Clearly, there are certain
5 things within vaccinations, characteristics of vaccinations and
6 its impact on infectious diseases like COVID, that he would be
7 qualified to give an opinion. What - what - what I'm happy to
8 do is consider what you're - to consider your question a little
9 bit further, maybe provide you with a written clarification on
10 that.
11 MS. KERAMATI: Yeah. I - I - I would - I would ask for
12 that clarification before I proceed with my questioning. So,
13 I'm happy to take a break and give you a few minutes to - to
14 clearly define the topic on which Dr. Rau is being presented as
15 an expert.
16 MR. PRESVELOS: To clearly define the topic on which he's
17 being presented as an expert.
18 MR. BACHAND: That's a - sorry. Off record, can we have
19 a break room or a separate room to maybe have a chat about that?
20 MR. PRESVELOS: Well, Samuel, it's - it’s - let’s just a 10-
21 minute break. And if we need to connect, we can....
22
23 OFF RECORD
24
25 MR. PRESVELOS: Okay. So, I'll clarify the expertise and -
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1 and the scope of expertise, although really that's - that's for
2 a trier of fact. Dr. Rau is an expert in microbiology and
3 infectious diseases. So, he is an expert in infectious diseases
4 and microbiology, but he's qualified to opine on, as he has,
5 matters of general epidemiology and trends, vaccination effects
6 and efficacy, and vaccination. The - when I say vaccination and
7 effects, that includes also the impacts on vaccinations, such
8 as waning, you know, waning immunity, as a result of
9 vaccinations. He's opine to - to - he's qualified - sorry - to
10 opine on matters of transmissions of infectious diseases, he's
11 opine to - he's qualified to opine on issues, such as natural
12 immunity in response to infectious diseases, such as COVID-19.
13 And as well as all discipline and sub-disciplines that might be
14 connected with these matters. So, that's - that's, you know,
15 you have - I've given you and you certainly have a lot of
16 latitude to ask Mr. Rau about his educational background, his
17 clinical experiences, and his academic participation in various
18 medical subject areas. And I'm not going to engage in a debate
19 as to whether or not you believe or, you know, whoever here
20 might believe he is properly qualified to opine on certain
21 things. Obviously, all the stuff - all the - all the matters
22 that he has provided an opinion on in his report, we - our
23 position would be that those are matters which through
24 experience and through his educational background, and
25 otherwise, he's certainly qualified to provide an opinion on to
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1 the Court. So, you know, take - take from that what you will,
2 ask whatever questions you will, and if there's going to be an
3 objection to Mr. Rau’s expertise in a particular area, that he
4 has commented on in his report, you know, we can have that fight
5 in front of the judge, and go through the - go through the
6 necessary tests to see whether or not he's - he's going to be
7 accepted as an expert in those specific areas.
8 MS. KERAMATI: So, just for the record, Counsel, the
9 Federal Court rules require, this is Section 52.2, that an
10 affidavit or statement of an expert witness, shall set out in
11 full, the proposed evidence and the expert’s qualifications and
12 areas, in respect of which it is proposed that he or she will
13 be qualified as an expert. So, it - it is certainly a
14 requirements for the applicants to set this out, but I - I will
15 also say that for - just for the record, Canada's position is
16 that Dr. Rau's training and experience does not qualify him as
17 an expert on vaccines. This....
18 MR. PRESVELOS: Well, you can define that - you can define
19 that - first of all, paragraph - the first paragraph of....
20 MS. KERAMATI: Please let me finish my - my sentence. So,
21 we will - this is a matter for - for argument, at this point.
22 MR. PRESVELOS: Sure. I mean, the very first paragraph sets
23 out his credentials, including an internal medicine, medical
24 microbiology, his specialized competence in infectious diseases.
25 So, if the Attorney General wants to take the position that he's
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1 not an expert in vaccines, I - I don't know what that means, but
2 I suspect that, you know, it's not as - it's not a simple
3 dichotomy that the Attorney General is trying to establish here.
4 Clearly, there are matters of vaccines and vaccinations that are
5 very relevant in Dr. Rau’s specialty, you've explored some of
6 them. He's described how those issues have presented in his
7 clinical experience, and his - and his research experience. So,
8 beyond that, you know, I don't know - I don't know what else to
9 say other than the statement that I've already made.
10 MS. KERAMATI: That’s fine.
11 MR. PRESVELOS: If you think an infectious disease
12 specialist cannot opine on the impacts and efficiencies of the
13 vaccines, that's going to be interesting.
14 MS. KERAMATI: Counsel, this is now - this is now for
15 argument. And we're - we're getting away from the purpose of -
16 of the cross-examination today. So, I'll - I - I have your
17 statement, and I'll move onto my questions. Before I do, I
18 wanted to enter the two documents that I screenshared as
19 exhibits. So, the first document was the screenshot of the IPAC
20 Canada website, as Exhibit 1. And the second document was the
21 Public Health Ontario definition of “Antimicrobial Stewardship,”
22 as Exhibit 2.
23 EXHIBIT NUMBER 1: Screenshot of the IPAC Canada website
24
25 EXHIBIT NUMBER 2: Public Health Ontario definition of
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1 “Antimicrobial Stewardship”
3 MS. KERAMATI: Dr. Rau, I'm going to take you to a few
4 excerpts from your Expert Report now.
5 A. Yes.
6 Q. Before I do, you would agree that as a medical
7 professional, it's your responsibility to continue to evaluate
8 emerging evidence?
9 A. Yes, that's correct.
10 Q. You would agree that it's important to keep an open
11 mind?
12 A. Yes.
13 Q. You would agree that peer-reviewed published medical
14 articles are more reliable sources for drawing scientific
15 conclusions than media articles?
16 A. Yes, however, in the absence of a peer-reviewed
17 article in a rapidly moving situation, sometimes one has to rely
18 on a media article. But the more reliable is something that's
19 published and it takes time for something to be peer-reviewed
20 and published. So often, in this outbreak, we've been relying
21 on pre-published information through an archive, which hasn't
22 been peer reviewed. And both myself and your experts, have
23 relied on such documents. Dr. Kindrachuk has numerous documents
24 that are have been archived referenced, and media articles
25 sometimes provide information on the local situation of. the
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1 giving country that’s not available in a published form yet.
2 Q. You would agree that pre-print medical articles are
3 not media articles? When I say, “Media articles,” I mean,
4 articles in newspapers, magazines.
5 A. Yes. I'm not making media articles an authority. But
6 I want to point out that the articles often link to data and
7 surveillance data in a hyperlink that is relevant. And it's
8 before it's been published in a rapidly moving situation like
9 COVID-19. If there were not an outbreak in emergence, I wouldn't
10 rely on media articles.
11 Q. I understand. Dr. Rau, can you turn to paragraph 3
12 of your report, please?
13 A. Yes.
14 MR. PRESVELOS: Sorry. When you say paragraph 3, is this -
15 is it paragraph number 3, or the third paragraph that appears
16 in this report?
17 MS. KERAMATI: Paragraph number 3. So, from now on, when
18 I refer to paragraph numbers, it's the number that comes in
19 front of the paragraph in - in Dr. Rau’s report. Do you have
20 that in front of you, Dr. Rau?
21 A. Yeah, I do. Yeah.
22 Q. In paragraph 3, you state, “Contrary to popular
23 belief, a recently published analysis demonstrated that case
24 growth in Canada during the early 2020 period, did not correlate
25 with the stringency, strictness of numerous non-pharmacological
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1 interventions, NPIs, implemented during the first phase.” Do
2 you see that statement?
3 A. Yes, I do. And that's ref - referring to the paper
4 by Vickers, that's cited, and it’s now published in a peer-
5 reviewed journal.
6 Q. Which is cited at footnote 2, correct?
7 A. Correct. But it's now even published in the
8 International Journal of Infectious Diseases. It was in med
9 archive at that time.
10 Q. Okay. I'm going to screenshare a portion of Dr. Dawn
11 Bowdish’s Expert Report with you.
12 A. Yes. Is Dr. Bowdish an expert in - in this area by
13 the way?
14 Q. I'm afraid that's not relevant for our - our cross-
15 examination today.
16 A. But you’re asking me to - okay. We’ll see what you’re
17 asking me to do.
18 Q. I’m simply asking you to review a portion of her expert
19 report, which...
20 A. Mm-hmm.
21 Q. ...I understand you - you have already reviewed.
22 So....
23 A. I need to see - I need to see what - it’s a massive
24 report. I’ll have to see which part it is and focus on...
25 Q. Well, I’m gonna - I’m gonna start at the first page,
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1 so, that you can see that this is the Affidavit of Doctor Dawn
2 Bowdish.
3 A. Mm-hmm.
4 Q. This is her affidavit.
5 A. Mm-hmm.
6 Q. You agree that this is Dr. Bowdish affidavit and
7 expert report?
8 A. Yes, I do.
9 Q. Okay. I’m going to scroll down now to page 40 of the
10 report...
11 A. Yup.
12 Q. ...which is page 146 of the PDF document.
13 A. Right.
14 Q. And page 40 of the report, there’s a heading that
15 states, “Non pharmaceutical interventions are effective at
16 reducing COVID-19 infections and hospitalizations.” Do you see
17 that Dr. Rau?
18 A. I see the statement.
19 Q. Okay. I'm going to scroll down, the first full
20 paragraph on the next page.
21 A. And I can't see this properly with my glasses. And
22 so, I’ll need you to magnify it, please.
23 Q. I’m happy to.
24 A. More. I still can’t see it well. Keep going. There.
25 Now I can see it.
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1 Q. Okay. I'm going to read this portion into the record
2 and then ask you some questions about it. The reference that
3 Dr. Rau provides in his Expert Report at paragraph 3, page 19,
4 reference 2, stating, “That non-pharmaceutical interventions
5 were not effective is not consistent with most studies
6 demonstrating effectiveness. Other studies that include
7 measures of mobility, workplace attendance and model longer lag
8 time between the introduction of the measure and the reduction
9 of infections have found them to be effective. And the Ontario
10 Science table uses these combined measures to make accurate
11 predictions about COVID-19 infections. In contrast to Dr. Rau’s
12 assertion, Rau Expert Report, at par. 4, page 19, masking is
13 associated with reduction with reducing cases and lifting mask
14 mandates has been shown to increase infection rates.” Do you
15 see that statement Dr. Rau?
16 A. I see that statement. Yeah. I don't agree with it,
17 but I see it.
18 Q. And you'll see that in support of her statement, Dr.
19 Bowdish has cited numerous footnotes, correct?
20 A. Yeah. So, let's go through those footnotes then,
21 because I'm not going to agree with this, without going through
22 each of those references. And I also...
23 Q. You’re one step ahead. Yeah.
24 A. Yeah. And the other point I want to make is the
25 Ontario Science Table, she says, “Uses them to make accurate
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1 predictions.” Every single model from the Ontario Science Table
2 has been inaccurate to date, including the most recent ones.
3 So, if you actually look at their predictions versus what's
4 happening, if you go to the - the models they have presented,
5 they have routinely over called an overshot of their predictions
6 about what would happen with hospitalizations and deaths in
7 Ontario, including the current wave.
8 Q. Okay. I'm going to scroll down to the references, Dr.
9 Bowdish’s references, and I'm gonna take you through the
10 references that she cites in support of the portion of a
11 paragraph that I read out to you.
12 A. Okay.
13 Q. The first is item 147. In arriving at your conclusion,
14 in your report, Dr. Rau, did you consider the study by Karaivanov
15 titled, “Face masks, public policies and slowing the spread of
16 COVID-19, Evidence from Canada,” published in the Journal of
17 Health Economics 2020.
18 A. No, I didn’t - I didn’t review that article. So, I
19 would like to see the article and have time to review it, if
20 this is relevant.
21 Q. Thank you.
22 A. It's also a Journal of Economics, health economics,
23 but that’s fine. I'm happy to look at that paper.
24 Q. But my - my question was, did you - I - I suppose
25 you've answered my question, but you didn’t review it in
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1 preparation for your report? Okay.
2 A. No.
3 Q. Paragraph 1, footnote 148, please.
4 A. Uh-hmm.
5 Q. In arriving at your conclusions in your report, did
6 you consider this study by Iezadi and others titled,
7 “Effectiveness of non-pharmaceutical public health
8 interventions against COVID-19: A systemic review and meta-
9 analysis,” 2021.
10 A. I didn't read the whole paper. So, I would need to
11 look at it in detail.
12 Q. Did you review part of the paper, prior in - in
13 preparation for your report?
14 A. No. Not - I - this is a paper that I have seen a bit
15 of at one point, but I have not reviewed it in detail. There
16 have been so many publications you can say. No, I haven’t, no.
17 Q. Thank you. Footnote 149, please, Dr. Rau. In arriving
18 at your conclusions in your report, did you consider the study
19 by Davies and others titled, “Effect of non-pharmaceutical
20 interventions on COVID-19 cases, deaths and demand for hospital
21 services in the UK: A modelling Study,” published in the Lancet
22 Public Health, 2020.
23 A. I have seen this paper because it came out early in
24 the pandemic. And I don't have a photographic memory of it.
25 So, I would have to look at it again with you, to go through it.
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1 Again, there have been so many publications, but I have seen
2 this paper.
3 Q. So, you're not sure whether you've considered this
4 paper in arriving at your conclusion in your report?
5 A. Well, I have seen this paper and I didn't discuss this
6 in my report, because it is a contrary conclusion to what I
7 think is a better paper done in Canada, based on the Canadian
8 jurisdiction, early pandemic, before we had a vaccine. And this
9 is a paper we can also discuss. But there are methodological
10 challenges in assessing many of these papers. And one of the
11 biggest pitfalls in all of these papers, when they assess the
12 first wave of COVID-19, is that they ignore that just the change
13 from winter to summer leads to a decrease in cases, in temperate
14 climates, including Sweden, which did no pharmacological
15 measures, or almost no pharmacological measures. Even in
16 Sweden, it went down, and it was before anyone was wearing masks.
17 There were no masks in 2020 in the first wave, and the numbers
18 went down.
19 Q. Looking at footnote 150, Dr. Rau, in your - in - in -
20 in arriving at your conclusions in your expert report, did you
21 consider the study by Public Health Ontario, or the article
22 rather, by Public Health Ontario, titled, “Association Between
23 Mask Mandates and Population Level COVID-19 Outcomes: What we
24 Know So Far?”
25 A. Again, I have seen this document. I don't have a
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1 photographic memory of it. I don't agree with their conclusions,
2 because, again, the seasonality is never considered in a lot of
3 these pithier papers, or - or opinion pieces, and subsequently
4 there are people talking more and more about seasonality. It's
5 getting to be quite clear there's a seasonality factor. Even
6 public health officials are saying it - on TV, that there's a
7 seasonality, and that the summer will be better and then we will
8 see a resurgence in the fall.
9 Q. Looking at item 154, Dr. Rau, in arriving at your
10 conclusions in your report, did you consider the study by Islam
11 and others titled, “Physical distancing interventions and
12 incidents of coronavirus disease 2019.”
13 A. Yes.
14 Q. “Natural experiment in 149 countries 2020.”
15 A. Yeah, I have seen this paper early in the pandemic.
16 Again, the problem with a lot of these papers is that there are
17 so many things going on at the same time, that it is very
18 difficult to tease out which of the interventions actually
19 worked. So, one can't just say it's because of physical
20 distancing that the numbers went down, when just the seasons
21 alone are dragging things down, or when capacity limits are
22 happening, and when masking is subsequently implemented. This
23 is from 2020, before masking, but I'm saying there are - there
24 were - so, as you've seen in the paper I have cited and even the
25 paper that you have provided to me by Li, there are so many
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1 pharmacological and non-pharmacological interventions going on,
2 that it is impossible to tease out one and say that that works.
3 It's - it's - there - there are so many things happening. If
4 that’s the challenge, and why do we need such sophisticated
5 retrospective analyses, that are highly mathematical to figure
6 out whether these actions work or not? I'm not saying they
7 don't work at all, but the degree to which they work is highly
8 debatable.
9 Q. Okay. So, Dr. Rau, I'm - you would agree that, so
10 far, you have not cited any of these articles or discussed any
11 of these articles in your report, correct?
12 A. That’s correct. I didn’t cite them. No. That - Dr.
13 Bowdish didn’t cite the papers I have cited by Dr. Grawl (ph),
14 as well, in Vickers, it’s not - it’s not one of the ones that’s
15 discussed in detail either.
16 Q. I believe Dr. Bowdish acknowledged that report,
17 but....
18 A. Hmm.
19 Q. I’m gonna screenshot - share my screen with you again.
20 A. Mm-hmm.
21 Q. There’s just two more - one moment, please. Do you
22 see my screen, Dr. Rau?
23 A. Yes.
24 Q. This is the same page that we were looking at previous
25 references from Dr. Bowdish. Okay.
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1 A. Okay. Yes.
2 Q. The next item is, item footnote 155.
3 A. Mm-hmm
4 Q. In arriving at your conclusions in your report, you
5 consider the study by Stevens and others, titled, “Estimating
6 the effects of non-pharmaceutical intervention and population
7 mobility on daily COVID-19 cases: evidence from Ontario Canadian
8 Public Policy, 2022.”
9 A. I didn't cite this. I have seen this as well. But
10 this is also a Canadian Public Policy. This is not a top-tier
11 medical journal, if I may say so, this is a policy journal.
12 This is not exactly a high - a high-level science journal. I
13 wouldn't use that as an authority in a report, myself.
14 Q. Now, 156, Dr. Rau. In arriving at your conclusions
15 in your report, did you consider the Ontario Dashboard Science
16 briefs of the Ontario COVID-19 Science Advisory Table?
17 A. So, I read all of these regularly, as a physician. I
18 don't cite these as authorities. These are summaries of other
19 people's work. They're not inaccurate, necessarily, they're not
20 authorities that I would use in reporting.
21 Q. Okay.
22 A There's a synopsis of what's happening.
23 Q. Dr. Rau, I'm going to pull up one additional study and
24 you should have it. It was in a package of documents sent to
25 you today. It's by Li and others.
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1 A. Yeah. Got it here. Mm-hmm.
2 Q. And I'll share my screen with you. Do you see that
3 document up on my screen, Dr. Rau?
4 A. I do. Yeah.
5 Q. You would agree that this is an article by Li and
6 others, titled, “The temporal association of introducing and
7 lifting non-pharmaceutical interventions...
8 A. Yeah.
9 Q. ...with the time-varying reproduction Number (R) of
10 SARS-CoV-2:...
11 A. Yes.
12 Q. ...A modelling study across 131 countries.”
13 A. Yes.
14 Q. Okay. I'm going to read the portion following the
15 word, “Interpretation,” into the record. Are you able to see
16 that on my screen, Dr. Rau?
17 A. You're talking about at the beginning under the
18 abstract?
19 Q. Um.
20 A. Where’s the abstract?
21 Q. It’s…
22 A. Yeah, yeah. It’s in the beginning, the abstract, I
23 see it. Yeah.
24 Q. On the first page of the document.
25 A. Mm-hmm.
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1 Q. Interpretation, individual NPIs, which I understand
2 are non-pharmaceutical intervention, from a non - let's see,
3 let's get it right - non-pharmaceutical interventions. So,
4 “Individual N - NPIs, including school closure, workplace
5 closure, public events ban, ban on gatherings of more than 10
6 people, requirements to stay-at-home, and internal movement
7 limits, are associated with reduced transmission of SARS-CoV-2,
8 but the effect of introducing and lifting the NPIs is delayed
9 by 1 to 3 weeks, with this delay being longer when lifting NPIs.
10 These findings provide additional evidence that can inform
11 policy-maker decisions on the timing of introducing and lifting
12 different NPIs, although R should be interpreted in the context
13 of its known limitations.” Do you see that statement, Dr. Rau?
14 A. I see that.
15 Q. Did you consider this paper in preparing your report,
16 Dr. Rau?
17 A. I'd seen this paper and I didn't cite this paper,
18 because I don't think it's a very good paper. I think it has a
19 lot of limitations. And if I (Inaudible) the discussion in the
20 paper, if we can go to that, towards the latter part of this
21 paper there - there, they mentioned a huge number of limitations
22 in this paper. They talk about the innate limitations of using
23 R as a measure of transmission. They talk about - there are
24 like four paragraphs talking about the limitations of this
25 paper. But we - we acknowledged several limitations of the
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1 methodology, for the R estimate used in our analysis. There are
2 so many limitations in this paper. And the other big problem
3 with this paper that I'm going to cite is that they talk about
4 how cases increase with the relaxation of restrictions, such as
5 school closures, but school closures are relaxed in the fall.
6 That's when cases go up. Public transportation increases during
7 the fall, when people go back to work. So, the problem is that
8 there's a seasonality factor that can be driving a lot of these
9 associations, that are not corrected or taken into account. So,
10 there can be natural forces at play. I'm not saying the whole
11 thing is natural forces. But it doesn't take - it - it doesn't
12 - it doesn't include that in its analysis, mathematically
13 speaking, but it should.
14 Q. So, in answer to my question, Dr. Rau, did you consider
15 this paper in preparing your report?
16 MR. PRESVELOS: He - he refused....
17 MS. KERAMATI: I...
18 MR. PRESVELOS: Sorry. Counsel, he responded that he saw
19 this paper and did not include it and for the reasons he just
20 cited to you.
21 MS. KERAMATI: That doesn’t answer my question on whether
22 he considered it for the purpose of this report.
23 MR. PRESVELOS: Sure, it does.
24 MS. KERAMATI: Can I - can we allow Dr. Rau to answer the
25 question?
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1 MR. PRESVELOS: No. No, because this is....
2 MS. KERAMATI: I’m sorry?
3 MR. PRESVELOS: No. No. This is getting pedantic. He
4 answered it. It's on the record. Okay. He said he considered
5 the report, but he didn't cite it, and he pointed you to several
6 paragraphs to talk about the report’s limitations in support of
7 why he decided not to cite this paper in his expert report.
8 That's literally what we spent the last, you know, eight minutes
9 talking about. He said...
10 MS. KERAMATI: Counsel....
11 MR. PRESVELOS: ...he didn’t include it because he disagrees
12 with it.
13 MS. KERAMATI: Counsel, I’d like to add this as Exhibit
14 Number 3.
16 MS. KERAMATI: I’m sorry?
17 MR. PRESVELOS: Go ahead. Yeah. Go ahead. Go ahead.
18 EXHIBIT NUMBER 3: Published Article by Li and others,
19 titled, “The Temporal Association of Introducing and Lifting
20 Non-Pharmaceutical Interventions with the Time-Varying
21 Reproduction Number (R) Of SARS-Cov-2: A Modelling Study Across
22 131 Countries”
23 MS. KERAMATI: Okay. Dr. Rau, please turn to paragraph 5
24 of your Expert Report. Are you at paragraph 5, Dr. Rau?
25 A. Yes. Yes, I am.
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1 Q. Okay. Okay. You'll see that paragraphs 5 to 9, under
2 the heading, “Strict Border Measures Do Not Stop Variants.”
3 A. Yes.
4 Q. Do you see that? Okay. In these paragraphs you
5 discuss the relationship between vaccination rates, travel
6 restrictions and case (Inaudible) in other countries, correct?
7 A. Correct.
8 Q. At paragraph 8, you state, “There is no evidence to
9 suggest that pre-existing high vaccination rates have blunted
10 the trajectory of daily new infections of the COVID-19 variant.”
11 Do you see that statement, Dr. Rau?
12 A. Yes, I do. We’re talking about number nine now, or
13 eight? Just a sec, we’re on eight?
14 Q. Paragraph 8.
15 A. Which state - which sentence are we at? Sorry. “There
16 is no evidence,” I see it. Yup. Okay.
17 Q. It's the first - the first.
18 A. Yup. Mm-hmm.
19 Q. And in support of these paragraphs, you cited
20 footnotes 4 to 13, correct?
21 A. In - sorry about that. I couldn’t hear?
22 Q. In support of para - in support of paragraph 5 to 9...
23 A. Yes.
24 Q. ...it’s cited footnotes 4 to 13, correct?
25 A. Four to thirteen, correct. And there’s even a more
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1 recent new journal publication that has come out that further
2 supports this opinion, but it was not available when I did the
3 report. Describing the outbreak in South Africa, which very
4 clearly supports what I'm saying. My counsel has that paper,
5 if you're interested.
6 Q. Thank you. I'm - I’m gonna share my screen with you
7 again, Dr. Rau.
8 A. Mm-hmm.
9 Q. This is a - I’m - I’m sharing Dr. Bowdish’s Expert
10 Report with you, again. Do you see that?
11 A. Yes.
12 Q. I’m going to go down to page 29 of the Expert Report,
13 which is page 135 in the PDF document.
14 A. Okay. Now, I don’t have the whole document downloaded
15 here. I had - I have to go in to....
16 MR. PRESVELOS: It’s - it’s on the screen.
17 Q. It’s on the screen, Dr. Rau.
18 A. Okay. You have to magnify the whole thing. I can’t
19 see it. Okay. Can you magnify it, please? I can’t see it.
20 Q. I will magnify it. I’m - I’m going to pinpoint where
21 the statement I’m reading. Okay. Do you see that Dr. Rau?
22 A. Yup. Mm-hmm.
23 Q. So, starting at about five lines from the bottom,
24 starting with the word, “In Canada.” Do you see that?
25 A. Yup.
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1 Q. Okay. “In Canada, Omicron infections are associated
2 with high rates of hospitalization, and poor outcomes in
3 unvaccinated individuals.”
4 A. Yes.
5 Q. Figure 10.
6 A. Yes.
7 Q. “However, having a highly vaccinated population
8 mitigated the effects of Omicron. Vaccination significantly
9 blunted the effects of Omicron in Canada, by reducing deaths and
10 hospitalizations in those who are unvac - who are vaccinated,
11 I'm sorry. However, hospitalization is still high in
12 unvaccinated individuals, Figure 10.” End quote. Do you see
13 that statement, Dr. Rau?
14 A. Yes.
15 Q. Okay.
16 A. Yes, I see that statement. And that refers to
17 something totally different from what I’m referring to in my
18 affidavit. I’m referring to whether it stops the infection from
19 coming in, not whether vaccines protect against severe disease.
20 Q. I understand.
21 A. So, we - we all agree that the vaccines prevented bad
22 outcomes, even with Omicron, despite the less effectiveness of
23 the vaccine against Omicron versus the original COVID strain,
24 or Alpha, or Delta. But the point is a high vaccination rate
25 did not stop the virus from taking hold in either South Africa
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1 or a low vaccination rate didn't, or in Japan with the high
2 vaccination rate, the virus still came in. That's the point I
3 was making in those statements.
4 Q. Okay. I - I’m going to scroll down just to the chart
5 right below the paragraph that I read to you from Dr. Bowdish’s
6 Report.
7 A. Mm-hmm.
8 Q. And this is the Figure 10, that Dr. Bowdish...
9 A. Yes.
10 Q. ...refers to in...
11 A. Mm-hmm. Can you magnify that, please?
12 Q. Can you see that figure?
13 A. Yeah from the Ontario Science Table. Yeah. Keep
14 going. Yeah. Please, bigger. Just a little bigger. Okay.
15 Q. I can’t make it any bigger than...
16 A. Okay.
17 Q. ...than that without it.
18 A. Right. And which - which ones are the...
19 Q. The...
20 A. ...which are the months in the bottom there, for each
21 of those? I can't remember.
22 Q. So, the months are August 10th, 2021.
23 A. Right.
24 Q. To April 19th, 2021.
25 A. Right. Mm-hmm..
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1 Q. Okay.
2 A. Right. Yup.
3 Q. You would agree - you would agree that this data is
4 from the Ontario Science - Science Table?
5 A. It's - it’s provincial data, they have copied, and I
6 agree with the data. It’s a graph. The graphs are accurate.
7 Yes.
8 Q. Okay. And Figure 10 is comprised of three graphs?
9 A. Yup.
10 Q. The first graph is titled, “COVID-19 Cases.”
11 A. Yup.
12 Q. The second is titled, “COVID-19 Patients in Hospital.”
13 A. Right.
14 Q. And the third is, “COVID-19 Patients in ICU.”
15 A. Correct.
16 Q. The data in these graphs is, with respect, as I noted
17 to the period of August 10th, 2021, to April 19th, 2022.
18 A. Right.
19 Q. You agree that – you agree that in each graph, Dr.
20 Rau, the orange line represents unvaccinated individuals...
21 A. Yes.
22 Q. ...who are vaccinated, at least two doses?
23 A. Right.
24 Q. And, Dr. Rau, in each graph, the orange line is higher
25 than the blue line, with the most significant difference being
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1 with respect to hospitalizations and death, correct?
2 A. That’s correct. Yeah. Mind you, the aggregate
3 numbers are not so high anymore. That's the point we're not
4 discussing. If you looked at the numbers earlier, for deaths,
5 it would be much higher than we saw in this wave. This is the
6 Omicron wave based on the timing. And the - what are the - what
7 is the range of - of numbers on the Y-axis there? I think what's
8 - what's the highest it goes?
9 Q. Twelve-hundred. Well, for COVID-19 cases, it goes up
10 to 1200, COVID-19 patients in hospitals, 1200, COVID-19 patients
11 in ICU, 300.
12 A. Three-hundred. Yeah.
13 Q. And the axis reads, “COVID-19 cases per 1 million.”
14 A. Yup. That’s on - on the cases. Yeah. But in the
15 hospital, it's per - a million, as well.
16 Q. One million. Yes.
17 A. Per million. So, it's population bracket, right.
18 Yeah. This is the provincial data. Mm-hmm..
19 Q. And just to be clear, the data, the charts start from
20 August 10th, 2021.
21 A. Right. The later part of this pandemic, so far, yeah.
22 Q. So - so, this data is from April 2022, after your
23 report, but you'd agree that that data would have been available
24 on the website at the time of your report?
25 A. Well, the - a censored to - to when I did the report.
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1 So, obviously, it’s - that’s - that's why I’m referring to later
2 date, myself.
3 Q. Dr. Rau, in preparing your report, did you consider
4 up-to-date data from the Ontario Science Table? And the rates
5 of COVID cases, COVID-19 patients in hospital, and COVID-19
6 patients in ICU for vaccinated and unvaccinated individuals?
7 A. So, I'm gonna issue a correction here. The data is
8 not from the Ontario Science Table. The Ontario Science Table
9 is a group of people, who are not even formally engaged by the
10 government, but they are giving advice, or on Twitter, they
11 issue documents. It's really Ontario epidemiology data that is
12 been summarized here. So, it's not data from the Ontario Science
13 Table. But the Ontario Science Table is not the authority.
14 This is the epidemiologic summary that I can find going to the
15 Ontario Ministry of Health website, or Public Health Ontario
16 website.
17 Q. So, did you consider rates of COVID cases? COVID-19
18 patients in hospitals?
19 A. Absolutely.
20 Q. Patients in ICU?
21 A. Absolutely.
22 Q. Or the....
23 A. I think I....
24 Q. I’m sorry. Let - I’m just going to finish my question.
25 A. Yes.
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1 Q. Vaccinated and unvaccinated individuals?
2 A. Yes, I did.
3 Q. In preparation - in consideration for your report?
4 A. Yes, I did. And I feel - I believe I gave even cited
5 links to the Ontario epidemiology reports in my - in my report,
6 as well.
7 Q. Okay. I'm going to stop sharing my screen with you
8 for a moment. Okay. Dr. Rau, I'm going to share my screen with
9 you again. I'm turning to the Government of Canada COVID-19
10 daily epidemiology update.
11 A. Which you’ve just sent me. Yeah.
12 Q. Thank you for that.
13 A. Mm-hmm..
14 Q. Do you see that document on my screen? Or on your
15 screen rather?
16 A. This is what you sent me this morning, right? The
17 update the summary? Yeah.
18 Q. Yes.
19 A. Okay. I got it here too. Okay.
20 Q. And do you agree that this is a document called,
21 “COVID-19, Daily Epidemiology Update.” Last updated, May 17th,
22 2022?
23 A. Yes, I do.
24 Q. Okay. And this website is updated daily?
25 A. Yes. Not on weekends, and some holiday periods, but
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1 yes, it is. Yeah. Generally.
2 Q. So, the first paragraph summarizes the website as
3 follows, “Summary of COVID-19 cases across Canada and over time,
4 contains detailed data about the spread of the virus over time
5 and in different regions of the country. Includes breakdowns
6 by age, and sex, or gender, provides an overview of
7 hospitalizations and deaths, testing variants of concern and
8 exposures.” Do you see that, Dr. Rau?
9 A. Yes, I do.
10 Q. I'm going to scroll down to Figure 5, which is at the
11 bottom of page 20 of the PDF document. Do you see Figure 5 on
12 my screen, Dr. Rau?
13 A. I’m looking here. Yes. I'm getting into it. Yup.
14 Mm-hmm.
15 Q. And Figure 5 is titled, “Distribution of Confirmed
16 COVID-19 cases reported to PHAC,” which is Public Health Agency
17 of Canada by vaccination status as of April 24th, 2022.
18 A. Yes.
19 Q. You'll note that Figure 5 is comprised of three
20 graphs.
21 A. Yes, I see it.
22 Q. The first graph is titled, “Cases.”
23 A. Yes. And “Hospitalizations” and then “Deaths.”
24 Q. That’s right.
25 A. You know, what's really remarkable about this graph
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1 is that if you add up the fully vaccinated and even fully
2 vaccinated with an additional dose percent, for all categories,
3 except hospitalizations, for the deaths, and for the - at least
4 for cases, you actually see more cases amongst fully vaccinated
5 and vaccinated, and with hospitalizations, it's about 33 per
6 cent of hospitalizations, now for people who are fully
7 vaccinated, or vaccinated with an additional dose compared to
8 57.4 per cent for hospitalizations, and you're even seeing now,
9 with the deaths, 17.6 - 17.6 plus 13.3 versus 59 per cent were
10 unvaccinated. So, what I'm trying to say is, as time is going
11 on, we're seeing more cases, more hospitalizations, or more
12 deaths, even amongst fully vaccinated people. Not to say it's
13 useless, but I'm just pointing out that the pandemic is changing,
14 that even with vaccination, we still see hospitalizations and
15 deaths with waning immunity.
16 Q. So, looking at - I'm sorry. I'm - I’m gonna pause for
17 one moment and put in headphones. I - I think I'm getting some
18 feedback.
19 MR. PRESVELOS: Yeah, there's a big echo.
20 MS. KERAMATI: Okay. Do you hear me, Dr. Rau?
21 A. Yes, I do.
22 Q. Okay. I apologize for that. Okay. So, looking at
23 the - at the figure, Dr. Rau, looking at the first graph.
24 A. Mm-hmm.
25 Q. You would agree that according to this graph, 45 per
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1 cent of COVID cases were among unvaccinated individuals,
2 compared to 34.7 per cent among fully vaccinated, and 12.9 per
3 cent among fully vaccinated individuals, with an additional
4 dose, correct?
5 A. So, if you add together fully vaccinated, fully
6 vaccinated with an additional dose, it's actually higher than
7 the unvaccinated for cases. And if I even add in partially
8 vaccinated, it’s even higher, in terms of where the contribution
9 of cases is now in Canada.
10 Q. And if you look at hospitalizations, you would see
11 that 57.4 per cent of COVID-19 hospitalizations are among
12 unvaccinated...
13 A. Yes.
14 Q. ...compared to 20.3 per cent among fully vaccinated,
15 and 13.3 per cent among fully vaccinated with one additional
16 dose, correct?
17 A. That's correct. So, not as high, when you add those
18 groups of vaccinated people together as unvaccinated. But if
19 you were to look at the earlier reports, earlier in this
20 outbreak, you would have seen quite a difference. If we went
21 back a year, it would seem to be a disease of the unvaccinated.
22 And now what we're starting to see is that even despite vaccine,
23 we have hospital admissions.
24 Q. Okay...
25 A. And the other point I should make though, in
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1 interpreting hospitalizations that are positive, there is an
2 issue of teasing out whether someone is admitted with COVID or
3 due to COVID. And this has been discussed by Public Health
4 Ontario in various reports and they've even changed how they’re
5 counting cases of hospitalizations now, to determine whether
6 patients are admitted with COVID or due to COVID. So, there's
7 also an - an interpretation issue, when it comes to
8 hospitalizations, but not so much with deaths.
9 Q. Okay. So, 59 per cent of deaths, according to this
10 graph, the third graph, were among unvaccinated individuals
11 compared to 17.6 per cent, among fully vaccinated, and 13.3 per
12 cent, among fully vaccinated with an additional dose, correct?
13 A. Right. So, if we - if we add the vaccinated group
14 here, which will also include partially, it's still less than
15 unvaccinated, but not so much of a difference, as we used to see
16 one year ago say, before Omicron and before Delta.
17 Q. Dr. Rau, in reviewing the - the graphs, that we were
18 reviewing...
19 A. Mm-hmm.
20 Q. ...you would agree, that we were reviewing percentage
21 of cases?
22 A. Percentage, we were talking about percentage of - of
23 all cases in Canada. Correct.
24 Q. And you would agree that there's approximately - that
25 approximately 80 per cent of the population is fully vaccinated?
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1 A. Actually, it's even higher than that. And if you look
2 at those who are eligible for vaccination, it's more like 90 per
3 cent, over age 12.
4 Q. So, the number of people that are....
5 A. (Inaudible).
6 Q. And so, the number of people available to contribute
7 to the total percentage of cases in hospital is much larger for
8 the fully vaccinated?
9 A. Yes, but as a percentage of - yes, that is correct.
10 That the - yup, the percentage. Yeah. Exactly. That’s true.
11 Yeah.
12 Q. Dr. Rau, in preparing your report, did you review up-
13 to-date data on case counts, hospitalizations, and deaths of
14 vaccinated and unvaccinated individuals?
15 A. Yes. Yes, I did.
16 MS. KERAMATI: Counsel I'd like....
17 A. Not just - not just in preparing the report. I do
18 this every week, as part of my job.
19 MS. KERAMATI: Counsel, I’d like to enter this as Exhibit
20 5, I believe. Are we at Number 4 or 5?
21 MR. PRESVELOS: I - I don’t know what number we’re at, but
22 you can go ahead and enter that as an exhibit.
23 MS. KERAMATI: Okay. I'm gonna enter it now. Thank you.
24 EXHIBIT NUMBER 4: Epidemiology Summary of COVID-19
25 MS. KERAMATI: And just to be clear, this exhibit is the
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1 Epidemiology Summary of COVID, the document that I had just up.
2 Okay. I'm going to share my screen with you again, Dr. Rau.
3 A. Okay. Good.
4 Q. One moment, please. Do you see my screen, Dr. Rau?
5 A. Yes.
6 Q. Okay.
7 A. This document?
8 Q. I have - I have on my screen, Science Table, COVID-19
9 Advisory for Ontario. An article titled, “Early Impact of
10 Ontario's COVID-19 Vaccine Rollout on Long-Term Care Home
11 Residents and Health Care Workers.” Do you see that Dr. Rau?
12 A. Yes, I see it.
13 Q. Okay. I'm going to read the two paragraphs under the
14 “Key Message,” heading.
15 A. Yes.
16 Q. “The rollout of COVID-19 vaccines to Ontario's Long-
17 Term Care, LTC homes, has substantially reduced SARS-CoV-2
18 infections, COVID-19 hospitalizations, and deaths among long-
19 term care residents and health care workers. Completing and
20 maximizing the uptake of the COVID - of the full COVID-19 vaccine
21 series, according to recommended schedules will maximize the
22 safety and well-being of Ontario's LTC residents and staff.” Do
23 you see that, Dr. Rau?
24 A. I see that.
25 Q. Okay. Thank you. And I've scrolled down now to the
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1 second page of this document. And I'm going to read the portion
2 under the heading, “Interpretation.”
3 A. Mm-hmm.
4 Q. “The rollout of COVID-19 vaccines in Ontario's long-
5 term care homes substantially reduced SARS-CoV-2 infections,
6 COVID-19 hospitalizations, and deaths, among long-term care
7 residents and HCWs, which stands for....
8 A. Health care workers.
9 Q. Health care workers. Thank you, Dr. Rau.
10 A. Mm-hmm.
11 Q. The paragraph continues with, “...completing and
12 maximizing the up - uptake of the full COVID vaccine - vaccine
13 series according to recommended schedules will maximize the
14 safety and well-being of Ontario long-term care residents and
15 staff.” Do you see that Dr. Rau?
16 A. Yes.
17 Q. Dr. Rau, in arriving at your conclusions at paragraphs
18 five to nine of your report, did you consider this finding?
19 This article?
20 MR. PRESVELOS: Sorry.
21 A. Actually, I’ve read this article. Sorry.
22 MR. PRESVELOS: Sorry. Just give me a sec.
23 DR. RAU: I just - I have some contractors...
24 MR. PRESVELOS: Sorry, Dr. Rau, Dr. Rau....
25 DR. RAU: ...outside my - the contractor outside my home.
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1 I need to tell them to turn off their bloody radio.
2 ... DR. RAU EXITS ROOM
3 DR. RAU: It’s - it’s - you guys. Could you just turn off
4 your radio? I’m - I’m doing work. Okay.
5 ... DR. RAU ENTERS ROOM
6 MR. PRESVELOS: Okay. Can you hear us, Dr. Rau?
7 DR. RAU: Yeah, I can.
8 MR. PRESVELOS: Okay. Counsel, so, you’ve directed Dr.
9 Rau’s attention to paragraph 5 to 9, 5 to 9 in his affidavit,
10 in - in his report, pardon me, which is proceeded by a title
11 called, you know, “Strict Border Measures Do Not Stop the
12 Variants.” You’ve put a document to Dr. Rau on the impact of
13 vaccines in Ontario’s long-term care homes. Now, maybe I’m
14 missing something, but it’s not readily apparent to me how this
15 interpretation is relevant to what Dr. Rau is discussing at
16 pars. 9 - 5 to 9. So, before I allow this question, I am going
17 to ask you to take me to the precise paragraphs, one or more in
18 Dr. Rau’s report, and draw that length to me, so, that I can
19 understand the relevance.
20 MS. KERAMATI: So, if you look at paragraph 8 of Dr. Rau’s
21 Report, Counsel.
22 MR. PRESVELOS: Right. Yeah.
23 MS. KERAMATI: Paragraph 8, starts with and - I read the
24 sentence out at the outset...
25 MR. PRESVELOS: Yes.
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1 MS. KERAMATI: ...of my question.
2 MR. PRESVELOS: Mm-hmm.
3 MS. KERAMATI: “Thus far, the future variants have emerged.
4 There is no evidence to suggest that pre-existing high
5 vaccination rates have blunted the trajectory of daily new
6 infections of a COVID-19 variant.”
8 MS. KERAMATI: He’s discussing. Okay. Are you satisfied
9 with that?
10 MR. PRESVELOS: No.
11 MS. KERAMATI: Dr. Rau....
12 MR. PRESVELOS: No. Sorry. That - that doesn’t satisfy
13 what...
14 MS. KERAMATI: It does.
15 MR. PRESVELOS: ... in this report. So, what Dr. Rau is
16 saying is that there’s no evidence to suggest that already having
17 high vaccination rates changes or dilutes the trajectory of how
18 many new daily infections you have of a new variant. And what
19 this interpretation is saying is that the rollout of COVID-19
20 vaccines have reduced SARS-CoV-2 infections, hospitalizations,
21 and deaths in long-term care residents. Um, I - I don’t see how
22 those two things are the same.
23 MS. KERAMATI: At paragraph 8, Dr. Rau is talking about
24 high vaccination rates, blunting the trajectory of daily new
25 infections. So, we’re talking about whether or not vaccination
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1 impacts infections...
2 DR. RAU: But....
3 MS. KERAMATI: But my question is....
4 DR. RAU: Sorry.
5 MR. PRESVELOS: Dr. Rau, sure, if you want to go ahead and
6 - and - and - I mean, I don’t see the relevance, but maybe you
7 want to go ahead and answer.
8 DR. RAU: I’d better - I’d like to just explain the
9 sentence. Okay. I’m referring to infections, not - when I say,
10 “...blunting the trajectory...” The number of cases, there may
11 be a difference from vaccination, in terms of hospitalizations
12 and deaths, but the infections still occur. And the other point
13 I want to make about that Science Table piece is even before we
14 had variants from March 2021, the analysis is from the earlier
15 phase of the pandemic. So, it’s - I think we may have had Alpha,
16 at that point, at most, but the analysis actually relates to the
17 rollout of the vaccine in December 2020, before we had variants.
18 Q. Okay. So, the other....
19 A. So, I’m trying to understand what the connection is
20 between my statement and this paper, and why - I can't understand
21 - I'd like to better understand your question, please.
22 Q. Okay. So, under the heading, “Interpretation,” you'll
23 see that it talks about reducing SARS-CoV-2 infections.
24 A. Let's just go to...
25 Q. COVID-19 vaccinations.
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1 A. We're - we're pulling up, I can get it myself here.
2 Just - Ontario Science Table. Yup. Okay.
3 Q. “COVID-19 vaccinations in Ontario's long-term care
4 homes...
5 A. Yup.
6 Q. ...substantially reduce SARS-CoV-2 infections,” and
7 it goes on. So, my question is...
8 A. Mm-hmm.
9 Q. ...whether or not, in your assessment, that there is
10 no evidence to suggest that pre-existing high vaccination rates
11 have blunted the trajectory of daily new infections. Did you
12 consider....
13 MR. PRESVELOS: Sorry. Of daily new infections of a COVID-
14 19 variant.
15 A. Yes.
16 MR. PRESVELOS: Let's just say the sentence in its entirety.
17 MS. KERAMATI: Daily new COVID - that’s - that’s fair.
18 Daily new COVID...
19 A. Variant.
20 Q. ...infections of a COVID-19 variant.
21 A. Yeah.
22 Q. Did you consider....
23 A. Absolutely.
24 Q. Is - did you consider this - this paper?
25 A. I - I didn’t, because I’m going to explain why. First
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1 of all, this is published March 8th, 2021. This analysis, and
2 you call it a paper, it's actually not peer reviewed. It's a
3 statement from the Ontario Science Table. It's a science brief.
4 Q. Mm-hmm.
5 A. It’s my - but that's fine. It's from - written by
6 people with whom I work, including Allison McGeer, who are also
7 authorities. They're analyzing the period from December 23rd to
8 February 13th, 2021. They're analyzing a period before we had
9 variants. It was COVID classic. All right. And so, this is a
10 pre-variant era, where you give people the vaccine, and you look
11 at the impact on case rates. What I was trying to say, I am
12 saying in my affidavit, is having a heavily pre-vaccinated
13 population doesn't blunt the number of infections, when a new
14 variant shows up. It's not a castle fortress, it’s not a wall
15 that keeps the virus out. It blunts the impact of the infection,
16 but it doesn't actually, in terms of deaths and
17 hospitalizations, but it doesn't actually stop the virus from
18 coming in. It doesn't stop the virus from propagating the
19 community. In the early phase of the pandemic, when the vaccine
20 was introduced, in the short period after the vaccine
21 introduction, we did see a transient drop in the number of cases,
22 but the longer time has gone on, with the emergence of variants,
23 and with the time since people have been vaccinated, this would
24 not apply. So, this is such an early paper, early analysis,
25 it's not applicable anymore. This is the - this is - these are
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1 the, in a way, the golden days of the pandemic, you could say,
2 because we actually didn't have variants.
3 Q. Okay. So, in answer to my question, your response was
4 that you did not consider this - these findings in preparation
5 for your report?
6 A. This paper was not admissible for the discussion in
7 my affidavit. It's not - it's not relevant, because it's a
8 different era. It's not applicable.
9 Q. So, you did not?
10 A. It’s not - it’s not wrong for its time, but it's not
11 applicable.
12 Q. Okay. I just - I just want to get an answer to my -
13 to my question. So, the answer would be no, you didn’t. The
14 reason is - you’ve - you've set out your reasons.
15 A. Yes.
16 Q. You would agree that the Alpha variant had been
17 identified by December 2020?
18 A. It had been identified, but it wasn’t the dominant
19 isolate in Ontario, until a little bit later. Into the winter,
20 it became more dominant, if one looks at the percentage. We
21 have that data is available. The distribution of variance in
22 Ontario, it started changing. The other point is that in late
23 2020, I don't think we realized the significance of variants,
24 so, we were not doing gene sequencing on every isolate. And
25 then as time went on, we started doing a more careful job of
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1 getting an idea of what the percentages were. But by winter of
2 2021, we were much more on the ball with these variants, the S-
3 gene dropout failure, that was sign - the signature of the Alpha
4 variant from the UK. The UK had an earlier problem with the
5 Alpha variant in September of 2021, but it wasn't a big issue
6 in Ontario until later. It was starting to emerge in late 2021.
7 Oh, sorry, late 2020. Correction.
8 Q. Okay, but you would agree that by December 2020, the
9 Alpha variant had been designated as a variant of concern?
10 A. It had been, but the Alpha variant did not describe
11 the epidemic curve, that’s shown in that analysis, where they -
12 where they show the - the graph on - on Figure A and B. It’s
13 mainly COVID classic, at that point, but it was starting to
14 become more Alpha. This graph goes from November 2020. At
15 that point, Alpha was not present in significant numbers in
16 Figure A and B.
17 MS. KERAMATI: Counsel, I'd like to enter this as Exhibit
18 4...
19 MR. PRESVELOS: Sure.
20 MS. KERAMATI: Or are we on five now?
21 COURT REPORTER: Five.
22 MS. KERAMATI: Okay. Thank you.
23 EXHIBIT NUMBER 5: Early Impact of Ontario’s COVID-19
24 Vaccine Rollout on Long-Term care Home Residents and Health Care
25 Workers.
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1 MR. PRESVELOS: Counsel, I can't help but notice that you
2 spend significant amounts of time looking at your screen. I
3 just wonder, do you have other counsel assisting you with the
4 questioning? Or do you have an expert assisting you with the
5 questioning to these cross-examinations?
6 MS. KERAMATI: Well, I have my notes up on my screen, which
7 I - I don't think you would object to me looking at when asking
8 my question.
9 MR. PRESVELOS: No, but I just want to - I just want to know
10 whether or not you have another individual, prompting questions
11 to you on your screen, or it's just your notes?
12 MS. TELLES-LANGDON: Mr. Presvelos, whether or not Ms.
13 Keramati has any counsel assisting her with questioning, is not
14 a relevant question.
15 MR. PRESVELOS: I - I guess my question is more focused on
16 whether or not there might be experts prompting questions in
17 live time to - as - as part of Dr. Rau’s cross-examination. I
18 - I - I - obviously you're all counsel for the same party. I
19 mean, of course, you can pass notes, and make suggestions, and
20 so on, and so forth, I'm just curious whether or not there are
21 - there are doctors, or scientists, that are also passing
22 questions, simultaneous contemporaneous with these cross-
23 examinations.
24 MS. TELLES-LANGDON: Mr. Presvelos, first of all, I don't
25 think that's a relevant question for you ask because counsel
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1 could - would be entitled to do that, in - in my view, but in
2 any event, the ZOOM attendees are evident, and I will confirm
3 on the record, that there are no doctors, participating experts,
4 in the background participating in this cross-examination. But
5 if you're thinking that that is a fair question, then I think
6 we'll be confirming that same question on the record with each
7 of you in your cross-examination of our...
8 MR. PRESVELOS: Oh, don’t worry.
9 MS. TELLES-LANGDON: I won't have any doctors or scientists.
10 That would be too chaotic for me to try to manage what they're
11 telling me with my questions and your witnesses answers, but it
12 was just, you know, thank you for clarifying that.
13 MS. TELLES-LANGDON: Sorry. Go ahead, Ms. Keramati.
14 MR. PRESVELOS: I wish I had that attention span.
15 MS. KERAMATI: Thank you. I would like to actually make
16 note of something. On - on a couple of occasions, when Dr. Rau
17 has provided a response, somebody has given a thumbs up on his
18 screen that becomes visible on his screen. So, I'm not sure if
19 that's you, Counsel, or - or someone else on the call, I would
20 just ask that.
21 MR. PRESVELOS: I don’t even know how you do it. Rau, are
22 you touching your ZOOM?
23 DR. RAU: I know - I'm far from my screen. All I see is
24 you and my own screen. I see nothing else.
25 MS. KERAMATI: Okay.
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1 MR. PRESVELOS: Weird. Sorry, Counsel. Would Counsel....
2 MS. KERAMATI: Let’s - I....
3 MR. PRESVELOS: No, that’s - you know what, I did see it
4 once and I thought it was weird. I just want to - that's a good
5 point that you make.
6 MS. KERAMATI: I saw it, at least - at least twice, I've
7 seen that.
8 MR. PRESVELOS: Yeah, that's a good point. You know, if any
9 other counsel is - is touching their - their ZOOM, I don't - I
10 don’t know how to do that, but don't do that.
11 DR. RAU: All I see is the person interviewing me and
12 myself, I have no other access.
13 MS. KERAMATI: Or perhaps it's - it’s some of the non-
14 counsel who are in attendance on ZOOM?
15 MR. PRESVELOS: Yeah, that's a good point too. For - anyone
16 on ZOOM, should refrain from giving any sort of indication,
17 whether it's by icon, or private message, or anything of that
18 sort. That’s not appropriate.
19 MS. KERAMATI: Dr. Rau, can you turn to paragraph 30 of
20 your report, please?
21 A. Mm-hmm.
22 Q. At paragraph 30, Dr. Rau, you state, “In addition,
23 based on recent household transmission study, performed during
24 the Delta variant era in the UK...
25 A. Yes.
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1 Q. ...those who are vaccinated and are infected, transmit
2 as easily as unvaccinated with infection.” Do you see that in
3 your report?
4 A. Yes, I do.
5 Q. Okay. And at paragraph 32(i)...
6 A. Yeah.
7 Q. ...you state, “Vaccination does not prevent
8 transmission of COVID-19. If one gets infected with COVID-19.”
9 Do you see that statement?
10 A. Yes.
11 Q. Okay. And just going back a few pages at paragraph
12 11(c). “C” as in cat, you state, “Vaccinated...” You state,
13 “Vaccination does not stop reinfection. Nor does it stop
14 transmission, in the event of a breakthrough infection. A recent
15 study in the New England Journal of Medicine found that the
16 reduction in transmission of the Delta variant, declined over
17 time, notwithstanding vaccination and reached transmission
18 levels that approached those of unvaccinated persons by 12 weeks
19 following vaccination.” Do you see this?
20 A. Yes. And that’s the paper, that you have shared with
21 me as well, this morning.
22 Q. Yes.
23 A. Yeah.
24 Q. Okay. I'm actually going to take you to that paper,
25 Dr. Rau.
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1 A. Mm-hmm.
2 Q. I'm going to share my screen.
3 A. Yeah.
4 Q. Do you see the paper on my screen, Dr. Rau?
5 A. Yes.
6 Q. Okay. And this is the same paper that you've cited
7 at footnote 19...
8 A. Yeah.
9 Q. ...titled, “Effect of COVID-19 vaccination on
10 transmission of Alpha and Delta variants.”
11 A. Yeah.
12 Q. One moment, please. Sorry. I'm having some...
13 A. It’s okay.
14 Q. ...technical difficulties.
15 A. Okay.
16 Q. If you could just give me a moment, Dr. Rau. Okay.
17 Okay. I'm going to read a passage from this article, Dr. Rau.
18 A. Mm-hmm.
19 Q. So, this passage appears on page 750 of this article.
20 A. Mm-hmm.
21 Q. Okay. So, it’s - it comes under the heading, “Duration
22 of Protection and Reductions in Transmission.” Okay. And before
23 I read the passage, would you agree that a BNT162b2 vaccine is
24 an mRNA vaccine?
25 A. Yes, I do.
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1 Q. Okay. I’m gonna highlight the portion, so, it's easy
2 for you to....
3 A. I’d like you to magnify it, as well, please.
4 Q. Yes, I will.
5 A. Thank you.
6 Q. Okay. Do you see that Dr. Rau?
7 A. Yup.
8 Q. Okay. Two weeks after the second BNT162b (sic)
9 vaccination, transmission of the Delta variant was reduced by
10 50 per cent.
11 A. Mm-hmm.
12 Q. And 12 weeks after the second, BNT162b2 vaccination,
13 transmission of the Delta variant was reduced by 24 per cent.
14 A. Yes.
15 Q. You see that statement, Dr. Rau?
16 A. Yeah, I do.
17 Q. Okay. So, in lay terms, this statement means that 12
18 weeks after the second mRNA vaccine, protection against
19 transmitted - transmitting the Delta variant was at 24 per cent
20 compared to those who are unvaccinated, correct?
21 A. Yeah. Well, in lay terms, what it means is, it was
22 good after two weeks at 50 per cent. It's not fantastic. And
23 by 12 weeks, it’s not very good. It's only 24 per cent. And
24 if you look at the graph and the actual papers, since your
25 excerpting this, if you look at the trends, again, so, if I look
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1 at Figure 1, which is above in the paper, the difference between
2 a vaccinate - you know, between someone who had their vaccine
3 or not, you - you start to see the trend getting worse and worse,
4 in terms of the chance of turning positive. Like you can see
5 where the slope is going, if we had a graphics extend longer and
6 longer. The problem is that a new variant came in, the Omicron
7 came in. They couldn't even study Delta, after a certain period
8 of time. But what I'm trying to say that excerpt is, you know,
9 really translates to, as time goes from when one gets the
10 vaccine, the protection is waning considerably. And other
11 papers have shown even more stark drop offs in protection over
12 time. Well, look at Figure A, Fig - Figure 1, Part A.
13 COURT REPORTER: I think we lost a bunch of counsel.
14 I’ll just go off the record, until they come back.
15
16 OFF RECORD
17
18 MS. KERAMATI: For the record, we - we got temporarily
19 disconnected, but we're now back on.
20 Q. Dr. Rau, I'm going to share my screen with you and
21 continue with the Eyre article that we were discussing.
22 A. Yup.
23 Q. Do you see the article up on my screen?
24 A. Yeah. MNI (ph) Section that's referring to the figure
25 that we were talking about, which is Figure 1.
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1 Q. That's right. Okay.
2 A. And it’s really Panel A that it’s describing, which
3 you can see graphically in Panel A.
4 Q. Okay. So, your assessment that at 12 weeks, for
5 clarity, your assessment that at 12 weeks transmission levels,
6 approach those of unvaccinated persons, is in reference to this
7 24 per cent, correct?
8 A. Correct.
9 Q. Okay.
10 A. And if we - if the timeline went out further than
11 that, it would probably get even worse, as it's been seen in
12 other analyses, especially with - and this is not even Omicron,
13 where - where the differences was even worse. I'm not saying
14 that the Pfizer vaccine isn't better than the AstraZeneca
15 vaccine, these - these two are comparing. But the Pfizer vaccine
16 looked a bit better. But as time went on, and we got to new
17 variants, this is just Delta, we start to see this trend, and
18 you see from Alpha, it looked like there was some protection
19 against transmission. With Delta, there was less, and the longer
20 you go from the vaccine, the lesson is - and as you get to
21 Omicron, as I described in other papers, it's even worse, as
22 time goes on from the vaccine, it's a transient benefit in
23 reducing transmission.
24 Q. That’s why....
25 A. And I believe - I will also say for the record, that
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1 I am - I have received three doses of vaccine myself and I got
2 Omicron.
3 MS. KERAMATI: Counsel, I'd like to enter this document as
4 Exhibit 6.
6 EXHIBIT NUMBER 6: Effect of Covid-19 Vaccination on
7 Transmission of Alpha and Delta Variants
8 Q. Dr. Rau, can you turn to paragraph 3 of your report?
9 A. Yup. Paragraph 3.
10 Q. No, I’m sorry. Paragraph 37 of your report.
11 A. Mm-hmm.
12 Q. In paragraph 37, you state, “COVID-19 vaccination,
13 though generally safe, has been associated with rare and
14 sometimes debilitating adverse effects.”
15 A. Yes.
16 Q. “Some of which became apparent only after large scale
17 administration.”
18 A. Yes.
19 Q. “For example - for example, the rare blood clotting
20 adverse effects of the Oxford AstraZeneca vaccine was not
21 apparent until April 2021, and primarily affected those healthy
22 women under age 60, within two weeks of their first dose.” Do
23 you see that statement, Dr. Rau?
24 A. Yes. Yes.
25 Q. Okay. And in support of your statement, you've cited
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1 footnote 36. Correct?
2 A. Yes.
3 Q. And footnote 36 is an article on the European Medicine
4 Agency, titled...
5 A. Yes.
6 Q. ...“AstraZeneca’s COVID-19 Vaccine. EMA finds a
7 possible link to very rare cases of unusual blood clots with low
8 blood platelets.”
9 A. Yes.
10 Q. Correct?
11 A. Yes.
12 Q. I'm gonna go to this article and share my screen with
13 you, Dr. Rau.
14 A. Mm-hmm. This is the piece by Mineka Pie (ph) that
15 you're sharing with me?
16 Q. This is the....
17 MR. PRESVELOS: There's nothing being shared yet, just give
18 it a....
19 MS. KERAMATI: It’s not being shared yet?
20 A. Okay.
21 Q. This is on the European Medicines Agency.
22 A. Yes.
23 Q. Okay.
24 A. Yes.
25 Q. So, this is the - the document that you're footnoted,
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1 correct?
2 A. Yes.
3 Q. Okay. And the document is dated April 7th, 2021.
4 A. Yes.
5 Q. Okay. The very first statement in the article, in
6 bold letters, says, “EMA confirms overall benefit risk remains
7 positive.” Do you see that?
8 A. Yes, yes, I see that.
9 Q. I’m gonna scroll down to the third paragraph.
10 A. Magnify it again, please?
11 Q. Yes. Let me - I’ll - I'll highlight it for you.
12 A. Mm-hmm.
13 Q. Do you see that?
14 A. Yes.
15 Q. Okay. “So far, most of the cases reported have
16 occurred in women under 60 years of age within two weeks of
17 vaccination.”
18 A. Yes.
19 Q. “Based on the currently available evidence, specific
20 risk factors have not been confirmed.” Do you see that?
21 A. Yes.
22 Q. Okay. I'm going to scroll down to the seventh
23 paragraph. I’ll highlight and zoom in. Do you see that, Dr.
24 Rau?
25 A. Yes.
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1 Q. So, this paragraph states, “COVID-19 is associated
2 with the risk of hospitalization and death, the reported
3 combination of blood clots and low blood platelets is a very -
4 it's very rare and the overall benefits of the vaccine in
5 preventing COVID-19 outweigh the risks of side effects.” Do you
6 see that, Dr. Rau?
7 A. Yes.
8 Q. Okay. I'm going to stop sharing. And I'm going to
9 share another document with you. Do you see my screen, Dr. Rau?
10 A. Yes.
11 Q. Okay. So, I'm sharing a Science Briefs from the
12 Ontario Science Table.
13 A. Mm-hmm.
14 Q. Titled, “Vaccine Induced.” I'm gonna have a hard time
15 pronouncing this. So, I'll just pronounce the abbreviation.
16 A. Yeah.
17 Q. Vaccine induced VITT...
18 A. Mm-hmm.
19 Q. ...Following Adenovirus Vector COVID-19 Vaccination.
20 A. Yes.
21 Q. Okay. And the Science Brief was published on May 7th,
22 2021.
23 A. Yes.
24 Q. Okay. And you'd agree that VITT is the blood clotting
25 event that you address at paragraph 37...
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1 A. Yes.
2 Q. ...of your report?
3 A. Yes.
4 Q. I’m gonna scroll down to page 5 of this PDF document.
5 Okay. I'm gonna read a portion. I'll do the same highlight and
6 zoom in. Do you see the highlighted portion clearly, Dr. Rau?
7 A. Yes.
8 Q. So, this comes under the heading, “Are certain
9 patients predisposed to VITT?”
10 A. Yes.
11 Q. “At this time, it is not clear if certain patients are
12 predisposed to be VITT. Early reported cases were predominantly
13 in younger women. However, these individuals may have been
14 overrepresented in the vaccinated population and reporting
15 countries.” Do you see that, Dr. Rau?
16 A. Yes.
17 Q. Dr. Rau, did you consider these findings in preparing
18 your report?
19 A. I did. And in fact, in some ways this further bolsters
20 my statements that there are idiosyncratic or random events,
21 that can happen following a vaccine rollout, notwithstanding my
22 personal decision to have been vaccinated, to be vaccinated
23 three times, that there are some people who can end up with an
24 adverse effect. And we don't know exactly what the risk factor
25 is for this adverse event. And it wasn't even evident until
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1 there was a large scale rollout of the vaccine. It didn't come
2 through in the product registration trials. So, in the early
3 phases use of a vaccine, there can be things that are not
4 predictable, they may be rare, there may well still be benefits
5 of vaccination that outweigh the - the - the risks, but these
6 risks are not available to those who are receiving the vaccine
7 at that time. It - these are - these are unknown risks until
8 time has gone on.
9 It is also true that the use of this vaccine dropped
10 remarkably, once this was reported. Within a month or two of
11 this being reported, no one was getting this vaccine. People
12 were literally asking for the - the other vaccines that were
13 available, Moderna and Pfizer.
14 Q. And to be clear, Dr. Rau, for the record, Adenovirus
15 is the AstraZeneca vaccine.
16 A. Correct.
17 Q. This is what you're referring to?
18 A. Correct. Correct. And also in the paper, we're were
19 discovering - discussing earlier with - by Eyre, that’s ChAd,
20 A-D is the Adenovirus and that's the AstraZeneca vaccine.
21 Q. Right. But I only too you....
22 A. For...
23 Q. Yes. I only took you to the portion of the Eyre
24 vaccine - of Eyre Report...
25 A. Yes.
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1 Q. ...that discussed the mRNA vaccine.
2 A. Yeah, but the - the part you highlighted, also I
3 believe referred to the ChAd, as well, right?
4 Q. I - I didn't highlight that portion.
5 A. Okay.
6 Q. That portion followed what I highlighted.
7 A. Well, it’s - it’s in the paper. It’s in the paper.
8 Q. It's in the paper. Yes.
9 A. Okay.
10 MS. KERAMATI: Okay. I'm - Counsel, I’m in my last series
11 of questions. So, I think we should just not take a break and
12 power through until we finish.
14 Q. Okay. Dr. Rau, can you turn to paragraph 21 of your
15 report?
16 A. Yes.
17 Q. Okay. At paragraph 21, you've stated, “Vaccine
18 efficacy,” which you define, as protection against infection.
19 A. Yes.
20 Q. “So, vaccine efficacy against variants was dropped
21 successive with the emergence of each variant.” Do you see
22 that?
23 A. Yes. I should have said, “Successively.” But anyway,
24 yes, “...with the emergence of each variant.”
25 MS. KERAMATI: Counsel, I would note that I saw the thumbs
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1 up on Dr. Rau’s screen again. Perhaps, the Registrar can disable
2 the chat functions? I’m not sure who’s doing that.
3 MR. PRESVELOS: Mm-hmm.
4 MS. KERAMATI: Though we're nearly done.
5 COURT REPORTER: I'm not sure how to disable it.
7 DR. RAU: I can't see any of this, if there's a concern.
9 DR. RAU: Okay.
10 MS. KERAMATI: And in support of your statement at
11 paragraph 21, you've cited footnote 31, correct?
12 A. Yes. Yes.
13 Q. Okay. Okay. I'm going to take you to this footnote.
14 Do you see my screen, Dr. Rau?
15 A. Yes.
16 Q. Okay. So, footnote 31 is an article titled,
17 “Effectiveness of COVID-19 vaccines against Omicron or Delta
18 infection”...
19 A. Mm-hmm/.
20 Q. ...by Buchan and others, correct?
21 A. Yes. This is from Ontario by the way and Jeff Kwong
22 from ICES.
23 Q. And - and Jeff Kwong. That’s right.
24 A. This is an Ontario publication. Yeah.
25 Q. Yes.
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1 A. Not yet peer-reviewed, but it's on that archive, as
2 we discussed earlier. Yeah. Mm-hmm.
3 Q. And you would note that the URL, on - on top of the
4 page matches the URL that you've noted at footnote 31.
5 A. Just a sec, I can't see properly. This is not
6 magnified. Just - just a sec here. Let me see what I get here.
7 Yes, I see that.
8 Q. And notably the URL ends with V-1. V as in Victor,
9 one.
10 A. Yes.
11 Q. Yes. Okay. You would agree that the study discusses
12 vaccine effectiveness for the Delta and Omicron variants only.
13 A. Correct.
14 Q. And there is a notation in bold and blue, stating that
15 this article is pre-print and not - and has not been pre - peer-
16 reviewed.
17 A. That's true. Every single piece on that archive, you
18 would see the same.
19 Q. Okay. But you haven't indicated in your report that
20 this article is pre-print, correct?
21 A. I put that into MedArchive, just as all experts have,
22 so far.
23 Q. Okay.
24 A. Okay. So, I - I didn't put any - I didn't distinguish
25 it from any other MedArchive one.
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1 Q. And on the top, and in - in - in red and white writing,
2 you'll see that there's a button that states - or be - before I
3 do that, you'll note that this this document was posted on
4 January 1st, 2022.
5 A. Yes.
6 Q. Okay. And you'll see a button that says, “View current
7 version of this article.” Do you see that?
8 A. Yes.
9 Q. Okay.
10 A. I don't know if that was present, when I looked at
11 this piece. I don't know when that's been added.
12 Q. Okay. So, before - before going there, I'm just going
13 to read under the “Abstract,” the conclusions of this - of this
14 version. Okay.
15 A. Mm-hmm.
16 Q. So, the conclusion states, “Two doses of COVID-19
17 vaccines are unlikely to protect against infection by Omicron.”
18 A. Yes.
19 Q. “A third dose provides some protection in the
20 immediate term, but substantially less than against Delta.”
21 A. Yes.
22 Q. “Our results may be confounded by behaviours that were
23 - that we were unable to account for in our analysis.”
24 A. Yes.
25 Q. “Further research is needed to examine protection
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1 against severe outcomes.”
2 A. Correct.
3 Q. Do you see that?
4 A. Yes.
5 Q. Okay. I'm going to scroll back up and click on the
6 button that says, “View current version of this article.”
7 A. Yeah.
8 Q. And you'll note, in the URL, the address now ends with
9 V2, presumably for Version 2.
10 A. Yeah.
11 Q. And you'll note that this is - post was posted on
12 January 28th, 2022.
13 A. Mm-hmm.
14 Q. And that was prior to your date of your report.
15 A. It - it might have been before I actually – it might
16 have been after I have reviewed the piece, when I was preparing
17 my response. So, anyway, whatever.
18 Q. So, I'm going to scroll down and read the conclusion
19 of this updated version of the report.
20 A. Mm-hmm.
21 Q. Do you see that, Dr. Rau?
22 A. Yes.
23 Q. “Conclusions, in contrast to high levels of protection
24 against both symptomatic infection and severe outcomes caused
25 by Delta, our results suggest that two doses of COVID-19 vaccines
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1 only offer modest and short-term protection against symptomatic
2 Omicron infection. A third dose improves protection against
3 symptomatic infection and provides excellent protection against
4 severe outcome for both variants.” Do you see that?
5 A. I do.
6 MS. KERAMATI: Okay. Okay. Counsel, I might be - I might
7 be done with the cross-examination. If we can take a 10-minute
8 break.
10 MS. KERAMATI: Before - before doing so, I'll just add this
11 as an exhibit, this article as an exhibit.
13 COURT CLERK: Did you want to add the last one into - as
14 an exhibit?
15 MS. KERAMATI: Yes, please.
16 COURT REPORTER: Okay. Perfect. I’ll go off the record
17 now.
19
20 OFF RECORD
21
22 MS. KERAMATI: Okay. So, just to confirm for the record,
23 during recess, I had asked for the last item, the - I’ll just
24 bring it up, the article titled, “Effectiveness of COVID-19
25 Vaccine Against Omicron or Deltan Infection,” both versions,
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1 Version 1 and Version 2 be made into exhibits.
2 EXHIBIT NUMBER 7: Article titled, “Effectiveness of
3 COVID-19 Vaccine Against Omicron or Deltan Infection,” Version
4 1
5 EXHIBIT NUMBER 8: Article titled, “Effectiveness of
6 COVID-19 Vaccine Against Omicron or Deltan Infection,” Version
7 2
8 MS. KERAMATI: Thank you. And, Counsel, do you agree with
9 that?
10 MR. PRESVELOS: Yeah, go ahead. You can do up an exhibit.
11 MS. KERAMATI: Okay. So, those are all my questions.
12 Thank you very much, Dr. Rau, for attending and answering my
13 questions. Your Counsel might have some questions to ask you
14 in redirect.
15 MR. PRESVELOS: Yeah, just a few questions, Doctor. I - I
16 won't - I won't keep you too long.
17
18 RE-EXAMINATION BY MR. PRESVELOS
19
20 MR. PRESVELOS: Let's go back to paragraph 21 of your
21 report. I can put it on the screen. Just give me a second.
22 Paragraph 20, 21.
23 A. Yeah.
24 Q. I don't know if you can see it on my screen or not.
25 A. Yeah.
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DR. NEIL VIVEK RAU, Re-Examination
1 Q. It says, “Vaccine efficacy against variants has
2 dropped successive,” and you noted grammatically, “successively
3 with the emergence of each variant. The vaccine efficacy
4 directed at the first COVID-19 strain, before the emergence of
5 variants was higher than subsequent variants. No new variants
6 has - has been developed. No new vaccine has been developed
7 yet, as noted above. The time since vaccination is an important
8 determinant of vaccine efficacy against infection and to a
9 lesser extent, severe outcomes.” Give me one second. I'm going
10 to take you back to an article that we had looked at here
11 earlier. This is the article from the New England Journal of
12 Medicine. I'm not going to pronounce the last name correct.
13 Eyre, Eyre.
14 A. Eyre, Eyre. It’s Eyre.
15 Q. Okay. So, I've highlighted the sentence here that I
16 think you just looked at, which is two weeks after the second -
17 this is the BNT, which is the mRNA vaccination, transmission of
18 the Delta variant was reduced by 50 per cent, and 12 weeks after
19 the second vaccination, transmission was reduced by 24 per cent.
20 And I believe in this report, there is a similar analysis for
21 the efficacy of the vaccine, as it pertains to the Alpha variant,
22 that I thought I'd highlighted. I’m just gonna take a second
23 here. It’s right here. It says, “Two weeks after the second
24 vaccination....” Opps.
25 A. Again, can you just magnify it for me, please? I’m a
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1 little distant.
2 Q. Yeah, I know. Sorry. Sorry, Doc. I’m just....
3 A. If not - yeah.
4 Q. I’m sorry. I’m just trying to - you know, you might
5 have to just give me a second, because I think I lost myself in
6 this journal.
7 So, read from the - where - where at the bottom of page
8 749, where it says, “Duration of protection and reductions in
9 transmission.” It’s - you can see it at the bottom of page
10 749...
11 A. Correct.
12 Q. ...on the bottom right-hand side, starting with,
13 “Vaccine associated reduction.”
14 A. Mm-hmm.
15 Q. To the end of that - to the end of that section of
16 this New England Journal of Medicine...
17 A. Yes.
18 Q. ...publication. I'll give you a second to do that.
19 A. Yeah.
20 Q. Have you - have you - are you already familiar with
21 the contents?
22 A. Yeah. Yeah.
23 Q. Does anything in that section contradict the - the
24 statement made in your report, that there is, you know,
25 successive waning of vaccine efficacy with respect to each
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1 variant?
2 A. I’m just gonna look at it again.
3 Q. Yeah. Take your time.
4 A. You have highlighted.
5 Q. Don't be distracted. Sorry. Don't be distracted by
6 what I’ve highlighted. I'm going to unselect it. I don't know
7 how to unselect it. Don't be distracted by what I highlighted,
8 I was keeping track of something else. I just wanted you to
9 read the duration of protection and reduction and transmission.
10 A. So, we see - with both - both with Alpha and Delta,
11 the same issue of waning, protect or decreasing vaccine efficacy
12 was noted over time following vaccine.
13 Q. And is that also between each of the two variants?
14 A. So, for - for each variant, the time from the vaccine,
15 your protection is better soon after you've gotten it, and it
16 drops over time.
17 Q. Right.
18 A. And then if one compares between Alpha and Delta, so,
19 I’m talking about Panel A and Figure 1, which shows it better,
20 you see a much steeper rising slope with the Delta variant than
21 you do with the Alpha variant. In other words, the protective
22 effect of vaccine on transmission. If I said vaccine efficacy,
23 that was an error. The protective effect on transmission is
24 dropping over time following the vaccine.
25 Q. And that observation applies equally as between the
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1 Alpha variant and the Delta variant. And that's what - that’s
2 what you're pointing to in Chart A, over here, with the title,
3 “Effective Vaccination of Index Patient on Transmission.”
4 A. Correct.
5 Q. Is that correct?
6 A. Correct. So, when I said, “vaccine efficacy,” that
7 was an error. I meant to say, “the effect on transmission.”
8 Okay. So, reductions and transmission were even worse with the
9 Delta variant, and also the impact of time, since the vaccination
10 was even greater, because you can see how the slope is steeper,
11 going up, over time. So, as that - as that graph gets to the
12 top, it means there's no impact on transmission at all. Okay.
13 And so, what you see in this trial is that with the AstraZeneca
14 vaccine, in particular, there was very poor effectiveness
15 against transmission, but some effectiveness with the Pfizer
16 vaccine, but it keeps - it reduced significantly. It wasn't
17 great to begin with at 50 per cent, but reduced to 24 per cent
18 with the Delta vaccine. Sorry. With the Delta strain.
19 Q. Dr. Rau, could you explain why the effect of the
20 vaccination on transmission as it pertains to previous VOCs,
21 remind me again, the terminology of concern, variants of
22 concern, might be relevant to your report?
23 A. So, well, first of all, some of the papers that were
24 presented to me today really retained - pertained to the earlier
25 era of the COVID Classic, as I call it, the original COVID
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1 strain, or the Alpha strain. And I think we have to be careful
2 not to make conclusions on the benefits of vaccination, based
3 on what happened in the era of the Alpha variant, when the
4 Omicron variant, now, is the dominant strain, and when the
5 Omicron variant might even be eclipsed by a new strain, as we
6 get into next fall. And even with Omicron, we've had an
7 evolution from BA. 1 to BA. 2. So, we've had an evolution within
8 the Omicron to another sub strain. So, I - I think it's
9 important to look at evolving information, to keep an open mind,
10 based on evolving information, and not base conclusions on what
11 might have been the case with the earlier variant.
12 Q. Dr. Rau, prior to you being aware of this particular
13 litigation, were you reviewing sources, academic, and other
14 sources as it pertains to COVID-19, and various aspects of COVID-
15 19? So, the transmission of COVID-19 hospitalizations, but you
16 know, the impact of vaccination, so on, and so forth? Or did
17 you only start reviewing such sources, on account of your
18 involvement in this action?
19 A. No. I've been doing this constantly, because I've
20 been frequently doing media appearances, I have to be on top of
21 those for media appearances, I have to do it for work. As the
22 medical director of my - as the hospital epidemiologist, as we
23 call ourselves, I - I have to do that as part of my job. It's
24 actually part of my job to do this. So, it’s - and also, I have
25 to make presentations - on the status of the COVID-19 in Ontario,
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1 and in Canada, and on forecasting trends. Well, I've been doing
2 this since the beginning of the outbreak.
3 Q. And, Dr. Rau, would you agree with me that there are
4 several sources that you would have reviewed and considered that
5 are not mentioned in your affidavit and that not have not been
6 put to you, as an exhibit, in your cross-examination? Is that
7 fair?
8 A. Yes.
9 Q. And I take it from your previous answer that part of
10 the reason why you reviewed various sources on COVID-19 and the
11 various issues, relating to COVID-19, is to stay informed. Is
12 that correct?
13 A. It's also to do my - my job, more than just to stay
14 informed. I actually need this for my work. This - this is
15 part of my administrative role. Because by following the trends,
16 we make decisions on what to do, in terms of precaution,
17 relaxation, or implementation in the hospital. And if we think
18 things are getting better, we make decisions to start relaxing
19 restrictions, that we have uncertainty, based on the trends, we
20 might not, at a hospital level, decide to relax certain physical
21 distancing, in the cafeteria restrictions, as an example.
22 Q. And, Dr. Rau, do you agree with me that you can - or
23 Doctor, have you ever reviewed sources that speak about a
24 specific matter in the context of COVID-19, which may contradict
25 each other, or come to a different conclusion, or opinion, about
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1 a specific matter and COVID-19?
2 A. Yes. There's - there's controversy in this field, for
3 sure. And so, I've seen multiple sources that are, you know,
4 that - that may give different conclusions for the same - even
5 interpretation of the same kind of data, can give different -
6 you can have different conclusions about what to do.
7 Q. Okay, thank you, Doctor. Those are all my questions.
10 CROSS EXAMINATION ENDS
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Court Transcriber
ACT ID: 2887221650
May 24th, 2022
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AR07520
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AR07521
ELSEVIER
Since January 2020 Elsevier has created a COVID-19 resource centre with
free information in English and Mandarin on the novel coronavirus COVID-
19. The COVID-19 resource centre is hosted on Elsevier Connect, the
company's public news and information website.
Elsevier hereby grants permission to make all its COVID-19-related

research that is available on the COVID-19 resource centre - including this
research content - immediately available in PubMed Central and other
publicly funded repositories, such as the WHO COVID database with rights
for unrestricted research re-use and analyses in any form or by any means
with acknowledgement of the original source. These permissions are
granted for free by Elsevier for as long as the COVID-19 resource centre
remains active.
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AR07522
Articles
The temporal association of introducing and lifting

non-pharmaceutical interventions with the time-varying
reproduction number (R) of SARS-CoV-2: a modelling study
across 131 countries
You Li, Harry Campbell, Durga Kulkarni, Alice Harpur, Madhurima Nundy, Xin Wang, Harish Nair, for the Usher Network for COVID-19 Evidence
Reviews (UNCOVER) group
Summary
Background Non-pharmaceutical interventions (NPIs) were implemented by many countries to reduce the Lancet Infect Dis 2021;
transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19. 21: 193–202
A resurgence in COVID-19 cases has been reported in some countries that lifted some of these NPIs. We aimed to Published Online
October 22, 2020
understand the association of introducing and lifting NPIs with the level of transmission of SARS-CoV-2, as measured
https://doi.org/10.1016/
by the time-varying reproduction number (R), from a broad perspective across 131 countries. S1473-3099(20)30785-4
See Comment page 151
Methods In this modelling study, we linked data on daily country-level estimates of R from the London School of Usher Institute, University of
Hygiene & Tropical Medicine (London, UK) with data on country-specific policies on NPIs from the Oxford COVID-19 Edinburgh, Edinburgh, UK
Government Response Tracker, available between Jan 1 and July 20, 2020. We defined a phase as a time period when (Y Li PhD, Prof H Campbell MD,
all NPIs remained the same, and we divided the timeline of each country into individual phases based on the status D Kulkarni BPT, A Harpur MBChB,
M Nundy MBBS, X Wang PhD,
of NPIs. We calculated the R ratio as the ratio between the daily R of each phase and the R from the last day of the Prof H Nair PhD)
previous phase (ie, before the NPI status changed) as a measure of the association between NPI status and Correspondence to:
transmission of SARS-CoV-2. We then modelled the R ratio using a log-linear regression with introduction and Prof Harish Nair, Usher Institute,
relaxation of each NPI as independent variables for each day of the first 28 days after the change in the corresponding University of Edinburgh,
NPI. In an ad-hoc analysis, we estimated the effect of reintroducing multiple NPIs with the greatest effects, and in the Edinburgh EH8 9AG, UK
harish.nair@ed.ac.uk
observed sequence, to tackle the possible resurgence of SARS-CoV-2.
Findings 790 phases from 131 countries were included in the analysis. A decreasing trend over time in the R ratio was
found following the introduction of school closure, workplace closure, public events ban, requirements to stay at
home, and internal movement limits; the reduction in R ranged from 3% to 24% on day 28 following the introduction
compared with the last day before introduction, although the reduction was significant only for public events ban
(R ratio 0·76, 95% CI 0·58–1·00); for all other NPIs, the upper bound of the 95% CI was above 1. An increasing trend
over time in the R ratio was found following the relaxation of school closure, bans on public events, bans on public
gatherings of more than ten people, requirements to stay at home, and internal movement limits; the increase in
R ranged from 11% to 25% on day 28 following the relaxation compared with the last day before relaxation, although
the increase was significant only for school reopening (R ratio 1·24, 95% CI 1·00–1·52) and lifting bans on public
gatherings of more than ten people (1·25, 1·03–1·51); for all other NPIs, the lower bound of the 95% CI was below 1.
It took a median of 8 days (IQR 6–9) following the introduction of an NPI to observe 60% of the maximum reduction
in R and even longer (17 days [14–20]) following relaxation to observe 60% of the maximum increase in R. In response
to a possible resurgence of COVID-19, a control strategy of banning public events and public gatherings of more than
ten people was estimated to reduce R, with an R ratio of 0·71 (95% CI 0·55–0·93) on day 28, decreasing to 0·62
(0·47–0·82) on day 28 if measures to close workplaces were added, 0·58 (0·41–0·81) if measures to close workplaces
and internal movement restrictions were added, and 0·48 (0·32–0·71) if measures to close workplaces, internal
movement restrictions, and requirements to stay at home were added.
Interpretation Individual NPIs, including school closure, workplace closure, public events ban, ban on gatherings of
more than ten people, requirements to stay at home, and internal movement limits, are associated with reduced
transmission of SARS-CoV-2, but the effect of introducing and lifting these NPIs is delayed by 1–3 weeks, with this
delay being longer when lifting NPIs. These findings provide additional evidence that can inform policy-maker
decisions on the timing of introducing and lifting different NPIs, although R should be interpreted in the context of
its known limitations.
Funding Wellcome Trust Institutional Strategic Support Fund and Data-Driven Innovation initiative.
Copyright © 2020 Elsevier Ltd. All rights reserved.
www.thelancet.com/infection Vol 21 February 2021 193

AR07523
Articles
Research in context
Evidence before this study eight individual NPIs among 131 countries. We found that
The time-varying reproduction number (R; also known as Rt), reopening schools, lifting bans on public events, lifting bans
defined by the expected number of secondary cases arising from on public gatherings of more than ten people, lifting
a primary case infected at time t, is a metric that describes viral requirements to stay at home, and lifting internal movement
transmission at the population level. An R value above 1 limits were associated with an increase in R of 11–25%
indicates a growing outbreak, and an R value below 1 indicates a on day 28 following the relaxation. However, the effects of
shrinking outbreak. We searched PubMed, medRxiv, and bioRxiv introducing and lifting NPIs were not immediate; it took a
for studies that reported the effects of introducing and lifting median of 8 days (IQR 6–9) following the introduction of NPIs
non-pharmaceutical interventions (NPIs) on R of severe acute to observe 60% of their maximum reduction in R and even
respiratory syndrome coronavirus 2 (SARS-CoV-2) published longer (17 days [14–20]) following the relaxation to
between Jan 1 and Aug 5, 2020, using the keywords “COVID-19”, observe 60% of the maximum increase in R. A similar delay in
“SARS-CoV-2”, “intervention”, and “transmission”. No language response to the introduction and relaxation of NPIs was also
restriction was applied. Studies in China, Hong Kong, identified using Google mobility data. We compared
South Korea, Singapore, and many European countries showed four different candidates of composite NPIs that countries
that several NPIs, including school closure, physical distancing, might consider in response to a possible resurgence of
and lockdown, could reduce R substantially to near or below 1. COVID-19.
However, little is known about the effects on R following the
Implications of all the available evidence
relaxation of these NPIs.
We quantified the change in transmission of SARS-CoV-2,
Added value of this study as measured by R, following the introduction and relaxation of
To the best of our knowledge, this study is the first to explicitly individual NPIs, and found a delay of 1–3 weeks in observing
quantify the effects of both introducing and lifting individual the effects of introducing and lifting these NPIs. These
NPIs on R over time. By linking a global dataset of country-level findings provide additional evidence that can inform policy-
daily R values with a global dataset of country-level policies on maker decisions on which NPIs to introduce or lift and when
NPIs, we modelled the change in R values (as R ratio) from to expect a notable effect following the introduction or the
day 1 to day 28 following the introduction and relaxation of relaxation.
Introduction required. If R remains below 1, then the epidemics will

The novel coronavirus severe acute respiratory syndrome eventually die out; if R is above 1, sustained epidemics
coronavirus 2 (SARS-CoV-2) that was first reported are expected.
in Wuhan (China) in December, 2019, has since spread Studies in China, Hong Kong, South Korea, Singapore,
worldwide, and as of Oct 21, 2020, the resulting and many European countries showed that several NPIs,
COVID-19 pandemic had caused more than 40 million including school closure, physical distancing, and lock
confirmed cases and more than 1 million deaths down, could reduce R substantially to near or below 1.1–11
For the COVID-19 Dashboard (see COVID-19 Dashboard). From early March, 2020, However, scant data are available regarding the effects
see https://coronavirus.jhu.edu/ population-level non-pharma ceutical interventions on R following the relaxation of these NPIs. We aimed to
map.html
(NPIs) to reduce SARS-CoV-2 transmission were intro assess the temporal association between introducing
duced in many countries affected by COVID-19, and and lifting different NPIs and levels of SARS-CoV-2
these have included school closures, bans on public transmission, as measured by R, across 131 countries.
events, restrictions on gathering sizes, and requirements
to stay at home. Since the beginning of May, 2020, several Methods
countries have started to lift some of these NPIs, and Data sources
some countries have witnessed a second surge in the In this modelling study, we included data on country-level
number of reported COVID-19 cases. In response to the estimates of R from the EpiForecasts project by the London
resurgence, several countries have reintroduced NPIs to School of Hygiene & Tropical Medicine (London, UK).12
reduce the transmission of SARS-CoV-2. It is important Briefly, the instantaneous reproduction number is
to understand the impact of introducing and lifting these estimated based on the daily counts of confirmed
NPIs on the transmission of SARS-CoV-2. COVID-19 cases reported by the European Centre for
The time-varying reproduction number (R; also Disease Prevention and Control. The instan taneous
known as Rt) is defined by the expected number of reproduction number represents the average number of
secondary cases arising from a primary case infected secondary cases that would arise from a primary case
at time t. R is an important metric for measuring infected at a given time if the conditions remained identical
time-specific trans missibility and could be used for after that time, and thus measures the instantaneous
assessing whether current interventions appear to be transmissibility.13 The modelling framework accounts for
effective, or whether additional interventions are reporting delay between symptom onset and case
194 www.thelancet.com/infection Vol 21 February 2021

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notification, right truncation of notification dates, and the timeline of each country into individual phases based on
delay between onset and infection based on empirical data the status of NPIs. We first described the duration of
to ensure that temporal variations in R can be compared phases, the frequency of introducing and lifting each
directly with the times at which NPIs were implemented.12 NPI, and the temporal order of introducing and lifting
We included data on country-specific policies on NPIs each NPI. For each phase, we defined Rday i as the R of the
from the Oxford COVID-19 Government Response ith day of that phase (ie, since the NPI status changed)
Tracker (OxCGRT).14 OxCGRT was established by a and defined Rday 0 as the R of the last day of its previous
dedicated team of public policy and governance experts, phase (ie, before the NPI status changed). As the effect
who collect publicly available information on indicators of of NPIs on transmission (measured as R) is expected to
government response. In OxCGRT, NPIs are grouped into be relative to its original level, we calculated the R ratio
the following eight categories: closure of schools, closure between Rday i and Rday 0 as a measure of the degree of
of workplaces, public events bans (eg, sports, festive, and association of introducing and lifting an NPI (or NPIs)
religious events), restrictions on the size of gatherings, with the trans mission of SARS-CoV-2 (figure 1).
closure of public transport, stay at home orders, res An R ratio of more than 1 indicates an increase in
trictions on internal movement, and restrictions on transmission since the change in the NPI (or NPIs), and
international travel. Country-specific information on an R ratio of less than 1 indicates a decrease in
each of the NPIs is available on a daily basis (since transmission. On the basis of the change of NPIs bet
Jan 1, 2020). We also included data on testing policy and ween two neighbouring phases and the corresponding
contact tracing of each country from OxCGRT for R ratio, we were able to assess the effect of introducing
sensitivity analyses. or lifting each of the NPIs.
In the main analysis, we modelled the R ratio using a
Data processing log-linear regression, with the following equation,
We linked the R and NPI datasets by country and date to for each day of the first 28 days following the
generate our working dataset, which contains a time change in the corresponding NPI (ie, a total of 28 separate
series of daily R estimates and the status of the models):
eight NPIs for 131 countries between Jan 1 and
July 20, 2020. Details on the start and end dates of our log(Y t)=β t0 + β t1X1t + β 2t X2t +...+ β t16X16t + β t17Z1t + β t18Z2t
working dataset for each country are available in the
appendix (pp 2–4). where Yt represents the R ratio on day t (t=1, 2, …, 28); See Online for appendix
The original variables for NPIs in the OxCGRT data
set were ordinal, ranging from “no inter vention” X1t to X16t
(0 points), to “recommend intervention” (1 point), and
then to “require intervention” (2 points). For this study, are binary indicators of whether each of the eight NPIs
we converted these NPI variables to a binary variable by are introduced and lifted, respectively; and
merging the variables “no intervention” and “recommend
intervention” to increase the statistical power of the Z1t and Z2t
analysis. Details of the conversion of each NPI variable
are available in the appendix (pp 5–6). are binary indicators of whether multiple NPIs
are intro
duced and lifted simultaneously, respectively.
Data analysis Hence,
We defined a phase as a time period when all of the
eight NPIs remained the same, and we divided the β t0
Change
Change in NPI(s)
Change in NPI(s)
in NPI(s)
Day 0 Day 1 ··
Day 0 Day 1 Day 2 ·· Day i ·· Day N3
Day 0 Day 1 Day 2 ·· Day i ·· Day N2
·· Day N1
Timeline
Phase 1 Phase 2 Phase 3 Phase 4

Rday i
R ratioday i =
Rday 0
Figure 1: Schematic presenting calculation of the R ratio

Day i is defined as the ith day of the phase (ie, since NPI status changed). Day N represents the last day of the phase. Note that different phases could have different
numbers of days. NPI=non-pharmaceutical intervention. R=time-varying reproduction number.

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represents the baseline change in R on day t in the to estimate the effect of reintroducing multiple NPIs
absence of changes in NPI status; (those with the greatest effects and following the observed
sequence of introducing NPIs) to tackle the possible
β t1 to β t16 resurgence of SARS-CoV-2. We considered four candidate
strategies for the reintroduction: candidate 1 included a
represent the individual effects of introducing and lifting ban on public events and gatherings of more than ten
NPIs on day t, respectively; and people; candidate 2 included workplace closure as well as
a ban on public events and gatherings of more than
β t17 and β t18 ten people; candidate 3 included workplace closure, a ban
on public events and gatherings of more than ten people,
represent the interaction between introducing and and internal movement limits; and candidate 4 included
lifting, respectively, multiple NPIs as they are introduced school and workplace closure, a ban on public events and
and lifted simultaneously. No days beyond the first gatherings of more than ten people, internal movement
28 days following the change were included due to limits, and requirements to stay at home.
limited data availability. All data analyses and data visualisation were done
For R codes and the On the basis of the model estimates, for each NPI, we in the R software (version 3.6.1). The R codes and the
corresponding working dataset calculated the time in days needed to reach 60% of its corresponding working dataset used for the analyses are
see https://github.com/
maximum effect (measured by the R ratio, which was available in GitHub.
leoly2017/COVID_NPI_R
required to be <0·95 or >1·05) in the first 28 days as a
measure of immediacy. Furthermore, we modelled the Role of the funding source
total visits to workplaces and the total time spent in The funders of the study had no role in study design,
residential areas using Google mobility data by applying data collection, data analysis, data interpretation, writing
the same regression model as for the main analysis of the manuscript, or the decision to submit for pub
among 101 countries (details in appendix p 7). We lication. All authors had full access to all the data in the
compared the immediacy results of introducing and study and were responsible for the decision to submit the
lifting workplace closure between using the R ratio and manuscript for publication.
using total visits to workplaces. We also compared the
immediacy results of introducing and lifting requirements Results
to stay at home between using the R ratio and using the 790 phases from 131 countries were included in the ana
total time spent in residential areas. lysis (see appendix pp 8–40 for details on daily R estimates
We did a series of sensitivity analyses. First, we replaced and NPI status for each country). The median duration of
the NPI of a ban on gatherings of more than ten people phases was 11 days (IQR 3–27), with the shortest median
with a ban on gatherings of more than 100 people in the duration observed in phases in which closure of schools
model to understand how limiting public gatherings of (3 days [1–8]) and public events bans (4 days [2–7]) were
different sizes could affect the transmission. Second, we introduced (appendix p 41). Requirements to stay at home
presented the effect of individual NPIs by only including and restrictions on internal movements were the most
phases in which just one NPI was changed. Third, we used common NPIs introduced, and were most often intro
a different comparator, the mean R for the 7 days before duced and lifted simultaneously (figure 2). With regard to
NPI status change (rather than R for the day before NPI the temporal sequence of introducing and lifting NPIs,
status change), when calculating the R ratio. Fourth, we closure of schools and public events bans were the
excluded early phases in which the country’s first NPI was first two NPIs introduced and were lifted later than most
introduced. Fifth, we excluded large countries that could NPIs. Requirements to stay at home and closure of public
have greater regional variability in NPI policies: Brazil, transport were the last two NPIs introduced and were
Canada, China, India, Russia, and the USA. Sixth, we did lifted earlier than most NPIs (figure 2).
20 sets of analyses, each of which randomly excluded ten According to the results from the main analysis, a
countries from the dataset, to understand how our decreasing trend over time in the R ratio was found in the
estimates had been affected by possible outliers. Seventh, first 14 days following the introduction of school closure,
we included only the phases with comprehensive testing workplace closure, public events bans, requirements to
(defined as the requirement to test anyone with COVID-19 stay at home, and internal movement limits (figure 3);
symptoms) in the analysis, since testing practice could the reduction in R ranged from 3% to 24% on day 28
affect the estimate of R. Eighth, we included only the following the introduction (table 1). The introduction of a
phases with comprehensive contact tracing (defined as the public events ban was associated with the highest
requirement to trace contacts for all COVID-19 cases) to reduction in R; the R ratio was 0·90 (95% CI 0·82–0·99)
understand how contact tracing could modify the effect of on day 7, 0·83 (0·68–1·00) on day 14, and 0·76 (0·58–1·00)
NPIs in our model. on day 28 (table 1). An increasing trend over time in the
In addition, based on the modelled effect of individual R ratio was found following the relaxation of school
NPIs from our main analysis, we did an ad-hoc analysis closure, bans on public events, bans on public gatherings

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A Introducing NPIs Lifting NPIs
International travel limits 3 1 3 0 1 0 1 44 International travel limits 0 0 1 1 1 1 2 13
Internal movement limits 4 16 3 11 10 36 97 1 Internal movement limits 2 10 5 13 8 23 74 2
Stay at home requirement 4 19 8 24 16 100 36 0 Stay at home requirement 1 15 4 12 12 74 23 1
Public transport closure 2 11 3 3 54 16 10 1 Public transport closure 0 10 2 7 44 12 8 1
Ban on gatherings of
3 7 12 75 3 24 11 0 Ban on gatherings of 2 12 12 52 7 12 13 1
>10 people
>10 people
Public events ban 11 12 58 12 3 8 3 3 Public events ban 3 16 37 12 2 4 5 1
Workplace closure 10 88 12 7 11 19 16 1 Workplace closure 4 50 16 12 10 15 10 0
School closure 60 10 11 3 2 4 4 3 School closure 25 4 3 2 0 1 2 0
3: International travel limits 24 57 40 76 75 79 73 0 7: International travel limits 0 43 50 11 14 0 10 0
6: Internal movement limits 18 30 12 41 45 30 0 24 3: Internal movement limits 73 51 70 35 21 22 0 70
8: Stay at home requirement 7 21 5 27 33 0 25 21 2: Stay at home requirement 79 56 83 57 23 0 33 88
7: Public transport closure 4 26 4 33 0 35 33 20 1: Public transport closure 100 50 83 45 0 35 54 71

Ranking
5: Ban on gatherings of 12 32 2 0 58 34 41 24 4: Ban on gatherings of 69 52 52 0 23 14 32 78

>10 people
>10 people
2: Public events ban 39 65 0 70 83 80 81 51 8: Public events ban 15 9 0 4 0 4 11 33
4: Workplace closure 15 0 15 56 46 52 47 41 6: Workplace closure 29 0 23 13 5 6 20 57
1: School closure 0 67 36 80 88 84 74 67 5: School closure 0 43 62 15 0 14 13 100

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Figure 2: Frequency (A) and order (B) of introducing and lifting NPIs
(A) Each number denotes the frequency of the co-occurrence of NPIs in the x and y axes. Numbers on the diagonal (from bottom left to top right) denote the frequency of the occurrence of NPIs
(with and without co-occurrence). (B) Each number in the graph denotes the percentage of NPI in the y axis that occurred earlier than the NPI in the x axis among countries with both NPIs ordered or
lifted. NPIs are ranked from earliest to latest based on the mean percentage of the row. NPI=non-pharmaceutical intervention.
of more than ten people, requirements to stay at home, interaction––ie, towards an R ratio of 1—was identified
and internal movement limits, especially after the first when multiple NPIs were introduced or lifted simul
week after relaxation; the increase in R ranged from taneously (appendix p 42).
11% to 25% on day 28 following the relaxation (figure 3). The immediacy of effect by introducing and lifting
The relaxation of school closure was associated with the NPIs differed. The effects of introducing and lifting NPIs
greatest increase in R on day 7 (R ratio 1·05, 95% CI were not immediate; it took a median of 8 days (IQR 6–9)
0·96–1·14) and day 14 (1·18, 1·02–1·36). The relaxation of following the introduction of an NPI to observe 60% of
a ban on gatherings of more than ten people was the maximum reduction in R and even longer (17 days
associated with the greatest increase in R on day 28, with [14–20]) following its relaxation to observe 60% of the
an R ratio of 1·25 (95% CI 1·03–1·51) on day 28. Negative maximum increase in R (appendix p 43). Similar delays

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1·6 Introduced School closure Workplace closure

Lifted
1·4
1·2
R ratio
1·0
0·8
0·6
1·6 Public events ban Ban on gathering of >10 people
1·4
1·2
R ratio
1·0
0·8
0·6
1·6 Public transport closure Stay at home requirement
1·4
1·2
R ratio
1·0
0·8
0·6
1·6 Internal movement limits International travel limits
1·4
1·2
R ratio
1·0
0·8
0·6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Time since introducing or lifting NPIs (days) Time since introducing or lifting NPIs (days)
Figure 3: Change over time in the R ratio following the introduction and relaxation of individual NPIs
For each NPI, the reference period is the day before introduction or relaxation of that NPI. An R ratio of more than 1 indicates increased transmission, and an R ratio of less than 1 indicates decreased
transmission. The error bars present the 95% CIs of the R ratios derived from the model. NPI=non-pharmaceutical intervention. R=time-varying reproduction number.
were noted for workplace closure and requirements to lifting the ban on gatherings of more than ten people and
stay at home when using R as well as when using Google 1·23 (1·07–1·42) for lifting the ban on gatherings of more
mobility data (appendix p 44). With Google mobility data than 100 people (figure 4).
it took an estimated 6 days and 12 days (compared Similar results in terms of the trend in R over time
with 6 days and 9 days when using R) following the following introduction and relaxation of NPIs (although
introduction and relaxation of workplace closure, with wider CIs due to data scarcity) were observed from
respectively, to observe 60% of the maximum change in sensitivity analyses that included only phases during
the total visits to workplace, and it took an estimated which only one NPI was changed (appendix p 46), used the
6 days and 17 days (compared with 6 days and 23 days mean R of the last 7 days (rather than the last day) in the
when using R) following the introduction and relaxation previous phase for calculating the R ratio (appendix p 47),
of requirements to stay at home, respec tively, to excluded early phases when the country’s first NPI was
observe 60% of the maximum change in the total time introduced (appendix p 48), excluded seven large countries
spent at residential areas. that could have greater regional variability in NPI policies
When comparing the effect of a ban on gatherings of (appendix p 49), excluded ten countries randomly
more than ten people with that of a ban on gatherings of (appendix p 50), included only phases with comprehensive
more than 100 people, we found that both bans were testing (appendix p 51), and included only phases with
associated with a decrease in the R ratio in the first week, comprehensive contact tracing (appendix p 52). Contrary
followed by an increase in the R ratio starting from the to the main analysis, we found that if a public events ban
second week, but the increase was more pronounced for was not introduced as the first intervention, it showed a
the ban on gatherings of more than 100 people, with non-significant reduction in R on day 28, with an R ratio of
R ratios above 1 after day 14 (figure 4). When lifting these 0·80 (95% CI 0·57–1·11).
two bans, we observed a delayed increase in R for the ban On the basis of the results from the main analysis, we
on gatherings of more than ten people (appendix p 45); estimated the effects of four candidates of composite
on day 14, the R ratio was 1·07 (95% CI 0·96–1·20) for NPIs (table 2; appendix p 53). The greatest reductions

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in R were seen for candidate 4 (school and workplace

Day 7 Day 14 Day 28
closure, plus a ban on public events and gatherings of
more than ten people, internal movement limits, and a School closure
requirement to stay at home) at all timepoints (table 2). Introduction 0·89 (0·82–0·97) 0·86 (0·72–1·02) 0·85 (0·66–1·10)
Relaxation 1·05 (0·96–1·14) 1·18 (1·02–1·36) 1·24 (1·00–1·52)
Discussion Workplace closure
To the best of our knowledge, this study is the first to Introduction 0·89 (0·83–0·96) 0·89 (0·78–1·02) 0·87 (0·73–1·03)
assess the temporal association between changing the Relaxation 1·04 (0·97–1·13) 1·10 (0·97–1·24) 1·01 (0·83–1·25)
status of a range of NPIs and the transmission of Public events ban
SARS-CoV-2, as measured by R, for all countries for Introduction 0·90 (0·82–0·99) 0·83 (0·68–1·00) 0·76 (0·58–1·00)
which data were available. On the basis of the empirical Relaxation 1·02 (0·93–1·11) 1·07 (0·92–1·24) 1·21 (0·97–1·50)
data from 131 countries, we found that individual NPIs, Ban on gatherings of more than ten people
including school closure, workplace closure, public Introduction 0·93 (0·87–0·99) 0·98 (0·87–1·10) 0·97 (0·83–1·14)
events bans, requirements to stay at home, and internal Relaxation 0·99 (0·93–1·06) 1·07 (0·96–1·20) 1·25 (1·03–1·51)
movement limits, were associated with reductions in R of Public transport closure
3–24% on day 28 after their introduction, compared with Introduction 0·97 (0·91–1·04) 0·98 (0·87–1·11) 0·99 (0·84–1·18)
the day before their introduction. Reopening schools, Relaxation 1·00 (0·93–1·07) 1·08 (0·96–1·22) 1·04 (0·85–1·27)
lifting bans on public events, lifting bans on public Requirements to stay at home
gatherings of more than ten people, lifting requirements Introduction 0·90 (0·85–0·97) 0·89 (0·79–1·00) 0·97 (0·83–1·14)
to stay at home, and lifting internal movement limits Relaxation 0·97 (0·91–1·03) 1·02 (0·92–1·13) 1·11 (0·94–1·32)
were associated with increases in R of 11–25% on day 28 Internal movement limits
after the relaxation. The effects of introducing and lifting Introduction 0·97 (0·90–1·03) 0·97 (0·87–1·10) 0·93 (0·79–1·10)
NPIs were not immediate; it took around 1 week Relaxation 0·98 (0·92–1·04) 1·06 (0·95–1·18) 1·13 (0·94–1·37)
following the introduction of an NPI to observe 60% of International travel limits
the maximum reduction in R and even longer Introduction 0·89 (0·81–0·98) 0·97 (0·81–1·16) 1·08 (0·85–1·38)
(almost 3 weeks) following the relaxation of an NPI to Relaxation 0·95 (0·84–1·07) 1·02 (0·81–1·28) 0·98 (0·68–1·40)
observe 60% of the maximum increase in R. Our analysis
Data are R ratio (95% CI). For each NPI, the reference period is the day before introduction or relaxation of that NPI.
suggests that, in the context of a resurgence of An R ratio of more than 1 indicates increased transmission, and an R ratio of less than 1 indicates decreased
SARS-CoV-2, a control strategy of banning public events transmission. NPI=non-pharmaceutical intervention. R=time-varying reproduction number.
and public gatherings of more than ten people would be
Table 1: Change in the R ratio over time on day 7, day 14, and day 28 after the introduction and relaxation
associated with a reduction in R of 6% on day 7, 13% on of each NPI
day 14, and 29% on day 28; if this strategy also included
closing workplaces, the overall reduction in R would be
16% on day 7, 22% on day 14, and 38% on day 28. These Our analysis demonstrates that the effect of intro
findings provide additional evidence that can inform ducing and lifting NPIs was not immediate and that the
policy makers’ decisions on the timing of introducing time required to reach certain levels of effect differed
and lifting different NPIs. by NPI. This finding provides important evidence to
Our findings on the effects of introducing NPIs were policy makers on when to expect a notable effect from
broadly in line with the findings from Flaxman and introducing or lifting an NPI. The observed delay of
colleagues’ multicountry study that assessed the impact effect could be explained by behavioural inertia, which is
of different NPIs among 11 European countries.4 Flaxman supported by the similar immediacy results of NPIs
and colleagues reported that several NPIs (eg, school between using R and using Google mobility data.
closure and public events ban), and lockdown in par School closure was widely adopted previously to
ticular, had a large effect (81%) on reducing transmission.4 control influenza outbreaks and pandemics, and was
However, Flaxman and colleagues did not assess changes shown to reduce and delay peaks of epidemics.16,17 For
over time in the effect of lockdown and assumed that the SARS-CoV-2, the role of children in its transmission is
effect was immediate. In this study, we estimated that an still unclear. A modelling study from China showed that
extreme intervention similar to lockdown, consisting of school closure alone could not interrupt transmission,
school and workplace closure, bans on public events and but it could potentially reduce peak incidence by 40–60%
gatherings, requirements to stay at home, and limits on and delay the epidemic of COVID-19.18 In this study, we
internal movement, could reduce R by 35% on day 7, showed that closing schools alone could decrease
42% on day 14, and 52% on day 28. Our findings on the transmission by 15% (R ratio 0·85, 95% CI 0·66–1·10)
effects of introducing NPIs were also qualitatively similar on day 28 and reopening schools could increase
to those from a study by Islam and colleagues that transmission by 24% (1·24, 1·00–1·52) on day 28. It
modelled the inci dence rate ratio of COVID-19 with should be acknowledged that in our analysis, we were
OxCGRT NPI data,15 although that study did not assess unable to account for different precautions regarding
the effects of lifting NPIs. school reopening that were adopted by some countries,

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1·8 Introduced Ban on gatherings of >10 people Ban on gatherings of >100 people
Lifted
1·6
1·4
R ratio
1·2
1·0
0·8
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Time since introducing or lifting NPIs (days) Time since introducing or lifting NPIs (days)
Figure 4: Change over time in the R ratio following the introduction and relaxation of a ban on public gatherings of different sizes
The error bars present the 95% CIs of the R ratios derived from the model. R=time-varying reproduction number.
Day 7 Day 14 Day 28

Candidate 1: ban on public events and gatherings of more than ten people 0·94 (0·85–1·03) 0·87 (0·73–1·05) 0·71 (0·55–0·93)
Candidate 2: workplace closure plus ban on public events and gatherings of more than ten people 0·84 (0·76–0·93) 0·78 (0·64–0·94) 0·62 (0·47–0·82)
Candidate 3: Workplace closure plus ban on public events and gatherings of more than ten people 0·81 (0·71–0·92) 0·76 (0·60–0·95) 0·58 (0·41–0·81)
plus internal movement limits
Candidate 4: School and workplace closure plus ban on public events and gatherings of more than 0·65 (0·54–0·78) 0·58 (0·42–0·78) 0·48 (0·32–0·71)
ten people plus internal movement limits plus stay at home requirement
Data are R ratio (95% CI). The reference period is the day before introduction of an NPI. An R ratio of more than 1 indicates increased transmission, and an R ratio of less than 1
indicates decreased transmission. NPI=non-pharmaceutical intervention. R=time-varying reproduction number.
Table 2: Modelled change in the R ratio over time on day 7, day 14, and day 28 after the introduction of different composites of NPIs
such as physical distancing within classrooms (eg, reduction is that a ban on public events was often the
limiting class sizes and placing transparent dividers first NPI to be introduced in countries; our sensitivity
between students) and outside classrooms (eg, physical analysis that excluded NPIs that were introduced first
distancing during meal times, recreation, and trans showed a non-significant reduction of transmission with
portation), enhanced hygiene (eg, routine deep cleaning banning public events, with an R ratio of 0·80 (95% CI
and personal handwashing and face masks), and others 0·57–1·11) on day 28.
(eg, thermal temperature checks on arrival).19,20 Such Our findings also suggest that, within 28 days, lifting
precautions are imperative for safer school reopening. A public events bans could increase transmission by 21%,
COVID-19 outbreak was reported in a high school in although the finding was not significant, and lifting bans
Israel 10 days after its reopening; students were in on gatherings of more than ten people could increase
crowded classrooms and were not instructed to wear transmission by 25%, which was the highest increase
face masks due to high temperatures.21 In addition, it among all NPIs. We did not observe a substantial
should be noted that we did not consider the normal reduction in transmission after introduction of bans on
school holidays in some countries. We were also unable gatherings of more than ten or more than 100 people,
to assess the effect of reopening different levels of school especially for more than 100 people, which showed
(eg, elementary vs middle schools) since the effect might an increase in transmission after day 14; possible
differ by finer age bands within school-age children and explanations for this finding include low adherence and,
adolescents.21,22 A report found that children younger for the ban on gatherings of more than 100 people, an
than 5 years with mild to moderate COVID-19 had increase in smaller-scale gatherings. In addition, it should
high viral loads in their nasopharynx compared with be noted that for bans on physical gatherings, we were
older children and adults, and thus could potentially unable to further stratify our analysis by indoor versus
be important drivers of transmission in the general outdoor settings due to scarcity of data.
population.23 Notably, we did not observe a substantial difference in
Our findings suggest that, as a single NPI, banning our results when including in a sensitivity analysis only
public events resulted in the greatest reduction in R, with phases with comprehensive contact tracing in place. This
an R ratio on day 28 of 0·76 (95% CI 0·58–1·00). This was not as expected since contact tracing was believed to
finding is unsurprising because a ban on crowded reduce transmission through early identification of
activities could prevent superspreading events, which infectious cases. This finding could be due to the lack of
were commonly reported at the beginning of the representativeness, since only 18% of our data were
COVID-19 pandemic.24 Another explanation for the high included in this sensitivity analysis. Never theless, a

AR07530
Articles
modelling study, which might explain our results, SARS-CoV-2 transmission. A modelling study found that
suggested that a contact-tracing strategy will contribute introduction of NPIs was strongly associated with growth
to containment of COVID-19 only if it can be organised of COVID-19 cases and, by comparison, humidity was
in a timely manner that minimises testing and tracing only weakly associated with the growth; no association
delays.25 However, our data lacked the necessary granu was found for latitude or temperature.26 Seventh, we only
larity to further explore timeliness of testing and tracing. assessed the effect of introducing and lifting NPIs for the
Additionally, similar to the findings by Islam and first 28 days after introduction and relaxation, and the
colleagues,15 we did not observe substantial effects of findings (including the trend) should not be generalised
public transport closure on the R ratio. to beyond 28 days. Finally, although our study could
There are some advantages to our study. First, both essentially be regarded as a natural experiment study,15
the method for the R calculation and the method for our findings do not necessarily imply causation.
recording NPIs remained consistent over time among We acknowledge several limitations of the methodology
different countries, which ensured comparability between for the R estimate used in our analysis. First, the
different phases in different countries in our analysis. adjustment for reporting delays was only done globally
Second, by dividing the timeline into different phases and not specific to each country due to the scarcity of
according to the changes in NPIs, we were able to assess available data on reporting delays. This could lead to
the effect of individual NPIs. Third, we were able to temporal inaccuracy of R, which could bias our findings
estimate the change in the effect of NPIs over time. on the immediacy of changes in R associated with NPIs.
We acknowledge several challenges and limitations Nonetheless, our findings on the immediacy of changes
regarding our analysis. First, our analysis was based on associated with NPIs were consistent with the results of
data on control policy rather than on actual population the analysis using Google mobility data, indicating that
behaviour. In particular, we were unable to account for the possible temporal inaccuracy of R might have had
the growing awareness of personal hygiene (including little impact on the overall findings. Second, the R estimate
wearing face coverings) among the public in response was subject to the specification of parameters (eg,
to the pandemic. These behavioural changes lead to a incubation period and generation time of SARS-CoV-2) in
further reduction of transmission and are likely to vary the model and could be biased upwards or downwards.
over time. We were also unable to examine compliance However, we believe it unlikely that this bias affected the
with these NPIs due to the scarcity of suitable data that main findings of our study because we used the R ratio as
were reliable across countries over time. Second, some the output metric (which cancels out all time-invariant
NPIs (eg, school closure and public events ban) elements related to the R estimate). Third, the modelling
were often introduced earlier than other NPIs (eg, framework for R was unable to account for the change
requirements to stay at home); therefore, we were unable over time in eligibility for testing, method of testing, or
to assess the effect of different rank orders of changes in case definition in different countries. This could bias both
NPI status. NPIs that were introduced earlier might have the R estimate and the R ratio in our analysis for the dates
had a longer-term effect on R and thus might bias the during which the changes were ongoing. For example, we
estimates for later NPIs. Third, our data on R and NPIs are likely to observe an artificial increase in R if a country
were at the national level, whereas both R and NPIs could increases the testing capacity within a short period. Last,
vary among different parts of a country. An increase in the uncertainty range of the national R estimate was based
national-level R could be due to a clustered outbreak in on the number of national reported cases and therefore
some areas or due to several scattered cases nationwide. did not reflect any variations in R within the country.
Fourth, we acknowledged the potentially high hetero We also acknowledge the innate limitations of R as a
geneity across different countries in terms of both NPIs measure of transmission of SARS-CoV-2. First, although
and COVID-19 case ascertainment. Our findings should R is often assumed to have straightforward interpretations
be regarded as a broad summary across the full dataset, in practice, estimating R during an ongoing outbreak is
and we did not intend to draw any separate conclusions complicated and associated with substantial uncertainty.
for individual countries. Our sensitivity analyses indi Second, the estimates of R become unreliable with wider
cated that our main findings were not sensitive to the uncertainty range if the number of cases is low, which
removals of different lists of countries. Fifth, individual reduces its applicability at the very local level or when the
awareness and personal hygiene have been changing number of cases in a large region is low. Third, R can be
over time since the pandemic started, which could sensitive to a surge in the number of cases in certain
contribute greatly to the change in transmission of settings (eg, care homes, schools, factories, and hospitals)
SARS-CoV-2 (eg, wearing face masks was uncommon and does not fully represent transmission in the general
before the COVID-19 pandemic); therefore, the impact population. Fourth, R is an average population-level
on R by future reintroduction and re-relaxation of measure of transmission and does not reflect the indi
NPIs might be substantially different. Sixth, we did not vidual-level transmission of SARS-CoV-2. The potential
consider the role of underlying seasonality or meteoro of SARS-CoV-2 transmission varies among individuals
logical factors (eg, temperature and humidity) in and is reflected by the reported superspreading events.7,24

AR07531
Articles
In summary, our findings provide additional evidence 8 Lemaitre JC, Perez-Saez J, Azman AS, Rinaldo A, Fellay J.
that can inform policy makers’ decisions on the timing of Assessing the impact of non-pharmaceutical interventions on
SARS-CoV-2 transmission in Switzerland. Swiss Med Wkly 2020;
introducing and lifting different NPIs. The decisions to 150: w20295.
reintroduce and relax restrictions should be informed by 9 Pan A, Liu L, Wang C, et al. Association of public health
various factors, including the capacity and resilience of interventions with the epidemiology of the COVID-19 outbreak
in Wuhan, China. JAMA 2020; 323: 1915–23.
the health-care system, and might be best made at 10 Ryu S, Ali ST, Jang C, Kim B, Cowling BJ. Effect of nonpharmaceutical
provincial or district rather than national levels in some interventions on transmission of severe acute respiratory syndrome
countries. coronavirus 2, South Korea, 2020. Emerg Infect Dis 2020; 26: 2406–10.
11 Tariq A, Lee Y, Roosa K, et al. Real-time monitoring the
Contributors transmission potential of COVID-19 in Singapore, March 2020.
YL, HC, and HN conceptualised the study. YL led data acquisition, BMC Med 2020; 18: 166.
analysis, and visualisation. HN, HC, and YL led the data interpretation 12 Abbott S, Hellewell J, Thompson R, et al. Estimating the time-
with substantial contribution from DK, AH, MN, and XW. YL wrote the varying reproduction number of SARS-CoV-2 using national and
draft report, and all other authors revised the report critically for subnational case counts [version 1; peer review: awaiting peer
important intellectual content. All authors have read and approved the review]. Wellcome Open Res 2020; 5: 112 (preprint).
final version of the report. YL and HN verified the data linkage of two 13 Cori A, Ferguson NM, Fraser C, Cauchemez S. A new framework
publicly available datasets and had full access to the linked data. and software to estimate time-varying reproduction numbers
during epidemics. Am J Epidemiol 2013; 178: 1505–12.
Declaration of interests
14 Hale T, Webster S, Petherick A, Phillips T, Kira B. Coronavirus
YL reports grants from WHO, outside the submitted work. HC reports government response tracker. 2020. https://www.bsg.ox.ac.uk/
grants from the Innovative Medicines Initiative, UK National Institute research/research-projects/oxford-covid-19-government-response-
for Health Research, and Bill & Melinda Gates Foundation, and grants tracker (accessed July 13, 2020).
and personal fees from WHO and Sanofi, outside the submitted work. 15 Islam N, Sharp SJ, Chowell G, et al. Physical distancing
HN reports grants from the Innovative Medicines Initiative, WHO, interventions and incidence of coronavirus disease 2019:
and the National Institute for Health Research; personal fees from natural experiment in 149 countries. BMJ 2020; 370: m2743.
the Bill & Melinda Gates Foundation, Janssen, and AbbVie; and grants 16 Bin Nafisah S, Alamery AH, Al Nafesa A, Aleid B, Brazanji NA.
and personal fees from Sanofi and the Foundation for Influenza School closure during novel influenza: a systematic review.
Epidemiology, outside the submitted work. All other authors declare no J Infect Public Health 2018; 11: 657–61.
competing interests. 17 Jackson C, Mangtani P, Hawker J, Olowokure B, Vynnycky E.
The effects of school closures on influenza outbreaks and pandemics:
Data sharing
systematic review of simulation studies. PLoS One 2014; 9: e97297.
The study data and corresponding R codes are freely available with
18 Zhang J, Litvinova M, Liang Y, et al. Changes in contact patterns
publication in GitHub at https://github.com/leoly2017/COVID_NPI_R.
shape the dynamics of the COVID-19 outbreak in China. Science
Acknowledgments 2020; 368: 1481–86.
This study was funded by the Wellcome Trust Institutional Strategic 19 Melnick H, Darling-Hammond L, Leung M, et al. Reopening
Support Fund and Data-Driven Innovation initiative. We acknowledge schools in the context of COVID-19: health and safety guidelines
Gerry Fowkes (University of Edinburgh, Edinburgh, UK) from the from other countries. May 15, 2020. https://learningpolicyinstitute.
UNCOVER group for his comments on the draft report. org/product/reopening-schools-covid-19-brief (accessed
July 28, 2020).
References 20 Sheikh A, Sheikh A, Sheikh Z, Dhami S. Reopening schools after
1 Cowling BJ, Ali ST, Ng TWY, et al. Impact assessment of the COVID-19 lockdown. J Glob Health 2020; 10: 010376.
non-pharmaceutical interventions against coronavirus disease 2019 21 Stein-Zamir C, Abramson N, Shoob H, et al. A large COVID-19
and influenza in Hong Kong: an observational study. outbreak in a high school 10 days after schools’ reopening, Israel,
Lancet Public Health 2020; 5: e279–88. May 2020. Euro Surveill 2020; 25: 2001352.
2 Davies NG, Kucharski AJ, Eggo RM, et al. Effects of 22 Götzinger F, Santiago-García B, Noguera-Julián A, et al. COVID-19
non-pharmaceutical interventions on COVID-19 cases, deaths, in children and adolescents in Europe: a multinational, multicentre
and demand for hospital services in the UK: a modelling study. cohort study. Lancet Child Adolesc Health 2020; 4: 653–61.
Lancet Public Health 2020; 5: e375–85.
23 Heald-Sargent T, Muller WJ, Zheng X, Rippe J, Patel AB,
3 Di Domenico L, Pullano G, Sabbatini CE, Boëlle PY, Colizza V. Kociolek LK. Age-related differences in nasopharyngeal severe acute
Impact of lockdown on COVID-19 epidemic in Île-de-France and respiratory syndrome coronavirus 2 (SARS-CoV-2) levels in patients
possible exit strategies. BMC Med 2020; 18: 240. with mild to moderate coronavirus disease 2019 (COVID-19).
4 Flaxman S, Mishra S, Gandy A, et al. Estimating the effects of JAMA Pediatr 2020; published online July 30. https://doi.
non-pharmaceutical interventions on COVID-19 in Europe. Nature org/10.1001/jamapediatrics.2020.3651.
2020; 584: 257–61. 24 Liu Y, Eggo RM, Kucharski AJ. Secondary attack rate and
5 Karnakov P, Arampatzis G, Kičić I, et al. Data-driven inference of superspreading events for SARS-CoV-2. Lancet 2020; 395: e47.
the reproduction number for COVID-19 before and after 25 Kretzschmar ME, Rozhnova G, Bootsma MCJ, van Boven M,
interventions for 51 European countries. Swiss Med Wkly 2020; van de Wijgert JHHM, Bonten MJM. Impact of delays on
150: w20313. effectiveness of contact tracing strategies for COVID-19:
6 Kucharski AJ, Klepac P, Conlan AJK, et al. Effectiveness of isolation, a modelling study. Lancet Public Health 2020; 5: e452–59.
testing, contact tracing, and physical distancing on reducing 26 Jüni P, Rothenbühler M, Bobos P, et al. Impact of climate and
transmission of SARS-CoV-2 in different settings: a mathematical public health interventions on the COVID-19 pandemic:
modelling study. Lancet Infect Dis 2020; 20: 1151–60. a prospective cohort study. CMAJ 2020; 192: e566–73.
7 Kucharski AJ, Russell TW, Diamond C, et al. Early dynamics of
transmission and control of COVID-19: a mathematical modelling
study. Lancet Infect Dis 2020; 20: 553–58.

AR07532 JML TRANSCRIPTION
l♦I
Government Gouvemement
of Canada du Canada µ 1-888-288-6817
DATE: ~ /~, a,Qq&
EX#: Y INITIALS: A ·Q
COVID-19 daily epidemiology update
Updated: May 17, 2022, 9 am EST
Summary of COVID-19 cases across Canada and over time. Contains detailed data about the spread of the
virus over time and in different regions of the country. Includes breakdowns by age and sex or gender.
Provides an overview of hospitalizations and deaths, testing, variants of concern and exposures.
·,
0 We are working with the provinces and territories to make changes to this page to reflect current
reporting. Watch for upcoming changes to the Key updates, Current situation and National overview
sections.
Key updates as of May 17, 2022, 9 am EST
cases today Total cases Deaths today Total deaths
1,559 3,825,388 7 40,265
Total tests performed Daily percent positive (last 7 days) Daily tests per 100,000 population (last 7 days)
61,538,265 11.5% 95
• We update these sections Monday to Friday at 9:00 AM EST: Key updates, Current situation and National
overview. Laboratory data represents specimens received by labs up to May 14, 2022 to allow time to
process results.
• We update these sections every Friday: COVID-19 variants in Canada, Epidemic curve, Demographics,
How people were exposed, and Severe illness and outcomes.
• The Cases following vaccination section is updated every Tuesday.
• Of the 3 jurisdictions reporting updates, no new cases were reported in O provinces and territories in the
past 24 hours.
• Of the 3 jurisdictions reporting updates, no new deaths were reported in 1 provinces and territories in the
past 24 hours.
• Due to changes in COVID-19 testing policies in many jurisdictions starting in late December 2021, case
counts will under estimate the total burden of disease.
• Resulting from the delays in data entry caused by the recent high number of cases, Nova Scotia issued a
press release on December 10 indicating that they would begin announcing the daily number of new
cases using laboratory test results, not data from Panorama (their public health disease information
JML TRANSCRIPTION
AR07533
1-888-288-6817
DATE: H:?j I ~. d'O ?:+ SCIENCE BRIEFS
EX #: s:: INITIALS: -A D
Early Impact of Ontario's COVID-19
• • •
• •
• Vaccine Rollout on Long-Term Care Home
SCIENCE TABLE Residents and Health Care Workers
COV I D - 19 ADVISORY FOR ONTARIO
. .. . Kevin A. Brown, Nathan ~- Stall, Thuva Vanniyasingam, Sarah A. Buchan, Nick

• •
. .. ... Daneman, Michael P. Hillmer, Jessica Hopkins, Jennie Johnstone, Antonina Maltsev,
Allison McGeer, Beate San\:ler, Rachel D. Savage, Tania Watts, Peter Juni, Paula A.
Rochon on behalf of the Congregate Care Setting Working Group and the Ontario
• • COVID-19 Science Advisory Table
Version 1.1
Key Message
Published: Mardi 8, 2021
Updated on March 8, 2021. Version 1.0 is
The rollout of COVID-19 vaccines to Ontario's long-term care (LTC) homes has
available undef- Additional Resources at substantially reduced SARS-CoV-2 infections, COVID-19 hospitalizations, and deaths
https://doi.org/10.47326/ocsat.2021.02.13.1.0. among LTC residents and health care workers.
citation: Brown KA. Stall NM, Vanniyasingam
T, et al. Early impact of Ontario's COVID-19 Completing and maximizing the uptake of the full COVID-19 vaccine series according
vaccine rollout on long-tenn care home to recommended schedules will maximize the safety and well-being of Ontario's LTC
residents and health care workers. Science
residents and staff.
Brieft af the Ontario COVID-19 Science
Advisory Tabte: 2021;2(13). https://
doi.org/10.47326/ocsat.2021.02.13.1.0
Summary
Author Affifaations: The affiliations of the
members of the Ontario COVID-19 Science Background
Advisory Table can be found at https://
covid19-sciencetable.ca/. While only accounting for 0.5% of Ontario's population, long-term care (LTC)
Declarations of Interest: The declarations of residents across the province have had disproportionately high rates of SARS-COV-2
interest of the members of the Ontario
infections and COVID-19 deaths.
COVID-19 Science Advisory Table can be
found at https://covid19-sciencetable.ca/. Ontario's COVID-19 vaccine rollout began in mid-December 2020, with LTC residents
About Us: The Ontario COVID-19 Science and staff identified as Phase 1 priority populations for vaccination.
Advisory Table is a group of scientific experts
and health system leaders who evaluate and
report on emerging evidence relevant to the
Question
COVID-19 pandemic, to inform Ontario's
What was the early impact of the COVID-19 vaccine on SARS-CoV-2 cases, COVID-19
response. Our mandate is to provide weekly
summaries of relevant scientific evidence for hospitalizations and deaths among Ontario's LTC residents and health care workers
the COVID-19 Health Coordination Table of (HCWs)?
the Province of Ontario, integrating
information from existing scientific tables,
Ontario's universities and agencies, and the
Findings
best global evidence. The Science Table
summarizes its findings for the Health
l TC home staff were the first to receive the vaccine in clinics starting on December
Coordination Table and the public in Science 14, 2020. Most LTC home residents started receiving first doses of t he COVID-19
Briefs. vaccine after December 23, 2020. All LTC residents in Ontario were offered at least
The Congregate Care Setting Working Group the first dose of a COVID-19 vaccine by February 13, 2021.
is a group of internationally recognized
researchers with expertise in older people As of February 23, 2021, more than 64,000 Ontario LTC residents (92%) received at
living in congregate care settings. The
least one dose of a COVID-19 vaccine, with over 46,500 of residents having received
Working Group evaluates emerging scientific
evidence related to congregate care settings both doses. Over 55,000 Ontario LTC staff (55%) also received at least one dose of a
to infonn Ontario's response to the COVID- COVID-19 vaccine, with more than 44,600 having received both d.oses.
19 pandemic. The Working Group reports its
findings to the public and the Science Table. As of February 23, 2021, COVID-19 vaccination in LTC homes prevented an
Its findings are also summarized in Science
estimated 2,079 SARS-CoV-2 infections, 249 COVID-19 hospitalizations, and 615
Briefs.
COVID-19 deaths in residents, and an estimated 330 SARS-CoV-2 infections, and 8
Correspondence to: Secretariat of the
Ontario COVID-19 Science Advisory Table COVID-19 hospitalizations and 1 COVID-19 deat h in HCWs.
(info@covid19-sciencetab1e.ca)
Sciefla! Briefs I https://covid19-sciencetable.ca/science-briefs Mardi 8, 2021 I 1

AR07534
Ontario COVID-19 Science Advisory Table Early Impact of Ontario’s COVID-19 Vaccine Rollout on Long-Term Care Home Residents and Health Care Workers
Copyright: 2021 Ontario COVID-19 Science
Advisory Table. This is an open access Eight weeks after the start of vaccination, the estimated relative reduction in SARS-
document distributed under the terms of the CoV-2 incidence was 89% in LTC residents and 79% in LTC HCWs. The estimated
Creative Commons Attribution License,
which permits unrestricted use, distribution,
relative reduction in COVID-19 mortality in LTC residents was 96% after 8 weeks.
and reproduction in any medium, provided
that the original work is properly cited. Interpretation
The views and findings expressed in this The rollout of COVID-19 vaccines in Ontario’s LTC homes substantially reduced
Science Brief are those of the authors and do
not necessarily reflect the views of all of the SARS-CoV-2 infections, COVID-19 hospitalizations and deaths among LTC residents
members of the Ontario COVID-19 Science and HCWs. Completing and maximizing the uptake of the full COVID-19 vaccine
Advisory Table, its Working Groups, and its
partners.
series according to recommended schedules will maximize the safety and well-being
of Ontario’s LTC residents and staff.
Background
In Ontario there are 626 LTC homes with 69,799 residents occupying 77,257 long-
stay beds as of January 2021.1,2 Fifty-five percent of Ontario’s LTC residents are 85
years of age or older3 and 70% are women.4 Ontario’s LTC homes employ
approximately 100,000 clinical and non-clinical staff, who are involved in clinical
work, caregiving, administration, housekeeping, food preparation, facilities
management, maintenance, and recreation.5 The majority of personal care for LTC
residents is provided by approximately 50,000 personal support workers (PSWs),
who represent the largest group of employees in the LTC sector, followed by
approximately 25,000 registered practical nurses, registered nurses, and nurse
practitioners. Nearly 90% of Ontario’s PSWs are women, half are between the ages
of 35 and 54 years, and more than 40% are visible minorities.5
While accounting for only 0.5% of Ontario’s population of 15 million, LTC residents
across the province have had disproportionately high rates of SARS-COV-2 infections
and COVID-19 deaths. As of February 23, 2021, there has been a total of 14,958
cumulative SARS-CoV-2 infections and 3,858 cumulative COVID-19 deaths among
LTC residents (55% of Ontario’s 6,940 COVID-19 deaths).
Ontario’s COVID-19 vaccine rollout began in mid-December 2020, with LTC residents
and staff identified as Phase 1 priority populations for vaccination.6 The Pfizer-
BioNTech vaccine was the first COVID-19 vaccine approved by Health Canada on
December 9, 2020, and also the first vaccine received in the Province of Ontario.
Due to vaccine stability concerns and regulations about the storage, handling, and
transportation of the Pfizer-BioNTech vaccine, Ontario LTC staff were the first to
receive the vaccine in hospital-based clinics starting on December 14, 2020. Most
LTC home residents received the Moderna vaccine, with vaccination starting after
Health Canada’s approval on December 23, 2020.
Ontario’s COVID-19 vaccine rollout began alongside a range of public health
measures implemented by the Province of Ontario to reduce community
transmission of SARS-CoV-2. This included a province-wide shutdown beginning on
December 26, 2020, followed by a province-wide stay-at-home order commencing
on January 14, 2021.7 On February 22, 2021, all Ontario regions had schools return
to in-class learning, and all regions except for Toronto, Peel, and North Bay-Parry
Sound lifted some of their public health restrictions, in accordance with a return to
Ontario’s COVID-19 response framework.8
Question
What was the early impact of the COVID-19 vaccine on SARS-CoV-2 cases, COVID-19
hospitalizations and deaths among Ontario’s LTC residents and health care workers?
Science Briefs | https://covid19-sciencetable.ca/science-briefs March 8, 2021 | 2

AR07535
Findings
Prioritization of Ontario LTC homes for COVID-19 Vaccination and Speed of the
Vaccine Rollout
In the pre-vaccination period between November 1 and December 13, 2020, there
were 2,433 reported SARS-CoV-2 infections among LTC residents, and 991 among
LTC HCWs. The COVID-19 vaccine rollout started in Ontario on December 14, 2020,
with LTC homes in the public health units (PHUs) of Toronto, Peel, York, and
Windsor-Essex prioritized for initial allocation of vaccine due to those regions having
the highest SARS-CoV-2 infection rates.
The Province set January 21, 2021, as the target date for the provision of first doses
of COVID-19 vaccines to LTC residents residing in those high priority regions, and
February 10, 2021, as the target date for the provision of first doses to all remaining
LTC residents across Ontario.9 All LTC residents in high priority regions were offered
the first dose of a COVID-19 vaccine by January 19, 2021. All remaining LTC residents
were offered the first dose of a COVID-19 vaccine by February 13, 2021.
COVID-19 Vaccination of Ontario LTC home Residents and Staff

As of February 23, 2021, more than 64,000 Ontario LTC residents received at least
one dose of a COVID-19 vaccine (92%), with over 46,500 of residents having
received both doses. Over 55,000 LTC staff have received at least one dose of a
COVID-19 vaccine (55%), with more than 44,600 having received both doses.
As of March 5, 2021, over 66,000 LTC residents received at least one dose of a
COVID-19 vaccine (95%) with 55,600 having received both doses. Over 67,000 LTC
staff have received at least one dose of a COVID-19 vaccine (68%), with over 47,500
having received both doses.
Early Impact of Ontario’s COVID-19 Vaccine Rollout on LTC Home Residents and
HCWs
The cumulative number SARS-CoV-2 infections reported between November 1,
2020, and February 23, 2021, was 8,007 among LTC residents and 3,625 among LTC
HCWs. LTC residents with SARS-CoV-2 infections were on average 85 years of age,
and 67% were women. LTC HCWs with SARS-CoV-2 infections were on average 43
years of age and 88% were women.
Figure 1 (A) shows the daily number of SARS-CoV-2 infections observed in LTC
residents during this period as compared with community dwelling older adults aged
70 years or above in Ontario who had not yet access to COVID-19 vaccine.10 Figure 1
(B) presents the daily number of SARS-CoV-2 infections found in observed in LTC
HCWs as compared with working age adults aged 18-64 years.
A decline in SARS-CoV-2 infections was demonstrated for both LTC home residents
and community-dwelling older adults, approximately 10 days following the
implementation of the Ontario government’s province-wide shutdown on December
26, 2020. However, the reduction in SARS-CoV-2 infections in LTC residents and
HCWs, considerably exceeded the reductions seen in the control populations.

AR07536
Figure 1. SARS-CoV-2 Infections Among Ontario LTC Residents and HCWs from November 1, 2020 to February 23,
2021
Line graphs of daily numbers and fitted curves of SARS-CoV-2 infections among Ontario LTC residents and HCWs from
November 1, 2020 to February 23, 2021. Panel A shows daily numbers and fitted curves of SARS-CoV-2 infections in
LTC residents and a control population of unvaccinated community-dwelling older adults aged 70 years or older.
Panel B shows daily numbers and fitted curves of SARS-CoV-2 infections in LTC HCWs and a control population of
unvaccinated working age adults 18-64 years of age. Daily numbers of SARS-CoV-2 infections are standardized and
expressed as a percentage relative to the number of SARS-CoV-2 infections observed on November 1, 2020. In the
absence of vaccination, LTC residents would have still benefited from the overall decline in the incidence of
community SARS-CoV-2 infections, realized with tightened public health restrictions. However, observed incidence
dropped substantially more with vaccination. LTC, long-term care.
Table 1 shows that the vaccination of Ontario’s LTC residents prevented an

estimated 2,079 SARS-CoV-2 infections, 249 COVID-19 hospitalizations and 615
COVID-19 deaths. Vaccination of Ontario’s LTC HCWs further prevented an
estimated 590 SARS-CoV-2 infections, and 8 COVID-19 hospitalizations and one
COVID-19 death between December 14, 2020, when the vaccine rollout in LTC
homes started, and February 23, 2021.
Table 1. Observed SARS-CoV-2 Infections, and COVID-19 Hospitalizations and Deaths and Prevented SARS-CoV-2
Infections, and COVID-19 Hospitalizations and Deaths Among Residents and HCWs of Ontario LTC homes from
December 14, 2020 to February 23, 2021
Table presenting model-based estimates of observed, expected and prevented SARS-CoV-2 infections, and COVID-19
hospitalizations and deaths among residents and HCWs of Ontario LTC homes from November 1, 2020 to February
23, 2021. Observed SARS-CoV-2 infections were modelled based on the Public Health Case and Contact Management
Solution (CCM), extracted on March 1, 2021. The estimated numbers of prevented events are based on a comparison
of the estimated number of events in LTC residents and HCWs, compared to the number of events in statistical
unvaccinated control populations. The estimated number of infections in the statistical unvaccinated control
populations were modelled based on fitted slopes of the epidemic curves of SARS-CoV-2 infections in community-
dwelling individuals aged ≥70 years (for LTC residents), and the working age population aged 18-64 years (for LTC
HCWs). LTC, long-term care.
Figure 2 shows the estimated impact of the vaccination rollout in LTC residents and
HCWs on daily SARS-CoV-2 infections in Ontario LTC homes over time since the
beginning of the COVID-19 vaccine rollout. Associated with an increase in vaccine
coverage until February 13, 2021, when all LTC residents and staff were offered the

AR07537
first dose of a COVID-19 vaccine, differences between groups become more

pronounced over time.
Figure 2. Cumulative SARS-CoV-2 Infections Among Ontario LTC Residents and HCWs from December 14, 2020 to
February 23, 2021
Line graph showing the model-based cumulative numbers of observed SARS-CoV-2 infections during the vaccine
rollout in LTC homes (solid lines) in comparison with the estimated SARS-CoV-2 infections that would have been
expected in the absence of vaccination in statistical unvaccinated control populations (dashed lines) for LTC residents
and HCWs. The estimated number of infections in statistical unvaccinated control populations were modelled based
on fitted slopes of the epidemic curves of SARS-CoV-2 infections in community-dwelling individuals aged ≥70 years
(for LTC residents), and the working age population aged 18-64 years (for LTC HCWs). LTC, long-term care.
Figure 3 presents the estimated relative risk of SARS-CoV-2 infections and COVID-19
deaths in LTC residents and of SARS-CoV-2 infections in LTC HCWs. The effect of
COVID-19 vaccines was substantial and became more pronounced with increasing
time since the start of vaccine rollout in individual PHUs.
At 8 weeks from the start of vaccination, the estimated relative reduction in the risk
of SARS-CoV-2 infection was 89% among LTC residents (relative risk 0.11, 95% CI
0.07 to 0.15), and 79% in healthcare workers (relative risk 0.21, 95% CI 0.15 to 0.29).
The estimated relative risk reduction of COVID-19 deaths was 96% among LTC
residents (relative risk 0.04, 95% CI 0.02 to 0.08). These estimated reductions were
above and beyond the estimated reductions associated with the province-wide
lockdown enacted on December 26, 2020, and stay-at-home order implemented on
January 14, 2021.
Figure 3. Relative Risk of SARS-CoV-2 Infections and COVID-19 Deaths in Ontario LTC residents and SARS-CoV-2
Infections in LTC HCWs as Compared with Appropriate Control Populations
Line graphs illustrating the relative risk of SARS-CoV-2 infections among LTC residents (A) and HCWs (B) as compared

AR07538
with statistical unvaccinated control populations. The estimated infections in statistical unvaccinated control
populations were modelled based on fitted slopes of the epidemic curves of SARS-CoV-2 infections in LTC residents
compared to community-dwelling individuals aged ≥70 years, and SARS-CoV-2 infections in LTC HCWs compared to
the Ontario working age population aged 18-64 years.
Interpretation
The rollout of COVID-19 vaccines in Ontario’s LTC homes has substantially reduced
SARS-CoV-2 infections, COVID-19 hospitalizations and deaths among LTC residents
and HCWs. The estimated vaccine effects account for the reduction in community
prevalence of SARS-CoV-2 infections following Ontario’s province-wide lockdown
enacted on December 26, 2020, and the stay-at-home order implemented on
January 14, 2021.
This early real-world evidence demonstrates the effectiveness of COVID-19
vaccination among Ontario’s LTC home population and workforce, with vaccination
resulting in a relative reduction in SARS-CoV-2 incidence of 80 to 90% in both
residents and HCWs compared to unvaccinated control populations.
Broad public health measures implemented in late December 2020 and early
January 2021 acted synergistically with COVID-19 vaccination to prevent SARS-CoV-2
infections. This emphasizes that public health measures will need to be maintained
alongside vaccination, until vaccine-based immunity has been afforded to the entire
population.
These data highlight the importance of accelerating vaccine rollout to priority
populations who are at disproportionately high risk of SARS-CoV-2 infection, COVID-
19 hospitalization and death.2,11 An earlier analysis projected that if all LTC residents
received the first dose of a COVID-19 vaccine by January 31, 2021, this would have
prevented a projected 600 COVID-19 cases and 115 deaths by March 31, 2021, as
compared with providing at least one dose of a COVID-19 vaccine to all LTC
residents by February 15, 2021.2
While COVID-19 vaccine uptake has been more than 90% among Ontario LTC
residents, the vaccine uptake among staff has been 68% as of March 5, 2021, which
is lower than the reported vaccination intention rate of 80.4% among Ontario’s
unionized healthcare workers.12 Closing this gap is essential, and may require
behavioural science informed education and communication about COVID-19
vaccines,13 as well as financial support such as paid time off, transportation for
vaccination, and guaranteed paid sick leave in case of vaccine side effects that result
in missed time from work.14
Emerging vaccine safety data from Ontario show that following the administration
of 687,271 COVID-19 vaccine doses as of February 27, 2021, the most frequent
adverse events reported to date were skin reactions, as well as pain and redness at
the injection site.15 There were 12 serious adverse events reported, three of which
were anaphylaxis. These safety data are consistent with early data from the United
States suggesting the safety of mRNA vaccines, including for frail older adults in
Ontario.16,17
There are several ways in which the COVID-19 vaccine impact demonstrated in this
analysis is different from the vaccine efficacy measured in randomized controlled
vaccine trials. First, we studied a population of LTC residents, who were severely
underrepresented in COVID-19 vaccine trials. Our findings therefore extend
knowledge on the protective effect of vaccines in this population. Second,
incomplete uptake of the vaccine in LTC residents and staff decreases the real-world
impact. Third, a substantial number of Ontario LTC home residents may have
already achieved some immunity to SARS-CoV-2 due to previous infection, thereby
AR07539
increasing the apparent benefit of the vaccine as compared with the statistical
unvaccinated control population we derived.18 Fourth, our data are based on
identified SARS-CoV-2 infections, and, as such, do not necessarily represent 100% of
infections.
As seen in other Canadian and international jurisdictions, COVID-19 vaccination in
Ontario has led to rapid declines in SARS-CoV-2 infections, COVID-19 hospitalizations
and deaths among LTC residents and HCWs.19,20 Completing and maximizing the
uptake of the full COVID-19 vaccine series according to recommended schedules will
maximize the safety and well-being of Ontario’s LTC residents and staff.
Methods Used for This Science Brief

Study Population and Design
We used a longitudinal study design to estimate the impact of COVID-19 vaccination
on SARS-CoV-2 incidence, COVID-19 hospitalizations and deaths among Ontario LTC
home residents and HCWs.
Data Sources
Data for this analysis were extracted from the Public Health Case and Contact
Management Solution database for all PHUs on March 1, 2021. Only cases publicly
reported between November 1, 2020 and February 23, 2021 were included.
Information on the earliest start date and end date for administration of the first
doses of COVID-19 vaccines for LTC residents and HCWs in each PHU was obtained
from PHU websites, news articles, Twitter posts, and personal communications. This
analysis includes all publicly announced vaccination completion dates up to and
including Feb 23, 2021.
Exposure
The primary exposure was time since the start of COVID-19 vaccination within LTC
homes in a PHU. Partial completion of PHU vaccination was interpolated from 0%
completion on the day prior to vaccination initiation in the PHU, 50% completion on
the midpoint date, to 100% on the date of completion itself.
Control Populations
A difference-in-differences analysis was performed by selecting control populations
of individuals with a similar age group who had a very low probability of being
vaccinated during the study period. The control population for LTC residents were
individuals 70 years of age or older and living outside of LTC homes. The control
population for LTC HCWs were individuals of working age between 18 and 64 years
who were not coded as HCWs. Since HCWs outside of LTC homes may have also
been vaccinated, these individuals were excluded from the comparisons.
Outcomes
The primary outcome was the daily number of LTC residents and HCWs with SARS-
CoV-2 infections in each PHU. The daily number of COVID-19 hospitalizations and
deaths were secondary outcomes.
Descriptive Statistics
Summary statistics were used to describe LTC residents and HCWs by age, sex, and
number of SARS-CoV-2 infections, COVID-19 hospitalizations and deaths. Counts and
percentages were used to report categorical outcomes.

AR07540
Estimation of Prevented SARS-CoV-2 Infections

Two separate difference-in-differences analyses were developed,21 one for counts of
LTC residents and their control population, and one for counts of LTC HCWs and
their control population. The models were implemented using quasi-Poisson
regression with each of the two models including 34 separate time-series panels
corresponding to each PHU. Within each PHU, the baseline trend prior to COVID-19
vaccine rollout was parallel on the log-scale for the two groups, and the baseline
trend was modeled using a penalized spline,22 with a knot for each two-week period.
The effect of vaccination was implemented as a change in the growth rate following
the start of LTC home vaccination. Daily numbers of SARS-CoV-2 infections were
standardized and expressed as a percentage relative to the number of SARS-CoV-2
infections observed on November 1, 2020 (50 for LTC residents, 77 for community-
dwelling individuals aged ≥70 years, 22 for LTC HCWs, and 792 for the working age
population aged 18-64 years).
The change in growth rates was estimated as a penalized spline of the time since the
start of COVID-19 vaccination, with knots for each 2-weeks of the post-intervention
periods and was forced to intersect on the day of vaccination initiation. Based on
these models, the estimated number of expected (without intervention), observed
(given intervention), and prevented cases of SARS-CoV-2 infection was determined
by comparing the predicted incidence in the absence of vaccination, versus the
observed incidence given the COVID-19 vaccination start and completion date for
every PHU.
Estimation of Prevented COVID-19 Hospitalizations and Deaths
To estimate the impact of vaccination on COVID-19 deaths among LTC residents, an
additional difference-in-differences model was used, using case-fatality as the
outcome. The case fatality model had a single spline for date (not PHU specific), and
a similar spline for time since start of vaccination. The estimated number of deaths
was the product of the estimated difference-in-differences of infection, multiplied
by the difference-in-differences of case fatality. The cumulative number of deaths
prevented was then calculated in the same way as infections above.
The estimated case hospitalization rate (CHR) for LTC residents and LTC healthcare
workers, and the estimated case fatality rate (CFR) for LTC healthcare workers were
calculated from CCM plus data from November 1, 2020 to December 31, 2020, as
the observed proportions (CHR for residents, 0.12; CHR for LTC HCWs, 0.01; CFR for
LTC HCWs, 0.001). The estimated number of COVID-19 hospitalizations and deaths
prevented among LTC HCWs was calculated by multiplying the estimated number of
cases prevented with the case fatality rate and hospitalization rate, respectively.
Author Contributions
KAB, NMS, PJ and PAR conceived the Science Brief and wrote the first draft. KAB and
TV performed the analysis. All authors revised the Science Brief critically for
important intellectual content, and approved the final version.
References
1. Stall NM, Brown KA, Maltsev A, et al. COVID-19 and Ontario’s long-term care
homes (full brief). Sci Briefs Ont COVID-19 Sci Advis Table. 2021;1(7). https://
doi.org/10.47326/ocsat.2021.02.07.1.0
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on COVID-19 Cases and Deaths in Ontario Long-Term Care Homes. Ontario COVID-19
AR07541
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doi.org/10.7717/peerj.6876

AR07543 T ht NEW ENGLAND JOURNAL of MEDICINE
l~l_________ o_R
_1G
_1_N
_A
_ L_A_R
_T
_ 1c_L
_E_________ ~II
Effect of Covid-19 Vaccination on Transmission
of Alpha ancl Delta Variants
David W. Eyre, B.M., B.Ch., D.Phil., 11onald Taylor, M.Math., Mark Purver, Ph.D.,
David Chapman, Ph.D., Tom Fowler, Ph.D., Koen B. Pouwels, Ph.D.,
A. Sarah Walker, Ph.D., .
, and Tim E.A. Peto, F.R.C.P.
ABSTRACT
IACICGROUND
The authors' affiliations are listed in the Before the emergence of the B.L617.2 (delta) variant of severe acute respiratory syn-
Appendix. Dr. Eyre can be contacted at
david.eyre@bdi.ox.ac.uk or at the Big
drome coronavirus 2 (SARS-CoV-2), vaccination reduced transmission ofSARS-CoV-2
Data Institute, Old Road Campus, Uni- from vaccinated persons who became infected, potentially by reducing viral loads.
versity of Oxford, Old Rd., Oxford, OX3 Although vaccination still lowers the risk of infection, similar viral loads in vac-
7LF, United Kingdom.
cinated and unvaccinated persons who are inrected with the delta variant call into
This artide was published on January S, question the degree to which vaccination prevents transmission.
2022, at NEJM.org.
METHODS
N Engl J Med 2022;386:744-S6. We used contact-testing data from England to perform a retrospective observational
DOI: 10.1056JNEJMoa2ll6597
G,pyrif)rt () 2fJ22 MDSSDd,- Mediwl SO<idy. cohort study involving adult contacts of SARS-CoV-2- infected adult index patients.
We used multivariable Poisson regression to investigate associations between trans-
mission and the vaccination status ofindex patients and contacts and to determine
how these associations varied with the B.Ll.7 (alpha) and delta variants and time
since the second vaccination.
RESULTS
Among 146,243 tested contacts of 108,498 index patients, 54,667 (37%) had positive
SARS-CoV-2 polymerase-chain-reaction (PCR) tests. In index patients who became
infected with the alpha variant, two vaccinations with either BNTI62b2 or ChAdOxl
nCoV-19 (also known as AZD1222), as compared with no vaccination, were indepen-
dently associated with reduced PCR positivity in contacts (adjusted rate ratio with
BNT162b2, 0.32; 95% confidence interval [Cl], 0.21 to 0.48; and with ChAdOxl
nCoV-19, 0.48; 95% Cl, 030 to 0.78). Vaccine-associated reductions in transmission
of the delta variant were smaller than those with the alpha variant, and reductions
in transmission of the delta variant after two BNTI62b2 vaccinations were greater ·
(adjusted rate ratio fur the comparison with no vaccination, 050; 95% Cl, 039 to 0.65)
than after two ChAdOxl nCoV-19 vaccinations (adjusted rate ratio, 0.76; 95% CI, 0.70
to 0.82). Variation in cycle-threshold (Ct) values (mdicative ofviral load) in index pa-
tients explained 7 to 23% ofvaccine-associated reductions in transmission of the two
variants. The reductions in transmission of the delta variant declined over time after
the second vaccination, reaching levels that were similar to those in 1111V,1ccinated
persons by 12 weeks in index patients who had received ChAdOx:1 nCoV-19 and at-
tenuating substantially in those who had received BNT162b2. Protection in contacts
also declined in the 3-month period after the second vaccination.
CONCLUSION S
Vaccination was associated with a smaller reduction in transmission ofthe delta variant
than of the alpha variant, and the effects of vaccination decreased over time. PCR. Ct
values at diagnosis ofthe index patient only partially explained decreased transmission.
(Funded by the U.K. Government Department ofHealth and Social Care and others.)
744 N ENGLJ MEO 386;8 NEJM.ORG FEBRUARY 24, 2022
The New England Journal of Medicine

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Copyright Cl 2022 Massachusetts Medical Society. All rights reserved.
AR07544 Covid-19 Vaccination and Tr ansmission of Variants
R
andomized, controlled trials1-3 face-to-face distance from an index patient, with-
and real-world population studies4,5 have in <1 m for ≥1 minute or within <2 m for ≥15
shown that vaccines against severe acute minutes) were eligible for inclusion in the study
respiratory syndrome coronavirus 2 (SARS-CoV-2), if they had undergone polymerase-chain-reaction
the virus that causes coronavirus disease 2019 (PCR) testing 1 to 10 days after the index patient
(Covid-19), have prevented infection and adverse had a positive PCR test (typically after the devel-
outcomes from several SARS-CoV-2 variants, in- opment of symptoms of Covid-19, but also after
cluding the B.1.1.7 (alpha) and B.1.617.2 (delta) positive asymptomatic antigen screening). The
variants.6-8 Vaccination may also prevent onward 1- to 10-day period was chosen to enrich for con-
transmission both by reducing symptomatic in- tacts for whom the index patient was the most
fections and asymptomatic infections (and there- likely source of any infection15 (details about al-
fore the number of infectious persons) and by ternative periods that were tested in a sensitivity
reducing onward spread from persons who have analysis are provided in the Supplementary Ap-
become infected despite vaccination. Household pendix, available with the full text of this article
studies have shown that vaccination reduced on- at NEJM.org).
ward transmission of the alpha variant from We included only index patients with PCR
persons who became infected despite vaccina- tests performed by one of three national “light-
tion.9-12 One hypothesized mechanism is that viral house” laboratories (Milton Keynes, Alderley Park,
loads observed in persons infected with the alpha and Glasgow) that used the same standardized
variant after vaccination7,13 are lower than those workflow and TaqPath PCR assay (Thermo Fisher
among unvaccinated persons, and the viral load Scientific) to test for three gene targets: spike (S),
is associated with the likelihood of infection in nucleocapsid (N), and open reading frame 1ab
contacts.14,15 (ORF1ab). Contacts could undergo testing at any
However, in persons infected with the delta community or hospital laboratory that reported
variant, viral loads are similar in vaccinated and results to Test and Trace. The vaccination status
unvaccinated persons,8,16 although the duration of patients and contacts was obtained from the
of viral shedding may be reduced.17,18 The absence National Immunisation Management Service (de-
of a reported difference in viral loads between tails are provided in the Supplementary Appendix).
vaccinated and unvaccinated infected persons calls Index patients who had undergone testing
into question whether vaccination controls the between January 1 and July 31, 2021, were includ-
ed. Cases were classified as alpha variant infec-
spread of the delta variant as effectively as it con-
trols the spread of the alpha variant and whether, tions on the basis of S-gene target failure while
with increased transmissibility,19 the maintained this was a reliable proxy (until June 6, after which
viral load after vaccination explains the rapid <6% of the patients had S-gene target failure).
After May 10, 2021, spread of the delta variant
global spread of the delta variant despite increasing
vaccination coverage. throughout the United Kingdom meant that more
We used national contact-testing data from than 98% of sequenced SARS-CoV-2 samples were
England to investigate the effect of vaccination classified as the alpha or delta variants,19 so S-gene
on onward transmission of SARS-CoV-2. We also detection after May 10 was used as a proxy for
examined how this effect varies with the alpha the delta variant (details are provided in the Supple-
and delta variants. mentary Appendix). In order to control as much as
possible for biases related to health-seeking be-
havior (including differences in behavior before
Me thods
and after vaccination), access to testing, and case
Index Patients, Contacts, and Variants ascertainment, we restricted our study to tested
We performed a retrospective observational cohort contacts.20
study involving adult contacts (≥18 years of age)
of symptomatic or asymptomatic SARS-CoV-2– Study Oversight
infected adult index patients. Data were obtained The study was performed as part of public health
from the National Health Service (NHS) Test and surveillance and NHS Test and Trace program
Trace, a contact-tracing and testing service. Con- quality assurance, under Section 251 of the NHS
tacts (persons living in the same household or in Act 2006, with approvals from Public Health
n engl j med 386;8 nejm.org February 24, 2022 745

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Copyright © 2022 Massachusetts Medical Society. All rights reserved.
AR07545 The n e w e ng l a n d j o u r na l of m e dic i n e
England and the Department of Health and Social dix). We accounted for nonlinearity, interactions,
Care. The Research Ethics and Governance Group and multiple testing. Heterogeneity rate ratios and
of Public Health England (the research ethics com- 95% confidence intervals were calculated with the
mittee of that organization) reviewed the study use of interaction terms and contrasts between
protocol and confirmed compliance with all regu- levels of categorical variables. Additional details
latory requirements. Given that no regulatory or of all statistical methods used are provided in
ethical issues were identified, it was decided that the Supplementary Methods section in the Sup-
full ethical review was not a requirement for this plementary Appendix.
study, and the protocol was approved. The au- We refitted models to include cycle-threshold
thors vouch for the accuracy and completeness (Ct) values (indicative of viral load21) in the index
of the data and for the fidelity of the study to the patient to investigate the relationship between Ct
protocol. values and transmission. We used these models
to perform a mediation analysis to assess whether
Statistical Analysis the effect of the vaccination status of the index
We used multivariable Poisson regression to inpatient was explained by Ct values at diagnosis.
vestigate associations between onward transmis-
sion (i.e., to contacts with PCR tests positive for R e sult s
SARS-CoV-2) and the vaccination status of index
patients (unvaccinated, partially vaccinated [from Patients and Contacts
the date of the first vaccination to 13 days after the We obtained data on 661,315 adult contacts of
second vaccination], or vaccinated twice [≥14 days 374,115 adult index patients; 173,460 of these con-
after the second vaccination]) and the vaccine type tacts (26%) had undergone PCR testing between
(ChAdOx1 nCoV-19 [also known as AZD1222; January 2 and August 2, 2021. The demographic
AstraZeneca] or BNT162b2 [Pfizer–BioNTech]). characteristics of the patients and contacts were
We investigated differences between transmission broadly representative of persons with Covid-19
from index patients infected with the alpha vari- in England (Table S2) and were similar in the con-
ant and transmission from those infected with tacts who had undergone testing and those who
the delta variant, and we used prespecified inter- had not undergone testing (Table S3).
action terms to assess whether vaccine associa- A total of 27,217 of the contacts who had un-
tions differed according to variant. We also in- dergone testing (16%) and had incomplete data
cluded model terms for the time since the second were excluded (see the Results section in the Sup-
BNT162b2 or ChAdOx1 nCoV-19 vaccination. plementary Appendix). Of the remaining 146,243
Adjustment was made for the following co- tested contacts of 108,498 index patients, 54,667
variates: the type of exposure between index pa- (37%) had positive SARS-CoV-2 PCR tests. The
tients and contacts (living in the same household median age of the index patients was 34 years
or residence, visiting a household, at activities or (interquartile range, 24 to 49; range, 18 to 102),
events, or at the workplace or an educational fa- and the median age of the contacts was 43 years
cility); index-patient characteristics (age, sex, and (interquartile range, 29 to 54; range, 18 to 107).
symptom status); contact characteristics (age, sex, A total of 55,354 of the index patients (51%) and
vaccination status, and time since vaccination, as 83,206 of the contacts (57%) were female (Tables
described above); socioeconomic disadvantage S4 and S5). Among the 147,279 exposures between
as assessed with an index of multiple deprivation index patients and contacts, 97,204 occurred with-
(a national indication of the level of social, in households and residences (66%), 16,505 during
health-related, and economic deprivation accord- visits to households (11%), 16,114 at events and
ing to local geographic area of residence); local activities (11%), and 16,420 at the workplace or
weekly incidence of SARS-CoV-2 infection as an educational facility (11%).
determined from national testing data; and cal-
endar time (reflecting temporal changes in be- Index-Patient Vaccination and Onward
havior and social distancing, the likelihood of Transmission
acquisition of SARS-CoV-2 from a third party, A total of 35,459 of 76,401 contacts of unvaccinated
population-wide vaccine uptake, and the percent- index patients (46%) had positive PCR tests, as did
age of unvaccinated persons who were previously 3878 of 11,236 (35%) contacts of index patients
infected) (Table S1 in the Supplementary Appen- who were partially vaccinated with ChAdOx1
746 n engl j med 386;8 nejm.org February 24, 2022

nCoV-19, 7947 of 31,039 (26%) contacts of index (adjusted rate ratio for the comparison with no
patients who were partially vaccinated with vaccination, 0.50; 95% CI, 0.39 to 0.65) than after
BNT162b2, 6067 of 21,421 (28%) contacts of pa- two ChAdOx1 nCoV-19 vaccinations (adjusted rate
tients vaccinated twice with ChAdOx1 nCoV-19, ratio, 0.76; 95% CI, 0.70 to 0.82) (heterogeneity
and 1316 of 6146 (21%) contacts of patients vac- rate ratio, 1.51; 95% CI, 1.15 to 1.97). Partial vac-
cinated twice with BNT162b2. Among the index cination was associated with limited reductions
patients who were vaccinated twice, the median in transmission (adjusted rate ratio with BNT162b2
time from the second vaccination to a positive PCR for the comparison with no vaccination, 0.83;
test for the alpha variant was 27 days (interquartile 95% CI, 0.81 to 0.86; and with ChAdOx1 nCoV-19,
range, 18 to 43) with the ChAdOx1 nCoV-19 vac- 0.95; 95% CI, 0.91 to 0.99). After the second
cine and 42 days (interquartile range, 26 to 63) BNT162b2 vaccination, decreases in transmission
with the BNT162b2 vaccine; the median time from of the delta variant were smaller than decreases
the second vaccination to a positive PCR test for in transmission of the alpha variant by a factor
the delta variant was 51 days (interquartile range, of 1.6 (adjusted rate ratio, 1.59; 95% CI, 1.07 to
35 to 70) and 90 days (interquartile range, 69 to 2.35), and this difference between decreases in
110), respectively. Among twice-vaccinated index transmission of the two variants was similar
patients, dosing intervals were more than 6 weeks after the second ChAdOx1 nCoV-19 vaccination
in 14,811 of 15,083 patients (98%) who received (adjusted rate ratio, 1.58; 95% CI, 0.97 to 2.56).
ChAdOx1 nCoV-19 and in 3759 of 4233 patients
(89%) who received BNT162b2. Vaccination in Contacts
In a multivariable model (Table 1 and Table S6), The estimated effect of the vaccination status of
vaccination with BNT162b2 in index patients in- contacts did not necessarily reflect overall vac-
fected with the alpha variant was independently cine effectiveness because contacts were includ-
associated with less PCR positivity in contacts ed in the study only if they had undergone testing.
than no vaccination; two vaccinations (adjusted However, PCR positivity was highest in unvacci-
rate ratio at 14 days after the second vaccination nated contacts (in 34,041 of 65,117 contacts [52%]),
as compared with no vaccination, 0.32; 95% CI, followed by those who were partially vaccinated
0.21 to 0.48) were associated with greater de- with ChAdOx1 nCoV-19 (3987 of 12,307 contacts
creases in transmission than partial vaccination [32%]) or BNT162b2 (6756 of 20,999 contacts
(adjusted rate ratio, 0.88; 95% CI, 0.85 to 0.91). [32%]). PCR positivity was lowest in contacts who
Similarly, two ChAdOx1 nCoV-19 vaccinations had been vaccinated twice with ChAdOx1 nCoV-
were associated with less transmission (adjusted 19 (7241 of 32,363 contacts [22%]) or BNT162b2
rate ratio, 0.48; 95% CI, 0.30 to 0.78) than partial (2642 of 15,457 contacts [17%]).
vaccination (adjusted rate ratio, 0.90; 95% CI, Independent of the effects of vaccination in
0.86 to 0.94). A difference between BNT162b2 and index patients, the incidence of positive PCR tests
ChAdOx1 nCoV-19 with respect to decreases in for the alpha variant was lower among contacts
transmission of the alpha variant after two vac- who were vaccinated twice with BNT162b2 (ad-
cinations was not observed (heterogeneity rate justed rate ratio 14 days after the second vaccina-
ratio, 1.51; 95% CI, 0.81 to 2.85). tion as compared with no vaccination, 0.15;
The delta variant was associated with more 95% CI, 0.11 to 0.21) than among contacts who
onward transmission from symptomatic index pa- received ChAdOx1 nCoV-19 (adjusted rate ratio,
tients than the alpha variant, in a contact age– 0.40; 95% CI, 0.27 to 0.59) (heterogeneity rate ratio,
dependent manner (e.g., adjusted rate ratio with 2.68; 95% CI, 1.61 to 4.47) (Table 1). Vaccinated
a contact age of 18 years, 1.24; 95% CI, 1.12 to contacts were more likely to have positive PCR
1.38) and with more onward transmission from tests for the delta variant than for the alpha vari-
asymptomatic index patients than the alpha variant because of increases in the transmissibility
ant (e.g., adjusted rate ratio with a contact age of of the delta variant, independent of vaccination
18 years, 1.40; 95% CI, 1.22 to 1.59), independent status. However, there was no strong evidence of
of patient and contact vaccination status. Associa- a difference between the alpha and delta variants
tions were attenuated as the contact age increased with respect to the effectiveness of two vaccina-
(Fig. S2). tions with BNT162b2 or ChAdOx1 nCoV-19, as
Decreases in transmission of the delta variant compared with no vaccination (heterogeneity rate
were greater after two BNT162b2 vaccinations ratio for BNT162b2 [delta variant as compared

748
Table 1. Relationship between Positive PCR Tests in Contacts and the Vaccination Status of Index Patients and Contacts.*
AR07547
Characteristic Transmission of Alpha Variant Transmission of Delta Variant Delta Variant vs. Alpha Variant
Index Patient– Adjusted Rate Index Patient– Adjusted Rate Rate Ratio for
Contact Ratio Contact Ratio Interaction
Pairs (95% CI) Pairs (95% CI) (95% CI)
number number
Vaccination status of index patient
Unvaccinated 52,566 — 23,835 — —
The
Partially vaccinated†
ChAdOx1 nCoV-19 3,619 0.90 (0.86–0.94) 7,617 0.95 (0.91–0.99) 1.06 (1.00–1.12)
BNT162b2 3,917 0.88 (0.85–0.91) 27,122 0.83 (0.81–0.86) 0.94 (0.90–0.99)
Vaccinated twice‡
ChAdOx1 nCoV-19 99 0.48 (0.30–0.78) 21,322 0.76 (0.70–0.82) 1.58 (0.97–2.56)
BNT162b2 176 0.32 (0.21–0.48) 5,970 0.50 (0.39–0.65) 1.59 (1.07–2.35)
Vaccination status of contact
Unvaccinated 52,321 — 12,796 — —
Partially vaccinated†
n e w e ng l a n d j o u r na l

of
ChAdOx1 nCoV-19 3,739 0.94 (0.91–0.98) 8,568 0.69 (0.66–0.72) 0.73 (0.69–0.77)
BNT162b2 3,829 0.85 (0.82–0.88) 17,170 0.67 (0.65–0.69) 0.79 (0.76–0.83)
Vaccinated twice‡
n engl j med 386;8 nejm.org February 24, 2022

ChAdOx1 nCoV-19 151 0.40 (0.27–0.59) 32,212 0.42 (0.38–0.45) 1.04 (0.70–1.53)

m e dic i n e
BNT162b2 337 0.15 (0.11–0.21) 15,120 0.19 (0.16–0.23) 1.28 (0.92–1.78)
* Results for index patients and contacts who received two vaccinations were estimated 14 days after the second vaccination. Adjustment was made for the type of exposure between pa-
tients and contacts, index-patient characteristics (age, sex, and symptom status), contact characteristics (age and sex), local deprivation, local incidence of severe acute respiratory syn-
drome coronavirus 2 infection, and calendar time. There was no evidence that adding an interaction between the index patient and contact vaccination status improved the model fit.
There was evidence of greater associated reductions in transmission of the delta variant after the second vaccination in the index patient with BNT162b2 than with ChAdOx1 nCoV-19
(heterogeneity rate ratio, 1.51; 95% confidence interval [CI], 1.15 to 1.97) but no evidence of a difference between the vaccines with respect to transmission of the alpha variant (hetero-
geneity rate ratio, 1.51; 95% CI, 0.81 to 2.85). Two BNT162b2 vaccinations in contacts were associated with greater reductions in the incidence of positive PCR tests than two ChAdOx1
nCoV-19 vaccinations for both the alpha variant (heterogeneity rate ratio, 2.68; 95% CI, 1.61 to 4.47) and the delta variant (heterogeneity rate ratio, 2.17; 95% CI, 1.78 to 2.65).
† Partial vaccination encompasses the period from the date of the first vaccination to 13 days after the second vaccination.
‡ Persons were considered to be vaccinated twice 14 or more days after the second vaccination.
A Effect of Vaccination of Index Patient on Transmission

Alpha Variant
Alpha Delta Variant
Unvaccinated index patient Unvaccinated index patient
1.0
Rate Ratio of Positive PCR Tests in Contacts as
Compared with Unvaccinated Index Patients
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
ChAdOx1 nCoV-19, index patient
0.1
BNT162b2, index patient
0.0
2 4 6 8 10 12 14 2 4 6 8 10 12 14
Weeks since Second Vaccination in Index Patient
B Effect of Vaccination of Contact on Transmission

Alpha Variant Delta Variant
Unvaccinated contact Unvaccinated contact
1.0
Rate Ratio of Positive PCR Tests in Contacts
as Compared with Unvaccinated Contacts
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
ChAdOx1 nCoV-19, contact
0.1
BNT162b2, contact
0.0
2 4 6 8 10 12 14 2 4 6 8 10 12 14
Weeks since Second Vaccination in Contact
Figure 1. Rate Ratios of Positive PCR Tests in Contacts, According to Time since the Second Vaccination in Index
Patients and Contacts, SARS-CoV-2 Variant, and Vaccine Type.
The rate ratios of positive polymerase-chain-reaction (PCR) tests in contacts according to index-patient vaccination
status (Panel A) and contact vaccination status (Panel B) are shown. The shaded areas indicate 95% confidence in-
tervals. There was no evidence that fitting different rates according to severe acute respiratory syndrome coronavi-
rus 2 (SARS-CoV-2) variant for the change in protection over weeks since the second vaccination improved the mod-
el fit. The broad confidence intervals for the alpha variant show that relatively few persons who were vaccinated
twice were infected before the delta variant became the dominant lineage.
with alpha variant], 1.26; 95% CI, 0.91 to 1.75; and ed rate ratio, 0.42; 95% CI, 0.38 to 0.45) (hetero-
heterogeneity rate ratio for ChAdOx1 nCoV-19, geneity rate ratio, 2.17; 95% CI, 1.78 to 2.65).
0.99; 95% CI, 0.67 to 1.45). Two BNT162b2 vac-
cinations remained more effective against the Duration of Protection and Reductions
delta variant (adjusted rate ratio as compared in Transmission
with no vaccination, 0.19; 95% CI, 0.16 to 0.23) Vaccine-associated reductions in onward trans-
than two ChAdOx1 nCoV-19 vaccinations (adjust- mission of the alpha and delta variants declined

over time after the second vaccination in index Figure 2 (facing page). Estimated Probabilities
patients (Fig. 1A). Independent of the vaccination of a Positive PCR Test among Contacts.
status of contacts, for each doubling of weeks Shown are the estimated probabilities of a positive
since 14 days after the second vaccination in in- PCR test among contacts, according to the type of ex-
dex patients, the percentage of persons with posi- posure between the index patient and contact and the
tive PCR tests increased by a factor of 1.08 (95% age of the index patient (Panel A), the type of exposure
and the age of the contact (Panel B), the sex of the in-
CI, 1.05 to 1.11) among contacts of patients dex patient and contact (Panel C), the sex of the con-
vaccinated with ChAdOx1 nCoV-19 and by a factor tact and the type of exposure (Panel D), and the type
of 1.13 (95% CI, 1.05 to 1.21) among contacts of of exposure and age of the index patient and contact
those vaccinated with BNT162b2, with no evi- (Panel E). For each panel, all the other covariates are
dence of a difference between vaccines (hetero- set to reference values for categorical values and to
median values for continuous variables (i.e., the type
geneity rate ratio, 0.96; 95% CI, 0.87 to 1.03). of exposure is set to household or residence; for index-
Two weeks after the second vaccination with patient characteristics, age is set to the median, sex to
BNT162b2 in index patients, transmission of the female, vaccination status to unvaccinated, and symp-
alpha variant was 68% (95% CI, 52 to 79) lower tom status to symptomatic; for contact characteristics,
than transmission of this variant from unvacci- age is set to the median, sex to female, and vaccina-
tion status to unvaccinated). Local deprivation rank
nated index patients; this decrease was 52% (socioeconomic disadvantage according to geographic
(95% CI, 29 to 67) by 12 weeks, with reductions area of residence) is adjusted for in the model along
of 52% (95% CI, 22 to 70) 2 weeks after the sec- with the other covariates listed; local deprivation rank
ond vaccination with ChAdOx1 nCoV-19 and 38% and the local incidence of SARS-CoV-2 infection and
(95% CI, −1 to 62) 12 weeks after the second vac- calendar time are set to the median. Shaded areas in
Panels A and B and I bars in Panels C and D indicate
cination with ChAdOx1 nCoV-19. Two weeks af- 95% confidence intervals.
ter the second BNT162b2 vaccination, transmis-
sion of the delta variant was reduced by 50%
(95% CI, 35 to 61), and 12 weeks after the sec-
ond BNT162b2 vaccination, transmission of the exposure between patients and contacts and the
delta variant was reduced by 24% (95% CI, 20 to age of the index patient, with the highest rates
28); the corresponding reductions after the sec- of PCR positivity after household exposure to
ond vaccination with ChAdOx1 nCoV-19 were index patients who were at least 40 years of age
24% (95% CI, 18 to 30) and 2% (95% CI, −2 to 6), and lower rates after exposure at the workplace
respectively. Figure S5 shows probabilities ac- or educational facility or at events or activities
cording to the vaccine status of the patients and (Fig. 2A). Contacts in their 30s and 70s had the
contacts. The findings were similar when the highest incidence of positive tests after exposure
analysis was restricted to contacts who had un- to an index patient in their household, whereas
dergone testing 2 to 7 days after testing in the contacts in their 20s had the highest incidence
index patient (Table S7 and Figs. S6 and S7). after exposure to an index patient outside their
Contacts who received BNT162b2 had a lower own home (Fig. 2B). Contacts of index patients
risk of testing positive throughout the 14 weeks of the opposite sex were more likely to test posi-
after the second vaccination than those who re- tive than contacts of index patients of the same
ceived ChAdOx1 nCoV-19, even though the pro- sex (Fig. 2C), and male contacts were more likely
tective effect of BNT162b2 waned faster (adjust- than female contacts to be infected outside the
ed rate ratio per doubling of weeks since 14 days home (Fig. 2D).
after second vaccination, 1.27; 95% CI, 1.21 to Contacts of asymptomatic index patients were
1.34) than that of ChAdOx1 nCoV-19 (adjusted less likely to test positive for the alpha variant
rate ratio per doubling of weeks since 14 days than those who were contacts of symptomatic
after second vaccination, 1.13; 95% CI, 1.10 to index patients (adjusted rate ratio, 0.53; 95% CI,
0.50 to 0.55); contacts of asymptomatic index
1.16) (heterogeneity rate ratio, 1.13; 95% CI, 1.07
to 1.20) (Fig. 1B). patients were also less likely to test positive for
the delta variant than those who were contacts
Other Risk Factors for Transmission of symptomatic index patients (adjusted rate ratio,
Multiple other factors were associated with posi- 0.59; 95% CI, 0.55 to 0.63). Contacts who lived in
tive PCR tests in contacts, including the type of more deprived areas and areas with a higher inci-

A B
Household Household Events or Workplace or Household Household Events or Workplace or
or residence visitor activities educational or residence visitor activities educational
facility facility
0.7 0.7
Probability of a Positive PCR Test in a Contact
Probability of a Positive PCR Test in a Contact

0.6 0.6
0.5 0.5
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
0.0 0.0
20 30 40 50 60 70 20 30 40 50 60 70
Index Patient Age (yr) Contact Age (yr)
C D
0.65 0.8 Female contact Male contact
Probability of a Positive PCR Test
Probability of a Positive PCR Test
0.60
0.6
in a Contact
in a Contact
0.55
0.4
0.50
0.2
0.45
0.40 0.0
Female→Female Female→Male Male→Female Male→Male Household Household Events or Workplace or
or residence visitor activities educational facility
Index Patient and Contact Sex
Type of Exposure between Index Patient and Contact
E
Probability of positive PCR test in a contact
0.2 0.4 0.6 0.8
Household Household Events or Workplace or
80 or Residence Visitor Activities Educational Facility
Contact Age (yr)
60
40
20
20 40 60 20 40 60 20 40 60 20 40 60
Index Patient Age (yr)

dence of SARS-CoV-2 infection (Fig. S3) were more asymptomatic index patients who were infected
likely to test positive. Positivity varied according to with the delta variant had lower Ct values than
calendar time (Fig. S4). those who were infected with the alpha variant
(Fig. 3). Increases in Ct values after vaccination
Ct Values and the Effect of Vaccination were smaller in index patients who were infected
on Transmission with the delta variant than those in index pa-
Index patients who were infected with the alpha tients who were infected with the alpha variant.
variant had higher PCR Ct values (lower viral loads) For example, in symptomatic index patients in-
at diagnosis if they had received two vaccinations fected with the delta variant who had received two
with BNT162b2 (e.g., in symptomatic index pa- BNT162b2 or ChAdOx1 nCoV-19 vaccinations, the
tients, median Ct value, 27.4; interquartile range, median Ct values were 18.0 (interquartile range,
19.7 to 32.1) or ChAdOx1 nCoV-19 (in symptom- 15.8 to 21.8) and 17.3 (interquartile range, 15.3 to
atic index patients, median Ct value, 23.9; inter- 20.6), respectively, as compared with 17.0 (inter-
quartile range, 18.1 to 32.5) than if they were quartile range, 15.1 to 20.3) in symptomatic index
unvaccinated (in symptomatic index patients, patients who were unvaccinated. Covariate-adjust-
median Ct value, 18.4; interquartile range, 15.7 ed estimates for Ct changes with vaccination are
to 22.5). Both symptomatic index patients and shown in Table S8.
Alpha variant Delta variant
Symptomatic Index Patient

40
30
Ct Value in the Index Patient at Diagnosis
20
10
0
Asymptomatic Index Patient
40
30
20
10
0
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Vaccination Status of Index Patient
Figure 3. Distribution of Ct Values, According to Vaccination Status of the Index Patient, SARS-CoV-2 Variant,
and Symptoms.
The violin plots show the observed frequency density of patients with a given result, and the solid line in each plot
indicates the median. Cycle-threshold (Ct) values are indicative of viral load. Lee et al.15 describe details of equiva-
lent viral loads in copies per milliliter (log10 viral load=12.0−0.328×Ct).

When we refitted our model for transmission through other mechanisms. This finding indi-
to include Ct values (Fig. 4A), lower Ct values cates that Ct values measured in diagnostic test-
(higher viral loads) were independently associ- ing are not necessarily a surrogate for the effect
ated with increased transmission of both the of vaccination on transmission. Ct values at di-
alpha variant and the delta variant, but with a agnosis are probably imperfectly representative
greater reduction in transmission as the Ct in- of viral loads at transmission, despite the relation-
creased (i.e., the viral load decreased) with the ship observed between Ct values and transmis-
alpha variant than with the delta variant (Fig. 4B). sion, because viral loads are dynamic over time.22
A small proportion of the effect of two vaccina- Vaccination may also act by facilitating faster
tions with BNT162b2 or ChAdOx1 nCoV-19 on clearance of viable infectious virions,17,18 but they
transmission was mediated through variation in may leave damaged ineffective virions behind that
Ct values at diagnosis in the index patient (Fig. 4C still contain PCR-detectable RNA. Studies of this
and Table S9). The proportion of the total effect possibility and of how antigen assays perform
(mediated by Ct values) of two vaccinations on after vaccination could lead to improvement in
transmission of the alpha variant was 18% (95% diagnostic tests after vaccination.
CI, 9 to 64) with the BNT162b2 vaccine and 16% We found differences between vaccines that
(95% CI, 1 to 80) with the ChAdOx1 nCoV-19 may have reflected their differing mechanisms
vaccine; the proportion of the total effect medi- of action. Index patients who were vaccinated
ated by Ct values of two vaccinations on trans- with BNT162b2 had contacts who were less likely
mission of the delta variant was 23% (95% CI, 17 to have positive PCR tests for the delta variant
to 33) and 7% (95% CI, 5 to 10), respectively. than those of index patients who had received
ChAdOx1 nCoV-19. There was potentially insuf-
ficient power to resolve differences between the
Discussion
vaccines with respect to the alpha variant because
We found that both the BNT162b2 and ChAdOx1 relatively few persons who were vaccinated twice
nCoV-19 vaccines were associated with reduced became infected before the delta variant became
onward transmission of SARS-CoV-2 from index the dominant lineage. The incidences of infections
patients who became infected despite vaccination. with the alpha variant and those with the delta
However, in index patients who were vaccinated variant were also lower among contacts vacci-
with BNT162b2 and probably in those who were nated twice with BNT162b2 than among those
vaccinated with ChAdOx1 nCoV-19, reductions in vaccinated twice with ChAdOx1 nCoV-19.
transmission of the delta variant were smaller Protection against onward transmission waned
than reductions in transmission of the alpha vari- during the 3-month period after the second vac-
ant. In population-based studies, vaccines have cination. Some protection against the alpha vari-
continued to provide protection against infection ant remained, but much of the protection against
with the delta variant, but to a lesser degree than onward transmission of the delta variant was lost,
against infection with the alpha variant.8 There- particularly with ChAdOx1 nCoV-19. Waning of
fore, the delta variant eroded vaccine-associated protective behaviors may explain some of the
protection against transmission both by making change, because the use of measures such as so-
infection more common and by increasing trans- cial distancing and mask wearing in vaccinated
mission from infected vaccinated persons. persons may have decreased. However, reductions
Vaccines have been hypothesized to reduce in antibody levels23 and vaccine effectiveness8 over
onward transmission by reducing viral loads.14,15 time provide support for the importance of bio-
In our study, vaccination was associated with logic explanations. In addition, some of the ob-
higher Ct values (lower viral loads) of the alpha served decline in protection may be attributed to
variant and, to a smaller extent, with higher Ct a longer period since vaccination in persons who
values of the delta variant. Higher Ct values were were vaccinated early; these persons may have
associated with less transmission (Fig. 4B). How- been clinically vulnerable, with immune systems
ever, we found that differences in Ct values at that were weaker than those of persons who
diagnosis in the index patient accounted for only were vaccinated more recently.
7 to 23% of the effect of vaccination, with most Contacts were also more likely to test positive
of the effect of vaccination probably occurring as the time since their second vaccination in-

A Rate Ratio of Positive PCR Tests in Contact as Compared with Unvaccinated Index Patient
Without Ct value adjustment With Ct value adjustment
1.1
1.0
0.9
0.8
Rate Ratio
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1.00
0.75
Probability
0.50
Delta variant
0.25
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15 20 25 30 35
Ct Value in Index Patient
C Proportion of Total Effect of Vaccination on Transmission Mediated by Variation in CT Value in Index Patient
1.0
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Figure 4 (facing page). Extent of Vaccine-Associated also imperfectly ascertained in national testing
Reductions in Transmission That Were Explained by programs. Increasing immunity arising from pre-
Variation in Ct Values at Diagnosis in the Index Patient. vious infection in the unvaccinated comparator
Panel A shows the effect of vaccination of the index pa- group potentially reduces estimates of vaccine
tient on onward transmission in models with and with- effectiveness over time; however, with adjustment
out adjustment for the Ct value in the index patient.
for calendar time, previous infection can be al-
Panel B shows the relationship between the Ct value in
the index patient and onward transmission in a model lowed for at a population level, along with chang-
with adjustment for the Ct value in the index patient at es in test-seeking behavior and the incidence of
the time of diagnosis. Panel C shows the proportion of other infections that cause symptoms that are
the total effect of vaccination of the index patient mediat- similar to those of Covid-19.25
ed by variations in the Ct value. I bars in Panels A and C
We used S-gene target failure and time, rather
and shaded areas in Panel B indicate 95% confidence in-
tervals. Apart from the SARS-CoV-2 variant, there was no than sequencing, as a proxy to distinguish infec-
evidence that interactions between the Ct value and any tion with the alpha variant from that with the
other main effect of the model improved the model fit. delta variant; thus, some low-viral-load delta vari-
ant infections with S-gene target failure may
have been misclassified as alpha variant infec-
creased. Although contacts who received BNT162b2 tions. However, we restricted the time period of
had increased protection throughout the 3-month our data set to minimize this effect. We consid-
period after the second vaccination, this protec- ered all PCR tests in contacts, including results
tion waned faster with BNT162b2 than with of assays without an S-gene target, so we could
ChAdOx1 nCoV-19, as was also seen with new not assess the concordance of patient–contact
infections in a representative survey in the United S-gene target failure as evidence supporting trans-
Kingdom.8 mission.
Our study has several limitations. In order to Finally, we did not have data to adjust for
minimize bias introduced by differences in test- coexisting conditions in clinically vulnerable
ing behavior arising for multiple reasons, includ- persons or for health care workers. Both of these
ing the vaccination status of contacts, we included groups were vaccinated earlier in the Covid-19
only contacts who had undergone PCR testing. pandemic and were more likely to have had
Therefore, we cannot estimate secondary attack shorter dosing intervals than those who were vac-
rates according to the vaccination status of pa- cinated later. This lack of adjustment may have
tients and contacts, and the absolute protective affected the findings, particularly on waning of
effects of vaccination on transmission may be vaccine protection over time and differences ac-
underestimated because vaccine-protected, unin- cording to vaccine type; it also precluded analy-
fected contacts may not have sought testing. Our sis of the effect of the dosing interval.8
approach is also unlikely to eliminate bias, par- The delta variant has spread globally and
ticularly if test-seeking behavior is related to per- caused resurgences of infection even in areas with
ceived vaccine efficacy, given the nonspecificity of high vaccination coverage. Increased onward trans-
many symptoms of Covid-19.24 mission from persons who become infected de-
Some contacts may have been infected by a spite vaccination is probably an important reason
source other than the identified “index patient”; for this spread. Booster vaccination campaigns
this would attenuate associations between index- that are being considered and implemented26 may
patient–related variables, including vaccination sta- help to control transmission as well as prevent
tus, and the outcome. To minimize this effect, we infections.
restricted our study to contacts who had under-
The views expressed in this article are those of the authors
gone testing 1 to 10 days after testing in an in- and not necessarily those of the National Health Service, the Na-
dex patient, with very similar findings when the tional Institute for Health Research, the Department of Health,
analysis was restricted to 2 to 7 days. Better data or Public Health England.
Supported by the U.K. Government Department of Health and
on symptom onset and the timing of exposures Social Care; the National Institute for Health Research (NIHR)
between patients and contacts could improve Health Protection Research Unit in Healthcare Associated In-
estimates. fections and Antimicrobial Resistance, Oxford University, in
partnership with Public Health England (NIHR200915); and
In addition, we did not have sufficient data to the NIHR Biomedical Research Centre, Oxford. Dr. Eyre is a
account for previous infection status, which is Robertson Foundation Fellow and an NIHR Oxford Biomedi-

cal Research Centre Senior Fellow; and Dr. Walker is an NIHR Applications to use the data in this study can be made to the
Senior Investigator. Data Access Request Service of NHS Digital (https://digital.nhs
Disclosure forms provided by the authors are available with .uk/services/data-access-request-service-dars).
the full text of this article at NEJM.org.
Appendix
The authors’ affiliations are as follows: the Big Data Institute (D.W.E.) and the Health Economics Research Centre (K.B.P.), the Nuffield
Department of Population Health, National Institute for Health Research Health Protection Research Unit in Healthcare Associated
Infections and Antimicrobial Resistance (D.W.E., K.B.P., A.S.W., T.E.A.P.), and the Nuffield Department of Medicine (A.S.W., T.E.A.P.),
University of Oxford, Oxford, and the Department of Health and Social Care, National Health Service Test and Trace (D.T., M.P., T.F.),
Deloitte MCS (D.C.), and William Harvey Research Institute, Queen Mary University of London (T.F.), London — all in the United
Kingdom.
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..l- " ,5'-' .l. V.l. I
AR07556
m ed Rxiv 0 § __BMJ Yale '1
·<,
)
0 0
;l\:istM _t.!!IJ,W'}> Ol. 2022
Effe.ctivencss of COVlD-19 vaccines llgOinst Omicron or Oc,lta infection
l
fJ O"""'oad POF ~
\air.ah A. &dun, H.i."l:I\VI Cmtr,e, ~,tt A. -Brown, Pl:~1),- C A.trt.t1t1 f#.~,-~r.t- 8- Fe!,J"..nJrt---411 8 GI.C0.1y.
')h.nQ Nasr~ J<eotm L. 'X'l-HirC?.f"'.irQ> f. ';,i,;{l(Rri-(1'1. Mm Ti&•A:~ Kuffl~ W,,soo. S-J,ih [.W.ISt...n.
J<""'1C.K..,,og
El p,,,_~s.,..,.. 0;i,::i11M1 ,.
-do i ; ~ dol..;,,rg 10.I IQl.2<!21. l .J02!268~65
This ~ttide- is .a- prepnnt and h .s.1 {'Ot biecn p4:"er~rcV1ewed [what does this me.~n?]. It:
Cl
II ' ." ,. "'
I;
r'e:portS tt~• mediul reSNl"dl thn has ~T to be evaluated an6 so should not be used to
cul.de dini.ca) p ~ e. •
f ultTo.-: COVI0- 19 SARS-CoV-2 preprints from

mcdRxiv and bioRxiv
ABSTRACT SW)Kt Ar:u
8ack91ouod The mrn:fence of SARS-CoV-2 tnf&uon. including among I.hose \'.ho ha-ve
recerfE'C 2 dos~-, of COVID-19 UC(f09-) h..~\ mol?as~d SlJbSl,Uttldlly SHl{f On-ttcron \'/dS
ftn11demmed rn t~ pro;•mce or Ontano. Canada Subject NHS
Method~App!y,ng there~t-n.egazr-:e dfsu1n w IITTked pro·.·1ncia) datu ~,e e">t1mat~

vaccm~ etfeuri.re,n~>'> aqaln)t tnlecuon or,e>pecuve of c..ympto-ms or \~'lem)':, caus~
~, Omtcron or Delta ber.\een November 22 and 0e-cemner 19 2021 \\e included
1ndtv1duai\ ',\ho J~d rece1ved al Jeast 2 COVID• l9 \acnne dos.e-s m1th at leasr t rnRNA
vucine- dose for Che pnmary sertes.1 and used multwana.bJe 1091-,nc regre-ssion m
e-stmat~ the o1ffect1\'e-~\S Oi {\'-.0 or {hr~ d0~f-S b\ (1mf SIO(~ fh~ lffli':ir'<Jo-H·
R~UIH Wf m::tudM J.442 OnncrOR·pG\11:\E! (d,C,tS 9 20t ~lta-po.,1111.t• (d.\i?~ anct

°""""""D'
471 545 H}~t-ne-gdO\t' controls After 2 do\es. of CO\ tD-19 varone 1c1ccme-
~fft:<tr..,:~ne--,l .ag:a:m~t Deltc tnfec:uon dechned ~teadify o,e-, u~ btll rec0>1cred to 93.,,., ..,,,
195'"•0 9l 9,r-.,\.:: 7 ct.ays artH re<eivrng an mRNA vaccme tor rhe fhffcJ dose 1n
conua\t re<e,pc of 2 doses of (OVID- i9 \a<.ttn~~ ,·.o:') net prou!uwe .a.gamst Qml{JOO
ettenwene-1,s ~ •tisl OmJCron ~,,1~ 3T-., 195'\,0. 19--So-1'.,, ~1 day~ Mt~•
V.tcClnP-
recer11ng an mRNA va.ccme- to, u-.e Ulud do\e
Conclusions T\•.o doses of COVI0-19 i-acone,s are uni,kety to protect ag.atnst ,nfecuon
by Omic-ron A th,rd d0ii-~ p-tOV1de'i- some p1otPCtion an the tr'Tltno?dtati? term but
\Ub\tdntl.dl,)i less. th41r Jgamst Delta. Our result$ may be confounded by behaviours
rhclr ~,.~ ',.\-effl unable: m AC(OHnt tor 1t1 our anclf'</'SK Jttrt~r rfsec1rch 1.i: n.,eae-d fO
excmine prot&uon agam\t \evere outcomes
IN TROOUCllON
"''"
The world H;);dth Olgamz,mon declared Omicron a \/anam ol C0!)(ern on No','Pmber
26. 202t due to it'i h1ghty Udf1;rn1\!lr.lte naturi! and rnk of 1rr.mun~ e,cs·on ,n
On~a.no c-,f\clda the t1:;.t cte1ened uw 0 omicron ~\as. 1ctenufH?d on Novem~, ?i
6
20l l 1o'\Jttut1 ,·.e-ehl

Ormc100 accounted frn tl're rr..:-1onty of ne;.•. CJS.e'i Oe5"plte \ ery
htgh l -dose COVi0-1 ~ 1,:,1cclll~ co\er.19e ,ss:i.~ c1mon9 [hose a.9ect 2 l2 ye.,u; by ,r,,d
Decembec,. tru.' rare of case~ among full\ ;.ace mated mt111,idua:ls mcre.as~d
subsr.mnal-'\ durtn(} fhl'> period
\'fh:tf reduced t1ftmaJ1z,ng ant,ooa,o.s ag.11nq om1uon rollO'Mfl9 -st'<onct and cn,rt1
doses. of rr.RNA vaccutes h.i\ b-t:en ~s.tc1b1t,hw real .\orl0 data e1aU.1.1trn9 \accme-
pe,formanc~ a9airt)t 0mJ<rort mfecuon cHf' more-hmi??d l• pamcu!arty 1r1 a North ~~
~ O()t
Amenc,m context The obJecrrve of this. \llKt\; ~-..a.,_ to esmnate-vai:c.me ettecnveness
c..
1\ EJ a9a1n}ot inrecuon c.au$e-d by Omicron or- Delta tr\ om.,mo r: !:
r-
METrlOO S
_. -I
Study popul.:l?ton. nttu 1g ~r-d ees,gl'!- ~
z ~(')
\\~ U!tt-d th~ te-~t-ne9atr1" d;;os19n and I nktd j)fOV·noa1 dat.a co e,snmate_\E We
mduded all mdtv duals. aged .i:. Is v1;1,cHs wnh prcrnnci.11 hedlih 111sur.mce \'.-ho had .a.
rt-.·e-rs.e- uan~cupnon reat-mne potyr:\"1ase cho1n re-Moon cPCR\ te\t to, SARS-CoV-2
~
~,,
~ \; :;;
~
81
~ N
~
beMe-'"n NO\embe'r n ana oecerrtbff i 9 202'1 :::!
I
0
\\"P t"-.:dude-d long-term care rtttdt>ms. 1ndr./lctuati .\ho ha::1 rec~..·ea onfy J 005i of z
COVl0-19 \·a-cone or \·.ho had re<.et•.e<J U1etr second do)e 7 days orio, to te:ng , ,.!
resr/il:l Hld1v1d,ta.1s 1.\h.o had ,~ce,"-oct} do-ses. of ChAt10x1 1Astto\Z1F>nec.1 va,.-ze,.-o.i
1 . • • __ _ _ I I •- - .1 · • ~
Page 2 of 7
AR07557
COVISHIELD) because VE tor that schedule Is known to be lower, tllose who had
Rha.1nY.tologr
received non-Health Canada authorized vaccine(s); and those who received the Janssen
Sous! and Rrproduc-1~ H hi!
Oohnson & Johnson) vaccine (which, while approved for use in Canada, was large ly Sport, ,.,.,.,,.,.
unavailable and very rarely used)
Data sources
We linked provincial SARS-CoV-2 labora tory testing, reportable disease. COVID-19

vaccination, and health administrative databases using unique encoded Identifiers and
analyzed them at ICES, a not-for-profit provincial resea rch institute (www ices.on ea).
outcomes
s.,,..,,,. o, Chan
Zuckerberg
Initiative
we Identified individuals with confirmed SARS-CoV-2 Infections using provincial
reportable disease data We Included confirmed COVID-19 cases Irrespective of
symptoms or severity. The specimen collectlon date was used as the index date. For
1nd1v1duals who tested negative for SARS-CoV-2 during the study period and were
considered as controls, we randomly selected one negative test to use as the index
date To ensure that negative tests were not associated With recem Illness , we
excluded con trols who tested positive for SARS·CoV-2 within the past 90 days.
Positive specimens identified through whole genome sequencing as B. l . l .529 lineage

or round to haves-gene Target Failure (SGTF, a proxy measure for Omicron resulting
from the amino acid 69-70 spike deletion that does not occur with Delta) were
considered Omicron Infections. and specimens sequenced as 8.1 617 lineage. found
to be negative for SGTF. or collected prior to Derember 3 (when the prevalence of
omicron was <5%) and had no SGTF Information, were considered Delta Infections. As
of December 6, 2021 . all specimens with a positive PCR result were re-tested using
Thermoflsher Taqpath'" COVID-19 PCR to Identify SGTF. Prior to this date, SGTF
specimens were only identified 1f the pamcular testing laboratory used the Taqpath,..,.
platform. Between December 6 and 20, all SGTF-posltlve specimens with cycle
threshold (CtJ values ~JO also underwent whole genome sequencing (WGS). In Ontario.
the estimated sensitivlry of SGTF relative to WGS for detecting Omicron among
samples with Ct s30 was 99. 5% and the specificity was 99.8%. 13
COVI0 ·19 vaccln.1t1on
To date, Ontario has primarily used 3 products (BNTl 62b2 (Plizer-BioNTech

Comlrnary]. mRNA·I 273 (Modern• Splkevax), and ChAdOxl) In Its COVID-19
vaccination program. Due to fluctuating vaccine supplies. both varying dosing
Intervals and mixed vaccine schedules were employed Using a centrallzed province-
wide vaccine registry to identify receipt of COVI0•19 vacc.ines. we classified Individuals
depending on whether they had received 2 or 3 doses of vaccine and the timing of
these doses relatrve to the index date. We considered che following vaccine schedules
for the primary 2-dose series receipt of at least 1 mRNA vaccine (since a mixed
schedu le consisting of ChAdOxl and an mRNA vaccine has previously been
demonstrated to have similar VE as 2 mRNA vacclnes),14 receipt of any combination or
2 mRNA vacc ines, and receipt ol 2 doses of BNTl 62b2 . For the third dose. we
considered receipt or any mRNA vaccine and also compared receipt of BNTI 62b2 with
mRNA-1273 . AU compari4ions used those who had no t yel received any doses (i .e.. •
unvacelnatedl by the testing date as the reference group
Third dose ellglbillty In Ontario began In August 2021 and expanded gradually."
Initial ly, only moderately or severely lmmunocompromised lnd1vlduals were eligible to
receive a third dose as part of an extended primary series. Shortly thereafter , third
doses (I e , 'boosters') were provided to residents of higher-risk congregate settings
for older adults (e.g ., long-term care homes. high-risk retirement homes). In early
October, older adults l1vlng 1n other congregate care settings, Including all remain ing
retirement homes, became eligible. All Individuals aged ~70 years and healthcare
workers became eligible on November 6, followed by individuals aged ~so years on
December 13 and Individuals aged~, s years on December 18. The standard Interval
for third dose ellglbillry was generally ~ 168 days follo1V1ng the second dose but was
shortened to ::?!84 days on December 1S.
Covari31ts
From various databases, we obtained Information on each lndlvldual's age, sex. public
health unit region of residence. number of SARS-CoV-2 PCR tests during the l months
prior to December 14, 2020 (as a proxy fo r healthcare worker status based on the
start date of the provincial COVID· 19 vaccine prog ram). past SARS-CoV-2 infection >90
days prior to testing date, comorbldltles associated with increased risk of severe
COVID-19, influenza vaccination status during the 2019/ 2020 and/ or 2020/ 2021
Influenza seasons (as a proxy for health behaviours). and neighbourhood-level
Information on median household Income. proportion of the working population
employed as non-health essential workers. mean number or persons per dWelllng , and
proportion of the populauon who self-identify as a Visible minoriry These databases
and definitions have been fully described elsewhere.••
https://www.medrxiv.org/content/10.1101/2021.12.30.21268565v1.full 2022-05-31
Page 3 of 7
AR07558
St3tistical analysis
For both Omicron and Delta lnfecuons. we calculated means (continuous variables)
and frequencies (categorical varlable.s) and compared teM-positlve cases and test•
nega!lve controls using standardized differences.
we used mul11var1able logIsuc regression to estimate odds rauos comparing the odds
of vaccination in each " time since latest dose'" interval among cases wnh the odds
among controls. while adjusting for all listed covariates and a categorical variable for
week of test. VE was calculated us,ng the formula VE-(1-OR)xl 00%. For both Omicron
and Della lnfecuons , we estimated VE by vaccine schedule and time since latest dose.
All analyses were conducted using SAS version 9.4 (SAS Institute Inc. . Cary, NC)_All
1em were two-sided and used p<0 OS as the level of stausllcal s,gniflcance
RESULTS
Between November 22 and December I 9, 2021 , we Included 3,442 Omicron-positive

cases, 9,201 Delta-positive cases. and 471 ,545 test-negative controls Compared co
controls. Omicron cases were substantially younger (mean age 34_9 years vs _45 .0
years); more likely co be male; less likely to have any comorbldnies; less likely 10 have
had multiple prior SARS-cov-2 tests, less likely to have received an Influenza vawne
during the previous 2 Influenza seasons more likely to have occurred during the latter
half of the study period, less likely to have previously tested poSlllve for SARS-CoV-2,
more likely 10 have received 2 doses of COVID-19 vaccines and less likely co have
received a third dose (Table I).
CMnetff'nClo(lofttudJ'SubJK'Ut~udtor SA.11.S-CoV.2 bnwttn ll N ~ l l n d ,, OeambrrlO'll 1n

Ono.t10,C::MUCU
In comrast. Oelra cases were more slmllar to controls than Omicron cases in some
respens (e.g. , age. comorblditles ) but were more different In others, such as being
more likely 10 have occurred during the Initial half of the study period. far more likely
10 be unvacelnated (33 .I %vs_ 7.5%), and less likely to have received 2 or 3 doses.
After 2 doses of COVID-19 vaccin es (wi th at least 1 mRNA vacci ne), VE. against Delta
declined steadily overtime from 84%(9S%CI, 81-86"1 7-59 days afcerthe second dose
to 71% (95%CI, 66-75") .:i-::240 days after the second dose, but recovered to 93%
(95%CI, 92-94%) ~7 days after recelVl ng an mRNA vaccine for the th ird dose (Table 2
Figure 1). In contrast, receipt of 2 doses of COVlD-19 vaccines was not protective
against Omicron lnfernon at any point In time, and VE was -38%(95%CI , -61 %, -I 8%)
120-179 days and - 42% (95%CI, - 69", -19%) 180-239 days after the second dose. VE
against Omicron was 37% (95%CI, 19-so-,,1 ~7 days after recelVlng an mRNA vaccine
for the third dose.
....
Vu:ane effKtl'l'MHs q;11Ml lm'ecdon by Omkron or Dela amon1 ldolB ;ased ;t l I ~;an by tmw Sina tltflt
.. .
Recelp1 of at least 1 mRNA vacc ine for lhe 2-doH primary~
"" •
l . ♦
•
j ,. . •
¥ .,. t • •
' ......
J
tt • • i
~
,
.
..
,,,,, tf'..~ ..
-v..~ ,.P-" .;f t}',t,t:!.:,r?,:.
'--------' '--------' '--------'
Al!fmRN,f, BHTIQtQ ~HA-121)
.-
-
V.icane ~fkctl'lt!nen l\lillft1.C infect,on by Omkron o, Oc4G .,,,on, adult,. ;agt!d 2: 11 yun by bme llnce t.uut
Findings were consisten t for any combinalion of 2 mRNA vaccines and 2 doses of
BNT162b2 for the primary series (Table SI , Figure S1)
DISCUSSION
Page 4 of 7
AR07559
Our result) demonstrate that the effectiveness of 2 doses of COVID-19 vaccines

against Infection (Irrespective of symptoms or severity) Is substantial ly lower for
Omicron than Oelta, and that VE against Omicron Infection was only 37", 7 days
following a third dose We also observed negative VE against Omicron among those
who had received 2 doses compared to unvacclnated Individuals.
Early e)timares of VE against the Omicron variant are ava.llabl e from several countries,
Including England. Scotland. Denmark. and South Afri ca In a rest-negative study
conducted in England Andrews et al. found substantial waning of VE afte r 2 doses,
and lower VE against symptomatic Infection from Omicron than Delta at each time
point following 2 or l doses. •0 17 While lower than for Delta, VE against Omicron was
restored 10 ~70% In the 4 weeks following a third dose and subsequently waned
Similar to those findings , our re.suits show a marked reduction m 2-dose effecnvenesc.;
against Omicron Infection relative to Delta. followed by Increased effectiveness after a
third dose. Whlle the panern of our results were similar. ou r absolute estimates were
lower. our results align more closely Y.llh recent Danish data, where VE was estimated
for both BNT162b2 and mRNA-1273 vacci nes between November 20 and December
12, 2021 " in both Ontario and Denmark. VE was estimated against any Infection.
these e)timate) are expected to be lower than agains t symptomatic infection In the
Danish study, there was no significant protection against Omicron lnfecuon beyond
31 days after the second dose of BNTl 62b2, with significant negative VE estimates
91-1 50 days after the second dose. we also observed a panern or non-ex istent. or
even negative VE in Ontario However, VE on Denmark (available for BNTl 62b2 only)
recovered to 55% In the first 30 days fo llowlng a third dose. The Danish ernmates are
also aligned with other study results from England.' 1 whe re an estimated VE of 0-20%
against symptomatic infection was observed ror th ose with 2 doses or BNTI 62b2 and
55-80'\ for those with l doses. and from Scotland. •• where relative VE against
Omicron following a third dose was estimated at 56-S7% In the 2 weeks following a
third dose compared to those who had recei ved 2 vaccine doses ,25 weeks before the
symptom onset date. Finally, a study from South Africa estimated VE against Infection
at 33% In the Omicron period compared to 77% 111 the pre-Omicron period ••
Direct comparisons to other Jurisdictions are challengIng 2• due to differences In study

methodology, outcome definitions O.e., symptomatic Infection vs. any Infection),
vaccination policies (I e , homologous vs. heterologous vaccine schedules, third dose
ellglblliry criteria, product-specific policies), population age structures, and public
health measures that were 10 place during the study period (e g., vawne certificates,
mask mandates11 ). Despite lhls, the general trends acros~ the studies are similar,
demonstrating substantially lower VE against Omicron Infection than for previous
SARS-CoV-2 variants
The behaviour of Individuals who are vaccinated. and the policies that apply to this
group, may differ from those who are unvacclnated such that vaccinated" status
could be associated with an Increased risk of exposure In Ontario, a vacc ine
certificate system was Introduced 111 the fall of 2021 , such that only Individuals who
have received 2 doses of vaco ne are permined to travel by air and rail. and to enter
restaurants, bars. gyms, and large cultural and sporting events. Younger adults may
be more likely to frequent such venues and have more social contactsll (and Omicron
cases In our study were younger). As such, the exposure risk of vaccinated IndIvIduals
may be higher than unvacclnated Individuals since vaccination Is a requirement to
participate In these social acuvltles . This may explain the negative VE following 2
doses observed for Omicron during this early study period In earlier work, we noted
negative VE In the first week following the second dose against previous variants. in
keeping with the hypothesis that a mistaken belief In Immediate protection post-
vaccination may lead to premature behaviour change. However. other hypotheses
should also be considered, lncludmg the possibility that antigenic lmpnnung could
Impact the Immune response to Omlcron. 21 Ontario has experienced a lo11ter
cu mu lative Incidence of reported Infections and has attained higher vacci ne cove rage,
and thus has a potentially dissimilar distribution of Infection-Induced versus vaccine•
Induced Immunity, than other countries that have estimated VE against Omicron to
date 24
In addition to the potential that behavioural patterns differ by age the characteristics
of lndIvlduaIs 1',hO received specific produm may differ due to a preferential
recommendation in Ontario or BNTI 62b2 for young adults 2526 This may be another
contrlbuung factor 10 observed differences In VE across products (l.e . higher VE for
mRNA-1273 than BNTl62b2) In other Studies mm
Although prior studies have demonstrated reduced neutralizing antibodies against

Omicron relative to other var iants ronowlng receipt or 2 mRNA vacc1nes•· 79 (bu t with
potent neuuallzatlon following a third dose 1910), CDS+ cyrorox1c T cells are less
Impacted by mutations In the omicron vartam and are likely to continue m provide
protection against severe disease .••" To date . little real -world data on protection
against hospitalization are available. In south Africa, effectiveness against
Page 5 of 7
AR07560
hosp1tallzat1on was reduced from 93'1, in lhe pre-Omicron period to 70% In the
Omicron period. 1• 12 In Eng land, VE against hospitalization due to Omicron also
appears to be be tter maintained relative to infection with Omicron 11 Further data on
effectiveness of 2 or 3 doses against severe outcomes are needed
Our analysis has several llmitatlons. First, we were unable to differentiate lndlVlduals
who received a third dose as part of an extended primary series U.e • severely or
moderately lmmunocompromlsed Individuals) as well as those who were eligible for a
third dose earlier (e .g , residents of retirement homes). As such the proportion ol our
sample wllh a third dose may reflect these highly vulnerable populations. and thus VE
may be lov.er tl>an ror the general populauon due to underlying comorbIdlt1es. for
example. Second. due to sample size constraints . we we re unable to provide age-
specific VE estimates Third, we were unable to estimate effectiveness against severe
outcomes. due to the lag between infection and hospitalization or death Fourth, there
may be residual confounding that was not accounted for In our analysis. This Includes
an Inability 10 control for previous undocumented Infections. which may be differential
by vaccination status. as well as confounding due to behavioural pattern s For
example, If vaccinated Individuals have more exposure to SARS-CoV-2, our VE
estimates are likely underestimated 21 Last. changes In testing patterns. Including
Increased use of rapid antigen rem (which are not captured In our data) and
decreased PCR resting availability, may have lmpaaed our estimates. but the direction
of any resulting bias is uncertain
Our findings have potentially Important Impllcat1ons for proof of vacClnatlon

require ments. If the goal of these policies Is to protect against Infection then
lndIvIduals who have received 2 doses or mRNA vaccmes may no longer be considered
fully vacClnated. However, If the primary goal of these policies Is to protect against
severe Illness and Impact on the health system, further data 111111 be needed to
determine the number of doses required to provide adequate protection against
severe outcomes caused by Omicron Ou r work adds to an emerging body of re search
that suggests that immunization status cannot be simply dichotomized. and that
protection Is Instead based on a variety of fa ctors such as type of vacc ine received.
age of recipient. time since latest dose. and circulating variant.
Conclu sions
Two doses of COVID-19 vaccines are unlikely to protect against Omicron Infection
Whlle VE against Omicro n lnrectlon 1s substantially lower than against Delta 1nrect1on.
a third dose or mRNA vawne affords some level of protection against Omicron
Infection In the Immediate term. However, the durauon of this protection and
effectiveness against severe disease are uncertain Additional tools beyond the
cu rrently availab le vaccines. such as pu blic healtll measures. antivirals. and updated
vace1nes, are likely needed to protect against Om,cron Infection
Ethics 3pprov3I
ICES IS a prescribed enur; under Ontario's Personal Health Inrormat1on Promuon Act
(PHIPA). Section 4S of PHIPA authorizes ICES to collect personal health information.
without consent. for the pu rpose of analysis or compiling statistical Information with
respect to the management of. evaluation or monitoring of, the allocauon or resources
to or planning for all or part or th e health system. Projects that use data collected by
ICES under section 45 of PHIPA, and use no other data, are exempt from REB reView
The use of the data In thlS project IS au thorized under secuon 45 and approved by
ICES' Privacy and Legal Office
03t3 3V3il,1bllity
The dataset from thlS study Is held securely In coded form at ICES While legal data
sharing agreements between ICES and data providers (e.g. , healthcare organizations
and government) prohibit ICES from making the dataset publicly available. access may
be granted to those who meet pre-specified cmeria for confidential access, available
at www ices on ea/OAS (email dasfat}ICes on ea)
Code 3Vallablll ty
The full dataset creation plan and underlyfng analytic code are available from the
au thors upon reques t undemanding that the compu ter programs may rely upon
coding templaces or macros that are uniqu e to ICES and are cherefore either
Inaccesslble or may require modIftcat1on
Author contrl budons
S.A.B, H.C.. and J.C.K. designed the study. H.C. ob tained the data and conducted all
Page 6 of 7
AR07561
ana,yses l0ata set ana vanaore creauon ana scan st1cc11 moaemng, ::, A ~ ana JL K
drafted the manuscript. All authors contribu ted to the analys is plan. Interpreted the
resulcs, crmcaliy reviewed and edited the manu m lpt, approved the fina l version. and
agreed to be accoun table fo r all aspects or the work
Competing Interests
K w Is CEO or CANlmmunlze and serves on th e data safety board for the Medicago
COVID-19 vaccine trial. The other authors declare no con flicts or Interest.
Funding .ind dlscliilmers
This work was supported by the Canadian Immunization Research Network (CIRN)
through a grant from the Public Health Agency or Canada and the Canadian Institutes
of Health Research (CNF 151 944) This project was also supponed by funding from
the PUbllc Health Agency or Canada, through the vaccine Surveil lance Reference Group
and the COVID•19 Immunity Task Force This Study was also supported by ICES, l'hich
Is funded by an annual grant from th e Ontario Ministry of Health (MOH). J CK Is
supported by Clinician-Scientist Award from the u111versIry of Toronto Department of
Family and communlry Medicine PC A Is supported by a Mid-Career Investiga tor
Awa rd from the Heart and Stroke Foundation
This .-ork was supported by 1'1.Jbllc Health Ontario This study was also supported by
ICES. which Is funded by an annual grant from the Ontario Ministry or Health (MOH)
and the Ministry of Long-Term Care (MLTC) This study was supported by the Ontario
Health Data Platform (OHDP), a Province of Ontario lnltlauve co support Ontario's
ongoing response co COVID- I 9 and Its re lated lmpam The study sponsors did not
participate In the design and conduct of the study, collectlon , management, analysis
and Inte rpretation or the data, preparation . review or approval of the manuscript. or
che decision co submit the manuscript for publlcaclon. Parts of this materia l are based
on data and/ or Information compiled and provided by ch e canadlan lnsmuce fo r
Health Info rmation (CIHI) and by Cancer Care On tario (CCOl. However, the analyses,
conclusions, opinions and statements express ed herein are solely those of the
au thor!i, and do not reflect those of the fund ing or data sources, no endorsement by
ICES, MOH Ml TC, OHDP, Its partners, th e Province or Ontario, CIHI or cco IS Intended
or should be Inferred
Acknowledgments
We would like 10 acknowledge Public Health Ontario for access 10 vacclnauon data
from covaxoN, case-level data from CCM and COVID-I 9 laboratory data. as well as
assmance with data Interpretation We also chank che staff of Ontario's public heal th
units who are responsible for COVID-19 case and contact management and data
colleccion wIchln CCM we chank IQVIA SOlu1Ions Canada Inc for use of their Drug
Information Database. The authors are grateful to the Ontario residents without whom
thI; research wou ld be impossible
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AR07562
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h1tpd11,~eb.puhlo,hir1.~llf""'lfep.uW~~s/?"""-'"p\old'IJ1tachmrnt_d.UINIIIID43A07/trd,ni<1I
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31 ..iRedd All N.vdrl A. K.artd H. et •L MitwN I crou-over between muuuont anomt~ Wllh Omicron varani. of SARS·
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10.1 1011l021,ll.o6.171++6 Abw..,ct1fllC.l hal h1:11l Goorl-Schol.v
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Ertrfj Med 2021 doc 10,IOS6/NEJMcl 119270 c..,,..w Goop Srhob,.
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AR07563
medRxiv • I
nu nDSl,tT SUVH '°' HJ:.A.\ TH S<ft:HCtS
C
El'foctiv,,ncss of COVlD-19 vaccin<>s ~nst Omicron or Oclta symptomatic,
1
infection and severe out-comes
5,,,irah A. &Khan. ttlM-Jh Ch\it~!Cf;~ A 8r,J'<V1'. F\:t.e, C.l,~t.ll. ~~qr~ e,. fEclt.~tb;m c~. e.
Sh.uiQ Natrttn. Ke-,m L Sc-h-...,.r-a ~ N f. \unchnm, t1ll'la TM:l"l)U't. Ka,n..";v.i WaW>n. >i:nh f. '-V,i..:~,
f.ef:'rE,, C. ~W(.f'li
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Th.is :a.rtjde rt a preprint and h..u not bcc-n pcer--n:-Yiewe-d (wh.at does this- me::an?J It Iii
reports new ffl.(!dic~J resc~rch char: h.u yet to be ~alu.2"<.it-d and so ,ho.uld not be used co :Ii
Juidc chnic.a1 practice-.
CICI mz::m
,. F COVID-19 SARS.CoV-2 preprints from
me<fRxiv aod bioRxiv
ABSTRACT
&a<kgrl)UrxJ The 1r1c1c:e-n!~ of "ARS-C0V·1 mffl<t1011. mctuamg t1mon9 tno5,e \',110 ftA-.e-
rece,;fd 2 doses of COVlO. H' -.accmes m.creat.ie-d substanttalt-1 fr,tJm4;,n9 the
~me,gence of Om,uon m Oruarao c.m.lda
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esrim,ned \ d.COnt efftcnvenes\ f\.itl Jgamst 5,ymptom.it1c mfE-Glon .;no iPJtfi?
outcome~ •ho5p.rtahzauon 01 de.3thi U!!Sed by OmKron or De-lr.a bc:l,weo De<t1-rrbt:r €>
anct 2&, 2021 We used mu lrr,.anable logtsnc rc•9r~s•imn m@stHTldU! rh~ etfectr:-,ness.
or 2 or 3 COV1D·l9 var.one do~e\ by time since U1e la[t>St do\e compared 10
um·McmJatt>d tnd!v1duaJs
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l 14 os; te!>t-ntgau·,t> conuok V[ ag.a,nst S)'mptomat1c Delta infe<:oon decfmed frvm
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t te.,IUi~•,.r
rnf@«ton and \tvPre outcomes c.1u!ed by ~lr.1, OU! rewtn suggest th.n 2 dose\ of
COVI0-1 ~ \'.l{Or)~\ Onfy OHt'r mode-St and shOtMe,m prot&<UOtl ,matnsi \\n'IJ)tOtl"'ld:IH.
Omicron 1ntecnon A thud do-se ,mproyes protecnon ag«1nst wmprnm,mc mfernon
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KW 1s CFO ot CANJmtnUrH7~ and .,,e,ve\ on the d,u.i s~rery boatd tor rhe M~d,O90
COV'IO 19 va<.ctne UJa-1 The, other authors deda,e no confl,cu of imtn~t
fh~ ci,ork was. S.UPDOHtd by lbe ( an.achan 1mrnt1niz.at100 Re~e.ud, N~t\·,01k KIRN)
,h, ough a grant from the PubHc Healrh Agenc)• ot (anaoa .and thi' Can.ad1an 1nsuruw,s
of Hea!1h Re\eatc_h tCNP 15 J944> Tht\ JUOJtC.l \'ra~ also wppone-o bv 1und•n9 frorn
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·-
Che- Pubhc He.alch Agenc-, of Canad• rhrough the V.accme, sun.-eLUance Re7er1?nce, Croup
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and the C0\.10-t 9 trnmunH\ Ta">k Force TIU!> ~tudy Win .af10 ~opponed by KCS \.\h1<h
is tunoed by an annu.a.1gr.ant :,om the Omano /.tsm">tr)' of Hult h CMOH}. JC K •~
\upported by Chnsoan-Sot1nt1st A\\ard from the Uni\en1ty of Torooto Oepattmem of c..
Fim~ .and Communir'I Me-Ot<lne p C A IS WP;>orted b) .. t.'lld CifNlf 11'\-\"es.ngatof i:
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He&l;h Ontdno T~s srudy Y.•s. ..tho SU;lponed by ICES i.\h1_ct\ IS. funded by ill .innu.1t
g,an-r from the Onld.UO Mrnlllf\,' ol Health (MOH} and lht l,1llM'iUy of tong-Te,m Care t~
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fML -re, lht, s-rurty\,.aS supported by thfi OntiUIO Heal{h Dfltd P1art0tm lOH0P) ,a z=l jCI>
&l £
P:ovmce of Ontario truuarKre co \upport omatK>s 009otn9 res.p()n~t to COVlO i 9 and
tt\. ret.1t@d ,mp.ins The, study HH>Mo-r, dJd 11ot par;1c1pat e in tlh? de\lgn .md ronctuc;
of the \tudy conernon mat1a9fmern. an.1fy~15 and un~•Prftat.ion of the data ~ ~~

f}l'epar.inon revlt\·, o, approvo:ll of O'i" manus.cup.1 o: the deus.t0n to ~u.bmu the
rrtanU¼HPt tor publ:c•uon Para of th1\ mauual a.re b.a;,ed oo dau and/~
1nfortlkll10n compiled' anct prov1ctt'd by tl tt c anadtan 1n~t1rn1~ tQr H~.,lllh 1ntorma1mn
•CIHI> ..tnd h\' C.anc.et,C.!re Ornauo (CCO) Ht)\\f\e,r the anat\Se'io conclu\lCn!. oprnt0n1>
tl-nd ~l,Ue-ment; expre\\ed t.ere1n dll? \ofely 1ho~t of 1ttP. ,;n.11hoi~ ~nd do not reft\"Ct .,, ,
\t 0
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1- • • ·· .. . II
Page 2 of 2
AR07564
those of the funding or data sources , no endorsement by ICES, MOH, MLTC, OHDP, Its Rh"""''°"'V
panners, the Province of Ontano, CIHI or CCO Is Intended or should be Inferred Saual and R,produrtM' Hr.akh
Spcrt,-...
Author Oecl:u.1t1ons
s..i,,y
I confirm all relevant ethical guidelines have been followed, and any necessary IRB r.......,,.
and/ or ethics committee approvals have been obtained.
Yes
The details of the IRS/ oversight body that provided approval or exemption for the
research demlbed are given below Chan
J.upponed &t Zucke rberg
Initiative
Sealon 45 of PHIPA au thorizes ICES to collect personal health Information, without
consent, for the pu rpose of analysis or compiling statistical Information wi th respect
to the management or, evaluation or mon1torIng or. the allocauon of resources to or
planning for al l or pan of the health system. Projects that use data collected by ICES
under section 45 or PHIPA. and use no other data, are exempt from REB review The
use of the data 111 this project Is authorized under section 45 and approved by ICES
Privacy and Legal Office.
I confirm that all necessary patient/ participant consent has been obtained and the
appropriate lnstltutlonal fo rms have been archived, and that any
patlent/ panlclpant/sample Identifiers Included were not known to anyone (e .g.,
hospital staff, patie nts or participants themselves) outside the research group so
cannot be used to identify Individuals.
Yes
I understand tha t all clinical trials and any othe r prospective lnterventional studies
must be registered wItI1an ICMJE-approved registry, such as c11nIcaITrlals gov. 1
confirm that any such study reponed In the manuscript has been registered and the
trial regIsuat1on ID Is provtded (no te If posting a prospecuve study registered
re trospectively, please provide a statement In the tria l ID fie ld explaining why the
stu dy was nm reg istered In advance)
Yes
I have followed all appropriate research reporti ng guidelines and uploaded the
relevant EQUATOR Network research reporting checklls t(s) and otlier pertin ent
material as supplementary flies , If applicable.
Yes
Papco:r 1n colie-won COVID 19 SARS-COV.2 ~pr•ntJ from medR>uv •nd bioR,trv
Copyrtght The c.opynght holder lo.- this prepr1nt il the •uthor/funder, who hu granted
m«IRx1v a lictnse to d11plly the prtp,tnt in perpttu1ty, It ,s madic 1vadab1,c
under• CC.BY'NC ND 4.0 lntcn'II.Uoml 111~.ense.
https://www.medrxiv.org/content/10.1101/2021.12.30.21268565v2 2022-05-31
AR07565
TAB 53
AR07566

FEDERAL COURT
BETWEEN:
NABIL BEN NAOUM
Demandeur
et
Défendeur

AND BETWEEN:
Demandeur
et
Défendeur

AND BETWEEN:
AND AEDAN MACDONALD
Applicants
and
Respondent
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2

AND BETWEEN:
Applicants
and
Respondent
_________________________________________________________________
CROSS-EXAMINATION OF DR. JENNIFER GRANT

May 19, 2022
_________________________________________________________________
Mahan Keramati For the Respondent

Sam Presvelos For Dr. Grant
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INDEX
PAGE
Exhibits ................................................... 4
Undertakings ............................................... 4
DR. JENNIFER GRANT

Cross-Examination by Ms. Keramati ..................... 5
Re-Examination by Mr. Presvelos ....................... 55
Proceedings Adjourned ................................. 57
Reporter’s Certification .............................. 58
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EXHIBITS
PAGE
1. Infectious viral load in unvaccinated and 34
vaccinated individuals infected with ancestral,
Delta, or Omicron SARS-CoV-2, article published
in Nature Medicine, 2022, by Puhach et al.
2. Protective Immunity After Recovery from SARS-CoV-2 38
Infection article by Kojima.
3. Limited cross-variant immunity from SARS-CoV-2 45
Omicron without vaccination, Nature article.
4. WHO document titled Covid-19 Natural Immunity, 48
footnote 54 of Dr. Grant’s report.
UNDERTAKINGS
1. Provide precise language for paragraphs that need to 9

be updated.
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1 MAY 19, 2022
4 DR. JENNIFER GRANT, affirmed, testified:
5 COURT REPORTER: Can you please just state your full
6 name for the record and then spell it?
7 MS. GRANT: Yes, my name is Dr. Jennifer Grant, J-
8 E-N-N-I-F-E-R and the family name is Grant, G-R-A-N-T.
9 COURT REPORTER: Perfect, thank you. Counsel, we’re on
10 the record, whenever you’re ready.
11
12 CROSS-EXAMINATON BY MS. MAHAN KERAMATI:
13
14 1 MS. KERAMATI: Thank you. Good afternoon, Dr. Grant. Thank
15 you for being with us today. My name is Mahan
16 Keramati and I’m counsel for the Attorney General of
17 Canada, the respondent in these proceedings. You have
18 been sworn in today?

19 A. Yes.
20 2 Q. For the benefit of the record, we’re doing this cross
21 examination by video conference. I’m located in
22 Toronto, Dr. Grant, where are you located?
23 A. I’m in Vancouver, British Columbia.
24 3 Q. Would you please confirm that you are the only person
25 in the room right now?
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1 A. Yes.
2 4 Q. Would you please also confirm that during any breaks
3 in this cross examination, you will not communicate
4 with any party outside of this virtual meeting or take
5 instructions from anyone including Mr. Presvelos or
6 anyone else from his office during the examination?
7 A. I, I, I agree regarding the proceedings of the
8 examination. I may go into the lunchroom and discuss

9 other things should I need to get water.
10 5 Q. That’s perfectly fine. Dr. Grant, do you have any
11 printed or electronic documents in front of you today?
12 A. No. Sorry, correction, I have the documents that were
13 sent to me by email within - 15 minutes ago.
14 6 Q. Okay. Would you please confirm that during the cross
15 examination you will not be viewing or referring to
16 any notes other than the documents that I have sent
17 you, and your affidavit, and report?
18 A. Yes.
19 7 Q. Would you please tell me what documents, Dr. Grant,
20 you reviewed in preparing for today’s cross
21 examination?
22 A. So I reviewed my own affidavit and the references
23 there, therein and any updates to those references
24 including if they have been changed from a preprint to
25 a publication. I also reviewed the documents that
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1 were sent to me by your time.
2 8 Q. Have you reviewed the affidavit of Dr. Dawn Bowdish?
3 A. Yes.
4 9 Q. Have you reviewed the affidavit of Elizabeth Harris?
5 A. No.
6 10 Q. Okay. Dr. Grant, you swore an affidavit on March 11,
7 2022, correct?
8 A. Correct.
9 11 Q. And your affidavit attaches as your CV Exhibit 1,
10 correct?
11 A. Correct.
12 12 Q. Exhibit A, I’m sorry.
13 A. Correct.
14 13 Q. And your CV is complete and accurate as of March 11,
15 2022?
16 A. It should be.
17 14 Q. Your affidavit attaches as Exhibit B, your expert
18 report dated March 10, 2022 that you wrote at the
19 request of counsel for Rickard applicants, correct?
20 A. Correct.
21 15 Q. And do you have your affidavit and report with you
22 today?
23 A. I do.
24 16 Q. And so, just to confirm, earlier when I asked what
25 documents you had, you only have your affidavit which
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1 attaches your CV and report, the three documents that
2 I provided you today?
4 17 Q. Okay. And the report you prepared truthfully reflects
5 your opinion at the time that it was authored?
6 A. Correct.
7 18 Q. I received a letter from your counsel this morning
8 making some minor corrections to a number of footnote

9 references. Other than those corrections, is there
10 anything else you wish to change or correct with your
11 affidavit or report before we begin?
12 A. Yes, there was another error I found while we were
13 viewing it last night. It says that my information
14 was up to date as of December 18, that is incorrect.
15 That was the original date, it was actually correct up
16 to, I believe, February 24.
17 19 Q. Could you tell me what page you’re referring to?
18 A. Good question. It is - I don’t, I don’t have the page
19 numbers on the paper copy, so I’m not able to...
20 20 Q. Okay. Is it...
21 A. But it is the last page, item 46 and 47, the date is
22 December 18, 2021, that should read February 24, 2022.
23 21 Q. Okay.
24 A. And I did want to make not so much a correction as a
25 grammatic clarification on point, 39 in the sentence
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1 that reads for example, during the 2009 H1N1 pandemic,
2 it - the, the way the sentence reads sounds like it
3 was 51% of all hospital beds. That is incorrect, that
4 - the, the point in that sentence is that there was a
5 peak that represented 51% of the beds taken up by the
6 pandemic. Not all hospital beds.
7 22 Q. Perhaps I can ask your counsel to make an undertaking
8 that you will provide the precise language for that

9 paragraph that you wish to update so that we can have
10 the precise language on hand.
11
12 UNDERTAKING NO.1: Provide precise language for
13 paragraphs that need to be updated.
14
15 MR. PRESVELOS: So a correction to that effect was made in
16 my letter this morning, but I will provide - what I
17 can provide is, you know, the whole paragraph,
18 perhaps, with the precise language in bold just so
19 it’s unequivocal what language is being adopted...
20 MS. KERAMATI: Yes.
21 MR. PRESVELOS: ...for the purpose of the report...
22 MS. KERAMATI: Yes. That would be...
23 MR. PRESVELOS: Give me a second. Let me write it down.
24 Okay.
25 MS. KERAMATI:
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1 23 Q. Dr. Grant, I also have a paper copy of your affidavit
2 and so when I take you to portions of the affidavit,
3 I’ll be referring to the paragraph numbers that you
4 have also been referring to.
5 A. Perfect, thank you. That’s right.
6 24 Q. Dr. Grant, I’m going to ask you some questions about
7 your education and experience.
8 A. Sure.
9 25 Q. You’re an infectious disease physician and medical
10 microbiologist, correct?
12 26 Q. In paragraph three of your report...
13 A. Mm-hmm.
14 27 Q. You have stated that a substantial part of my practice
15 is infection prevention and control, do you see that?
16 A. Yes.
17 28 Q. Going forward, I’m going to refer to infection
18 prevention and control as IPAC.
19 A. Fair enough.
20 29 Q. Based on your experience and publications, is it fair
21 to say that your work focuses on IPAC and antibiotic
22 stewardship?
23 A. That is one aspect of my career, but it is not by any
24 means the only aspect of my career.
25 30 Q. Would you say it’s the focus?
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1 A. No, I would not.
2 31 Q. Your practice in IPAC has been as an IPAC officer at
3 Richmond Hospital in Vancouver, a rehabilitation
4 center, and long-term care homes in British Columbia,
5 correct?
6 A. That is correct for my specific administrative
7 responsibilities, however, we hold responsibility for
8 all of Vancouver Coastal Health which we manage

9 clinically when we’re covering the service.
10 32 Q. And in your administrative role, you oversee the IPAC
11 procedures at these institutions, correct?
12 A. Correct.
13 33 Q. And IPAC procedures include procedures like hand
14 hygiene, use of personal protective equipment.
15 A. Amongst others, yes.
16 34 Q. Amongst other - would you agree that transmission of
17 virus varies with the environment?
18 MR. PRESVELOS: Oh, you cut out there.
19 MS. KERAMATI: Oh, I’m sorry. Would you agree that
20 transmission varies with the environment?
21 A. Amongst other things, that is an element, yes.
22 35 Q. Okay. Dr. Grant, you’re currently involved with the
23 British Columbia Clinical Therapeutics Committee for
24 Covid-19?
25 A. Correct.
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1 36 Q. The Canadian Treatment for Covid-19?
2 A. No.
3 37 Q. Is that not CATCO?
4 A. No. That, sorry, you’re talking about a therapeutics
5 committee. I am the chair of that committee. CATCO
6 is a clinical trial.
7 38 Q. Yes, so my next question was - let me rephrase that,
8 you’re currently involved with the British Columbia

9 Clinical Therapeutics Committee.
10 A. Correct.
11 39 Q. You’re also involved with the Canadian Treatment for
12 Covid-19.
13 A. The study, yes, CATCO.
14 40 Q. Yes.
15 A. As, as a PI for Richmond Hospital.
16 41 Q. Yes. And you’re involved in Solidarity.
17 A. CATCO is a sub arm of Solidarity.
18 42 Q. Okay. These committees and studies deal with
19 treatment of Covid-19 infection, correct?
20 A. Correct.
21 43 Q. And the focus is not on Covid-19 vaccines.
23 44 Q. Dr. Grant, from 2008 to 2011, you were a travel
24 medicine consultant at a travel medicine clinic,
25 correct?
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13
1 A. Correct.
2 45 Q. And this role necessarily required that you be
3 familiar with the catalogue of vaccines available,
4 correct?
6 46 Q. In your role at the clinic, you were not involved in
7 vaccine development, correct?
8 A. No.
9 47 Q. You were not involved in testing vaccine efficacy,
10 correct?
11 A. Correct.
12 48 Q. And you were not involved in testing vaccine safety,
13 correct?
14 A. Correct.
15 49 Q. Dr. Grant, you have not published on the subject of
16 vaccine efficacy, correct?
18 50 Q. You have not published on the subject of vaccine
19 safety, correct?
20 A. Correct.
21 51 Q. You are not a vaccinologist.
22 A. That is something that has a nebulous definition. I
23 am required as part of my Royal College training and
24 explicitly examined on efficacy, use, safety, and
25 epidemiology of vaccines. So I am unaware of the
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14
1 specific definition of vaccinologist, however, I am
2 expected as part of my regular job both IPAC and
3 infectious diseases to have a strong working knowledge
4 of the clinical applicability of vaccines.
5 52 Q. You would agree that you’re not an expert in vaccine
6 development though.
7 A. Not in vaccine development, no. I ...
8 53 Q. You would agree that you’re not an expert in vaccine

9 safety.
10 A. Again, I have expertise in vaccine safety specifically
11 in counselling patients and as they - and applying
12 their use clinically.
13 54 Q. You have no graduate educational training in the field
14 of vaccine safety, correct?
15 A. That is depending on how you want to define graduate
16 training. I have seven postgraduate years in medical
17 training where that expertise was expected and taught.
18 55 Q. You have no publications in vaccine safety.
20 56 Q. Correct. And you’ve conducted no clinical or
21 preclinical trials in vaccine safety?
22 A. I have not.
23 57 Q. You are not an expert in vaccine efficacy, correct?
24 A. I disagree with that statement. Again, as part of my
25 training for medical - as a medical microbiologist as
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1 an infectious diseases specialist, that is an expected
2 expertise on which we are tested.
3 58 Q. You would agree that you have no publications on
4 vaccine efficacy.
5 A. Yes.
6 MR. PRESVELOS: Sorry, haven’t we - where are we going?
7 Like haven’t we asked these questions already? I have
8 my notes, efficacy, safety, testing, development, she

9 hasn’t published on development, she hasn’t published
10 on vaccine safety. I thought we established that
11 already?
12 MS. KERAMATI: Is there an objection in your statement?
13 MR. PRESVELOS: Yeah, it’s repetitive. So I mean let’s just
14 keep track of the questions and move forward
15 because...
16 MS. KERAMATI: I...
17 MR. PRESVELOS: We’re asking the same things multiple times.
18 According to my...
19 MS. KERAMATI: We are not asking the same things. This line
20 of questioning is whether or not Dr. Grant is an
21 expert in these areas which I have not yet asked. Dr.
22 Grant, I’m sorry, you are not an expert in the
23 efficacy of vaccines you said. You disagree with that
24 statement?
25 A. No, I - no.
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1 59 Q. No, no, no, you disagreed with that...
2 A. I disagreed.
3 60 Q. ...statement and I was moving on. You have no
4 publications on vaccine efficacy, correct?
6 61 Q. And you’ve conducted no clinical or preclinical trials
7 on vaccine efficacy.
8 A. No.
9 62 Q. Thank you. Dr. Grant, in your CV you do not list any
10 education publications or research projects in
11 immunology, correct?
13 63 Q. You are not...
14 A. No, sorry. I’m going to...
15 64 Q. An...
16 A. I’m going to correct the statement, sorry.
17 65 Q. Yes.
18 A. I have no publications in immunology. Again, part of
19 the expectations of training in infectious diseases,
20 medical microbiology, and IPAC is a strong working
21 understanding of immunology as it applies to
22 infectious diseases.
23 66 Q. You are not an immunologist, correct?
24 A. Correct.
25 67 Q. And in your CV you have not listed any training,
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1 publications, or research project in Public Health,
2 correct?
3 A. Again, I have several publications in Public Health,
4 specifically looking at personal protective equipment
5 and vaccine efficacy for preventing disease in our
6 healthcare workers. I have, again, as part of my
7 training for medical microbiology, infectious
8 diseases, a requirement to understand and be able to

9 apply the principles and practice of Public Health as
10 it applies to infectious diseases.
11 68 Q. So you have published in the area of PPEs, for
12 example, for medical professionals.
13 A. Correct.
14 69 Q. Correct? And this would be in a hospital setting?
15 A. No, it would imply across the care continuum from
16 community care all the way to hospital settings and
17 ICUs.
18 70 Q. And I wonder if you can pinpoint that in your
19 publications for me, Dr. Grant.
20 A. Sure, I will ha - I did not print out my own CV so I
21 will have to look at it on the computer. Is that
22 okay?
23 71 Q. Yes, that’s okay. And you don’t need to do it now.
24 A. It’s, it’s, it’s the PLOS ONE article on protection of
25 healthcare workers and there were several preprints
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1 with the same group.
2 72 Q. Thank you. You’re not a Public Health expert though,
3 Dr. Grant, correct?
4 A. I am - I do not practice in the field of Public
5 Health. Much of - many Public Health experts do
6 actually come from an infectious diseases background.
7 So I have the trai - the same - very similar training
8 to somebody who does practice in Public Health.

9 73 Q. Would you hold yourself out as a Public Health expert?
10 A. Depends on what my standard is, but I certainly have
11 expertise in Public Health.
12 74 Q. In your CV, you do not list any training,
13 publications, or research projects in epidemiology,
14 correct?
15 A. Again, depending on what definition we’re using for
16 epidemiology because some of my publications, in fact,
17 do address the question of epidemiology either of
18 antimicrobial resistance which is a question of
19 epidemiology, they protect - again, the PPE and
20 vaccine uptake publications are also considered, at,
21 at least in part, epidemiology.
22 75 Q. You have no graduate training in epidemiology?
23 A. I have training as part of my infectious diseases
24 training in which we are required to take epidemiology
25 courses, but they aren’t specifically listed out as
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1 courses. They are part of the training.
2 76 Q. You’re not an epidemiologist?
3 A. I am not an epidemiologist.
4 77 Q. Dr. Grant, am I correct that none of your peer
5 reviewed published work is on respiratory viruses?
6 A. That is incorrect.
7 78 Q. Could you show me which publications specifically?
8 A. Hang on, let me see if I can find this. So in my

9 affidavit su - I guess, end note or, or footnote
10 number one, facial protective equipment, personnel
11 pandemics on H1N1, that is viral. Number five,
12 infection control, occupational health measures
13 including mRNA-based vaccinations to protect
14 healthcare workers against Covid. Mixed methods with
15 Arnold Ocupani (ph) is also an - viral...
16 79 Q. Sorry, what number is that?
17 A. That’s number six. Number seven, also, is about
18 Covid, so that is viral as specifically respiratory
19 viruses. And that eight and nine are also about
20 treating respiratory viruses.
21 80 Q. Okay. So I’ll ask you one question, so you mentioned
22 number seven, for example...
23 A. Yes.
24 81 Q. It’s about respiratory viruses. So number seven is a
25 study about the rate of vaccination among healthcare
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1 workers, correct?
2 A. That is correct, yeah.
3 82 Q. So it’s called Covid-19 infection and vaccination risk
4 in healthcare workers in British Columbia, Canada: A
5 Longitudinal Urban versus Rural Analysis of the Impact
6 of the Vaccine Mandate.
7 A. Correct.
8 83 Q. This is footnote seven.

9 A. Yeah.
10 84 Q. And so this study was focused on the vaccine status of
11 healthcare workers.
12 MR. PRESVELOS: Is that a question or a statement? Are you
13 asking what the study was focused on?
14 MS. KERAMATI: No, I put to her what my understanding is and
15 she responded, correct. Am I correct, Dr. Grant?
16 A. Yes.
17 85 Q. Thank you. Dr. Grant, in your professional capacity,
18 would you agree that it’s your responsibility to
19 continue to evaluate emerging evidence?
20 A. Yes, I would agree.
21 86 Q. Would you agree that it’s important to keep an open
22 mind?
23 A. Generally speaking, yes.
24 87 Q. Counsel, could you confirm the scope that Dr. Grant is
25 being put forth for scope of expertise?
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1 MR. PRESVELOS: I’m going to adopt the same answer I gave in
2 yesterday’s cross examination.
3 MS. KERAMATI: That’s fine. Could you state it for the
4 record?
5 MR. PRESVELOS: Well I don’t remember the exact details of
6 what I said yesterday because my memory’s not that
7 good, but it’s something along the lines of that Dr.
8 Grant is an expert in infectious diseases and in

9 medical microbiology and as part of her expertise, she
10 has the knowledge on vaccine efficacy, immunity,
11 natural immunity, vaccine immunity, and is qualified
12 to opine on those matters and the other matters that I
13 enumerated in that much more comprehensive list given
14 yesterday.
15 MS. KERAMATI: So it’s your position that Dr. Grant is being
16 put forward in the exact same capacity scope of
17 expertise as Dr. Rau?
18 MR. PRESVELOS: Including with all the qualifications that I
19 made yesterday. And it shouldn’t surprise anyone
20 considering that she has the same background although
21 perhaps different clinical experience and obviously
22 some different publications which could - there are
23 some relevance in terms of what additional knowledge
24 she might have on the issues that she has published in
25 and on her clinical practice, which I understand also
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1 includes Covid-19 research and therapeutics. But I
2 can be corrected by Dr. Grant if my – if I’m not
3 understanding correctly there.
4 A. Okay. You are correct, Sam. Neil and I have the same
5 training, we practice slightly differently and I am in
6 - heavily involved in clinical therapeutics for Covid.
7 MS. KERAMATI:
8 88 Q. Thank you. Dr. Grant, I’m going to take you to

9 portions of your report now.
10 A. Okay.
11 89 Q. Would you please turn to paragraph 15 of your report?
12 A. Yes.
13 90 Q. One moment. I’m sorry, paragraph 17 of your report,
14 Dr. Grant. So at paragraph 17 you state current data
15 from the four most populous provinces show that the
16 majority of infections are in people who have been
17 previously vaccinated. Do you see that, Dr. Grant?
18 A. Yes.
19 91 Q. And in support or an illustration of this point,
20 you’ve included a figure at paragraph 18A, do you see
21 that?
22 A. Yes.
23 92 Q. And 18A is Ontario data and it’s a graph titled Covid-
24 19 Cases by Vaccination Status. Do you see that?
25 A. Yes.
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1 93 Q. Dr. Grant, would you agree that approximately 80% of
2 the Canadian population are fully vaccinated?
3 A. Yes.
4 94 Q. And would you agree, therefore, that the number of
5 people available to contribute to the total number of
6 cases of infection is much larger for fully
7 vaccinated?
8 A. Yes, which is precisely the point I made in point

9 number - I’m going to have to find it. But
10 essentially, that is the point I’m making.
11 95 Q. Thank you.
12 A. Numerically, you’re going to have more people who are
13 vaccinated than unvaccinated. Sorry, it’s point
14 number 16 where I make that point.
15 96 Q. When you say point you mean paragraph, just for
16 clarity.
17 A. Paragraph number 16.
18 97 Q. Okay, thank you. Dr. Grant, could you please turn to
19 paragraph 19.
20 A. Yes.
21 98 Q. So paragraph 19 comes under the heading Vaccination is
22 ineffective at preventing transmission of Sars. Do
23 you see that?
24 A. Yes.
25 99 Q. Okay. And at paragraph 19 you state, quote,
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1 vaccinated individuals do not pose a more significant
2 transmission risk when infected, end quote. Do you
3 see that?
4 A. Yes.
5 100 Q. Am I correct that implicit in this statement is that
6 vaccinated individuals do pose less transmission risk,
7 but in your assessment, the difference is not
8 significant?
9 A. I think there’s numerous ways to interpret that, but
10 generally speaking once you are infected, your
11 likelihood of transmission is not significantly, and
12 using the very specific term of, statistical
13 significance.
14 101 Q. I understand. Dr. Grant, I’m going to pull up Dr.
15 Dawn Bowdish’s reports and I’m going to share my
16 screen with you. Can you see my screen, Dr. Grant?
17 A. Yes, I can.
18 102 Q. And you see that this is the affidavit of Dr. Dawn
19 Bowdish which you have reviewed previously.
20 A. I, I didn’t see that, but...
21 103 Q. Oh.
22 A. I believe you, okay.
23 104 Q. Okay. Do you see her name, affidavit...
24 A. Yes.
25 105 Q. ...of Dr. Dawn Bowdish, okay. I’m going to scroll
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1 down to page 33 of her expert report which is page 139
2 of this PDF document.
3 A. Okay.
4 106 Q. Okay. So at page 33, there’s a heading that says
5 vaccination reduce transmission. Do you see that?
6 A. Yes.
7 107 Q. Okay. And I’ve highlighted a portion, is that big
8 enough for you to see?

9 A. Yeah, that’s perfect. Thank you.
10 108 Q. Okay. So I’m going to read the highlighted portion
11 into the record and then ask you some questions. So
12 quote,
13
14 “Dr. Grant, Grant expert report at para 20 to 25
15 concludes that because viral loads are equivalent
16 between vaccinated and unvaccinated people in
17 many studies, the vaccination - I’m sorry, that
18 vaccination must have no effect on transmission.
19 There’s a very important technical consideration
20 to consider when interpreting these studies.
21 Most studies measure viral loads as - viral loads
22 - most studies measuring viral loads use PCR
23 tests which measure the amount of the virus’s
24 nucleic acid and does not distinguish between
25 viable and dead virus. Studying the amount of
26 viable virus is incredibly difficult and time
27 consuming, but when it is done it is clearly
28 shown that vaccinated people carry less viable
29 virus than unvaccinated people. The PCR test may
30 say that they have the same amount of virus, but
31 due to their pre-existing immunity, vaccinated
32 people kill more of the virus and so the ratio
33 viable to dead is much lower in vaccinated
34 people.”
35 Did you see - do you see that statement highlighted,
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1 Dr. Grant?
2 A. Yes, I do.
3 109 Q. Okay, thank you. So, Dr. Grant, would you agree with
4 the following statement in the context of
5 transmissibility of Covid-19 vaccine? PCR tests
6 measure viable and nonviable virus whereas invitro
7 culture tests only viable virus.
8 A. I think that that is a statement that superficially

9 appears to be true, but there’s an, an, an enormous
10 amount of nuance that is missed in stating so. The
11 first thing is that yes, PCR tests viable and
12 nonviable virus, but that virus had to be viable at
13 some point in order for the DNA to have been made. So
14 that’s one point. The other point is that viral
15 culture is very insensitive and misses the vast
16 majority of viable viruses. And so while it is a
17 valuable test when positive, it does not rule out
18 viable virus if it is negative. And this has been
19 well known for years which is why we’ve generally
20 switched to PCR for most diagnostics.
21 110 Q. And you would agree that it’s only the viable virus
22 that causes disease?
23 A. Yes, that is true.
24 111 Q. And invitro culture is a more accurate measure of
25 viability of the Covid-19 disease than PCR?
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1 A. I would disagree with that. Viral culture is - it is
2 only useful when positive. But failure to culture a
3 viable virus is actually not disproven by viral
4 culture because viral culture is very insensitive and
5 as a result, you are missing multiple copies of viable
6 virus even if you do viral culture.
7 112 Q. And invitro culture is difficult and time consuming to
8 perform, you would agree with that?

9 A. It is difficult, it is time consuming, it is finnicky,
10 and very insensitive.
11 113 Q. Dr. Grant, you’ll note that at footnote 105...
12 A. Mm-hmm.
13 114 Q. Of the paragraph that I read to you from Dr. Bowdish’s
14 report...
15 A. Mm-hmm.
16 115 Q. Or rather she cites footnote 105 and I’m going to
17 scroll down to her list of authority so that you could
18 see what footnote 105 is. Do you see footnote 105?
19 A. I do.
20 116 Q. It’s a study by Puhach and others titled Infectious
21 viral load in unvaccinated and vaccinated individuals
22 nfected with ancestral, Delta, or Omicron SARS-CoV-2
23 published in Nature Magazine, (sic) 2022. Is that
24 correct?
25 A. Well it’s in Nature Medicine, not Nature Magazine.
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1 117 Q. Nature Medicine, thank you for that correction. I’m
2 going to take you to that article now. Just stop
3 sharing, oh, actually I think I can simply pull it up.
4 Okay. Do you see the article up on my screen, Dr.
5 Grant?
6 A. Yes.
7 118 Q. Okay. I’m going to scroll down to read you an excerpt
8 under - in the abstract heading which I’ve

9 highlighted. Do you see that document?
10 A. Yes.
11 119 Q. Okay. So starting at line 34...
12 A. Mm-hmm.
13 120 Q. It states, “In this study we quantified infectious
14 viral load in SARS-CoV-2 infected individuals during
15 the first 5 symptomatic days by in vitro culturability
16 assay in unvaccinated or vaccinated individuals
17 infected with pre-variants of concern (pre-VOC), SARS-
18 CoV-2, Delta, or Omicron. Do you see that?
19 A. I do.
20 121 Q. Okay. I’m going to scroll down further to page six
21 under the heading fully vaccinated subjects. Okay, do
22 you see that under the heading fully vaccinated
23 subjects have lower infectious viral loads in Delta
24 infected individuals?
25 A. I do.
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1 122 Q. Okay. So I’m going to read you the highlighted
2 excerpt. “Overall, RNA genome copies were
3 significantly lower in vaccinated vs. unvaccinated
4 patients” and there’s some figures in parentheses.
5 “The decrease in infectious viral load was even more
6 pronounced in vaccinated patients” followed by figures
7 as well. In lay terms, am I correct that this means
8 that PCR testing showed that vaccinated Delta infected

9 individuals had 28 times less viable and nonviable
10 Covid virus than Delta infected unvaccinated
11 individuals?
12 A. I’m sorry, I’m going to have to break that one down.
13 And I...
14 123 Q. So...
15 A. And I think we need to get into the, the, the real
16 nitty gritty of the methodology of this paper because
17 this is not representative of the entire infection.
18 But if you can put your question to me exactly as you
19 want me to answer it, that would be very helpful and
20 I’m pulling the paper up so I can have a quick...
21 124 Q. That would be helpful if you could pull the paper up.
22 A. So precisely, what is your question again?
23 125 Q. So my question is am I correct that PCR testing - or
24 rather, let me ask you a more, I suppose,
25 straightforward, am I correct that vaccinated Delta
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1 infected individuals had 47.8 times less viable virus
2 than Delta infected unvaccinated individuals?
3 A. So, so based on their numeric assessment, there is a
4 2.8 fold log difference, mean difference, in
5 infectious viral load and when you look at the, the
6 viral culture, there is a mean difference. However, I
7 do encourage you to scroll to figure, what figure
8 number is this, I think it’s figure 2A, so you can

9 have a visual understanding of what that actually
10 means. Can you scroll to figure 2 please?
11 126 Q. I can, but before moving on, could I just make sure
12 that I’ve got an answer to my question and then I’d be
13 happy to move to the figure.
14 A. You are, you are correct that the point estimate shows
15 a log fold difference both in CT value and viral load.
16 But I do want to put that in context because the point
17 value is one thing, but you need to look at the
18 distribution on which you will see is actually not
19 substantially different even though there is
20 statistical difference. And that’s an important
21 consideration when we look at things because just
22 because something’s statistically different, in fact,
23 does not mean that it’s clinically different.
24 127 Q. Give me a sec.
25 A. Okay, you just passed it. Go up. There.
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1 128 Q. Oh.
2 MR. PRESVELOS: It’s page 19, I think. There.
3 A. No.
4 MS. KERAMATI: This is page 19.
5 A. Okay, keep going down. There we go, can you twist it?
6 129 Q. Now you are testing my technological abilities.
7 A. I believe if you go to view you can rotate it, rotate
8 view. In the middle, slightly to the left of the

9 middle, there you go. Right.
10 130 Q. Okay. Okay so for the record you’re referring to page
11 21 of the document.
12 A. Okay. Yes, figure A. And so what you can see there,
13 that’s the, the red are those people who are
14 unvaccinated and the black are those people who are
15 vaccinated. And as you can see, the, the center bar,
16 the center line, is the mean, that’s the point
17 estimate and then the top and bottom are the standard
18 deviations. So that’s - within that should be about
19 75% of all values. And well, yes, the mean is
20 numerically different. In fact, if you look at the
21 distributions, the distributions wildly overlap. And
22 so, yes, there is a point difference, however, in
23 terms of whether that’s infectious or not or whether
24 there’s a difference in terms of infectivity or not is
25 certainly not shown by these data.
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1 131 Q. So I’m going to scroll back up to line 218 under
2 discussions. And just for the record, I’d like to
3 note that, Dr. Grant, you did take the time to review
4 the document before answering the questions, so I
5 appreciate that. If we can look at - do you see my
6 page, Dr. Grant?
7 A. Yes, I do.
8 132 Q. Okay. So under discussions, I’ve highlighted a

9 portion that I’ll just read to you. Quote,
10
11 “To our knowledge, this is the first study to
12 quantify infectious viral loads in individuals
13 infected with different SARS-CoV-2 variants and
14 in vaccination breakthrough cases. We
15 demonstrate a higher infectious viral load in
16 unvaccinated Delta-infected compared to pre-VOC-
17 infected individuals and showed that a
18 significant reduction of infectious viral loads
19 in fully vaccinated Delta-infected individuals.
20 However, only booster vaccinations significantly
21 reduced infectious viral load in Omicron infected
22 individuals. Furthermore, we found a lower
23 infectious viral load in Omicron compared to
24 Delta breakthrough cases.”
25 Do you see that...
26 A. I do, yeah. Yes.
27 133 Q. Dr. Grant, this study was published online after you
28 completed your report. So I take it that it could not
29 have been considered - you didn’t consider it in
30 preparing your report. Have you reviewed it before
31 today?
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1 A. Yes, I had.
2 134 Q. You had, okay. If this study in fact demonstrates
3 that vaccinated people can carry significantly less
4 viable virus than unvaccinated, would you then agree
5 that vaccinated individuals pose a more significant
6 transmission - I’m sorry, did you...
7 A. Sorry, that’s just my...
8 135 Q. There was an interruption.

9 A. That’s my, that’s my computer just telling me...
10 136 Q. That’s fine. I’m going to repeat my statement. If
11 this study in fact demonstrates that vaccinated people
12 carry significantly less viable virus than
13 unvaccinated people, would you agree that unvaccinated
14 individuals pose a more significant transmission risk
15 when infected?
16 A. I do not.
17 137 Q. Okay.
18 A. And I do not for several reasons. One is that this is
19 not a study of transmission, this is just a study of
20 culture. Culture does not equal transmission. Both
21 the CT value and viral culture are imperfect proxies.
22 And more importantly, the fact that they find less
23 viable virus in Omicron, which is clearly more
24 transmissible, puts into question the validity of this
25 as a measure of infectivity.
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1 138 Q. Counsel, I’d like to enter this study as Exhibit 1.
3 EXHIBIT 1: Infectious viral load in unvaccinated and
4 vaccinated individuals infected with ancestral, Delta,
5 or Omicron SARS-CoV-2, article published in Nature
6 Medicine, 2022, by Puhach et al.

9 MS. KERAMATI:
10 139 Q. Dr. Grant, could you please turn to paragraph 27 of
11 your report? Do you see that document?
12 A. Yes, I do.
13 140 Q. Okay. So at paragraph 27 you state,

14
15 “In contrast to other viral diseases for which
16 vaccine mandates exist, previous Covid-19
17 infection is not accepted as a form of immunity
18 in Canada. Despite the existing body of medical
19 literature supporting the premise that infection
20 induced immunity is robust.”
21 Do you see that statement in your report?
22 A. I do.
23 141 Q. Okay. In support of this statement, you’ve cited
24 footnote 48 and footnote 50, correct?
25 A. Hang on. No, 48 and 49 referred to Public Health
26 Agency of Canada standard vaccine recommendations and
27 number 50, if I’m not mistaken, is a review article
28 that was published in the (indiscernible) looking at
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1 natural immunity. So...
2 142 Q. Yes.
3 A. 50 is - 50 supports the statement, 48 and 49 are
4 background.
5 143 Q. Perfect. Footnote 48 is a link, as you said, to the
6 Public Health Agency of Canada...
7 A. Correct.
8 144 Q. Immunization Guide with respects to the measles

9 vaccine, correct?
10 A. Correct.
11 145 Q. And you are citing measles as an example of a viral
12 disease for which vaccine mandates exist and a
13 previous exception - I’m sorry, a previous infection
14 is accepted as a form of immunity.
15 A. Correct.
16 146 Q. Okay. And footnote 50, as you said, is a report, or
17 rather, an article by Kojima and others titled
18 Protective Immunity After Recovery from SARS-CoV-2
19 Infection, correct?
20 A. Yes.
21 147 Q. Okay. I’m going to pull up this article and it’s also
22 been provided to Dr. Grant. I’m going to share my
23 screen with you again.
24 A. Okay.
25 148 Q. Do you see my screen, Dr. Grant?
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1 A. Yeah.
2 149 Q. Okay. And you see that this is the article that
3 you’ve cited at footnote 50?
4 A. Correct.
5 150 Q. Okay. I’m going to read the first paragraph of this
6 article into the record. You’ll see it highlighted on
7 my screen. Is that large enough for you to see?
8 A. Yes.
9 151 Q. “
10
11 “The SARS-CoV-2 pandemic is now better controlled
12 in settings with access to fast and reliable
13 testing and highly effective vaccination
14 rollouts. Several studies have found that people
15 who recovered from Covid-19 and tested zero
16 positive for anti-SARS-CoV-2 antibodies have low
17 rates of SARS-CoV-2 reinfection. There are still
18 looming questions surrounding the strength and
19 duration of such protection compared with that
20 from vaccination”
21 Do you see that, Dr. Grant?
22 A. I do.
23 152 Q. Okay. I’m going to scroll down to the last full
24 paragraph on the same page, whoops, and read this
25 sentence.
26
27 “Although those studies show that protection from
28 reinfection is strong and persists for more than
29 ten months of follow-up, it is in unknown how
30 long protective immunity will truly last. Many
31 systemic viral infections such as measles confer
32 long term, if not, lifelong immunity whereas
33 others such as influenza do not due to changes in
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1 viral genetics.
3 A. Yes, I do.
4 153 Q. Okay. And I’m going to scroll down one more time.
5 I’m now on the last paragraph of this...
6 A. Mm-hmm.
7 154 Q. ...article. And I’m going to read starting from the
8 middle of the last paragraph on page two of the
9 article.
10
11 “Acquired immunity from vaccination is certainly
12 much safer and preferred. Given the evidence of
13 immunity from previous SARS-CoV-2 infection,
14 however, policy makers should consider recovery
15 from previous SARS-CoV-2 infection equal to
16 immunity from vaccination for purposes related to
17 entry to public events, businesses, and the
18 workplace, or travel requirements.
19
21 A. I do.
22 155 Q. Dr. Grant, do you agree that this is an emerging area
23 of understanding still under study?
24 A. Yes and no. We are still learning. We know a lot.
25 Depends on exactly what you mean by that question.
26 156 Q. There is uncertainty and there is still much to be
27 learned and understood.
28 A. Yes, that’s, that’s almost always true.
29 157 Q. Okay. And you would agree that studies are still
30 ongoing and being published on the subject of natural
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1 immunity for Covid-19?
2 A. Yes and, and continue to show more or less equivalence
3 with vaccination and in terms of protection for
4 subsequent infection and severe disease.
5 158 Q. Counsel, I’d like to enter this as Exhibit 2.
7 EXHIBIT 2: Protective Immunity After Recovery from
8 SARS-CoV-2 Infection article by Kojima.

9
11 MS. KERAMATI: Is this a good time to take a ten minute health
12 break before returning?
14 A. Sure.
15 MS. KERAMATI: I won’t be much longer after that.
16
17 OFF RECORD
18
19 MS. KERAMATI:
20 159 Q. Okay. Dr. Grant, just before we broke for the break,
21 you mentioned that emerging new evidence generally
22 shows that natural immunity or rather natural - let me
23 rephrase that, you said that infection induced
24 immunity is as robust as vaccine induced immunity.
25 A. To date, the balance, and the literature shows that
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1 those who have been infected compared to those who
2 have been vaccinated have at least similar outcomes
3 regarding subsequent infection and need for
4 hospitalization.
5 160 Q. Okay, that’s clear. Dr. Grant, there was a study
6 published yesterday in Nature Magazine. I wonder if
7 you’ve had a chance to review it. I’m going to share
8 my screen with you.

9 MR. PRESVELOS: Sorry, if there was a study published
10 yesterday, why didn’t you provide it ahead of the
11 cross examination?
12 MS. KERAMATI: As we’ve stated before, counsel, it’s a
13 courtesy that the AGC is providing documents before
14 the examination, and I’ve provided a number of
15 documents before the examination. I’m pulling this up
16 now, I’d be happy to provide it to you and the court
17 reporter so that it can be added as an exhibit.
18 MR. PRESVELOS: So I would certainly like a copy and I’d
19 like to see how long it is because then I think it’s
20 appropriate that Dr. Grant takes her time to read the
21 article before she asks - answers questions about it.
22 MS. KERAMATI: That’s absolutely fair.
23 MR. PRESVELOS: And I want to be clear about this idea of
24 courtesy. I mean...
25 MS. KERAMATI: Please.
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1 MR. PRESEVELOS: ...I understand why you say it’s a
2 courtesy, but let’s be clear, for the purposes of
3 having an officiant cross examination, I think it’s in
4 all the parties’ best interests to serve such
5 materials with sufficient time before the cross
6 examination. Because surely you wouldn’t want to get
7 a wrong or misleading answer that might be occasioned
8 by the fact that the witness has not had sufficient

9 time to review the material. I think it’s in
10 everyone’s mutual interest to ensure that the expert
11 being cross examined has time to fully read the
12 article. And what happens is, when we don’t send it
13 early enough, now we take a ten minute break, we waste
14 everybody’s time just to accomplish what could’ve been
15 accomplished by sending the same article 30 minutes
16 before the cross examination. So I get what the rules
17 require or do not require us to do, but I think as a
18 matter of procedural logistics and what might make
19 sense for everyone going forward, it would be nice to
20 make sure that we get such records ahead of time, at
21 least 30 minutes so we don’t have to do exactly what
22 we’re about to do here.
23 MS. KERAMATI: So, so far I would say, counsel, that the
24 cross examinations have been proceeding smoothly.
25 Certainly, anytime that a witness needs the
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1 opportunity to review a document as Dr. Grant said
2 with the previous document that I entered in as an
3 exhibit, we’ve provided her with the opportunity, or
4 them with the opportunity, to sufficiently review it
5 and answer the question based on their understanding
6 of the article.
7 MR. PRESVELOS: Okay, so let...
8 MS. KERAMATI: We’ve asked for a half a day cross

9 examination and I assure you that we won’t need more
10 than that required time for today’s cross examination.
11 So if Dr. Grant needs the time to review the document,
12 that’s perfectly fine. So, Dr. Grant, I apologize.
13 I’m going to pull up the article. Do you see my
14 screen, Dr. Grant?
15 A. I do.
16 161 Q. Okay. It’s an article from Nature titled Limited
17 cross-variant immunity from SARS-CoV-2 Omicron without
18 vaccination. Do you see that?
19 A. I do.
20 162 Q. Okay, have you reviewed this article?
21 A. No, not if it came out yesterday.
22 163 Q. You haven’t, okay. That’s fine. I’m going to read a
23 portion of the summary to you.
24 MR. PRESVELOS: Okay, sorry, I thought, sorry, I thought I
25 had just asked for a copy of the article and to -
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1 like, I would like to, before you start your cross -
2 your questioning on this article, I personally would
3 like a PDF copy of that so I can see the article in
4 its totality.
5 A. And I, I would like the reference as well, please.
6 MS. KERAMATI: Okay. So why don’t we take a 15 minute
7 break.

9 MS. KERAMATI: I will provide the article to your counsel,
10 Dr. Grant. He can forward it to you and when we come
11 back I can refer to the article.
12 A. Okay. I just, I just want to put on the record that
13 15 minutes is insufficient to read an article in
14 detail, understand methodology, et cetera. So I will
15 not be able to answer in 15 minutes in depth questions
16 about the article.
17 MS. KERAMATI: That’s fine. If after 15 minutes you require
18 more time to answer the question that I ask, then we
19 can certainly provide more time. Okay.
20 MR. PRESVELOS: Okay, thank you.
21
22 OFF RECCORD
23
24 MS. KERAMATI: Thank you. So we’re back on the record.
25 Counsel, I just wanted to mention one additional point
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1 that the article only became relevant to the cross
2 examination in light of Dr. Grant’s answers to the
3 questions that preceded the first break.
4 MR. PRESVELOS: What answer to what question did it become
5 relevant?
6 MS. KERAMATI: The question on the emerging evidence with
7 respect to the natural immunity. And this is an
8 article that was released yesterday on this very

9 topic, that was published yesterday on this very
10 topic.
11 MR. PRESVELOS: Okay...
12 MS. KERAMATI: And as you know, we’re in cross examination
13 and it’s completely appropriate in the context of
14 cross examinations to put documents to witnesses.
15 MR. PRESVELOS: That wasn’t the point I was making earlier.
16 Give me a sec. Sorry, go ahead.
17 MS. KERAMATI:
18 164 Q. Dr. Grant, during the break you had about 20 minutes
19 to review the article. Have you had a chance to
20 briefly review it?
21 A. I have, I have done a brief review.
22 165 Q. Okay. I’m going to pull up my - the article on my
23 screen as I have done with the other articles. Do you
24 see my screen, Dr. Grant?
25 A. I do.
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1 166 Q. Okay. And just scrolling up, this is the Nature
2 article titled Limited cross-variant immunity from
3 SARS-CoV-2 Omicron without vaccination, yes?
4 A. Yes, it is.
5 167 Q. Okay. I’m going to scroll down, under the heading
6 summary.
7 A. Yeah.
8 168 Q. And I’m going to read the summary into the record.
9
10 “SARS-CoV-2 Delta and Omicron are globally
11 relevant variants of concern (VOCs). While
12 individuals infected with Delta are at risk to
13 develop severe lung disease, infection with
14 Omicron often causes milder symptoms especially
15 in vaccinated individuals. The question arises
16 whether widespread Omicron infections could lead
17 to future cross variant protection, accelerating
18 the end of the pandemic. Here we show that
19 without vaccination, infection with Omicron
20 induces a limited humoral immune response in mice
21 and humans. Sera from mice over expressing the
22 human ACE2 receptor and infected with Omicron
23 neutralize only Omicron but no other VOCs whereas
24 other cross variants neutralization was observed
25 after WA1 and Delta infections. Unlike WA1 and
26 Delta, Omicron replicates to low levels in the
27 lungs and brains of infected animals leading to
28 mild disease with reduced pro-inflammatory
29 cytokine...”
30 A. Cytokine.
31 169 Q. Cytokine, thank you, Dr. Grant.
32
33 “... expression and diminished activation of lung
34 resistant T cells. Sera from unvaccinated
35 Omicron infected individuals show the same
36 limited neutralization of only Omicron itself.
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1 In contrast, Omicron breakthrough infection

2 induced overall higher neutralization titers
3 against all VOCs. Our results demonstrate that
4 Omicron infection enhances pre-existing immunity
5 elicited by vaccine, but on its own may not
6 confer broad protection against non-Omicron
7 variants in unvaccinated individuals”.
9 A. I do.
10 170 Q. Okay. So based on this summary, would you agree that
11 some of the emerging evidence suggests that infection
12 induced immunity is not of the same caliber as vaccine
13 induced immunity?
14 A. I do not.
15 171 Q. Okay. I’m going to stop sharing my screen with you
16 now. Okay. I’d like to enter this as an exhibit,
17 counsel.
18
19 EXHIBIT 3: Limited cross-variant immunity from SARS-
20 CoV-2 Omicron without vaccination, Nature article.
21
23 MS. KERAMATI: Thank you.
24 COURT REPORTER: It’s Exhibit 3.
25 MS. KERAMATI:
26 172 Q. Okay. I’m going to return to paragraph 27 of your
27 report, Dr. Grant. So midway through paragraph 27...
28 A. Yes.
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1 173 Q. The sentence reads, “Many jurisdictions including the
2 European Union, Israel, and the WHO accept immunity
3 through infection as a valid form of protection
4 against reinfection.” Do you see that?
5 A. I do.
6 174 Q. Okay. And in support of this statement, you cite a
7 number of footnotes including footnote 54.
8 A. Yes.
9 175 Q. Is that right? Okay. And footnote 54 is a WHO
10 document titled Covid-19 Natural Immunity, correct?
11 A. It is, yes.
12 176 Q. Okay. I’m going to pull up the document.
13 MR. PRESVELOS: Is that the same document you emailed
14 earlier?
15 MS. KERAMATI: It is. I do want to note that this is a
16 living document from the WHO. The date on this is the
17 10th of May - oh sorry, I apologize, I saw 2021 instead
18 of - 2022 instead of 2021.
19 A. Okay.
20 MS. KERAMATI:
21 177 Q. Are you able to see my screen, Dr. Grant?
22 A. Yes.
23 178 Q. And this is the WHO document titled Covid-19 Natural
24 Immunity that you’ve cited at footnote 54?
25 A. Correct.
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1 179 Q. And this is the version that you’ve referenced in your
2 affida - in your report.
3 A. I cannot answer that. As I’ve said, the WHO does
4 change its documents. I would have to look at any
5 evidence of it having been updated or changed. But...
6 180 Q. So the document is dated...
7 A. It see, it seems, it seems not since it was from the
8 10th of May, 2021, but I cannot guarantee...

9 181 Q. Yes.
10 A. ...that WHO didn’t change it in the interim. I’m not
11 monitoring it at all times.
12 182 Q. Okay. But you accessed it on December 30, 2021.
13 A. Correct.
14 183 Q. So it would be fair to presume that the documents
15 which predates the date that you accessed it and
16 continues to bear that date has not changed.
17 A. A, as, as far as I know. But again, since it’s on the
18 Internet, you never know if something’s changed.
19 184 Q. So I’m going to scroll down to where it says
20 conclusions.
21 A. Okay.
22 185 Q. Do you see that? And I’ve highlighted it.
23 A. I do.
24 186 Q. Okay. I’m going to read the conclusions.

25
26 “Current evidence points to most individuals
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1 developing strong protective immune response

2 following natural infection from SARS-CoV-2.
3 However, inaccurate immunodiagnostic test may
4 falsely indicate infected individuals as naïve to
5 the virus, parentheses, not previously infected,
6 close parentheses, or may falsely label
7 noninfected people as positive for immune markers
8 of recent infection. To conclude, available
9 tests and current knowledge do not tell us about
10 the duration of immunity and protection against
11 reinfection, but recent evidence suggests that
12 natural infection may provide similar protection
13 against symptomatic disease as vaccination, at
14 least for the available follow up period. The
15 emergence of variants of concerns poses
16 challenges as their potential to evade immunity
17 elicited by either natural infection or by
18 vaccination needs to be closely monitored.”
19 Do you see that statement?
20 A. I do.
21 187 Q. Do you recall seeing that statement or something
22 similar to it at the time of reviewing the document?
23 A. Most likely. I don’t remember the precise moment I
24 read it or what I was thinking, but it seems like I
25 would’ve read it and agreed with it, yes.
26 188 Q. Okay, thank you.
27 A. I’m going to enter this as an exhibit, counsel.
28
29 EXHIBIT NO.4: WHO document titled Covid-19 Natural
30 Immunity, footnote 54 of Dr. Grant’s report.
31
33 MS. KERAMATI:
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1 189 Q. And, Dr. Grant, do you agree that recent studies have
2 found that previous infection has not protected
3 against Omicron infections?
4 A. Yes. And that is true of all, not only previous
5 infections, but also vaccination. So Omicron is
6 fundamentally different. It is engaging an immune
7 evasion as we expect and see with all coronaviruses,
8 that this is the pattern that you have a good immunity

9 to what is present and then that virus changes and so
10 you see new infections is what we saw with the Omicron
11 variant. Both vaccine and previous infection is -
12 it’s called escape immunity and it is expected in
13 coronaviruses.
14 190 Q. Okay. Dr. Grant, can you please turn to paragraph 32
15 of your report under the heading transportation is not
16 a major source of SARS-CoV-2 transmission in
17 travellers regardless of vaccination status? Do you
18 see that, Dr. Grant?
19 A. Yes.
20 191 Q. Okay. At paragraph 32 you state,

21
22 “The most effective means of ensuring that people
23 are not infectious on flights, vaccinated or not,
24 is to use testing to rule out the possibility of
25 an undetected infection. PCR testing assays are
26 commercially available for travellers and have
27 sensitivity of more than 99%, is close to 100% in
28 detecting infection.”
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2 A. Yes.
3 192 Q. Okay. Dr. Grant, in preparing for today’s
4 examination, I believe you said that you have not
5 reviewed the affidavit of Elizabeth Harris.
6 A. I don’t think I have. I don’t recall if I have.
7 Sorry, if I can correct that, I don’t recall if I
8 have.
9 193 Q. You don’t recall.
10 A. I, I don’t recall.
11 194 Q. I’m going to pull up the affidavit on here and share
12 my screen with you. Do you see my screen, Dr. Grant?
13 A. I do.
14 195 Q. Okay. So, oops, this is the affidavit of Elizabeth
15 Harris.
16 A. Okay.
17 196 Q. I’ll scroll down. Let me know if this jogs your
18 memory. Elizabeth Harris is the scientific director
19 of the testing directorates in the Infectious Disease
20 Prevention and Control branch of the Public Health
21 Agency of Canada, PHAC, which establishes pilot
22 programs and testing initiatives. And this is out of
23 paragraph one of her affidavit. Okay. I’ll read you
24 a portion of her - I’ll take you to the relevant
25 portions of her affidavit that you need to respond to
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1 my questions. At paragraph five, is that big enough
2 for you to see, Dr. Grant?
3 A. Yeah, it’s fine.
4 197 Q. Okay. At paragraph five, she states,
5
6 “The directorate is a unit within PHAC which
7 establishes pilot programs and testing
8 initiatives. Along with the National
9 Microbiology Laboratory, also within PHAC, it
10 provides epidemiological recommendations on best
11 testing protocols. Among its roles during the
12 Covid-19 pandemic, the directorate has been
13 tracking the rates at which individuals entering
14 Canada from abroad were found to be infected with
15 Covid-19.”
16 Do you see that?
17 A. Yeah.
18 198 Q. Okay. At paragraph seven, she states,

19
20 “Beginning on January 7, 2021, all travellers
21 entering Canada by air were required to provide
22 proof of a negative pre-departure Covid-19
23 molecular test, example PCR test, prior to
24 boarding a flight to Canada. As of February 15,
25 2021, that same requirement applied to travellers
26 entering Canada by land. On February 28, 2022,
27 the requirement for pre-departure testing was
28 expanded to include pre-departure antigen test
29 within 24 hours of the traveller’s scheduled
30 arrival into Canada as an alternative to
31 molecular testing.
32 Do you see that?
33 A. Yes.
34 199 Q. Okay. At paragraph nine, Ms. Harris defines the term
35 day one test as a test taken on arri - as the PCR test
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1 taken on arrival.
2 A. Yeah.
3 200 Q. Okay. And at paragraph eleven, she states, “Where I
4 refer to the positivity rate, I refer to the
5 percentage of tests indicating a positive result of
6 Covid-19 out of all tests administered for a
7 particular data set of travellers.”
8 A. Okay.
9 201 Q. Do you see that?
10 A. Yeah.
11 202 Q. Okay. So now I’m going to take you to paragraph 35.
12 So do you see paragraph 35 on my screen?
13 A. Mm-hmm.
14 203 Q. Yes?
15 A. I do.
16 204 Q. Okay. So paragraph 35 states,
17
18 “From July 5, 2021 to November 27, 2021, the day
19 one positivity rate among unvaccinated slash
20 partially vaccinated travellers was generally
21 four to five times that among fully vaccinated
22 travellers. Since the emergence of the Omicron
23 variant in November 2021, the positivity rate
24 among unvaccinated slash partially vaccinated
25 travellers was generally two times that among
26 fully vaccinated travellers. This later ratio
27 remains stable sin - has remained stable since
28 December 2021.”
29
30 Do you see that?
31 A. Mm-hmm.
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1 205 Q. So knowing this information now, would you then agree
2 that vaccination provides an additional layer of
3 protection?
4 A. From what?
5 206 Q. From Covid-19 infection.
6 A. So the unfortunate thing about these numbers is that
7 they’re taken entirely out of context. What I don’t
8 know is the absolute versus relative rate reduction

9 and I also don’t know the number of travellers because
10 one presumes that after the travel ban was put in
11 place that there are very, very few unvaccinated
12 travellers and they may be travelling under duress.
13 So without having context for those numbers, it’s very
14 hard to know what they mean.
15 207 Q. Okay. Would you agree that vaccination provides an
16 additional layer of protection when compared to
17 testing alone?
18 MR. PRESVELOS: Sorry, testing...
19 A. I, I...
20 MR. PRESVELOS: ...provide - sorry, when you say testing are
21 you implying that testing provides protection against
22 transmission? I don’t understand, I don’t understand
23 the question.
24 MS. KERAMATI: Okay. I’ll rephrase. That’s fair, I’ll
25 rephrase the question. Would you agree that
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1 vaccination provides an additional layer of reduction
2 of importation of cases into Canada when compared to
3 testing alone?
4 A. I cannot conclude that from these numbers. It doesn’t
5 mean it’s true or not true. Unfortunately, without
6 context these numbers are not helpful.
7 208 Q. Okay. Counsel, if we can take a brief five minute
8 break. I think I might be finished, I’m just going to

9 review my notes.
11
12 OFF RECORD
13
14 MS. KERAMATI:
15 209 Q. Thank you very much, Dr. Grant. Those are all my
16 questions. We appreciate you being here today.
17 A. You’re welcome.
18 MR. PRESVELOS: I’ll take a - I’m going to take a bit of a
19 break just to go through my notes and see if there’s
20 something I need to re-examine Dr. Grant on. I -- if
21 I do, it’ll be very brief, but if we could take
22 another break, I need to go through my notes and I’ll
23 come back and let you know whether or not I’ll be
24 doing that.
25 OFF RECORD
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2 RE-EXAMINATON BY MR. SAM PRESVELOS:
3 1 Q. Thank you. Dr. Grant, I just have a few questions to
4 ask you based on the questions my friend asked you on
5 the Limited-cross variant immunity from SARS-CoV-2
6 Omicron without vaccination. So that was the article
7 that you hadn’t read, you took about 20 minutes to
8 read that today during your cross examination.

9 A. Yes.
10 2 Q. Do you have a copy of that article before you?
11 A. I do.
12 3 Q. Okay. I’d ask you just to pull it up for your
13 reference. Would you agree with me that the study in
14 this article looks at neutralizing antibodies?
15 A. In part. Specifically, specifically the human part of
16 the study is on neutralizing antibodies.
17 4 Q. Okay. So as it pertains to the human part of the
18 study, they neutralized antibodies, correct?
19 A. Correct.
20 5 Q. And would you agree with me that neutralizing
21 antibodies is not actually the same thing as being
22 exposed to the SARS-CoV-2 virus?
23 A. Correct.
24 6 Q. And could you explain to me what does neutralizing an
25 antibody actually measure? So what part of the immune
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1 response would that measure?
2 A. So that’s, as they quite clearly state in the paper,
3 measures humoral anti - humoral immune response, not
4 cell mediated.
5 7 Q. And can you explain the difference between those two
6 responses?
7 A. So humoral anti response is one where you have
8 antibodies or other circulating proteins in the blood.

9 It’s what attaches to the virus to mark it for immune
10 destruction, however, it does not engage an immune
11 destruction. Immune destruction is done by cell
12 mediated immunity. As a general rule, cell mediated
13 immunity is much more relevant and important in viral
14 (indiscernible).
15 8 Q. And Dr. Grant, if somebody does not have antibodies,
16 does that mean they are therefore not protected
17 against other strains or variants of concerns?
18 A. Not necessarily.
19 9 Q. And I think you mentioned in your previous answer that
20 this study does not show cellular immunity, correct?
21 A. Not in humans, no.
22 10 Q. Not in humans. And I think your previous answer
23 explained why it’s relevant or why it would be
24 relevant to show cellular immunity in humans, did I
25 understand your answer correctly?
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2 11 Q. Okay, Dr. Grant. I have no further questions for you.
3 Thank you very much for your time.
6 CROSS EXAMINATION ENDS
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Court Transcriber
ACT ID: 2887221650
May 20th, 2022
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nature medicine https://doi.org/10.1038/s41591-022-01816-0
Accelerated Article Preview
Infectious viral load in u.nvaccinated and

vaccinated individuals infected with
ancestral, Delta or Omicron SARS-CoV-2
Received: 24January 2022 Olha Puhach, Kenneth Adea, Nicolas Hulo, Pascale Sattoru-, Camille Genecand.Anne lten,
Accepted:6April2022 Frederique Jacquerioz Bausch, Laurent Kaiser, Pauline Vetter, Isabella Eckerle&
Benjamin Meyer
Published online: 08 April 2022
Cite this article as: Puhach, 0 .. etal. This is a PDF file ofa peer-reviewed paper that has been accepted for publication.
Infectious viral load in urwaccinated and Although unedited, the content has been subjectedto preliminary formatting.
vaccinated individuals infected with Nature Medicine is providingthis earlyversion ofthe typeset paperasa service to our
ancestral. Delta or Omicron SARS-CoV-2. authors and readers. The text and figures will undergocopyediting and a proof review
Nature Medicine https:f/doi.org/10.1038/
beforethe paper is published in its final form. Please notethat during the production
s41591-022-01816-0 (2021).
process errors may be discovered which could a1fectthe content, and all legal
disclaimers apply.
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NATURE MEDICINE I www.nature.com/naturemedicine

AR07625
1 Infectious viral load in unvaccinated and vaccinated individuals infected with

2 ancestral, Delta or Omicron SARS-CoV-2
3 Olha Puhach1, Kenneth Adea1, Nicolas Hulo2, Pascale Sattonnet1, Camille Genecand3, Anne Iten4,
4 Frédérique Jacquérioz Bausch5,6,7, Laurent Kaiser5,8,9, Pauline Vetter5,8,9,*,#, Isabella Eckerle1,5,9,*,#,
5 Benjamin Meyer10,*,#
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6 Affiliations:
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1
7 Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva,
8 Geneva, Switzerland
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2
9 Service for Biomathematical and Biostatistical Analyses, Institute of Genetics and Genomics,
10 University of Geneva, Geneva, Switzerland
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3
11 Cantonal Health Service, General Directorate for Health, Geneva, Switzerland
4
12 Service of Prevention and Infection Control, Directorate of Medicine and Quality, University
13 Hospital Geneva, HUG, Geneva, Switzerland
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5
14 Geneva Centre for Emerging Viral Diseases, Geneva University Hospitals, Geneva, Switzerland
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15 Division of Tropical and Humanitarian Medicine, Geneva University Hospitals, Geneva, Switzerland
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16 Primary Care Division, Geneva University Hospitals, Geneva, Switzerland
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17 Laboratory of Virology, Division of Laboratory Medicine, Geneva University Hospitals & Faculty of
18 Medicine, University of Geneva, Geneva, Switzerland
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9
19 Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland
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20 Centre for Vaccinology, Department of Pathology and Immunology, University of Geneva, Geneva,
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21 Switzerland
22
#
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23 Corresponding authors
24 Benjamin Meyer: Benjamin.Meyer@unige.ch

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25 Isabella Eckerle: Isabella.Eckerle@hcuge.ch
26 Pauline Vetter: Pauline.Vetter@hcuge.ch

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27 * Equally contributed
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28 Abstract
29 Infectious viral load (VL) expelled as droplets and aerosols by infected individuals partly determines
30 SARS-CoV-2 transmission. RNA VL measured by qRT-PCR is only a weak proxy for infectiousness.
31 Studies on the kinetics of infectious VL are important to understand the mechanisms behind the
32 different transmissibility of SARS-CoV-2 variants and the effect of vaccination on transmission, which
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33 allows to guide public health measures.
34 In this study we quantified infectious VL in SARS-CoV-2 infected individuals during the first 5
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35 symptomatic days by in vitro culturability assay in unvaccinated or vaccinated individuals infected
36 with pre-variant of concern (pre-VOC) SARS-CoV-2, Delta, or Omicron. Unvaccinated individuals
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37 infected with pre-VOC SARS-CoV-2 had lower infectious VL compared to Delta-infected unvaccinated
38 individuals. Full vaccination (defined as >2weeks after reception of 2nd dose during primary
39 vaccination series) significantly reduced infectious VL for Delta breakthrough cases compared to
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40 unvaccinated individuals. For Omicron breakthrough cases, reduced infectious VL was only observed
41 in boosted but not in fully vaccinated individuals compared to unvaccinated subjects. In addition,
42 infectious VL was lower in fully vaccinated Omicron- compared to fully vaccinated Delta-infected
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43 individuals, suggesting that other mechanisms than increased infectious VL contribute to the high
44 infectiousness of SARS-CoV-2 Omicron. Our findings indicate that vaccines may lower transmission
45 risk and therefore have a public health benefit beyond the individual protection from severe disease.
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46
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47 Introduction
48 As of 6 March 2022, the coronavirus disease 2019 (COVID-19) pandemic has caused more than 443
49 million cases and just over 5.9 million deaths globally 1. Severe acute respiratory coronavirus 2
50 (SARS-CoV-2), the causative agent of COVID-19, primarily infects the cells of the upper respiratory
51 tract (URT) where viral load (VL) increases during the course of infection 2.
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52 The two key measurements of VL are RNA levels, often expressed in cycle threshold (Ct) values, and
53 infectious virus that is assessed by virus isolation in cell culture. Although the transmission process is
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54 complex, higher VL can serve as a proxy for greater risk of transmission. In several epidemiological
55 studies, higher VL measured by viral RNA was associated with increased secondary transmission in
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56 household settings 3, 4. Infectious SARS-CoV-2 is shed in the URT, starting on average from two days
57 before symptom onset. In most studies, infectious virus was not detected in respiratory samples
58 collected from non-hospitalized immunocompetent individuals later than 8 days post onset of
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59 symptoms (DPOS) 5-7. Moreover, viral RNA detection did not correlate with infectiousness in an
60 animal model 8. Instead, isolation success in cell culture, i.e. the ability to replicate the virus in cell
61 culture, was found to correlate with the ability to shed and transmit fully competent viral particles 9.
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62 Virus isolation success from respiratory tract samples can only give information about the presence
63 or absence of infectious virus, but is not able to quantify the infectious viral titre in samples of the
64 URT 10. C
65 Since the start of the pandemic, SARS-CoV-2 has constantly evolved, leading to the emergence of
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66 new variants. While most variants vanished quickly, others such as D614G, and the variants of
67 concern (VOCs) Alpha, Beta, Gamma, Delta and Omicron harbour an apparent selection advantage
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68 and outcompeted other variants locally or even globally. These VOCs exhibit various mutations 11
69 that lead to immune evasion and/or higher transmissibility, to which increased viral shedding
70 (among other factors, like environmental stability) may significantly contribute 12, 13. For Alpha, an
71 approximately 10-fold higher RNA VL was described compared to pre-VOC viral strains, which was
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72 correlated with increased isolation success 14, 15. Similarly, Delta also showed 10- to 15-fold higher
73 RNA levels compared to pre-VOC strains in some studies 15, 16. In contrast, a study using longitudinal
74 samples did not find a difference between peak RNA VL of pre-VOC, Alpha and Delta 17. However,
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75 little is known about the quantity of shed infectious viral particles for VOCs including Omicron.
76 There is extensive evidence that vaccines against SARS-CoV-2, which target the original strain,
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77 reduce infection case numbers and disease severity. However, the effect of vaccination on infectious
78 viral shedding and transmission from vaccinated individuals remains controversial. All currently
79 approved vaccines are administered intramuscularly, thus the titre of neutralizing antibodies on the
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80 mucosal surfaces lining the URT might be limited, and any sterilizing mucosal immunity might be
81 transient 18. Epidemiological studies of the secondary attack rate in households of vaccinated vs
82 unvaccinated index cases report contradictory results on the potential effect of vaccination 19, 20, 21.
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83 Multiple factors can influence the secondary attack rate in these studies, including: patient
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84 behaviour, age, comorbidities, the infecting variant, time since vaccination and the vaccine used.
85 Therefore, differentiating the effect of vaccination on VL from other factors in purely
86 epidemiological studies is difficult. To our knowledge, no study has directly quantified infectious VL
87 of different VOCs in URT samples of vaccinated and unvaccinated COVID-19 patients.
88 The dynamics of infectious viral shedding in vaccinated and unvaccinated individuals infected with
89 relevant VOCs require detailed investigation. Understanding of viral shedding in patients would help
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90 shape public health decisions to limit community transmission 22. Here we compare RNA and
91 infectious VL between pre-VOC strains, Delta and Omicron in unvaccinated individuals as well as in
92 fully vaccinated (2 doses) or boosted (3 doses) subjects infected with Delta and Omicron using
93 respiratory samples from mildly symptomatic patients of different age and sex, sampled in the first 5
94 DPOS.
95
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96 Results
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97 In this study, we analysed the VL characteristics in the URT of unvaccinated pre-VOC-infected as well
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98 as fully vaccinated, boosted and unvaccinated Delta- or Omicron-infected individuals up to 5 DPOS.
99 We included a total of 565 samples in our cohort of which 118 originated from individuals infected
100 with pre-VOC SARS-CoV-2, 293 from subjects infected with Delta and 154 from individuals infected
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101 with Omicron. Of Delta infected subjects, 166 were fully vaccinated prior to infection and 127 were
102 unvaccinated. Among Omicron infected individuals, 91 were fully vaccinated prior to infection, 30
103 were boosted and 33 were unvaccinated. None of the individuals infected with pre-VOC SARS-CoV-2
104 were vaccinated as vaccines were unavailable at the time of infection. All infected individuals had
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105 mild symptoms at the time of sampling, but the further course of the disease is unknown. Individuals
106 with asymptomatic infection at the time of sampling were excluded from the study. All infected
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108
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individuals except 5 (2 with Delta vaccine-breakthrough and 3 with Omicron breakthrough
infections) were immunocompetent. Samples of pre-VOC infected individuals were collected
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109 between April 7th and September 9th 2020, before detected circulation of any VOCs, samples of
110 Delta-infected subjects were collected from June 26th until December 13th 2021, and samples of
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111 Omicron-infected individuals from December 11th 2021 until February 19th 2022. Each infected
112 individual provided only one sample at a single time point. All vaccinated individuals included in this
113 study were diagnosed positive at least 14 days after dose 2 or dose 3, which complies with the
vaccination breakthrough definition of the Centers for Disease Control and Prevention 23. 274/287
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115 patients were vaccinated with mRNA vaccines (Comirnaty or Spikevax), one was vaccinated with a
116 non-replicating viral vector vaccine (CoviVac), one with inactivated virus vaccine CoronaVac, one
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117 with viral vector vaccine AZD1222 and for ten patients the type of vaccine was not reported by the
118 patient. The median time in days between 2nd dose and breakthrough infection was 69 (IQR 38-122),
119 160 (IQR 137-183), and 154 (IQR 86-198) for Delta infections titrated on Vero E6 or Vero E6-TMPRSS
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120 and Omicron infections, respectively. All groups of patients (pre-VOC, Delta-unvaccinated, Delta-
121 vaccinated (2 doses), Omicron-unvaccinated, Omicron vaccinated (2 or 3 doses)) had a similar age
122 and sex distribution (see Table).
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123 We quantified genome copies and infectious viral titres in SARS-CoV-2-positive nasopharyngeal
124 swabs (NPS) using qRT-PCR and focus forming assays (FFA). Only specimens with CT-values below 27
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125 for the E-gene qRT-PCR diagnostic target (Cobas, Roche), as determined by the clinical laboratory at
126 the University Hospital of Geneva (HUG) at the time of diagnosis, were included in our study, as it
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127 was shown previously that infectious virus cannot be reliably isolated from samples with higher CT-
128 values 9, 24. In our hands, no infectious virus was detected in 46 pre-VOC and Delta samples with CT-
129 values ≥27. We also compared overall percentages of samples with a Ct ≥27 for time periods with
130 almost exclusive circulation of pre-VOC, Delta and Omicron by analysing the overall diagnostic data
131 set from our outpatient testing centre and separating patients by vaccination status and DPOS.
132 Among pre-VOC samples, 19.4% had a Ct ≥27, while in the Delta-infected unvaccinated and
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133 vaccinated as well as in the Omicron-infected unvaccinated and vaccinated groups 21.4%, 17.6%,
134 21.4% and 20.7% of samples fell into this category, respectively. No major difference was observed
135 between the proportion of Ct-value ≥27 when divided by DPOS (see Supplementary Table).
136 To validate our FFA, we compared it to the ability to successfully isolate virus in cell culture. Virus
137 isolation success has been used as a correlate of infectious viral shedding for SARS-CoV-2 6, 25-27, but
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138 lacks the ability to differentiate between high and low VL samples. We were able to quantify viral
139 titres using the FFA in 91.9%, 91.7%, 83.8%, 95 % and 85.7% of culture positive samples in the pre-
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140 VOC, Delta-unvaccinated, Delta- fully vaccinated (2 doses), Omicron-unvaccinated and Omicron- fully
141 vaccinated (2 doses) groups, respectively, indicating a high sensitivity (Extended Data Fig. 1A).
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142 Overall, the Cohens kappa agreement, which measures the level of agreement between two
143 methods, was 0.69, 0.41, 0.51, 0.66 and 0.47 for the 5 groups, showing a moderate to substantial
144 agreement (Extended Data Fig. 1B).
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145 Low correlation between genome copies and infectious VL
146 First, we investigated whether RNA genome copies are a good proxy for infectious virus shedding.
147 We observed only a very low correlation (R2 = 0.1476, p=0.0001) between viral genome copies and
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148 infectious virus particles for pre-VOC samples (Figure 1A). Likewise, low to moderate correlations
149 between RNA genome copies and infectious viral titres were observed for the samples from
150
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unvaccinated and vaccinated Delta patients (R2 =0.3114, p <0.0001 and R2 =0.4021, p <0.0001,
151 respectively) (Figure 1B, C), as well as unvaccinated and vaccinated Omicron patients (R2 =0.3638,
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152 p=0.0002 and R2 =0.3055, p <0.0001, respectively) (Figure 1D,E).
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153 Next, we tested if infectious VLs are associated with patient age and sex. We did not observe any
154 correlation between the age and infectious VL for all four groups (Extended Data Fig. 2). Similarly,
155 no significant differences of infectious VLs between male and female patients were detected for pre-
156 VOC, Delta (fully vaccinated or unvaccinated) or Omicron (fully vaccinated) samples (Extended Data
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157 Fig. 3).
158 Delta-infected unvaccinated subjects have higher infectious VL

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159 Next, we compared genome copies and infectious VLs in pre-VOC and Delta samples from
160 unvaccinated patients during the first 5 DPOS. Overall, pre-VOC samples had significantly more
161 genome copies (2.98 fold, 0.4744 log10, p=0.001) compared to Delta samples, but infectious viral
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162 titres were significantly higher in Delta-infected individuals (2.2 fold, 0.343 log10, p=0.0373) (Figure
163 2A). We found that genome copies for pre-VOC samples were higher at one and two DPOS, but
164 similar to Delta samples at 0, 3, 4, 5 DPOS (Figure 2B). Conversely, infectious virus shedding was
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165 higher for Delta at 3-5 DPOS, but similar at 0-2 DPOS (Figure 2C). In addition, we observed that
166 genome copies remained largely stable until 5 DPOS, with only a minimal lower number at day 5,
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167 while infectious VL was significantly lower for pre-VOC (linear model, between day 0 vs and day 5,
168 slope significantly < 0, p= 0.00036), but not for Delta (linear model, between day 3 vs and day 5,
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169 slope not significantly < 0, p= 0.07741) (Figure 2B and C).
170 The association of the infectious shedding levels with patient age and sex is highly debated 14. In this
171 study we did not detect a correlation between patient age or sex and infectious VL. However, there
172 is increasing evidences of more severe outcomes of COVID-19 disease in older male patients 25, 27.
173 Thus, to eliminate possible confounders, 84 Delta-infected patients were matched with pre-VOC
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174 infected patients in regard to sex, age and DPOS (Extended Data Fig. 4A). Similarly, significantly
175 higher infectious VLs (3.23 fold, 0.51 log10, p=0.00117) were detected in Delta samples compared to
176 matched pre-VOC samples (Extended Data Fig. 4B).
177 Fully vaccinated subjects have lower infectious VL in Delta infected individuals
178 To determine vaccination’s association with virus shedding, we compared genome copies and
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179 infectious VLs in unvaccinated (n=127) and vaccinated (n=104) patients infected with Delta for 5
180 DPOS. Overall, RNA genome copies were significantly lower in vaccinated vs. unvaccinated patients
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181 (2.8 fold, 0.44 log10, p=0.0002). The decrease in infectious VL was even more pronounced in
182 vaccinated patients (4.78 fold, 0.68 log10, p<0.0001) (Figure 3A). The kinetics of RNA genome copies
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183 were largely similar between vaccinated and unvaccinated patients until 3 DPOS with a faster
184 decline for vaccinated patients starting at 4 DPOS (Figure 3B). In contrast, infectious VL were
185 substantially lower in vaccinated patients at all DPOS with the biggest effect at 3-5 DPOS (Figure 3C).
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186 Still, at 5 DPOS infectious virus was detectable in 7/13 (53.8%) vaccinated and 11/13 (84.6%)
187 unvaccinated patients. Additionally, 79 Delta-infected unvaccinated individuals were matched with
188 Delta vaccine-breakthrough patients in regard to age, sex and DPOS (Extended Data Fig. 4A).
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189 Infectious VLs were elevated in unvaccinated patients in comparison to vaccine-breakthroughs (8.12
190 fold, 0.91 log10, p<0.0001) (Extended Data Fig. 4C) confirming a significant reduction of infectious
191 VLs among vaccinated patients. We further analysed whether infectious VLs correlate with the time
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192 interval since the administration of the last vaccine dose. A high heterogeneity between patient
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193 samples resulted in no significant correlation between the time post vaccination and infectious viral
194 shedding (Extended Data Fig. 5A).
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195 Booster vaccination leads to lower infectious VL in Omicron infected individuals
196 Upon the emergence of Omicron, we analysed the infectious viral shedding in unvaccinated, fully
197 vaccinated and boosted individuals infected with this variant. We compared RNA and infectious VLs
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198 in NPS samples of 91 Omicron- and 62 Delta-infected patients, who received 2 doses of vaccine >2
199 weeks prior to diagnosis. Since Omicron can only be titrated on Vero E6-TMPRSS cells, we also
200 titrated another set of samples from vaccinated Delta infected patients on this cell line to assure
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201 comparability between infectious VLs. Omicron breakthrough infections in fully vaccinated patients
202 resulted in similar genome copies compared to Delta, but significantly lower infectious VLs (14 fold,
203 1.146 log10, p<0.0001) (Figure 4A). A significant reduction of infectious VLs was also observed for
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204 Omicron samples when matching patients for age, sex and DPOS (16.4 fold, 1.214 log10, p =0.0003
205 (Extended Data Fig. 4D). Similar to Delta-infected fully vaccinated individuals, the RNA VLs only
206 slightly decreased over 5 DPOS, while infectious VLs declined towards 5 DPOS (Figure 4B, C). Next,
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207 we evaluated whether the vaccination status, i.e. unvaccinated, fully vaccinated or boosted, has an
208 influence on RNA or infectious VLs for Omicron infected individuals. We found no reduction of RNA
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209 or infectious VL in fully vaccinated compared to unvaccinated subjects. However, a significantly

210 lower infectious VL, but not RNA VL, was observed for boosted individuals (5.3 fold, 0.7280 log10, p=
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211 0.0004) (Figure 4D). Similar to Delta-infected, fully vaccinated patients, no significant correlation was
212 found between days post vaccination and infectious VL in fully vaccinated Omicron-infected patients
213 (Extended Data Fig. 5B).
214
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215 Discussion
216 In this study we analysed virus shedding in COVID-19 patients infected with pre-VOC, Delta and
217 Omicron variants and evaluated the impact of vaccination on VL in the URT during the first 5 DPOS.
218 To our knowledge, this is the first study to quantify infectious VLs in individuals infected with
219 different SARS-CoV-2 variants and in vaccination-breakthrough cases. We demonstrate a higher
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220 infectious VL in unvaccinated Delta-infected compared to pre-VOC-infected individuals and showed
221 a significant reduction of infectious VLs in fully vaccinated Delta-infected individuals. However, only
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222 booster vaccination significantly reduced infectious VL in Omicron-infected individuals. Furthermore,
223 we found a lower infectious VL in Omicron compared to Delta breakthrough cases.
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224 The magnitude and timing of infectiousness of COVID-19 patients is critical information necessary to
225 make informed public health decisions on the duration of isolation of patients and on the need to
226 quarantine contacts. Infectiousness is strongly influenced by VL in the URT of infected patients 4.
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227 However, VL is often measured as RNA copy numbers and not actual infectious virus. In this study
228 we could show that RNA copy numbers in NPS samples poorly correlated with infectious virus
229 shedding. This is in line with several other studies that found that RNA is a poor infectiousness
230 indicator especially in the presence of infection-induced neutralizing antibodies 9, 26. Nevertheless, in
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231 our study correlation between RNA and infectious VL was equally low between fully vaccinated and
232 unvaccinated Delta infected patients indicating that other factors than mucosal neutralizing
233
234
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antibodies may be important for the reduction in infectious VL. In addition, in an animal model it
was demonstrated that infectious virus, but not RNA, is a good proxy for transmission 8.
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235 Virus isolation in cell culture is widely used as a proxy for infectiousness 6, 9, 28. Several studies have
236 shown that isolation success significantly drops when RNA VLs are below 6 log10 copies per mL in
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237 NPS, or samples were collected after 8 DPOS 6. Of note, with only a qualitative result isolation
238 success cannot distinguish between high and low infectious VLs in a patient sample, a key
239 determinant of the potential size of the transmitted inoculum. Differences in infectious VL can
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240 impact transmission probability, therefore, we used a FFA that can reliably quantify infectious viral
241 particles from NPS. FFAs have long been a standard to quantify viral shedding in animal infection
242 models for respiratory viruses such as influenza and have recently been used to quantify infectious
243 viral load in a SARS-CoV-2 human challenge trial, showing that they are considered as one of the best
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244 available proxies for infectiousness 29-31. However, while we can assume that higher infectious VL
245 leads to higher transmission risk, we currently do not know how many focus-forming units per mL
246 are required for a patient to actually transmit the virus.
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247 Within 5 DPOS, we found higher RNA VLs but lower infectious VLs in swabs of unvaccinated patients
248 with pre-VOC infections compared to Delta. These results disagree with other studies that analysed
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249 only nucleic acid detection and found 3-10-fold higher RNA copy number in Delta-infected patients
250 compared to pre-VOC 15, 32. However, these studies did not control for DPOS, age or sex. Other
251 studies found either no difference in RNA VL between Delta and pre-VOC swabs 33 or more than
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252 1000-fold higher VL for Delta 34, documenting the difficulty of comparing RNA VLs of virus variants
253 during different phases of the pandemic, especially without additional information such as DPOS.
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254 Conversely, in agreement with our results, a higher virus isolation success rate was observed for
255 Delta compared to pre-VOC SARS-CoV-2 or Alpha 35.
256 Vaccines have been shown to tremendously reduce symptomatic SARS-CoV-2 infections. However,
257 vaccination’s impact on breakthrough case infectiousness is unclear. We show that infectious VL and
258 RNA VL is reduced in fully vaccinated Delta patients during the first 5 DPOS. In this time period
259 approximately 50% of transmissions occur for pre-VOC strains 5, indicating that reduced VL could
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260 considerably decrease secondary attack rate. Other studies showed no difference in RNA VL
261 between the vaccinated and unvaccinated early after symptom onset 36, 37, but found a lower virus
262 isolation rate 36. Conversely, another study detected up to 10-fold reduced RNA VL in vaccinated
263 patients but only for 60 days after full vaccination 38. Similarly, two more studies reported decreased
264 RNA VL for vaccine-breakthrough infection with pre-VOC and Alpha SARS-CoV-2 39, but no effect
265 around 6 months post vaccination when Delta dominated 40. Of note, we were still able to detect
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266 infectious viral particles in 53.8% of fully vaccinated Delta infected subjects at 5 DPOS, indicating
267 that shortening of the isolation period to 5 days, as recommended by the CDC, should be carefully
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268 evaluated 41. Whether lower infectious VL translates into lower secondary attack rates remains
269 controversial and depends on other influencing factors, such as environmental stability of virus
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270 particles. Several studies found a correlation between VL and secondary attack rate, with VL of the
271 index case being the leading transmission correlate 3, 4. In agreement with these findings,
272 epidemiological studies showed reduced transmission from vaccinated index cases, but the effect
size depends on the prevalent variant, the vaccine used and the time since vaccination 19. In
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273
274 contrast, another study found that the index case vaccination status did not influence the secondary
275 attack rate 21. While VL is a key element of transmission, the process of human-to-human
276 transmission is complex and other factors, such as varying recommended protection measures,
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277 overall incidence, perceived risks and the context of contacts (household vs community
278 transmission) can influence outcomes in the studies reported.
279
280
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To date, few data exist on VL in vaccine-breakthrough infections caused by Omicron due to its recent
emergence in late November 2021. Reduced neutralization of Omicron by infection- and vaccine-
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281 derived antibodies was reported in vitro, but the effect was less pronounced for boosted individuals
42, 43
282 . Furthermore, epidemiological studies show an increased risk of (re-) infection with Omicron in
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283 vaccinated and recovered individuals 44 with high secondary attack rates among fully vaccinated and
284 boosted individuals 45-47. Higher RNA VLs as described in some studies were discussed as one
285 potential contributing factor for the emergence of Alpha and Delta, although for Delta we could only
286 confirm this for infectious VL in our data. Recent studies have shown that infection with Omicron
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287 caused shorter viral RNA shedding and lower peak viral RNA concentrations in comparison to Delta
288 variant 48, 49. In contrast other studies found a similar RNA VL for Omicron and Delta infected patients
46, 50
289 . These finding are in line with our study, where only infectious VL but not RNA VL was
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290 significantly lower in Omicron compared to Delta breakthrough cases. In combination these results
291 indicate that the observed high transmissibility of Omicron is not caused by elevated VLs and the
292 mechanism behind the higher transmissibility remains to be investigated. First in vitro data hint
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293 towards alternative entry mechanisms as well as early replication peaks in cell culture 51, 52, but no
294 clinical data for these exist so far. Our findings indicate that with lower infectious VL, the higher
295 transmissibility in Omicron seems to be unrelated to an increased shedding of infectious viral
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296 particles in vaccinated individuals. Furthermore, we could show that in the case of Omicron
297 breakthrough infections only boosted subjects had lower infectious VL, but not RNA VL, compared to
298 unvaccinated individuals. These findings are partially in agreement with a recent household
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299 transmission study from Denmark where both fully vaccinated and boosted primary cases showed
300 reduced onward transmission 46.
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301 Our study has several limitations. We included only samples from symptomatic but not
302 asymptomatic infected individuals that were collected ≤5 DPOS with Ct-values <27. Therefore,
303 absolute RNA copy numbers are biased towards higher VLs as patients with low VL were not
304 included here. However, patients with low VL have likely little relevance in terms of transmission and
305 the fraction of patients with Ct-values ≥27 was similar for all groups at all DPOS. Furthermore, our
306 focus was on infectious virus shedding and it has been shown that SARS-CoV-2 culture is unlikely to
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307 be successful from samples with higher Ct-values24 and that the vast majority of secondary
308 transmission occurs before 5 DPOS although this requires assessment in Omicron cases 5. Other
309 factors, such as poor swab quality can be a confounding factor leading to low VLs. Also, our results
310 could be impacted if the timing between peak VL and the observed onset of symptoms would be
311 considerably different between the variants or between unvaccinated and vaccinated subjects.
312 However, VL trajectories of variants and of vaccinated and unvaccinated subjects run in parallel,
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313 indicating that they largely follow similar kinetics. Also, we would like to emphasize that there is
314 currently no agreed cut-off for focus-forming units per mL above which a patient could reliably be
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315 classified as infectious. In addition, comparisons between variants, i.e. between pre-VOC and Delta
316 as well as Delta and Omicron, might be affected by differences in adaption of variants to the cell
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317 lines used in this study. Lastly, we also would like to mention that almost all individuals in this study
318 were vaccinated with mRNA vaccines that induce high titres of neutralizing antibodies in the blood
319 but relatively low mucosal antibodies. Therefore, our results cannot be generalized to other
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320 vaccines, i.e. those that are used mainly in low- and middle-income countries.
321 In conclusion, this study provides strong evidence for higher infectiousness of SARS-CoV-2 Delta as
322 well as a significant impact of full vaccination on infectious VL and its speed of clearance. In addition,
323 we show that Omicron has lower infectious VLs compared to Delta in fully vaccinated subject. Last,
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324 after Omicron infection, lower infectious VL is only observed in boosted individuals. Our findings
325 highlight the beneficial effect of vaccinations beyond the individual protection from severe disease
326
327
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and underscore the importance of booster vaccination. Thereby we provide guidance for public
health measures such as shortening of the isolation period and vaccination certificates.
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328 Acknowledgments
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329 We thank all patients for their willingness to participate in our research. We thank the staff of the
330 laboratory of virology from the University Hospitals of Geneva for their support. We would like to
331 thank Manel Essaidi-Laziosi for helpful advice, Yves Cambet, Vincent Jaquet and Anna Rita Corvaglia
332 for technical help. We also thank Eric Boehm for help with editing the manuscript.
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333 Author contributions
334 OP, PV, IE and BM designed the study. OP, KA and PS performed the laboratory experiments. CG, AI,
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335 FJB, LK and PV contributed to data collection. OP, NH, IE and BM analysed and interpreted the data.
336 IE and BM supervised the work. OP, IE and BM wrote the manuscript. OP, KA, NH, PS, CG, AI, FJB, LK,
337 PV, IE and BM reviewed the manuscript.
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338 Funding
339 This work was supported by the Swiss National Science Foundation 196644 (IE), 196383 (IE), NRP
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340 (National Research Program) 78 Covid-19 Grant 198412 (IE, BM), the Fondation Ancrage
341 Bienfaisance du Groupe Pictet (IE) and the ondation riv e des pitau niversitaires de en ve
342 (IE). The funders had no role in study design, data collection and analysis, decision to publish or
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343 preparation of the manuscript.

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344 Declaration of interests
345 The authors declare no conflict of interest.
346
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347 Table
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Unvaccinated SARS-CoV-2 Unvaccinated SARS-CoV-2 Vaccinated SARS-CoV-2 Vaccinated SARS-CoV-2 Unvaccinated SARS-CoV-2 Vaccinated SARS-CoV-2
Pre-VOC Delta VOC Delta VOC Delta VOC Omicron VOC Omicron VOC
Number 118 127 104 62 33 121 (among these 30 are
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boosted)
Sampling dates April 7 -September 9 2020 June 26 –August 29 2021 July 8 -December 4 2021 October 8 -December 13 December 16-February 19 2022 December 11 2021 – February
2021 19 2022
Cell line used for Vero E6 Vero E6 Vero E6 Vero E6 -TMPRSS Vero E6-TMPRSS Vero E6-TMPRSS
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titration
Age (years)
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Median (range) 36 (17-82) 37 (16-83) 41 (16-83) 41.5 (20-70) 32 (17-68) 36 (14-71)
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<25 22 (18.6%) 19 (14.9 %) 12 (11.5%) 3 (4.8%) 5 (15.2 %) 14 (11.6 %)
25-35 37 (31.4%) 38 (29.9%) 30 (28.8%) 14 (22.6 %) 14 (42.4 %) 37 (30.6%)
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35-50 30 (25.4%) 41 (32.3%) 37 (35.6%) 25 (40.3 %) 6 18.2%) 43 (35.5%)
50-65 23 (19.5%) 25 (19.7%) 21 (20.2 %) 18 (29 %) 4 (12.1 %) 26 (21.5 %)
>65
Sex
6 (5.1%) 4 (3.1%) ED 4 (3.8%) 2 (3.2 %) 4 (12.1 %) 1 (0.8 %)
Female 50 (42.4%) 65 (51.2%) 53 (51 %) 32 (51.6 %) 17 (51.5 %) 63 (52 %)

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Male 68 (57.6%) 62 (48.8%) 51 (49 %) 30 (48.4 %) 16 (48.5 %) 58 (48 %)
RT-PCR result, CT (E- 13.9-26·6 13.8-26.3 16.3-26.1 15.9-26.1 16.6-26.7 14.6-26.7

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gene target, Cobas

6800, Roche)
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DPOS Median 2 (0,5) 3 (0,5) 2 (0,5) 2 (0,5) 2 (0,5) 2(0,5)

(Min,Max)
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Number of samples
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selected per each DPOS
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DPOS 0 15 17 15 11 2 12
DPOS 1 22 29 23 11 13 30
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DPOS 2 25 17 15 10 9 31
DPOS 3 21 24 18 11 6 23
DPOS 4 21 27 20 9 2 19
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DPOS 5 14 13 13 10 1 6
Interval vaccination to na na 69 (IQR 38-122) 160 (IQR 137-183) na 154 (IQR 86-198)
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infection, days, median
(IQR)
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Vaccine
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BNT162b2 (Comirnaty) na na 38 28 na 43
mRNA-1273 (Spikevax) na na 61 32 na 72*
CoviVac na na 1 - na -
AZD1222
CoronaVac
na
na
na
na
ED -
-
1
1
na
na
-
-
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Vaccine unknown na na 4 - na 6
348 Table 1. Patient characteristics of the specimens used in this study. RT-PCR, reverse transcription polymerase chain reaction; CT, cycle threshold; IQR,
349 interquartile range; DPOS, days post onset of symptoms; na, not applicable; * 4 subjects were boosted with Comirnaty.
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350
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351 Figure Legends
352 Figure 1. Relationship between RNA viral loads and infectious viral titers. Linear regression analysis
353 of infectious viral titers in FFU/mL and the corresponding RNA viral loads in nasopharyngeal swabs
354 from the unvaccinated patients infected with pre-VOC (A), unvaccinated patients infected with Delta
355 VOC (B), fully vaccinated patients infected with Delta (C) titrated in Vero E6 cells and unvaccinated
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356 patients infected with Omicron VOC (D), fully vaccinated or boosted patients infected with Omicron
357 (E) titrated in Vero-TMPRSS cells. Error bars represent 95% confidence bands of the best-fit line.
358 Two-tailed F test was used to determine statistical significance, no adjustments were made for
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359 multiple comparisons.
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360
361 Figure 2. RNA viral load and infectious viral titers for unvaccinated individuals infected with pre-
362 VOC SARS-CoV-2 vs. Delta (A) Genome copies (left panel) and infectious virus (right panel) for pre-
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363 VOC and Delta unvaccinated patients. Infectious titers (FFU>0) were detected in 94 pre-VOC and 112
364 Delta unvaccinated patients, no titers (FFU=0) were detected in 24 pre-VOC and 15 Delta
365 unvaccinated patients. Error bars indicate mean±SD. Two-tailed t-test was used to determined
366 differences of means. *p=0.0373; *** p=0.001. Genome copies (B) and infectious viral loads (C)
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367 measured for pre-VOC and Delta VOC infected patients at different DPOS. The solid lines represent
368 the fitted curve calculated using (locally estimated scatterplot smoothing) LOESS method. Error bars
369 represent 95% confidence bands of the best-fit line.
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370
371 Figure 3. RNA viral load and infectious viral titers for unvaccinated vs. vaccinated individuals
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372 infected Delta (A) Genome copies (left panel) and infectious virus (right panel) for fully vaccinated
373 and unvaccinated Delta-infected patients. Infectious titers (FFU>0) were detected in 112
374 unvaccinated and 75 fully vaccinated Delta infected patients, no titers (FFU=0) were detected in 15
375 unvaccinated and 29 fully vaccinated Delta infected patients. Error bars indicate mean±SD. Two-
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376 tailed t-test was used to determined differences of means. ***p=0.0002; ****p<0.0001. Genome
377 copies (B) and infectious viral loads (C) measured for vaccinated and unvaccinated Delta-infected
378 patients at different DPOS. The solid lines represent the fitted curve calculated using (locally
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379 estimated scatterplot smoothing) LOESS method. Error bars represent 95% confidence bands of the
380 best-fit line.
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381
382 Figure 4. SARS-CoV-2 infectious viral loads in vaccine-break through infections with Omicron or
383 Delta. (A) Genome copies (left panel) and infectious virus (right panel) for fully vaccinated patients
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384 infected with Delta or Omicron VOC. Infectious titers (FFU>0) were detected in 53 Delta and 66
385 Omicron fully vaccinated patients, no titers (FFU=0) were detected in 9 Delta and 25 Omicron
386 infected patients. Error bars indicate mean±SD. Two-tailed t-test was used to determined
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387 differences of means ****p<0.0001; ns: nonsignificant. Genome copies (B) and infectious viral loads
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388 (C) measured for fully vaccinated Omicron and Delta infected patients at different DPOS. The solid
389 lines represent the fitted curve calculated using (locally estimated scatterplot smoothing) LOESS
390 method. Error bars represent 95% confidence bands of the best-fit line. (D) Genome copies (left
391 panel) and infectious virus (right panel) for unvaccinated, fully vaccinated or boosted Omicron
392 breakthrough cases. Infectious viral loads for Delta and Omicron samples were determined by focus-
393 forming assay on Vero E6-TMPRSS cells. Infectious titers (FFU>0) were detected 24 unvaccinated, 66
394 fully vaccinated and 18 boosted Omicron infected patients, no titers (FFU=0) were detected in 9
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395 unvaccinated, 25 fully vaccinated and 12 boosted Omicron infected patients. Error bars indicate
396 mean±SD. Significance was determined by one-way ANOVA. ns: nonsignificant; *p=0.0256;
397 ***p=0.0004. Genome copies (E) and infectious viral loads (F) measured for fully vaccinated (2 doses)
398 and boosted (3 doses) Omicron infected patients at different DPOS. The solid lines represent the
399 fitted curve calculated using (locally estimated scatterplot smoothing) LOESS method. Error bars
400 represent 95% confidence bands of the best-fit line.
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401 Extended Data Fig. 1 Quantitative infectious viral loads versus overall virus isolation success (A)
402 Vero E6 (Pre-VOC and Delta) or Vero E6-TMPRSS (Omicron) cells were inoculated with 10-fold serial
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403 dilutions of nasopharyngeal swabs collected from SARS-CoV-2 infected individuals. Plates were fixed
404 27 h post-infection and following the staining with SARS-CoV-2 specific antibodies, the number of
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405 focus forming units (FFU)/mL was calculated for each sample. Error bars indicate mean±SD. p-values
406 were calculated using one-way ANOVA. ***: p<0.0003; ****p<0.0001. (B) The total number of
407 positive and negative samples defined by titration and virus isolation for each patient group.
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408 Patients with detectable foci-forming units were assigned to the (+) group while patients without
409 detectable focus-forming units were assigned to the (-) group). Cohens kappa agreement is shown.
410 Extended Data Fig. 2 Correlation between age and infectious viral loads Linear regression analysis
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411 of SARS-CoV-2 titers in FFU/mL and the corresponding age of the patient. Error bars represent 95%
412 confidence bands of the best-fit line.
413
414
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Extended Data Fig. 3 Infectious viral loads by sex Comparison of infectious viral shedding measured
in female and male patients. Error bars indicate mean±SD. Two-tailed t-test was used to determine
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415 differences of means. ns= nonsignificant. Each graph contains following number of patients: 24
416 female and 38 male (A), 26 female and 30 male (B), 35 female and 28 male (C), 30 female and 34
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417 male (D), 23 female and 30 male (E), 30 female and 21 male (F), 26 female and 27 male (G), 22
418 female and 16 male (H).
419 Extended Data Fig. 4 Infectious viral load in matched samples (A) Flow chart demonstrating the
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420 algorithm used for matching of the samples. The samples were matched first by DPOS, then by sex
421 and finally by age group. SARS-CoV-2 infectious viral loads detected in unvaccinated patients
422 infected with pre-VOC or Delta (B), unvaccinated and vaccinated patients infected with Delta (C),
423 vaccinated patients infected with Delta or Omicron (D) matched by age, sex, and dpos. Flow charts
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424 on the left side of each graph represent the numbers of samples in each category that were
425 matched. Error bars indicate mean±SD. Two-tailed t-test was used to determine differences of
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426 means. **p=0.00117; ***p=0.003; ****p<0.0001; ns=nonsignificant.
427 Extended Data Fig. 5 Correlation between days post vaccination with infectious viral load Linear
428 regression analysis of infectious viral shedding and time since the completion of two vaccine doses in
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429 Delta (A) and Omicron (B) infected patients. Error bars represent 95% confidence bands of the best-
430 fit line.
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431
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471 16. Imai K, Ikeno R, Tanaka H, Takada N. SARS-CoV-2 Delta variant saliva viral load is 15-fold
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475 18. Mostaghimi D, Valdez CN, Larson HT, Kalinich CC, Iwasaki A. Prevention of host-to-host
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480 Vaccination on Transmission of Alpha and Delta Variants. N Engl J Med. 2022.
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481 21. Singanayagam A, Hakki S, Dunning J, Madon KJ, Crone MA, Koycheva A, et al. Community
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484 22. Badu K, Oyebola K, Zahouli JZB, Fagbamigbe AF, de Souza DK, Dukhi N, et al. SARS-CoV-2
485 Viral Shedding and Transmission Dynamics: Implications of WHO COVID-19 Discharge Guidelines.
486 Front Med (Lausanne). 2021;8:648660.
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487 23. COVID-19 Vaccine Breakthrough Infections Reported to CDC — United States, January 1–
488 April 30, 2021. 2021 May 28, 2021.
489 24. Essaidi-Laziosi M, Perez Rodriguez FJ, Hulo N, Jacquerioz F, Kaiser L, Eckerle I. Estimating
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490 clinical SARS-CoV-2 infectiousness in Vero E6 and primary airway epithelial cells. Lancet Microbe.
491 2021;2(11):e571.
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492 25. Chen PZ, Bobrovitz N, Premji ZA, Koopmans M, Fisman DN, Gu FX. SARS-CoV-2 shedding
493 dynamics across the respiratory tract, sex, and disease severity for adult and pediatric COVID-19.
494 Elife. 2021;10.
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495 26. Jefferson T, Spencer EA, Brassey J, Heneghan C. Viral Cultures for Coronavirus Disease 2019
496 Infectivity Assessment: A Systematic Review. Clin Infect Dis. 2021;73(11):e3884-e99.
497 27. Takahashi T, Ellingson MK, Wong P, Israelow B, Lucas C, Klein J, et al. Sex differences in
498 immune responses that underlie COVID-19 disease outcomes. Nature. 2020;588(7837):315-20.
499 28. Corman VM, Landt O, Kaiser M, Molenkamp R, Meijer A, Chu DK, et al. Detection of 2019
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500 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 2020;25(3).
501 29. Wong L-YR, Li K, Sun J, Zhuang Z, Zhao J, McCray PB, et al. Sensitization of Non-permissive
502 Laboratory Mice to SARS-CoV-2 with a Replication-Deficient Adenovirus Expressing Human ACE2.
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503 STAR Protocols. 2020;1(3):100169.
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504 30. Ben Killingley AM, Mariya Kalinova, Alison Boyers, Niluka Goonawardane, Jie Zhou, Kate
505 Lindsell, Samanjit S. Hare, Jonathan Brown, Rebecca Frise, Emma Smith, Claire Hopkins, Nicolas
506 Noulin, Brandon Londt, Tom Wilkinson, Stephen Harden, Helen McShane, Mark Baillet, Anthony
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507 Gilbert, Michael Jacobs, Christine Charman, Priya Mande, Jonathan S. Nguyen-Van-Tam, Malcolm G.
508 Semple, Robert C. Read, Neil M. Ferguson, Peter J. Openshaw, Garth Rapeport, Wendy S. Barclay,
509 Andrew P. Catchpole, Christopher Chiu. Safety, tolerability and viral kinetics during SARS-CoV-2
510 human challenge. Research Square. 2022.
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511 31. Blazejewska P, Koscinski L, Viegas N, Anhlan D, Ludwig S, Schughart K. Pathogenicity of

512 different PR8 influenza A virus variants in mice is determined by both viral and host factors. Virology.
513 2011;412(1):36-45.
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514 32. Christian von Wintersdorff JD, Lieke van Alphen, Petra Wolffs, Brian van der Veer, Christian
515 Hoebe, Paul Savelkoul. Infections caused by the Delta variant (B.1.617.2) of SARS-CoV-2 are
516 associated with increased viral loads compared to infections with the Alpha variant (B.1.1.7) or non-
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517 Variants of Concern2021.

518 33. Tani-Sassa C, Iwasaki Y, Ichimura N, Nagano K, Takatsuki Y, Yuasa S, et al. Viral loads and
519 profile of the patients infected with SARS-CoV-2 Delta, Alpha, or R.1 variants in Tokyo. J Med Virol.
520 2021.
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521 34. Wang Y, Chen R, Hu F, Lan Y, Yang Z, Zhan C, et al. Transmission, viral kinetics and clinical
522 characteristics of the emergent SARS-CoV-2 Delta VOC in Guangzhou, China. EClinicalMedicine.
523 2021;40:101129.
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524 35. Luo CH, Morris CP, Sachithanandham J, Amadi A, Gaston DC, Li M, et al. Infection with the
525 SARS-CoV-2 Delta Variant is Associated with Higher Recovery of Infectious Virus Compared to the
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526 Alpha Variant in both Unvaccinated and Vaccinated Individuals. Clin Infect Dis. 2021.
527 36. Shamier MC, Tostmann A, Bogers S, de Wilde J, IJpelaar J, van der Kleij WA, et al. Virological
528 characteristics of SARS-CoV-2 vaccine breakthrough infections in health care workers. medRxiv.
529 2021:2021.08.20.21262158.
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530 37. Chia PY, Ong SWX, Chiew CJ, Ang LW, Chavatte JM, Mak TM, et al. Virological and serological
531 kinetics of SARS-CoV-2 Delta variant vaccine breakthrough infections: a multicentre cohort study.
532 Clin Microbiol Infect. 2021.
533 38. Levine-Tiefenbrun M, Yelin I, Alapi H, Katz R, Herzel E, Kuint J, et al. Viral loads of Delta-
534 variant SARS-CoV-2 breakthrough infections after vaccination and booster with BNT162b2. Nature
535 Medicine. 2021;27(12):2108-10.
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536 39. Emary KRW, Golubchik T, Aley PK, Ariani CV, Angus B, Bibi S, et al. Efficacy of ChAdOx1 nCoV-
537 19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory
538 analysis of a randomised controlled trial. Lancet. 2021;397(10282):1351-62.
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539 40. Pouwels KB, Pritchard E, Matthews PC, Stoesser N, Eyre DW, Vihta K-D, et al. Effect of Delta
540 variant on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK.
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541 Nature Medicine. 2021;27(12):2127-35.
542 41. Prevention CfDCa. CDC Updates and Shortens Recommended Isolation and Quarantine
543 Period for General Population. December 27, 2021.
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544 42. Eggink D, Andeweg SP, Vennema H, van Maarseveen N, Vermaas K, Vlaemynck B, et al.
545 Increased risk of infection with SARS-CoV-2 Omicron compared to Delta in vaccinated and previously
546 infected individuals, the Netherlands, 22 November to 19 December 2021. medRxiv.
547 2021:2021.12.20.21268121.
548 43. Carreño JM, Alshammary H, Tcheou J, Singh G, Raskin AJ, Kawabata H, et al. Activity of
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549 convalescent and vaccine serum against SARS-CoV-2 Omicron. Nature. 2022;602(7898):682-8.
550 44. Pulliam JRC, van Schalkwyk C, Govender N, von Gottberg A, Cohen C, Groome MJ, et al.
551 Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South
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552 Africa. medRxiv. 2021:2021.11.11.21266068.
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553 45. Brandal LT, MacDonald E, Veneti L, Ravlo T, Lange H, Naseer U, et al. Outbreak caused by the
554 SARS-CoV-2 Omicron variant in Norway, November to December 2021. Euro Surveill. 2021;26(50).
555 46. Lyngse FP, Mortensen LH, Denwood MJ, Christiansen LE, Møller CH, Skov RL, et al. SARS-CoV-
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556 2 Omicron VOC Transmission in Danish Households. medRxiv. 2021:2021.12.27.21268278.

557 47. Kuhlmann C, Mayer CK, Claassen M, Maponga T, Burgers WA, Keeton R, et al. Breakthrough
558 infections with SARS-CoV-2 omicron despite mRNA vaccine booster dose. Lancet.
559 2022;399(10325):625-6.
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560 48. Hay JA, Kissler SM, Fauver JR, Mack C, Tai CG, Samant RM, et al. Viral dynamics and duration
561 of PCR positivity of the SARS-CoV-2 Omicron variant. medRxiv. 2022:2022.01.13.22269257.
562 49. Sentis C, Billaud G, Bal A, Frobert E, Bouscambert M, Destras G, et al. SARS-CoV-2 Omicron
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563 variant, lineage BA.1, is associated with lower viral load in nasopharyngeal samples compared to
564 Delta variant. medRxiv. 2022:2022.02.02.22269653.
565 50. Migueres M, Dimeglio C, Trémeaux P, Abravanel F, Raymond S, Lhomme S, et al. Influence of
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566 immune escape and nasopharyngeal virus load on the spread of SARS-CoV-2 Omicron variant. J
567 Infect. 2022.
568 51. Peacock TP, Brown JC, Zhou J, Thakur N, Newman J, Kugathasan R, et al. The SARS-CoV-2
569 variant, Omicron, shows rapid replication in human primary nasal epithelial cultures and efficiently
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570 uses the endosomal route of entry. bioRxiv. 2022:2021.12.31.474653.

571 52. Hui KPY, Ho JCW, Cheung MC, Ng KC, Ching RHH, Lai KL, et al. SARS-CoV-2 Omicron variant
572 replication in human bronchus and lung ex vivo. Nature. 2022.
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573
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574 Methods
575 Participants
576 Ethical approval
577 The study was approved by the Cantonal ethics committee at the University Hospital of Geneva
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578 (CCER Nr. 2021-01488). All study participants and/or their legal guardians provided informed
579 consent.
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580 Sample collection and setting
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581 Nasopharyngeal swabs (NPS) collected from symptomatic (self-reported) individuals by trained
582 professionals in the outpatient testing centre of the Geneva University Hospital (HUG), for SARS-
583 CoV-2 qRT-PCR diagnostics, were included in this study. Samples from asymptomatic individuals
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584 were not included. Infection with SARS-CoV-2 was diagnosed by qRT-PCR assay (Cobas 6800, Roche).
585 For this study samples were included between 7th of April 2020 and February 19th 2022.
586 Only specimens with CT-values below 27 for the E-gene qRT-PCR diagnostic target were included in
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587 our analyses. All samples originated from the diagnostic unit of the hospital’s virology laboratory and
588 were received for primary diagnosis of SARS-CoV-2. Remaining sample volume was stored at -80°C,
589 on the same day or within 24h. All samples had only one freeze-thaw cycle for the purpose of this
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590 study. All specimens from unvaccinated and vaccinated Delta-infected individuals were
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591 characterized by full genome sequencing for their infecting SARS-CoV-2 variant. Initial identification
592 of Omicron was done by S-gene target failure of the TaqPath COVID19 assay (Thermofisher) and
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593 confirmed by partial Sanger sequencing of Spike 1 followed by next-generation sequencing. No

594 sequence information was obtained for samples collected before the first detection of VOCs in
595 Switzerland, i.e. pre-VOC samples. Clinical information of the patients was collected by a
596 standardized questionnaire in our testing Centre and/or through the Cantonal Health Service. The
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597 day of symptoms onset was defined as day 0 in this study. Only specimens collected within the first 5
598 DPOS were selected for this study.
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599 Viral load quantification by qRT-PCR

600 For initial inclusion of samples into this study, CT-values for the E-gene target of the diagnostic qRT-
601 PCR (Cobas 6800, Roche), determined by the diagnostic laboratory of the HUG at the time of
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602 sampling, were used. Afterwards, to minimize variability between measurements, all selected
603 samples were re-extracted after thawing and RNA VL in each sample was determined by E-gene qRT-
604 CR using SuperScript™ III latinum™ One-Step qRT-PCR Kit (Invitrogen) in our research laboratory.
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605 Quantification of genome copy numbers was performed using an in-vitro transcribed RNA standard
606 for the E gene assay as described previously 2. Only results obtained from this latter measurement
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607 were used for further analysis.

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608 Quantification of SARS-CoV-2 by focus-forming assay.
609 Vero E6 and Vero E6-TMPRSS were cultured in complete DMEM GlutaMax I medium supplemented
610 with 10% fetal bovine serum, 1x Non-essential Amino Acids, and 1% antibiotics
611 (Penicillin/Streptomycin) (all reagents from Gibco, USA). Vero E6-TMPRSS were kindly received from
612 National Institute for Biological Standards and Controls (NIBSC, Cat. Nr. 100978). All infection
613 experiments were performed under BSL3 conditions.
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614 Focus-forming assay used in this study was adapted from published protocol 3. NPS samples were
615 serially diluted and applied on a monolayer of Vero E6 cells in duplicates. Following 1 hour at 37°C,
616 the media was removed and prewarmed medium mixed with 2.4% Avicel (DuPont) at a 1:1 ratio was
617 overlaid. Plates were incubated at 37°C for 24 hours and then fixed using 6% paraformaldehyde for 1
618 hour at room temperature. Cells were permeabilized with 0.1% Triton X-100 and blocked with 1%
619 BSA (Sigma). Plates were incubated with a primary monoclonal antibody targeting SARS-CoV-2
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620 nucleocapsid protein (Geneva Antibody facility, JS02, diluted to 0.2 µg/ml) for 1 hour at room
621 temperature and then with peroxidase-conjugated secondary antibody (Jackson ImmunoResearch,
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622 #109-036-09, diluted to 1:2000) for 30 minutes at room temperature. Foci were visualized using True
623 Blue HRP substrate (Avantor) and imaged on an ELISPOT reader (CTL). We defined a cluster of
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624 adjacent cells expressing viral antigen as a foci. Foci were counted and expressed as focus forming
625 units per ml (FFU/mL). Focus forming assays for comparison of infectious VLs in Delta vs Omicron
626 were performed in Vero E6-TMPRSS cells using the same protocol.
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627 Virus isolation
628 Nasopharyngeal samples were applied on Vero E6 cell monolayers in 24-well plates. 100 µl of each
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629 sample was added and incubated for 1 hour at 37°C. Following the incubation, the infectious
630 supernatant was discarded and virus culture medium was added. 50 µL of the medium was collected
631 to determine VL by RT-qPCR as described above at day 0. 3-4 days post inoculation the medium was
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632 replaced, and 6 days post infection the infectious medium was collected to determine VL. A genome
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633 copy number change of at least 1 log of from day 0 to 6 indicated a successful isolation.
634 Statistical analysis

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635 Data collection was done using Excel 2019. All statistical analyses were performed using R Statistical
636 Software version 4.1.1 (Foundation for Statistical 185 Computing, Austria) and Prism version 9.3.1
637 (GraphPad, San Diego, CA, USA). All focus forming units and RNA genome copies were log10
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638 transformed and samples with no detectable FFU were set to 1 FFU/mL for the purpose of analysis.
639 Data availability statement

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640 All data is included as a source data file in this manuscript.
641
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642 Methods-only References

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643 1.Sabine Yerly LK, Manuel Schibler, Isabella Eckerle. Protocol for specific RT-PCRs for marker regions
644 of the Spike indicative of the Omicron variant (B.1.1.529). Geneva, Switzerland: Centre for Emerging
645 Viral Diseases, Geneva University Hospitals; December 2,2021.
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646 2. Corman VM, Landt O, Kaiser M, Molenkamp R, Meijer A, Chu DK, et al. Detection of 2019 novel
647 coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 2020;25(3).
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648 3. Case JB, Bailey AL, Kim AS, Chen RE, Diamond MS. Growth, detection, quantification, and
649 inactivation of SARS-CoV-2. Virology. 2020;548:39-48.
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@®~.Protective immunity after recovery from SARS-CoV-2

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infection
PublishedOnlllW! The SARS-CoV-2 pandemic is now better controlled in We reviewed studies published in PubMed from
November8. 2021
https://doiorg/10.1016/
settings with access to fast and refiable testing and highly inception to Sept 28, 2021., and found well conducted
S1473-3099(21)00676-9 effective vaccination rollouts. Several studies have found biological studies showing protective immunity
that people who recovered from COVID-19 and tested after infection (panel). Furthermore, multiple
seropositive for anti-SARS-CoV-2 antibodies have low epidemiological and clinical studies, including studies
rates of SARS-CoV-2 reinfection. There are still looming during the recent period of predominantly delta
questions surrounding the strength and duration of such (B.1.617.2) variant transmission, found that the risk of
protection compared with that from vaccination. repeat SARS-CoV-2 infection decreased by 80-5-100%
among those who had had COVID-19 previously
Panel: Biological, epidemiological, and clinical evidence that previous COVID-19 (panel). The reported studies were large and conducted
infection reduces the risk for reinfection throughout the world. Another laboratory-based study
Biological studies that analysed the test results of 9119 people with
• Dan et al (2021):' about 95% of participants tested retained immune memory at previous COVID-19 from Dec 1, 2019, to Nov 13, 2020,
about 6 months after having COVID-19; more than 90% of participants had CD4' found that only 0-7% became reinfectedn In a study
T-cell memory at 1 month and 6-8 months after having COVID-19 conducted at the Cleveland Clinic in Cleveland, OH,
• Wang et al (2021):2 participants with a previous SARS-CoV-2 infection with an USA, those who had not previously been infected had a
ancestral variant produce antibodies that cross-neutralise emerging variants of
concern with high potency COVID-19 incidence rate of 4·3 per 100 people, whereas
those who had previously been infected had a COVID-19
Epidemiological studies
incidence rate of O per 100 people.6 Furthermore, a
Hansen et al (2021):3 in a population-level observational study, people who had had
COVID-19 previously were around 80-5% protected against reinfection study conducted in Austria found that the frequency
Pilz et al (2021):4 in a retrospective observational study using national Austrian of hospitalisation due to a repeated infection was
SARS-CoV-2 infection data, peoplewho had hadCOVID-19 previously were around five per 14840 (0-03%) people and the frequency
91% protected against reinfection of death due to a repeated infection was one per
Sheehan et al (2021):' in a retrospective cohort study in the USA, people who had had
14840 (0-01%) people.4 Due to the strong association
COVID-19 previously were 81-8% protected against reinfection
Shrestha et al (2021):' in a retrospective cohort study in the USA, people who had had and biological basis for protection,12 clinicians should
COVID-19 previously were 100% protected against reinfection consider counselling recovered patients on their risk for
Gazit et al (2021):' in a retrospective observational study in Israel, SARS-CoV-2-naive reinfection and document previous infection status in
vaccinees had a 13-06-times increased risk for breakthrough infection with the delta medical records.
(B.1.617.2) variant compared with those who had had COVID-19 previously; evidence
of waning natural immunity was also shown
Although those studies show that protection from
• Kojima et al (2021):1 in a retrospective observational cohort of laboratory staff reinfection is strong and persists for more than
routinely screened forSARS-CoV-2, people who had had COVID-19 previously were 10 months of follow-up.3 it is unknown how long
100% protected against reinfection protective immunity will truly last. Many systemic viral
Clinical studies infections, such as measles, confer long-term, if not
• Hall et al (2021):9 in a large, multicentre, prospective cohortstudy, having had lifelong, immunity, whereas others, such as influenza,
COVID-19 previously was associated with an 84% decreased risk of infection do not (due to changes in viral genetics).4 We are limited
• Letizia et al (2021):"' in a prospective cohort of US Marines, seropositiveyoung adults by the length of current reported follow-up data to
were 82% protected against reinfection
know with certainty the expected duration that previous
12 www.thelancet.com/infection Vol 22 jaooary 2022

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Comment
infection will protect against COVID-19. Encouragingly, equal to immunity from vaccination for purposes related
authors of a study conducted among recovered to entry to public events, businesses, and the workplace,
individuals who had experienced mild SARS-CoV-2 or travel requirements.
infection reported that mild infection induced a robust NK has received consulting fees from Curative. JDK serves as an independent
medical director of Curative.
antigen-specific, long-lived humoral immune memory
in humans.13 *Noah Kojima, Jeffrey D Klausner
It important to note that antibodies are incomplete nkojima@ucla.edu
Department of Medicine, University of California Los Angeles, Los Angeles, CA
predictors of protection. After vaccination or infection, 90095, USA (NK); Departments of Population Health and Public Health Sciences
many mechanisms of immunity exist within an and Medicine, Keck School of Medicine, University Southern California,
Los Angeles, CA, USA (JDK)
individual not only at the antibody level, but also at
1 Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2
the level of cellular immunity.14–16 It is known that assessed for up to 8 months after infection. Science 2021; 371: eabf4063.
SARS-CoV-2 infection induces specific and durable T-cell 2 Wang L, Zhou T, Zhang Y, et al. Ultrapotent antibodies against diverse and
highly transmissible SARS-CoV-2 variants. Science 2021; 373: eabh1766.
immunity, which has multiple SARS-CoV-2 spike protein 3 Hansen CH, Michlmayr D, Gubbels SM, Mølbak K, Ethelberg S. Assessment
targets (or epitopes) as well as other SARS-CoV-2 protein of protection against reinfection with SARS-CoV-2 among 4 million
PCR-tested individuals in Denmark in 2020: a population-level
targets. The broad diversity of T-cell viral recognition observational study. Lancet 2021; 397: 1204–12.
serves to enhance protection to SARS-CoV-2 variants,15 4 Pilz S, Chakeri A, Ioannidis JP, et al. SARS-CoV-2 re-infection risk in Austria.
Eur J Clin Invest 2021; 51: e13520.
with recognition of at least the alpha (B.1.1.7), beta 5 Sheehan MM, Reddy AJ, Rothberg MB. Reinfection rates among patients
who previously tested positive for COVID-19: a retrospective cohort study.
(B.1.351), and gamma (P.1) variants of SARS-CoV-2.17 Clin Infect Dis 2021; published online March 15. https://doi.org/10.1093/
Researchers have also found that people who recovered cid/ciab234.
6 Shrestha NK, Burke PC, Nowacki AS, Terpeluk P, Gordon SM. Necessity of
from SARS-CoV infection in 2002–03 continue to have COVID-19 vaccination in previously infected individuals. medRxiv 2021;
memory T cells that are reactive to SARS-CoV proteins published online June 19. https://doi.org/10.1101/2021.06.01.21258176
(preprint).
17 years after that outbreak.15 Additionally, a memory 7 Gazit S, Shlezinger R, Perez G, et al. Comparing SARS-CoV-2 natural
immunity to vaccine-induced immunity: reinfections versus breakthrough
B-cell response to SARS-CoV-2 evolves between 1·3 and infections. medRxiv 2021; published online Aug 25. https://doi.
6·2 months after infection, which is consistent with org/10.1101/2021.08.24.21262415 (preprint).
8 Kojima N, Roshani A, Brobeck M, Baca A, Klausner JD. Incidence of severe
longer-term protection.18 acute respiratory syndrome coronavirus-2 infection among previously
Some people who have recovered from COVID-19 infected or vaccinated employees. medRxiv 2021; published online July 8.
https://doi.org/10.1101/2021.07.03.21259976 (preprint).
might not benefit from COVID-19 vaccination.6,19 In fact, 9 Hall VJ, Foulkes S, Charlett A, et al. SARS-CoV-2 infection rates of antibody-
one study found that previous COVID-19 was associated positive compared with antibody-negative health-care workers in England:
a large, multicentre, prospective cohort study (SIREN). Lancet 2021;
with increased adverse events following vaccination 397: 1459–69.
10 Letizia AG, Ge Y, Vangeti S, et al. SARS-CoV-2 seropositivity and subsequent
with the Comirnaty BNT162b2 mRNA vaccine (Pfizer– infection risk in healthy young adults: a prospective cohort study.
BioNTech).20 In addition, there are rare reports of serious Lancet Respir Med 2021; 9: 712–20.
11 Qureshi AI, Baskett WI, Huang W, Lobanova I, Naqvi SH, Shyu CR.
adverse events following COVID-19 vaccination.21 Re-infection with SARS-CoV-2 in patients undergoing serial laboratory
In Switzerland, residents who can prove they have testing. Clin Infect Dis 2021; published online April 25. https://doi.
org/10.1093/cid/ciab345.
recovered from a SARS-CoV-2 infection through a 12 Goel RR, Apostolidis SA, Painter MM, et al. Distinct antibody and memory
positive PCR or other test in the past 12 months are B cell responses in SARS-CoV-2 naïve and recovered individuals following
mRNA vaccination. Sci Immunol 2021; 6: eabi6950.
considered equally protected as those who have been 13 Turner JS, Kim W, Kalaidina E, et al. SARS-CoV-2 infection induces long-
lived bone marrow plasma cells in humans. Nature 2021; 595: 421–25.
fully vaccinated.22 14 Doshi P. Covid-19: do many people have pre-existing immunity?
Although longer follow-up studies are needed, BMJ 2020; 370: m3563.
15 Le Bert N, Tan AT, Kunasegaran K, et al. SARS-CoV-2-specific T cell
clinicians should remain optimistic regarding the immunity in cases of COVID-19 and SARS, and uninfected controls.
protective effect of recovery from previous infection. Nature 2020; 584: 457–62.
16 Shrotri M, van Schalkwyk MCI, Post N, et al. T cell response to SARS-CoV-2
Community immunity to control the SARS-CoV-2 infection in humans: a systematic review. PLoS One 2021; 16: e0245532.
epidemic can be reached with the acquired immunity 17 Redd AD, Nardin A, Kared H, et al. CD8+ T-cell responses in COVID-19
convalescent individuals target conserved epitopes from multiple prominent
due to either previous infection or vaccination. Acquired SARS-CoV-2 circulating variants. Open Forum Infect Dis 2021; 8: ofab143.
immunity from vaccination is certainly much safer and 18 Gaebler C, Wang Z, Lorenzi JCC, et al. Evolution of antibody immunity to
SARS-CoV-2. Nature 2021; 591: 639–44.
preferred. Given the evidence of immunity from previous 19 Goldberg Y, Mandel M, Woodbridge Y, et al. Protection of previous
SARS-CoV-2 infection, however, policy makers should SARS-CoV-2 infection is similar to that of BNT162b2 vaccine protection: a
three-month nationwide experience from Israel. medRxiv 2021; published
consider recovery from previous SARS-CoV-2 infection online April 24. https://doi.org/10.1101/2021.04.20.21255670 (preprint).
www.thelancet.com/infection Vol 22 January 2022 13

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20 Raw RK, Kelly CA, Rees J, Wroe C, Chadwick DR. Previous COVID-19 22 Schengen Visa Info. Switzerland plans to extend COVID certificate
infection, but not long-COVID, is associated with increased adverse events requirement until mid-November. Oct 22, 2021. https://www.
following BNT162b2/Pfizer vaccination. J Infect 2021; 83: 381–412. schengenvisainfo.com/news/switzerland-plans-to-extend-covid-
21 Centers for Disease Control and Prevention. Selected adverse events certificate-requirement-until-mid-november/ (accessed Nov 2, 2021).
reported after COVID-19 vaccination. Oct 26, 2021. https://www.cdc.gov/
coronavirus/2019-ncov/vaccines/safety/adverse-events.html
(accessed Nov 2, 2021).
Serial antigen rapid testing in staff of a large acute hospital

Published Online Point-of-care (lateral flow) assays with an antigen ART was introduced as a more sustainable, less resource-
December 6, 2021
https://doi.org/10.1016/ rapid test (ART) for SARS-CoV-2 became commercially intensive method of ensuring early identification of
S1473-3099(21)00723-4 available in November 2020 worldwide, as a supplement COVID-19-positive staff to mitigate transmission to
to real-time PCR (rtPCR).1 ARTs are self-administered patients at a time when community levels of COVID-19
and detect SARS-CoV-2 antigens from anterior nares were increasing.7 In addition, symptomatic staff were
swabs and return results within minutes. Depending asked to present immediately for testing. Universal mask
on the kit, ART has a sensitivity of 40·2–74·1% and wearing for staff had been in place since February, 2020.
specificity 93·6–99·8% in asymptomatic individuals, Serial ART is an emerging testing strategy and few
which is inferior to that of rtPCR (86–92% and 99%, real-world examples of its use have been published. ARTs
respectively).2,3 However, ARTs are cheaper, easier to performed every 3 days can break chains of transmission
implement at scale, and give faster results than rtPCR of SARS-CoV-2.8,9 Although a single ART is not as sensitive
testing.3 Various institutions are using ARTs to detect or specific as a single rtPCR test, serial testing two or
and reduce the transmission of SARS-CoV-2.4–6 three times a week can outperform a single weekly rtPCR
Singapore is a densely populated city state of test. The National University Hospital’s implementation
5·7 million residents. As of late July, 2021, the incidence required all asymptomatic clinical staff to self-administer
of SARS-CoV-2 was 23·6 cases per million people per ART twice a week, routinely. Staff then submitted time-
day, with a fully vaccinated rate of 60%. Mandatory stamped photographs of their ARTs to a co-worker (their
mask wearing, limits on the size of social gatherings, ART buddy), which could be reviewed by reporting officers
thorough contact tracing, and supervised quarantine of on-demand. Any symptomatic staff were not to make use
all cases and contacts were already in place by this date. of this system; rather, they needed to promptly present to
Since the start of the COVID-19 pandemic, The National the occupational health clinic for rtPCR testing.
University Hospital, a tertiary academic medical centre Staff read a simple guide based on manufacturer’s
employing 8000 clinical staff with a capacity of over instructions and electronically signed an acknowledge
1200 beds, had adhered to a national strategy of ment stating that they would comply to twice weekly
fortnightly rtPCR surveillance in all asymptomatic staff, ARTs. Reports from ART buddies and spot audits
95% of whom were vaccinated. On July 30, 2021, serial suggested that staff were engaged and compliant. They
Advantages Disadvantages
Diagnostic performance (1) Lower sensitivity and specificity than rtPCR, mitigated by a (1) More false positives and false negatives than rtPCR;
strategy of more frequent antigen rapid testing; (2) negative (2) variable performance among kits; and (3) variable
result can predict non-infectiousness; and (3) enables ad hoc swabbing technique, reading of results among individuals,
quick screening of congregate, vulnerable settings (such as especially when self-administered
hospitals)
Implementation (1) Self-administration does not require specially trained staff (1) Test kits can be expensive; (2) large number of test kits are
or rtPCR reagents or machines; (2) almost immediate results; required, which might not be readily available in all settings;
(3) scalable depending on local prevalence and test availability; and (3) poor compliance could be an issue if testing is
and (4) reduced barrier to testing as kits can be made easily unsupervised and results are self-reported
available to staff for home use
rtPCR=real-time PCR.
Table: Advantages and disadvantages of serial testing for SARS-CoV-2 with antigen rapid tests
14 www.thelancet.com/infection Vol 22 January 2022

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nature https://dol.org/10.1038/s41586-022-0486S-0

•
Limited cross-variant i1pmunityfrom
SARS-CoV-2 Omicron without vaccination
Received: 13'January2022 Rat.ilK.Suryawanahl, Irene P. Chen. Tongcul Ma,Abdullah M. Syed. Noah Brazar, Prach! Sal-
Accepted:12 May 2022 dhl, Camille R. Simoneau, Alison CHlng, Mir M. Khalid, Bharath S'l'eekumar, Pel-YI a.en,
G. Aenulra Kl.mar, Mauricio MOICalllC>, Ronne8-on, ChlH.in Teou, MlguelA. Garda-lCnlght.
A<:celeratedArticle Preview AliclaSoto111ayor-Gomatez. VenlceServellila,AmeliaGllwa.JannyNguyan,lnNSllva,
Bilal Mllbes.Noah ICofana.Victoria Heaa. Marla Shacraaw, Lauren Lopez. Mattt- Brobedc.
Cite this article as: Sury.twanshi, R. K. Fred Turner, FrankW. Sovag.Aahl&J F. George,Xiaohul Fang. Mazharul Maishan.
et al Limited cross-variant Immunity from Michael Matthay, Mary Kate Morris. Debra Wafford, Carl Hanson, WamerC. Greene,
SARS-CoV-2Omicron without vaccination. Raul Andino. lee Spraggon, Nacria R. Roan. C2larlesY. aaiu, Jennifer A. Doudna & Melanie Ott
Nature https://dolorg/10.1038/s41586-022-
04865-0(2022).
This is a PDF file ofa peer-reviewed paper that has been accepted for publication.
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is providingthisearlyversion ofthe typeset paperas a servicetoour authors and
readers. The textand figures will undergo copyediting and a proofreview before the
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DATE:
EX#: e INIT1ALS: A ·D
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Nature I www.nature.com
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1 Limited cross-variant immunity from SARS-CoV-2 Omicron without vaccination

2
3 Rahul K. Suryawanshi1,20, Irene P Chen1,2,3,4,20, Tongcui Ma1,5,20, Abdullah M. Syed1,6, Noah
4 Brazer7, Prachi Saldhi7, Camille R Simoneau1,3,4, Alison Ciling1,6, Mir M. Khalid1, Bharath
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5 Sreekumar1, Pei-Yi Chen1, G. Renuka Kumar1, Mauricio Montano1,8, Ronne Gascon1, Chia-Lin
6 Tsou1, Miguel A Garcia-Knight9, Alicia Sotomayor-Gonzalez7, Venice Servellita7, Amelia Gliwa7,
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7 Jenny Nguyen7, Ines Silva10, Bilal Milbes10, Noah Kojima10, Victoria Hess10, Maria Shacreaw10,
8 Lauren Lopez10, Matthew Brobeck10, Fred Turner10, Frank W Soveg1, Ashley F. George1,11,
9 Xiaohui Fang12, Mazharul Maishan12, Michael Matthay12, Mary Kate Morris13, Debra Wadford13,
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10 Carl Hanson13, Warner C. Greene1,3,8,9, Raul Andino9, Lee Spraggon10, Nadia R. Roan1,11 ,
11 Charles Y. Chiu3,5-7,14 , Jennifer A. Doudna1,6,15-19 , Melanie Ott1,3,4,14
12
PR
1
13 Gladstone Institutes, San Francisco, CA, USA.
2
14 Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco,
15 CA, USA.
3
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16 Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
4
17 Quantitative Biosciences Institute COVID-19 Research Group, University of California San
18 Francisco; San Francisco, CA, USA. C
5
19 UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA.
6
20 Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
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7
21 Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA
22 94158, USA.
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8
23 Michael Hulton Center for HIV Cure Research at Gladstone; San Francisco, CA, USA.
9
24 Department of Microbiology and Immunology, University of California, San Francisco, San
25 Francisco, CA, USA.
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10
26 Curative Inc., 430 S Cataract Ave San Dimas, CA, USA.
11
27 Department of Urology, University of California, San Francisco, San Francisco, USA.
12
28 Department of Medicine and Department of Anesthesia, Cardiovascular Research Institute,
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29 University of California San Francisco, San Francisco, CA, USA.

13
30 California Department of Public Health, Richmond, CA 94804, USA.
14
31 Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
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15
32 Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
16
33 Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National
34 Laboratory, Berkeley, CA, USA.
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17
35 Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA.
18
36 Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
C
19
37 California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley,
38 USA.
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20
39 These authors contributed equally: Rahul K. Suryawanshi, Irene P. Chen, Tongcui Ma.
40 e-mail: melanie.ott@gladstone.ucsf.edu, doudna@berkeley.edu, charles.chiu@ucsf.edu,
41 nadia.roan@gladstone.ucsf.edu
42
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43
44 Summary
45
46 SARS-CoV-2 Delta and Omicron are globally relevant variants of concern (VOCs). While
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47 individuals infected with Delta are at risk to develop severe lung disease, infection with
48 Omicron often causes milder symptoms, especially in vaccinated individuals1,2. The question
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49 arises whether widespread Omicron infections could lead to future cross-variant protection,
50 accelerating the end of the pandemic. Here we show that without vaccination, infection with
51 Omicron induces a limited humoral immune response in mice and humans. Sera from mice
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52 overexpressing the human ACE2 receptor and infected with Omicron neutralize only
53 Omicron, but no other VOCs, whereas broader cross-variant neutralization was observed
54 after WA1 and Delta infections. Unlike WA1 and Delta, Omicron replicates to low levels in
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55 the lungs and brains of infected animals, leading to mild disease with reduced pro-
56 inflammatory cytokine expression and diminished activation of lung-resident T cells. Sera
57 from unvaccinated, Omicron-infected individuals show the same limited neutralization of
58 only Omicron itself. In contrast, Omicron breakthrough infections induce overall higher
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59 neutralization titers against all VOCs. Our results demonstrate that Omicron infection
60 enhances preexisting immunity elicited by vaccines but, on its own, may not confer broad
61 protection against non-Omicron variants in unvaccinated individuals.
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62
63
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64 Since the beginning of the COVID-19 pandemic, multiple waves of infection have occurred from
65 SARS-CoV-2 VOCs that continue to arise and out-compete preceding variants. VOCs with
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66 worldwide relevance are Delta (B.1.617.2) and most recently Omicron (BA.1), while Alpha
67 (B.1.1.7), Beta (B.1.351), and Gamma (P.1) variants spread more locally. Compared to ancestral
68 isolate (WA1 or B.1) Omicron is characterized by a large number of unique mutations in spike as
69 well as in other structural proteins, select nonstructural proteins, and accessory open reading
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70 frames. Omicron bears over 50 mutations across its genome, including ~37 mutations (28 being
71 unique and nine overlapping with other variants) in the spike glycoprotein, which may contribute
72 to its antigenic differences39.
73 The constellation of mutations in the Omicron spike protein has been associated with
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74 increased transmission10, decreased spike cleavage11, and decreased cell-to-cell fusion11,12.

75 Importantly, Omicron spike mutations limit efficacies of neutralizing antibodies generated by
76 previous infections, vaccines, and monoclonal antibody treatment39,13. Indeed, the risk of
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77 breakthrough infections and re-infections is increased with Omicron1315. However, disease

78 severity is lower with Omicron than Delta1,2,13, and prior infection or vaccination reduces the risk
79 of hospitalization with Omicron16,17. Pressing questions are how effective Omicron-induced
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80 immunity is, and whether it is cross-protective against other variants.

81
82 Omicron cause less severe infection
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83 To answer these questions, we studied WA1, Delta, and Omicron infections in mice. Because WA1
84 and Delta variants cannot infect regular laboratory mice18, we used transgenic mice overexpressing
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85 human ACE2 (K18-hACE2)19. We intranasally infected (104 PFU) these mice with the three viral
86 isolates and over 7 days monitored their body temperature and weight, which serves as indicators
87 of disease progression (Fig. 1a). While Delta- and WA1-infected mice showed progressive
88 hypothermia and severe weight loss during this time, Omicron-infected mice exhibited very mild
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89 symptoms with only a small increase in body temperature and no weight loss (Fig. 1b, c). Five
90 days after infection, the WA1- and Delta-infected mice were hunched or lethargic, but the
91 Omicron-infected mice appeared completely normal (Extended Data Fig. 1a). All of the
92 Omicron-infected mice survived the 1-week experiment; yet, 100% of WA1- and 60% of the
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93 Delta-infected animals reached the humane end-point during this time (Fig. 1d). This replicates
94 previous findings from infected individuals, mice, and hamsters that show mild disease with
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95 Omicron, but not with Delta and WA1 infections1,2,2024.
96 To assess viral replication dynamics, we quantified infectious particle production (Fig. 2a,
97 b), and viral RNA expression (Extended Data Fig. 2a, b) in the respiratory tracts and lungs of
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98 infected mice over time. Across all time points, high titers of infectious virus were present in upper
99 airways (nasal turbinates and bronchi) and lungs of WA1- and Delta-infected mice, whereas
100 Omicron replication was significantly lower in these organs, as reported2022. Lung histology
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101 showed that Omicron infection resulted in small localized foci of infected cells (marked by
102 nucleocapsid staining, green) (Extended Data Fig. 1b, c, d). A similar pattern but enhanced
103 numbers were observed after WA1 infection, and Delta infection showed large patches of infected
104 cells, indicative of enhanced cell-to-cell spread, as reported in human lung organoids and cell
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105 lines11 (Extended Data Fig. 1b, c, d). In addition, brain tissue, which is a target for viral replication
106 in K18-hACE2 mice, showed lower Omicron replication 4 and 7 days after infection. Omicron
107 also produced fewer infectious particles in human airway organoids and the human alveolar A549
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108 epithelial cell line overexpressing ACE2 than WA1 and Delta infections (Fig. 2c, d), which is
109 consistent with our findings in the mice.
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110
111 Immune markers differ between variants
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112 As severe COVID-19 is associated with cytokine storms in conjunction with exhaustion of T
113 cells25, we next assessed cytokine expression and T-cell phenotypes in infected mouse lungs.
114 While infection with WA1 and Delta readily induced proinflammatory markers of severe COVID,
115 such as CXCL10 and CCL226, induction by Omicron was significantly reduced early after
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116 infection (Extended Data Fig. 3a). Induction of interleukin 1 (IL1 ) was not significantly
117 different between the three viral isolates, but trended towards lower expression in Omicron-
118 infected animals 2 days post-infection (Extended Data Fig. 3a). Although no significant
119 differences between the viral variants were observed in the induction of interferon- (IFN ) or
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120 relevant downstream induced genes, such as interferon-stimulated gene 15 (ISG15) and 2'-5'-
121 oligoadenylate synthetase 1 (OAS1), we cannot exclude that this is caused by low number of
122 animals at later time points (Extended Data Fig. 3a-b).
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123 To determine if the pro-inflammatory response we observed in WA1-infected mice is also

124 associated with T-cell exhaustion in late infection, we generated single-cell suspensions from the
125 lungs of mock- and WA1-infected mice, and performed Cytometry by Time of Flight (CyTOF)
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126 mass spectrometry before and after stimulation with overlapping 15-mer peptides spanning the
127 entire spike protein. tSNE visualization of the CyTOF data corresponding to total immune
128 (CD45+) cells from the unstimulated specimens revealed that both CD4+ and CD8+ T cells of
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129 infected mice segregate distinctly from their respective counterparts in the mock-infected mice,
130 indicating profound phenotypic changes in pulmonary T cells upon WA1 infection, including
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131 upregulation of activation/exhaustion marker programmed cell death 1 (PD1) on T cells from the
132 infected animals (Fig. 3a).
133 When similar experiments were performed with infections by WA1, Delta, and Omicron,
134 we found elevated expression of not only PD1 but also cytotoxic T-lymphocyte-associated protein
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135 4 (CTLA4, another activation/exhaustion marker) on pulmonary T cells in all infected animals,
136 although to a significantly lesser extent in the Omicron-infected mice (Fig. 3b, c). Despite
137 evidence of pulmonary T-cell exhaustion in mice infected with all three isolates, functional SARS-
138 CoV-2-specific T cells were still generated in the lungs, as demonstrated by our identification of
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139 IFN - and TNF -producing cells specifically in the peptide-stimulated specimens (Fig. 3d, e, f).
140 These results suggest the diminished pro-inflammatory cytokines and activated/exhausted
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141 pulmonary T cells elicited by Omicron associates with diminished Omicron pathogenicity and the
142 23 logs decrease in Omicron replication.
143
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144 Cross-variant neutralization
145 To determine humoral immune responses induced by infection with the three different isolates, we
146 collected sera from mice at 7 days after infection, and tested their neutralization efficiency against
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147 SARS-CoV-2 isolates: WA1, Alpha, Beta, Delta, and Omicron. We determined the plaque-
148 forming units at different serum dilutions and calculated the 50% neutralization titers (NT50) (Fig.
149 4, Extended data Fig. 5). As expected, sera from uninfected mice showed no neutralization across
150 all variants (Fig. 4a). Sera from WA1-infected mice showed effective neutralization of WA1 and
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151 Alpha and, to a lesser extent, Beta and Delta isolates, but no efficacy against Omicron (NT50 6)
152 (Fig. 4b). In contrast, sera from Delta-infected mice effectively neutralized Delta (NT50 422),
153 WA-1 (NT50 275), Alpha (NT50 356), and to a lesser extent Omicron (NT50 115) and Beta (NT50
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154 62), with the latter significantly decreased, compared to Delta and Alpha (Fig. 4c). Omicron
155 infection, however, only induced neutralization of Omicron (NT50 113), but no other isolate
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156 (NT50 37) (Fig. 4d). This was repeated and confirmed in a second experiment in which, 9 days
157 after infection, all mice infected with Omicron showed significant serum neutralization of Omicron
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158 (NT50 92), but no other VOC (NT50 7-16) (Fig. 4e). These results indicate limited cross-variant
159 neutralization induced by Omicron relative to other isolates, which may be due to its highly
160 mutated spike protein or its lower replicative capacity (Fig. 2). Notably, Delta and WA1, despite
161 having similar replicative and inflammatory capacities, exhibited different neutralization profiles,
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162 underscoring the role of the different spike (and possibly other viral) proteins in eliciting cross-
163 variant neutralization.
164 These data were confirmed with sera from 10 unvaccinated individuals, who had recovered
165 from Omicron infection (Extended Data Table 1). These sera showed the same limited cross-
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166 variant neutralization as observed in mice with effective neutralization of only Omicron itself
167 (NT50 1452) and a ~15-fold decrease in neutralizing titers against non-Omicron isolates (NT50
168 1596) (Fig. 5a, Extended data Fig. 6). Analysis of sera from 11 matched, unvaccinated
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169 individuals with Delta infection showed a similar pattern: highest neutralization of Delta itself
170 (NT50 2811), followed by WA1 (NT50 619) and decreased neutralization of Alpha, Beta and
171 Omicron (NT50 41-62) (Fig. 5b, Extended data Fig. 7). Sera from uninfected, unvaccinated
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172 individuals showed no neutralization across all variants as expected (Extended Data Fig. 4a).
173 Notably, sera from vaccinated individuals with confirmed Omicron or Delta breakthrough
174 infections showed high neutralizing titers against all isolates, with highest titers against WA1
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175 (NT50 17994 and 23308) and lowest against Omicron (NT50 1241 and 1692) (Fig. 5c-d). These
176 values exceeded neutralizing titers induced by the third shot of Pfizer/BioNTech vaccines where
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177 titers were, on average, 10 times lower than those observed after breakthrough infections
178 (Extended Data Fig. 4b, Extended data Fig. 8). These results suggest that Omicron and Delta
179 breakthrough infections can boost existing immunity conferred by vaccination, thereby eliciting a
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180 form of hybrid immunity that is effective against not only itself, but also other SARS-CoV-2
181 variants.
182 Collectively, our study shows that, while the Omicron variant is immunogenic, infection
183 in unvaccinated individuals may not elicit effective cross-neutralizing antibodies against non-
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184 Omicron variants. In vaccinated individuals, however, Omicron infection effectively induces
185 immunity against itself and enhances neutralization of other variants. This, together with our
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186 finding that Delta infection also elicits broad cross-variant neutralization in vaccinated individuals,
187 supports the inclusion of Omicron- and Delta-based immunogens in future heterologous or
188 multivalent vaccination strategies for broad protection against variants.
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189
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191 References
192
193 1. Sigal, A. Milder disease with Omicron: is it the virus or the pre-existing immunity? Nat.
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194 Rev. Immunol. 22, 6971 (2022).
195 2. Wolter, N. et al. Early assessment of the clinical severity of the SARS-CoV-2 omicron
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196 variant in South Africa: a data linkage study. Lancet 399, 437446 (2022).
197 3. Dejnirattisai, W. et al. SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from
198 neutralizing antibody responses. Cell (2022) doi:10.1016/j.cell.2021.12.046.
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199 4. Syed, A. M. et al. Omicron mutations enhance infectivity and reduce antibody
200 neutralization of SARS-CoV-2 virus-like particles. medRxiv (2022)
201 doi:10.1101/2021.12.20.21268048.
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202 5. Mannar, D. et al. SARS-CoV-2 Omicron variant: Antibody evasion and cryo-EM structure
203 of spike protein-ACE2 complex. Science eabn7760 (2022).
204 6. Cao, Y. et al. Omicron escapes the majority of existing SARS-CoV-2 neutralizing
205 antibodies. Nature (2021) doi:10.1038/s41586-021-04385-3.
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206 7. VanBlargan, L. A. et al. An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes
207 neutralization by therapeutic monoclonal antibodies. Nat. Med. (2022) doi:10.1038/s41591-
208 021-01678-y. C
209 8. Hoffmann, M. et al. The Omicron variant is highly resistant against antibody-mediated
210 neutralization: Implications for control of the COVID-19 pandemic. Cell 185, 447456.e11
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211 (2022).
212 9. Planas, D. et al. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization.
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213 Nature (2021) doi:10.1038/s41586-021-04389-z.

214 10. Espenhain, L. et al. Epidemiological characterisation of the first 785 SARS-CoV-2 Omicron
215 variant cases in Denmark, December 2021. Euro Surveill. 26, (2021).
216 11. Meng, B. et al. SARS-CoV-2 Omicron spike mediated immune escape, infectivity and cell-
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217 cell fusion. bioRxiv 2021.12.17.473248 (2021) doi:10.1101/2021.12.17.473248.

218 12. Sato, K. et al. Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant.
219 Research Square (2022) doi:10.21203/rs.3.rs-1207670/v1.
220 13. Dejnirattisai, W. et al. Reduced neutralisation of SARS-CoV-2 omicron B.1.1.529 variant
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221 by post-immunisation serum. Lancet (2021) doi:10.1016/S0140-6736(21)02844-0.

222 14. Pulliam, J. R. C. et al. Increased risk of SARS-CoV-2 reinfection associated with
223 emergence of the Omicron variant in South Africa. MedRxiv (2021).
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224 15. Miyamoto, S. et al. Vaccination-infection interval determines cross-neutralization potency

225 to SARS-CoV-2 Omicron after breakthrough infection by other variants. bioRxiv (2022)
226 doi:10.1101/2021.12.28.21268481.
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227 16. Report 50 - Hospitalisation risk for Omicron cases in England. Imperial College London
228 https://www.imperial.ac.uk/mrc-global-infectious-disease-analysis/covid-19/report-50-
229 severity-omicron/.
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230 17. England, P. H. SARS-CoV-2 variants of concern and variants under investigation in
231 England. technical briefing 12 (2021).
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232 18. Shuai, H. et al. Emerging SARS-CoV-2 variants expand species tropism to murines.
233 EBioMedicine 73, 103643 (2021).
234 19. Winkler, E. S. et al. SARS-CoV-2 infection of human ACE2-transgenic mice causes severe
235 lung inflammation and impaired function. Nat. Immunol. 21, 13271335 (2020).
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236 20. Bentley, E. G. et al. SARS-CoV-2 Omicron-B.1.1.529 Variant leads to less severe disease
237 than Pango B and Delta variants strains in a mouse model of severe COVID-19. bioRxiv
238 2021.12.26.474085 (2021) doi:10.1101/2021.12.26.474085.
239 21. Halfmann, P. J. et al. SARS-CoV-2 Omicron virus causes attenuated disease in mice and
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240 hamsters. Nature (2022) doi:10.1038/s41586-022-04441-6.
241 22. Shuai, H. et al. Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529
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242 Omicron. Nature (2022) doi:10.1038/s41586-022-04442-5.
243 23. McMahan, K. et al. Reduced Pathogenicity of the SARS-CoV-2 Omicron Variant in
244 Hamsters. bioRxiv 2022.01.02.474743 (2022) doi:10.1101/2022.01.02.474743.
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245 24. Abdelnabi, R. et al. The omicron (B.1.1.529) SARS-CoV-2 variant of concern does not
246 readily infect Syrian hamsters. Antiviral Res. 198, 105253 (2022).
247 25. Le Bert, N. et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS,
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248 and uninfected controls. Nature 584, 457462 (2020).
249 26. Coperchini, F., Chiovato, L., Croce, L., Magri, F. & Rotondi, M. The cytokine storm in
250 COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system.
251 Cytokine Growth Factor Rev. 53, 2532 (2020).
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254 C
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281
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282 Methods
283
284 Human lung organoids
285 Whole human lung tissue was digested to a single-cell suspension and plated in basement
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286 membrane extract as published27. Briefly, organoids were maintained in DMEM supplemented
287 with supplemented with 10% (vol/vol) R-spondin1 conditioned medium, 1% B27 (Gibco), 25
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288 ng/mL Noggin (Peprotech), 1.25 mM N-acetylcysteine (Sigma-Aldrich), 10 mM nicotinamide
289 (Sigma-Aldrich), 5 nM Herefulin Beta-1 (Peprotech), and 100 µg/mL Primocin (InvivoGen). HAO
290 medium was further supplemented with 5 µM Y-27632, 500 nM A83-01, 500 nM SB202190, 25
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291 ng/mL FGF-7, and 100 ng/mL FGF-10 (all from Stem Cell Technologies). HAO medium was
292 replaced every 3-4 days.
293 A549 cells expressing ACE2 (A549-ACE2) from ATCC and Vero cells expressing
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294 TMPRSS (Vero-TMPRSS2) were a gift from O. Schwartz and S.P.J. Whelan, respectively. A549-
295 ACE2 and Vero-TMPRSS2 cells were cultured in DMEM supplemented with 10% FBS and
296 blasticidin (20 g/ml) (Sigma) at 37°C and 5% CO2. Short terminal repeat analysis by the Berkeley
297 Cell Culture Facility authenticated these as A549 cells with 100% probability.
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298 Vero stably co-expressing human ACE2 and TMPRSS2 cells (gifted from A. Creanga and
299 B. Graham at NIH) were maintained at 37°C and 5% CO2 in DMEM (Gibco) supplemented with
300 10% fetal calf serum, 100 g/mL penicillin and streptomycin (Gibco) and 10 g/mL of puromycin
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301 (Gibco).
302 293T cells stably co-expressing ACE2 and TMPRSS2 were generated by sequential
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303 transduction of 293T cells with TMPRSS2-encoding (generated using Addgene plasmid #170390,
304 a gift from Nir Hacohen and ACE2-encoding (generated using Addgene plasmid #154981, a gift
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305 from Sonja Best) lentiviruses and selection with hygromycin (250 µg/mL) and blasticidin (10
306 µg/mL) for 10 days, respectively. ACE2 and TMPRSS2 expression was verified by western blot.
307
308 SARS-CoV-2 virus culture
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309 SARS-CoV-2/human/USA/USA-WA1/2020 (WA1) (BEI NR-52281), B.1.1.7 (California

310 Department of Health), B.1.351 (BEI NR-54008), B.1.617.2 (California Department of Health)
311 and B.1.1.529 (California Department of Health, BA.1) were used for animal infection studies or
312 serum virus neutralization. The virus infection experiments were performed in a Biosafety Level
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313 3 laboratory. Working stocks of SARS-CoV-2 were made in Vero-TMPRSS2 cells and were stored
314 at -80°C until used.
315 The Omicron variant was isolated from a nasopharyngeal swab sample from a patient
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316 hospitalized with COVID-19 at the University of California, San Francisco (UCSF). A 200 L
317 aliquot of the sample was serially diluted 1:1 with medium (DMEM supplemented with 1x
318 penicillin/streptomycin) in a 96-well plate for five dilutions, in duplicate. Then, 100 L of freshly
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319 trypsinized Vero-hACE2-TMPRSS2 cells, resuspended in infection medium (made as above but
320 with 2x penicillin/streptomycin, 5 g/mL amphotericin B [Bioworld] and no puromycin) were
321 added to the nasal sample dilutions at 2.5x105 cells/mL concentration. Cells were cultured at 37°C
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322 and 5% CO2 and checked for cytopathic effects (CPEs) from day 2-3. Vero-hACE2-TMPRSS2
323 cells formed characteristic syncytia upon infection with SARS-CoV-2, enabling rapid and specific
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324 visual evaluation for CPE. Supernatants were harvested on day 3 after inoculation. A 200 l aliquot
325 of P0 was used to infect a confluent T25 flask to generate a P1 culture, harvested after 3 days.
326 Virus stocks were titered by plaque assay, and the sequence was confirmed by nanopore
327 sequencing.
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329 K18-hACE2 mouse infection model
330 All protocols concerning animal use were approved (AN169239-01C) by the Institutional Animal
331 Care and Use committees at the University of California, San Francisco and Gladstone Institutes
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332 and conducted in strict accordance with the National Institutes of Health Guide for the Care and
333 Use of Laboratory Animal28. Mice were housed in a temperature (65-75 F) and humidity (40-60%)
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334 controlled pathogen-free facility with 12-hour light/dark cycle and ad libitum access to water and
335 standard laboratory rodent chow.
336 Briefly, the study involved intranasal infection (1X104) of 68-week-old female K18-
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337 hACE2 mice with Delta and Omicron, and WA1 served as a control isolate of SARS-CoV-2. A
338 total of 15 animals were infected for each variant. Five mice from each group were euthanized at
339 days 2, 4 and 7 post-infection. The brain, lungs, and upper respiratory tract, including bronchus
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340 and nasal turbinates, were processed for further analysis of virus replication.
341
342 Cellular infection studies
343 A549-ACE2 cells were seeded into 12-well plates. Cells were rested for at least 24 hours prior to
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344 infection. At the time of infection, medium containing viral inoculum (MOI 0.01 and 0.1) was
345 added on the cells. At 1 h after addition of inoculum, the medium was replaced with fresh medium
346 without viral inoculum. Supernatants were harvested at 24, 48, and 72 h post-infection for further
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347 plaque assays.
348
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349 Organoid infection studies
350 Organoids were plated on geltrex-coated plates (ThermoFisher, 12760013) with 100,000 cells per
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351 well, and infected at an MOI of 1. At 2 h after addition of the inoculum, the supernatant was
352 removed, cells were washed with PBS, and fresh HAO medium was added. Supernatants were
353 harvested for a plaque assay at 24 and 48 h.
354
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355 Virus neutralization assay

356 K18-hACE2 mice infected with 1X104 plaque forming units of WA1, B.1.617.2 and B.1.1.529
357 (n=5). With the early humane endpoints with WA1 and B.1.617.2, more animals (n=15) were
358 infected for these groups. Serum samples from mice were collected at 7 days post-infection. Mock-
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359 infected animals served as controls. Serum dilutions (50 µL) were made to get final dilutions of
360 1:30, 1:90, 1:270, 1:810, 1:2430, and 1:7290 in serum-free DMEM. Dilutions were separately
361 added with 50 PFU (50 µL) of SARS-CoV-2 WA1, Alpha, Beta, Delta, and Omicron. The mixture
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362 was mixed gently, incubated at 370C for 30 mins, followed by a plaque assay. Similar assays were
363 performed for serum samples from Omicron-infected (5 x 102) mice obtained at 9 dpi, and human
364 serum samples acquired from ongoing clinical trials led by Curative and UCSF or from
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365 hospitalized patients at UCSF (Extended Data Table 1). The virus neutralization efficacy of sera
366 was presented as 50% neutralization titer (NT50) and the average of each variant and compared to
367 others in terms of fold-change. NT50 graphs were generated by MATLAB (Version 9.12). Data
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368 analysis was performed by using GraphPad Prism version 9.3.

369
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370 Plaque assays

371 Tissue homogenates and cell supernatants were analyzed for viral particle formation for in vivo
372 and in vitro experiments, respectively. Briefly, Vero-TMPRSS2 were seeded and incubated
373 overnight. Cells were inoculated with 10-1 to 10-6 dilutions of the respective homogenates or
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374 supernatant in serum-free DMEM. After the 1-h absorption period, the media in the wells were
375 overlaid with 2.5% Avicel (Dupont, RC-591). After 72 h, the overlay was removed, and the cells
376 were fixed in 10% formalin for 1 h and stained with crystal violet for visualization of plaque
377 forming units. Data analysis was performed by using GraphPad Prism version 9.3.
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378
379 Quantitative polymerase chain reaction
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380 RNA was extracted from cells, supernatants, or tissue homogenates with RNA-STAT-60
381 (AMSBIO, CS-110) and the Direct-Zol RNA Miniprep Kit (Zymo Research, R2052). RNA was
382 then reverse-transcribed to cDNA with iScript cDNA Synthesis Kit (Bio-Rad, 1708890). qPCR
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383 reaction was performed with cDNA and SYBR Green Master Mix (Thermo Scientific) using the
384 CFX384 Touch Real-Time PCR Detection System (Bio-Rad). See Extended Data Table 2 for
385 primers sequences. N gene standards were used to generate a standard curve for copy number
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386 quantification. N gene standard was generated by PCR using extracted genomic SARS-CoV-2
387 RNA as template. A single product was confirmed by gel electrophoresis, and DNA was quantified
388 by Nanodrop.
389
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390 CyTOF analysis of mouse lung specimens
391 The mice used in the CyTOF study were infected with 5x102 PFU of WA1 and monitored for
392 clinical signs of infection (e.g., body weight and body temperature) starting from day 1 to day 9
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393 post-infection. CyTOF was conducted as described29. Single-cell suspensions of lung tissue
394 specimens processed using the GentleMACS system (Miltenyi) were treated with 25 M cisplatin
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395 (Sigma) for 60 sec as a viability dye. Cells were then quenched with CyFACS buffer (PBS
396 supplemented with 0.1% BSA and 0.1% sodium azide) and fixed for 10 min with 2%
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397 paraformaldehyde (PFA; Electron Microscopy Sciences). Cells were then washed twice with
398 CyFACs and frozen at 80°C until CyTOF antibody staining. Prior to antibody staining, specimens
399 were barcoded using the Cell IDTM 20 Plex PD Barcoding kit (Fluidigm, South San Francisco,
400 CA, USA). Fc blocking was performed by treating the cells with 1.5% mouse and rat sera (both
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401 from Thermo Fisher) for 15 min at 4°C. After washing with CyFACS, cells were stained for 45
402 min at 4°C with the cell-surface antibodies listed in Extended Table 3. Antibodies were purchased
403 pre-conjugated from Fluidigm or conjugated using the Maxpar® X8 antibody labeling kit
404 (Fluidigm). After staining, cells were washed with CyFACS and fixed overnight at 4°C in 2% PFA
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405 and permeabilized for 30 min with Foxp3 Fix/Permeabilization Buffer (Fisher Scientific). After
406 two washes with Permeabilization Buffer (Fisher Scientific), cells were Fc blocked again for 15
407 min at 4°C with mouse and rat sera diluted in Permeabilization Buffer. After washing with
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408 Permeabilization Buffer, cells were stained for 45 min at 4°C with the intracellular antibodies
409 listed in Extended Data Table 3. The details about the antibody dilutions have been provided in
410 the Extended Data Table 3. Prior to CyTOF analysis, cells were incubated for 20 min with a
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411 1:500 dilution DNA intercalator (Fluidigm), and then washed twice with CyFACS and once with
412 Cell Acquisition Solution (CAS, Fluidigm). Acquisition was performed in the presence of EQTM
413 Four Element Calibration Beads (Fluidigm) diluted in CAS. Cells were analyzed on a CyTOF 2
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414 instrument (Fluidigm) at the UCSF Parnassus Flow Core. For data analysis, CyTOF datasets were
415 normalized to EQ calibration using CyTOF software (6.7.1014, Fluidigm) and manually gated
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416 using the FlowJo software (10.7.2, FlowJo LLC, BD Biosciences). tSNE visualizations of the
417 datasets were performed in Cytobank (9.1, 2022 Cytobank, Inc.), with default settings.
418
419
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420 Histology
421 Mouse lung tissues were fixed in 4% paraformaldehyde (Sigma 47608) for 24 h, washed three
422 times with PBS, and stored in 70% ethanol. Briefly, tissues were processed and embedded in
423 paraffin, and tissue sections were stained for SARS-CoV-2 Nucleocapsid (Genetex, GTX135357).
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424 The sections were then imaged using Leica Aperio ImageScope.
425
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426 Human serum samples
427 Human serum samples were acquired from two ongoing clinical trials led by Curative and UCSF.
428 The Curative clinical trial protocol was approved by Advarra under Pro00054108 for a study
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429 designed to investigate immune escape by SARS-CoV-2 variant (University of California, Los
430 Angeles Protocol Record PTL-2021-0007, ClinicalTrials.gov Identifier NCT05171803). Sample
431 specimens were collected from adults (1850 years) who either had been vaccinated for COVID-
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432 19 and/or had a history of COVID-19. Sample acquisition involved standard venipuncture
433 procedure to collect a maximum of 15 ml of whole blood, incubation at ambient temperature for
434 3060 min to coagulate, centrifugation at 22002500 rpm for 15 min at room temperature, and
435 storage on ice until delivered to the laboratory for serum aliquoting and storage at 80 ºC until
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436 use. A quantitative SARS-CoV-2 IgG ELISA was performed on serum specimens (EuroImmun,
437 Anti-SARS-CoV-2 ELISA (IgG), 26069621G, New Jersey). Remnant plasma samples from
438 patients hospitalized with COVID-19 at UCSF were obtained from UCSF Clinical Laboratories
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439 daily, based on availability. Remnant samples were aliquoted and biobanked and the retrospective
440 medical chart review for relevant demographic and clinical metadata were performed under a
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441 waiver of consent and according to no subject contact protocols approved by the UCSF
442 Institutional Review Board (protocol number 10-01116). Plasma samples were also collected
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443 through the UMPIRE (UCSF EMPloyee and community member Immune REsponse) study
444 (protocol number 20-33083), a longitudinal COVID-19 research study focused on collection of
445 prospective whole-blood and plasma samples from enrolled subjects to evaluating the immune
446 response to vaccination, with and without boosting, and/or vaccine breakthrough infection. The
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447 study cohorts included (1) fully vaccinated individuals with either two doses of Emergency Use
448 Authorization (EUA)-authorized mRNA vaccine (Pfizer or Moderna). Consented participants
449 came to a UCSF CTSI Clinical Research Service (CRS) Laboratory where their blood was drawn
450 by nurses and phlebotomists. At each visit, two to four 3-mL EDTA tubes of whole blood were
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451 drawn, and one or two EDTA tubes were processed to plasma from each timepoint. Relevant
452 demographic and clinical metadata from UMPIRE participants were obtained through participant
453 Qualtric surveys performed at enrollment and at each blood draw. Serum samples were heat
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454 inactivated at 56°C for 30 mins prior to use in neutralization assays.

455 For adequate sample selection, the criteria were age, disease severity, and days after
456 infection for serum collection. A Wilcoxon-Mann-Whitney significance test was performed
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457 between the unvaccinated + Omicron infected and unvaccinated + Delta infected individuals,
458 which showed no statistical significance in serum collection days after infection (p=0.147540),
459 disease severity index (p=0.820174) and age of the individuals (p=0.591680). A Wilcoxon-Mann-
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460 Whitney significance test was also performed between the vaccinated + Omicron infected and
461 vaccinated + Delta infected individuals and showed no significant difference in serum collection
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462 days after infection (p-value: 0.5267) and age of the individuals (p=0.065).
463
464
465 References:
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466
467 27. Sachs, N. et al. Long-term expanding human airway organoids for disease modeling. EMBO
468 J. 38, (2019).
469 28. National Research Council, Division on Earth and Life Studies, Institute for Laboratory
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470 Animal Research & Committee for the Update of the Guide for the Care and Use of
471 Laboratory Animals. Guide for the Care and Use of Laboratory Animals: Eighth Edition.
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472 (National Academies Press, 2011).
473 29. Neidleman, J. et al. mRNA vaccine-induced T cells respond identically to SARS-CoV-2
474 variants of concern but differ in longevity and homing properties depending on prior
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475 infection status. Elife 10, (2021).
476
477
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478 Acknowledgements
479
480 This research is funded by grants from the National Institutes of Health: NIH/NIAID (F31
481 AI164671-01) to I.P.C., NHLBI U54HL147127 to M.M. A.M.S is supported by Natural Sciences
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482 and Engineering Research Council of Canada (NSERC PDF-533021-2019). M.O. and W.C.G also
483 received support from the Roddenberry Foundation, from Pam and Ed Taft and the Gladstone
484 Institutes. M.O. thanks Fast Grants and the Innovative Genomics Institute for support. J.A.D.
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485 acknowledges support from the National Institutes of Health (R21AI59666) and support from the
486 Howard Hughes Medical Institute and the Gladstone Institutes. N.R.R. acknowledges support from
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487 the Van Auken Private Foundation, David Henke, and Pamela and Edward Taft; and Awards
488 #2164 and #2208 from Fast Grants, a part of Emergent Ventures at the Mercatus Center, George
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489 Mason University. C.Y.C thanks the staff at UCSF Clinical Laboratories and the UCSF Clinical
490 Microbiology Laboratories for help in identifying and aliquoting nasal swab and plasma samples.
491 CYC acknowledges support by the Innovative Genomics Institute at UC Berkeley and UCSF, US
492 Centers for Disease Control and Prevention contract 75D30121C10991, Abbott Laboratories, and
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493 the Sandler Program for Breakthrough Biomedical Research at UCSF. We thank Stanley Tamaki
494 and Claudia Bispo for CyTOF assistance at the Parnassus Flow Core, and the lab of Eliver Ghosn
495 for guidance on lung cell processing. We thank the Gladstone Histology Core. The group also
496 acknowledges support from the James B. Pendleton Charitable Trust. The funders had no role in
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497 study design, data collection and analysis, decision to publish, or preparation of the manuscript.
498
499 Data Availability Statement
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500 The datasets generated during and/or analyzed during the current study are available in the
501 manuscript or in the Extended data set.
502
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503 Author Contributions

504 Conceptualization: RKS, IPC, MO
505 Investigation: RKS, IPC, TM, AMS, CRS, AC, MMK, BS, PC, AG
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506 Anti-sera: NB, PS, AS, VS, AG, JN, IS, BM, NK, VH, MS, LL, MB, FT, FWS, CYC, LS
507 Omicron virus culture: MAG, MKM, DW, CH, RA
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508 Lung tissue for organoids: XF, MM, MM

509 BSL3 facility maintenance: MM
510 Supervision: LS, JAD, NRR, CYC, MO
511 Writing - original draft: RKS, IPC, MO
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512 Writing - reviewing, & editing: RKS, IPC, GRK, WCG, TM, NR, MO
513
514 Competing Interests
515 J.A.D. is a cofounder of Caribou Biosciences, Editas Medicine, Scribe Therapeutics, Intellia
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516 Therapeutics, and Mammoth Biosciences. J.A.D. is a scientific advisory board member of Vertex,
517 Caribou Biosciences, Intellia Therapeutics, eFFECTOR Therapeutics, Scribe Therapeutics,
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518 Mammoth Biosciences, Synthego, Algen Biotechnologies, Felix Biosciences, The Column Group,
519 and Inari. J.A.D. is a director at Johnson & Johnson and Tempus and has research projects
520 sponsored by Biogen, Pfizer, AppleTree Partners, and Roche. C.Y.C. is the director of the UCSF-
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521 Abbott Viral Diagnostics and Discovery Study and receives research support from Abbott
522 Laboratories. C.Y.C. also receives support for SARS-CoV-2 research unrelated to this study from
523 Mammoth Biosciences.
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524
525
526 Figure Legends
527
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528 Fig. 1 | Robust infection of K18-hACE2 mice with Delta and ancestral variant, but not
529 Omicron. a, Schematic of the experiment. Fifteen mice per group were intranasally infected with
530 104 PFU of the indicated variant. Body temperature and weight were monitored daily. At days 2,
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531 4, and 7 post-infection (dpi), the upper respiratory tract and lungs were harvested and processed
532 for downstream analysis. n=5 per group b, Changes in body temperature of mice infected with
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533 WA1 (grey), Delta (purple), and Omicron (teal). Data are shown as the average ± SD and analyzed
534 by 2-way ANOVA and adjusted for multiple testing using the Bonferroni test. c, Severe weight
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535 loss of WA1- and Delta-infected mice. Data are shown as the average ± SD and analyzed by 2-
536 way ANOVA and adjusted for multiple testing using the Bonferroni test. d, Probability of survival
537 of variant-infected mice.
538
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539 Fig. 2 | Robust viral replication of WA1 and Delta, but not Omicron, in mice and human
540 airway cells. a, Plaque assay titers from the upper airway (nasal turbinates and bronchus) of WA1-
541 (grey), Delta- (purple), and Omicron- (teal) infected mice at the indicated time points. Data are
542 shown as the average ± SEM analyzed by the two-tailed unpaired students t-test. Each dot
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543 represents infectious virus titer in an individual mouse, 2 dpi (n=5), 4 dpi (n=5), and 7 dpi (WA1
544 infection group n=2, Delta n=2 and Omicron n=5). b, Plaque assay titers from the lungs of infected
545 mice at the indicated time points. Data are shown as the average ± SEM at each time point and
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546 analyzed by the two-tailed unpaired students t-test. Each dot represents infectious virus titer in
547 individual mice 2 dpi (n=5), 4 dpi (n=5), and 7 dpi (WA1 infection group n=2, Delta n=2 and
548 Omicron n=5). c, Plaque assay titers from supernatants of infected human airway organoids
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549 (multiplicity of infection [MOI] of 1). Data are shown as the average. Each dot represents
550 independent experiment using human lung airway organoids generated, 24h n=2, 48h n=3 where
551 each dot represents independent experiment using human lung airway organoids. d, Plaque assay
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552 titers from supernatants of infected A549-ACE2 cells (MOI of 0.1), n= 2 represents infectious
553 virus titer in independent experiment.
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554
555 Fig. 3 | Ancestral and variant of concern SARS-CoV-2 elicit immune responses in lungs of
556 mice. a, T cells from lungs of infected mice (n=3) were phenotypically distinct and expressed PD1.
557 Single-cell suspensions of lungs from mock infected (top two rows) and WA1-infected (bottom
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558 two rows) K18-hACE2 mice were harvested 9 dpi and analyzed by CyTOF. Shown are tSNE plots
559 gated on total immune cells (CD45+) from the lungs of the mice, colored by expression levels of
560 the antigen listed at the top (red = highest expression, blue = lowest expression). Islands of CD4+
561 and CD8+ T cells unique to the infected mice (identified by the green and purple arrows,
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562 respectively, in the third row) express especially high levels of the activation/exhaustion marker
563 PD1, as demonstrated in the right-hand column. b-c, T cells from lungs of infected mice (n=3)
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564 expressed elevated levels of the activation/checkpoint antigens PD1 and CTLA4. The proportions
565 of CD4+ and CD8+ T cells expressing PD1, CTLA4, or both PD1 and CTLA4, are indicated. d,
566 SARS-CoV-2-specific T cells are elicited in lungs of SARS-CoV-2-infected mice. Representative
EV
567 plots corresponding to pulmonary T cells from uninfected (Mock) and WA1-infected K18-hACE2
568 mice, stimulated for 6 h with (bottom) or without (top) overlapping SARS-CoV-2 spike peptides.
569 Note SARS-CoV-2-specific T cells (those producing IFN and/or TNF ) were only detected in
PR
570 infected mice after peptide stimulation, (n=3). e-f, SARS-CoV-2-specific T cells are elicited in
571 lungs of mice infected with WA1 (n=6), Delta (n=3), and Omicron (n=3). The proportions of CD4+
572 and CD8+ T cells expressing IFN and/or TNF (gated as shown in panel C) are indicated. CD4+
573 T-cell responses trended highest in Delta-infected mice, and the CD8+ T-cell responses were
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574 highest in Delta- and Omicron-infected mice n=3. b-c and e-f, data are shown as the average ±
575 SEM analyzed by the two-tailed unpaired students t-test.
576 C
577 Fig. 4 | Cross-variant neutralization of SARS-CoV-2 isolates by sera from infected mice. K18-
578 hACE2 mice were infected with 1x104 PFU of WA1, Delta or Omicron. Virus neutralization assay
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579 was carried out with sera collected at 7 dpi. Data points in the graph represent individual sera
580 samples showing 50% neutralization titer (NT50) against SARS-CoV-2 isolates. The numbers in
AR
581 parentheses indicate the fold-change in neutralization efficacy or resistance of respective isolates
582 relative to NT50 of ancestral isolate (WA1). The grey band at the bottom of the graph indicates
583 the limit of detection. a-d, Graphs representing NT50 of sera from a, naive, b, WA1-infected, c,
584 Delta-infected, and d, Omicron-infected mice against different viral isolates. n=5 mouse in each
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585 group. e, K18-hACE2 mice were infected with 5x102 PFU of Omicron, n=5. Virus neutralization
586 assay was carried out with serum collected at 9 dpi. Data are presented as average ± SEM and
587 analyzed by 2-way ANOVA and two-tailed unpaired students t-test.
588
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589 Fig. 5 | Cross-variant neutralization of SARS-CoV-2 isolates by human sera. a-d, Graphs
590 representing NT50 of variants by sera from a, Unvaccinated individuals with likely Omicron
591 infection (based on date of collection), n=10, b, unvaccinated individuals with likely Delta
ER
592 infection (based on date of collection), n=11, c, vaccinated individuals with a confirmed Omicron
593 infection, n=8, and d, vaccinated individuals with a Delta infection (based on date of collection).
594 Data points in the graph represent individual serum samples. The grey band at the bottom of the
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595 graph indicates the limit of detection. Data are presented in a-d is average ± SEM and analyzed by
596 2-way ANOVA and two-tailed unpaired students t-test. The details regarding samples (group,
597 age, sex, COVID-19 infection status, vaccination dates, and sample collection dates after
C
598 infection/symptoms are summarized in Extended Data Table 1).

599
AC
600 Figure legends for extended data

601
602 Extended Data 1| Physical conditions of the infection mice at 5 dpi. a, Representative images
603 of WA1-, Delta-, and Omicron-infected mice 5 dpi. WA1-infected mice were lethargic and had a
AR07673
604 hunched posture, ungroomed coat, and squinted eyes. Delta-infected mice are mildly lethargic.
605 Omicron-infected mice appeared normal. b, Representative images of lungs from mice infected
606 with WA1, Delta, or Omicron at 2 dpi (n=5), 4 dpi (n=5), and 7 dpi (WA1 infection group n=2,
607 Delta n=2 and Omicron n=5). SARS-CoV-2 nucleocapsid is stained in green and nucleus is stained
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608 in blue. Scale bar, 2 mm. c, Representative images of tissue sections from lung tissue infected with
609 WA1, Delta, or Omicron collected at 7 dpi (WA1 infection group n=2, Delta n=2 and Omicron
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610 n=5). SARS-CoV-2 nucleocapsid is stained in green and nucleus is stained in blue. Scale bar, 300
611 m. d, Representative images of mock infected lungs. SARS-CoV-2 nucleocapsid is stained in
612 green and nucleus is stained in blue. Scale bar, 2 mm (left panel) and 300 m (right panel), n=5
EV
613 mice.
614
615 Extended Data 2 | Lower viral replication of Omicron in mice and human cells. a, RT-qPCR
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616 of SARS-CoV-2 N RNA isolated from upper respiratory tract (nasal turbinates and bronchus) of
617 WA1-(grey), Delta-(purple), and Omicron-(teal) infected mice at indicated time points. Data are
618 expressed in absolute copies/ g based on a standard curve of N gene with known copy number.
619 Data are shown as an average ± SEM at 2 dpi (n=5), 4 dpi (n=5), and 7 dpi (WA1 infection group
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620 n=2, Delta n=2 and Omicron n=5) and analyzed by two-tailed unpaired students t-test. b, RT-
621 qPCR of SARS-CoV-2 N RNA isolated from lungs of infected mice at indicated time points. Data
622 are expressed in absolute copies/ g based on a standard curve of N gene with known copy number.
C
623 Data are shown as an average ± SEM at 2 dpi (n=5), 4 dpi (n=5), and 7 dpi (WA1 infection group
624 n=2, Delta n=2 and Omicron n=5) and analyzed by the two-tailed unpaired student's t-test. c,
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625 Plaque assay titers from the brains of infected mice at indicated time points. Data are shown as an
626 average ± SEM at 4 dpi (n=5) and 7 dpi (WA1 infection group n=2, Delta n=2 and Omicron n=5)
AR
627 and analyzed by the two-tailed unpaired students t-test. d, RT-qPCR of SARS-CoV-2 N RNA
628 isolated from brains of infected mice at indicated time points. Data are expressed in absolute
629 copies/ g based on a standard curve of N gene with known copy number. Data are shown as an
630 average ± SEM at 4 (n=5) and 7 (n=25) dpi and analyzed by the two-tailed unpaired student's t-
ED
631 test. e, Plaque assay titers from supernatants of infected A549-ACE2 (MOI of 0.01). Data are
632 shown as average ± SEM, n=2.
633
AT
634 Extended Data 3 | Differential expression of proinflammatory markers in lungs of infected

635 mice. a, RT-qPCR of proinflammatory cytokines and chemokines from RNA isolated from lungs
636 of infected mice at the indicated time points. Data are expressed relative to mock-infected mice.
637 Data are shown as the average ± SEM at 2 dpi (n=5), 4 dpi (n=5), and 7 dpi (WA1 infection group
ER
638 n=2, Delta n=2 and Omicron n=5) and analyzed by two-tailed unpaired students t-test. b, RT-
639 qPCR of interferon-stimulated genes from RNA isolated from lungs of infected mice at the
640 indicated time points. Data are expressed relative to mock-infected mice. Data are shown as the
EL
641 average ± SEM at 2 dpi (n=5), 4 dpi (n=5), and 7 dpi (WA1 infection group n=2, Delta n=2 and
642 Omicron n=5) and analyzed by the two-tailed unpaired students t-test.
643
C
644 Extended Data 4 | Cross-variant neutralization of SARS-CoV-2 isolates by human sera.

645 Graphs representing NT50 of sera from a, naive and b, vaccinated and Pfizer-boosted individuals
AC
646 against different viral isolates, n=5 in each group. The average neutralization efficacies of sera
647 from each graph are shown and fold-changes relative to ancestral isolate (WA1) are shown in
648 parentheses. The grey band indicates the limit of detection. Data are shown as the average ± SEM
649 and analyzed by 2-way ANOVA and adjusted for multiple testing using the Bonferroni test.
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650
651 Extended Data 5 | Sera neutralizing titer assays of from SARS-CoV-2-infected mice.
652 Neutralization assays of sera from a, naive (representative), b, WA1-, c, Delta-, and d, Omicron-
653 infected mice at 7 days post-infection against WA1, Alpha, Beta, Delta, and Omicron isolates. e,
W
654 Neutralization assays of sera from Omicron-infected mice at 9 days post-infection against WA1,
655 Alpha, Beta, Delta, and Omicron isolates.
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656
657 Extended Data 6 | Sera neutralizing titer assays of individuals infected with Omicron.
658 Neutralization assays of sera from a, unvaccinated and b, vaccinated individuals infected with
EV
659 Omicron (likely based on time of collection) against WA1, Alpha, Beta, Delta, and Omicron
660 isolates.
661
PR
662 Extended Data 7 | Sera neutralizing titer assays from individuals infected with Delta.
663 Neutralization assays of sera from a, unvaccinated and b, vaccinated individuals infected with
664 Delta (likely based on time of collection) against WA1, Alpha, Beta, Delta, and Omicron isolates.
665
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666 Extended Data 8 | Sera neutralizing titer assays from individuals. Neutralization assays of sera
667 from a, naive and b, vaccinated and Pfizer boosted individuals against WA1, Alpha, Beta, Delta,
668 and Omicron isolates. C
669
670 Extended data Table 1: Clinical data of patients. (N=47) included in the study. The human
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671 samples were acquired through clinical trials led by Curative Inc. and University of California,
672 San Francisco (UCSF). F= Female, M= Male, N/A- Not applicable, severity index: 1-mild, 2-
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673 moderate, 3-severe.

674
675 Extended data Table 2: List of qPCR primers for mouse studies. The primers used to analyze
676 cytokine expression in SARS-CoV-2- or mock-infected mice are listed.
ED
677
678 Extended data Table 3: List of CyTOF-staining antibodies for mouse studies. The table
679 describes antibody reagents used to analyze the immune response in SARS-CoV-2- or mock-
680 infected mice by CyTOF.
AT
ER
EL
C
AC
AR07675
W
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EV
PR
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a b 4
temperature (oC)
2
K18-hACE2, Intranasal
Change in
WA1, Delta, Omicron 0
p<0.0001
C -2
-4
-6
TI
DPI: -8
Harvest Tissue 0 1 2 3 4 5 6 7
for qPCR and Plaque Assay Days post infection
AR
c d
10
Probability of Survival
100
0
% Weight
-10 50
ED
-20
-30 0
0 1 2 3 4 5 6 7 0 2 4 6 8
Days post infection Days post infection
WA1 Delta Omicron
AT
ER
EL
C
AC
AR07676
W
IE
EV
PR
108 108 108
107 107 107
106 106 106
PFU/mL
105 105 105
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104 104 104
103 103 103
102 102 102
101 101 C 101
108 108 108

TI
107 107 107
106 106 106
105 105 105
AR
104 104 104

103 103 103
102 102 102
101 101 101
ED
Human Airway Organoids A549-ACE2

104 107
106
103
PFU/mL
105
AT
104
102
103
101 102
ER
24hpi 48hpi 24hpi 48hpi 72hpi
WA1 Delta Omicron

EL
C
AC
AR07677
W
IE
EV
PR
LE
C
TI
AR
% PD1+ CD4+ % CTLA4+ CD4+ % PD1+ CTLA4+ CD4+ % SARS-CoV-2 Specific CD4+
100 60 60 4
3
ED
80 2
40 40 1
60
0.2
40
20 20
20 0.1
0 0 0 0.0
AT
% PD1+ CD8+ % CTLA4+ CD8+ % PD1+ CTLA4+ CD8+ % SARS-CoV-2 Specific CD8+
100 50 50 0.4
80 40 40
0.3
60 30 30
0.2
ER
40 20 20
20 10 10 0.1
0 0 0 0.0
Mock WA1 Delta Omicron
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C
AC
AR07678
W
IE
EV
PR
1024 1024
NT50
NT50
32 32
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C
TI
1024 1024
AR
NT50
NT50
32 32
ED
WA1
1024
AT
Alpha
Beta
NT50
32
Delta
ER
Omicron
EL
C
AC
AR07679
W
IE
EV
PR
Unvaccinated + Omicron Unvaccinated + Delta
32768 32768
LE
1024 1024
NT50
NT50
32
C 32
TI
AR
Vaccinated + Omicron Vaccinated + Delta

ED
32768 32768
1024 1024
NT50
NT50
AT
32 32
ER
WA1 Alpha Beta Delta Omicron

EL
C
AC
c
a
d
b
Mock Infected 7 dpi 4 dpi 2 dpi
AC
C
AR07680
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Extended Data Fig. 1
WA1
ER
AT
ED
AR
Delta
TI
C
LE
PR
Omicron
EV
IE
W
AR07681
a 2 dpi 4 dpi 7 dpi
p<0.0001
p=0.031
p=0.04
105 105 p=0.039 105
Copies of N/ug of RNA

p=0.02
104 104 104
103 103 103
W
102 102 102
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101 101 101
EV
A1
ta
A1
ta
A1
ta
n
ro
ro
ro
el
el
el
W
W
ic
ic
ic
D
D
m
m
O
O
b 107 p=0.0002
107 107 p=0.02
PR

106 106 106
105 105 105
104 104 104
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103 103 103
102 102 C 102
101 101 101

TI
A1
ta
A1
ta
A1
ta
n
ro
ro
ro
el
el
el
W
W
ic
ic
ic
D
D
m
m
AR
O
O
4 dpi 7 dpi
c p<0.0001
e
p<0.001 p<0.0001 A549-ACE2
1011 1011
105
ED
1010 1010
109 109
104
108 108
107 107
PFU/mL
PFU/mL
103
PFU/mL
AT
106 106
105 105 102
104 104
103 103 101
ER
102 102
101 101 100
24hpi 48hpi 72hpi
A1
ta
A1
ta
on
ro
EL
el
el
r
W
W
ic
ic
D
D
m
WA1 Delta Omicron

O
p=0.003
d p=0.0006
C
106 106
105 105
AC
104 104
103 103
102 102
101 101
100 100
A1
ta
A1
ta
n
ro
ro
el
el
W
W
ic
ic
D
D
m
m
O
O
AR07682
a CXCL10 IL1
CCL2
p=0.008 8
250 8000
0.006
Relative Expression
Relative Expression
Relative Expression
200 6
6000
p=0.006
150
4000 p=0.001 4
p=0.03
100
2000 2
50
0 0
W
0
2dpi 4dpi 7dpi 2dpi 4dpi 7dpi
2dpi 4dpi 7dpi
ISG15 IFN 4 OAS1

b
IE
200 15 4
p=0.008
Relative Expression
Relative Expression
Relative Expression
EV
150 3
10
100 2
PR
5
50 1
0 0 0
2dpi 4dpi 7dpi 2dpi 4dpi 7dpi 2dpi 4dpi 7dpi
LE
WA1 Delta Omicron
C
TI
AR
ED
AT
ER
EL
C
AC
AR07683
a Naïve b Vaccinated + Boost
p=0.0194
p=0.006
32768 1466
32768
347 354
181 156
W
(4.2x) (4.1x)
(8.1x) (9.4x)
1024
IE
1024
NT50
NT50
EV
32 32
PR
LE
A1
ta
ta
n
ph
ro
A1
ta
a
ta
n
Be
el
W
ph
ro
ic
D
Be
el
Al
W
m
ic
D
Al
O
m
C
O
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AR
ED
AT
ER
EL
C
AC
a
Omicron Delta Alpha Beta WA1
1
Extended
AR07684
AC
b
d
Omicron Delta Alpha Beta WA1 Omicron Delta Alpha Beta WA1
Data Fig. 5
1
1
EL
2
2
ER
3
3
AT
4
4
ED 5
5
AR
e
c
Omicron Delta Alpha Beta WA1 Omicron Delta Alpha Beta WA1
TI
C
1
1
LE
2
2
PR
3
3
EV
4
4
I EW
5
5
AR07685
a
O11 O13 O14 O15 O52 O55 O57 O59 O64 O68
WA1
Beta
EW
Alpha
Delta
I
EV
Omicron
PR
b
O1 O4 O9 194 205 209 228 UMPIRE-1 UMPIRE-2
WA1
LE
Beta
C
Alpha
TI
AR
Delta
Omicron
ED
AT
ER
EL
C
AC
AR07686
a
UD5 UD6 UD7 UD8 UD9 UD10 UD11 UD12 UD14 UD15 UD16
WA1
Beta
EW
Alpha
Delta
I
EV
Omicron
PR
b B4 B5 B6 B47 B61 B71 B75 B83
WA1
LE
Beta
C
Alpha
TI
AR
Delta
Omicron
ED
AT
ER
EL
C
AC
AR07687
a
CUR01 CUR02 CUR03 CUR04 CUR05
WA1
EW
Beta
I
EV
Alpha
PR
LE
Delta
C
TI
Omicron
AR
b P0501 P0521 P0534 P0543 P0545

ED
WA1
AT
ER
Beta
EL
Alpha
C
AC
Delta
Omicron
Extended Data Table 1
AR07688
W
IE
EV
PR
LE
C
TI
AR
ED
AT
ER
EL
C
AC
AR07689
W
IE
EV
PR
LE
C
TI
AR
ED
AT
ER
EL
C
AC
AR07690
W
IE
EV
PR
LE
C
TI
AR
ED
AT
ER
EL
C
AC
AR07691
AR07692
AR07693
α
β
α
γ
̊
AR07694
AR07695
Key Messages:
• Within 4 weeks following infection, 90-99% of individuals infected with the SARS-CoV-2 virus develop detectable
neutralizing antibodies.
• The strength and duration of the immune responses to SARS-CoV-2 are not completely understood and currently available
data suggests that it varies by age and the severity of symptoms. Available scientific data suggests that in most people
immune responses remain robust and protective against reinfection for at least 6-8 months after infection (the longest
follow up with strong scientific evidence is currently approximately 8 months).
• Some variant SARS-CoV-2 viruses with key changes in the spike protein have a reduced susceptt"bility to neutralization
by antibodies in the blood. While neutralizing antibodies mainly target the spike protein, cellular immunity elicited by
natural infection also target other viral proteins, which tend to be more conserved across variants than the spike protein.
The ability of emerging virus variants (variants of interest and variants of concern) to evade immune responses is under
investigation by researchers around the world.
• There are many available serologic assays that measure the antt"body response to SARS-CoV-2 infection, but at the present
time, the correlates of protection are not well understood.
Objective of the scientific brief

This scientific brief replaces the WHO Scientific Brief entitled "'Immunity passports' in the context of COVID- I 9", published 24
1
April 2020. This update is focused on what is currently understood about SARS-CoV-2 immunity from natural infection. More
information about considerations on vaccine certificates or "passports"will be covered in an update of WHO interim guidance, as
requested by the COVID-19 emergency committee.2
Methods
A rapid review on the subject was undertaken and scientific journals were regularly screened for articles on COVID-19 immunity
to ensure to include all large and robust studies available in the literature at the time of writing.
COVID-19 immune responses to natural infection

Prior exposure to SARS-CoV-2 can be assessed by detecting the presence of virus-specific antibodies in serum. Functional
neutralizing antibodies (NAb) are those able to neutralize the virus by blocking its entry into the cell.
Large cohort studies have reported that 90-99% of SARS-CoV-2 infected individuals develop neutralizing antibodies within 2-4
weeks after infection.3-7 A small proportion of individuals do not develop NAb after SARS-CoV-2 infection for reasons that are
7
unclear. Individuals with mild or asymptomatic infection tend to have lower antibody levels than those with severe disease, and
some studies have suggested that in some individuals waning of antl"body levels occurs within several months after infection.6--lO
Studies aimed to detect immunological memory including the assessment ofcellular immunity by testing for the presence ofmemory
B cells, and eo4+ and cog+ T cells, observed robust immunity at 6 months post-infection in 95% of subjects under study, which
included individuals with asymptomatic, mild, moderate and severe infections. 11
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COVID-19 natural immunity: Scientific brief
AR07696
Correlates of protection against disease
How much cellular versus humoral immunity contributes to protection after natural infection is not fully understood. Studies point
at NAb as a key element of immunoprotection, with cellular immunity likely to provide additional longer-term protection especially
against severe disease and death.12- 15 How long overall protection may last remains unclear, and this may differ depending on the
disease severity.7 For other human coronaviruses (hCoV), hCoV-OC43 , hCoV-229E, hCoV-NL63 and hCoV-HKU-1 , which cause
the common cold, antibodies last for at least a year after infection with significant inter-human variability, 16 while antibodies to
more closely related MERS-CoV and SARS-CoV-1 , which cause, respectively, middle east respiratory syndrome and severe acute
respiratory syndrome, can be detected for years.11- 2 1
Reinfection
Though rarely reported to date, reinfection with SARS-CoV-2 can occur. Four large studies from the United Kingdom, the United
States of America and Denmark estimated that infection with SARS-CoV-2 provided 80-90% protection from reinfection up to 7
months, and up to 94% protection against symptomatic disease .22- 25 The level of protection against re-infection as assessed by PCR
positivity was estimated to be 50% in people aged over 65 years old.24
SARS-CoV-2 variants and implications for immunity

The more the SARS-CoV-2 virus circulates, the more opportunities it has to change through natural evolution. The emergence of
virus variants can pose new challenges. Currently, three virus variants, B.1.1. 7, B.1.351 and P. l , with increased transmissibility or
potential to partially escape immunity, are characterized as global Variants of Concern (VOC) by WHO and are circulating in many
countries. Evidence of reduced susceptibility to neutralization by serum antibodies of some SARS-CoV-2 variants (e.g. P.l and
B.1.351) to natural (or vaccine-induced) neutralizing antibodies has been reported,2 6-29 raising the concern that reinfection after
natural infection (or breakthrough infection after vaccination) may increase in settings where these variants broadly circulate.30 Of
note, recent studies found that current global VOCs are unlikely to have an impact on CD4+ and cos+ T cell reactivity in COVID-
19 exposed donors and vaccinees, but how this observation applies to protection against reinfection or breakthrough infection after
vaccination remains unclear.
Measuring immune responses

The immune response following infection with a virus can be measured by the detection of virus-specific antibodies such as IgA,
IgM, IgG or total antibodies through immunoassays, as well as by the detection of sensitized memory B cells and/or CD4+ and
CDS+ T cells, which require more complicated assays. The most commonly measured immune response is the presence of antibodies
in serum. Serologic assays to detect the antibody response are usually based on enzyme immunoassays, which detect the presence
of virus-specific antibodies in the blood or by live or pseudo-virus neutralization assays, which detect functional NAb. While
serologic testing has limited use in clinical management because it does not capture active infection, it can be very useful in
determining the extent of infection or estimating attack rates in given populations.
Interpreting the results of serologic testing, however, is complex: there are several antibody types and subtypes and multiple
antigenic determinants/epitopes that can be used to target these antibodies, and the results may differ substantially depending on the
combinations chosen. The results will also depend on the manufacturing specifics of the assay used. The most frequently used assays
for detection of antibodies to SARS-CoV-2 are enzyme-linked immunosorbent tests, chemiluminescent tests, and lateral flow rapid
diagnostic tests (RDTs). Advice on the use ofRDTs for antibody detection is available on the WHO website.32
Conclusions
Current evidence points to most individuals developing strong protective immune responses following natural infection with SARS-
CoV-2. However, inaccurate immunodiagnostic tests may falsely indicate infected individuals as nai:Ve to the virus (not previously
infected) or may falsely label non-infected people as positive for immune markers of recent infection.
To conclude, available tests and current knowledge do not tell us about the duration of immunity and protection against reinfection,
but recent evidence suggests that natural infection may provide similar protection against symptomatic disease as vaccination, at
least for the available follow up period. 33 The emergence of variants of concern poses challenges and their potential to evade
immunity elicited by either natural infection or by vaccination, needs to be closely monitored.
AR07697 COVID-19 natural immunity: Scientific brief
Plans for updating

WHO continues to monitor the situation closely for any changes that may affect the information in this Scientific brief. Should any
factors change, WHO will issue a further update. Otherwise, the validity of this brief will be reviewed 3 months after the date of
publication.
Contributors
Lorenzo Subissi, Mick Mulders, Martin Friede, Maria Van Kerkhove, Mark Perkins.
Acknowledgments
We thank Stanley Perlman for critical reading of this scientific brief.
References
1. World Health Organization. “Immunity passports” in the context of COVID-19. Available from: https://www.who.int/news-
room/commentaries/detail/immunity-passports-in-the-context-of-covid-19
2. World Health Organization. Statement on the seventh meeting of the International Health Regulations (2005) Emergency
Committee regarding the coronavirus disease (COVID-19) pandemic. Available from: https://www.who.int/news/item/19-
04-2021-statement-on-the-seventh-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-
the-coronavirus-disease-(covid-19)-pandemic
3. Wajnberg A, Mansour M, Leven E, et al. Humoral response and PCR positivity in patients with COVID-19 in the New York
City region, USA: an observational study. Lancet Microbe [Internet] 2020 [cited 2021 Mar 26];1(7):e283–9. Available from:
https://linkinghub.elsevier.com/retrieve/pii/S2666524720301208
4. Guthmiller JJ, Stovicek O, Wang J, et al. SARS-CoV-2 Infection Severity Is Linked to Superior Humoral Immunity against
the Spike. mBio [Internet] 2021 [cited 2021 Mar 26];12(1):e02940-20, /mbio/12/1/mBio.02940-20.atom. Available from:
https://mbio.asm.org/content/12/1/e02940-20
5. Wu J, Liang B, Chen C, et al. SARS-CoV-2 infection induces sustained humoral immune responses in convalescent patients
following symptomatic COVID-19. Nat Commun 2021;12(1):1813.
6. Huang C, Huang L, Wang Y, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort
study. The Lancet [Internet] 2021 [cited 2021 Apr 22];397(10270):220–32. Available from:
7. Arkhipova-Jenkins I, Helfand M, Armstrong C, et al. Antibody Response After SARS-CoV-2 Infection and Implications for
Immunity : A Rapid Living Review. Ann Intern Med 2021;
8. Seow J, Graham C, Merrick B, et al. Longitudinal observation and decline of neutralizing antibody responses in the three
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WHO reference number: WHO/2019-nCoV/Sci_Brief/Natural_immunity/2021.1
-4-
AR07699
TAB 54
AR07700

FEDERAL COURT
BETWEEN:
NABIL BEN NAOUM
Demandeur
et
Défendeur

AND BETWEEN:
Demandeur
et
Défendeur

AND BETWEEN:
AND AEDAN MACDONALD
Applicants
and
Respondent
JML TRANSCRIPTION
AR07701
2

AND BETWEEN:
Applicants
and
Respondent
_________________________________________________________________
CROSS-EXAMINATION OF DR. JOEL KETTNER

May 30, 2022
_________________________________________________________________
Robert Drummond For the Respondent

Sam Presvelos For Dr. Kettner
JML TRANSCRIPTION
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3
INDEX
PAGE
Exhibits ................................................... 4
Undertakings .............................................. 5
DR. JOEL KETTNER

Cross-Examination by Mr. Drummond ...................... 6
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4
EXHIBITS
PAGE
1. Overview of testing document dated Feb. 11/22........... 25
2. Ministry of Health article version 14.1 dated Apr.19/22. 53
3. Public Health Agency of Canada report dated Nov.25...... 58
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5
UNDERTAKINGS
PAGE
1. Provide a copy of Dr. Kettner’s notes................... 14
2. Provide a list of all of the documents before Dr.
Kettner............................................ 15
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6
1 MAY 30, 2022:
2 CROSS-EXAMINATION
4 DR. JOEL KETTNER, affirmed, testified:
5 COURT REPORTER: Doctor, do you solemnly affirm the
6 evidence you’re about to give today shall be the
7 truth, the whole truth and nothing but the truth?
8 DR. KETTNER: I do.
9 COURT REPORTER: Can you please just state and then spell
10 your full name for the record?
11 DR. KETTNER: Joel David Kettner, J-O-E-L D-A-V-I-D
12 K-E-T-T-N-E-R.
13
14 CROSS-EXAMINATON BY MR. DRUMMOND:
15
16 MR. DRUMMOND: Thank you, good morning, Dr. Kettner.
17 Can you confirm for me that you are the Joel Kettner
18 who swore an affidavit on March 11, 2022, in court

19 file T-1991-21 Shawn Rickard and others against the
20 Attorney General and others? That sounds familiar?
21 Okay. All right, I’m just going to share my screen
22 with you for a second. Dr. Kettner, do you see that?
23 MR. KETTNER: No.
24 1 MR. DRUMMOND: Can other people can see this? I have
25 been informed, I mean, of course I can see it, perhaps
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1 your counsel can advise?
2 MR. PRESVELOS: Yeah, this is just the affidavit that
3 was sworn.
4 MR. KETTNER: I’m not seeing it. Give me another
5 minute to see if I can. I got it.
6 MR. DRUMMOND: Okay.
7 MR. KETTNER: Sorry about that.
8 1 Q. That’s quite all right. So, you see this document that
9 is entitled Affidavit of Dr. Joel Kettner?
10 A. I do.
11 2 Q. Okay. I’m just going to scroll down a couple of pages,
12 and I hope you can see on the right hand side of the
13 page there’s a signature, is that your signature?
14 A. Electronic.
15 3 Q. Yeah. Is it an electronic version of your signature?
16 A. It is.
17 4 Q. Okay. Thank you. And so, this is the affidavit that
18 you swore for the purposes of this matter?
19 A. I can’t see the rest of it, but I’m confident that
20 that would be the one.
21 5 Q. Okay. If I scroll down, is that, would that be
22 familiar to you?
23 A. It is.
24 6 Q. Okay. Thank you. And I’m going to stop sharing my
25 screen, Dr. Kettner. Now in that affidavit you
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1 attached as Exhibit A, a copy of your curriculum vitae
2 dated December 1, 2022. Is that a current version of
3 your affidavit?
4 A. I think I might have updated it somewhat last month,
5 or since that, signing that I guess now.
6 7 Q. And can you advise in what aspects you updated it?
7 A. No, I’m trying to think. There may have been another
8 court case that I provided an extra report and a

9 couple of events at the university that I added to it.
10 8 Q. Can you advise if there is any additional training
11 that you have received since December 2022?
12 A. Not relevant to public health or everything else but.
13 9 Q. Okay. And no additional certifications since December
14 2022?
15 A. Correct.
16 10 Q. Any changes in employment since December 2022?
17 A. No.
18 11 Q. And you attached as Exhibit B to your affidavit the
19 expert report you prepared in this matter, is that
20 correct?
21 A. Sorry, I couldn’t hear what you said, there’s some
22 background.
23 12 Q. I’m sorry, Dr. Kettner, I just asked and you attached
24 as Exhibit B to your affidavit an expert report you
25 prepared in this matter, and that’s correct?
JML TRANSCRIPTION
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1 A. Yes.
2 13. Q. Dr. Kettner, what did you review to prepare for this
3 cross-examination today?
4 A. Well, I guess I’ll divide this in two parts; the work
5 I did to prepare my expert report. As I described I
6 think in the report, my focus for this report was to
7 look for and to use relevant information from what I
8 would call official government websites or websites and

9 organizations either funded by or authorized by
10 governments to provide [indiscernible] advisory
11 reports, and that would be mostly Canadian sources. I
12 also looked at what I considered to sort of be official
13 senior or significant international organizations of a
14 similar nature, so that would include the Oral Health
15 organization, Centers for Disease Control of United
16 States of America, American Centers for Disease
17 Control. So, that was I guess I call a second group. I
18 also included in some circumstances a specific report
19 or source of information that I thought was
20 particularly relevant and also may be missing from the
21 information I was looking for in those other sites. So,
22 that’s what I was looking for and that’s what I was
23 using, and I’ll probably explain why a little bit later
24 why that was true, or I could do it now if you want,
25 but where those reports took me to other reports that
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1 were cited you know, as references then I would also
2 include those if I thought they were relevant to answer
3 the questions that I was asked to answer. Now, what’s
4 the method to do this is you know, there’s a little
5 more, it’s a little less straight forward than I think
6 I just described. You know, in the old days we would do
7 what was called a literature search you know, you would
8 go to a library, or you would use an online method to

9 put in a lot of search words and you would hone down
10 your search by specific criteria. For a variety of
11 reasons, that was not as use, did not turn out to be as
12 useful for the kinds of documents I was looking for.
13 So, I did what probably most people do nowadays, which
14 is search through the internet with various methods to
15 find these kinds of sources of information, or I’ll go
16 directly to the websites of these official
17 organizations since I knew which ones I was
18 particularly interested in. And in this case for
19 example, that would be mostly Health Canada, or the
20 Public Health Agency of Canada or Agencies of the
21 Government of Canada related to transportation. Because
22 of the federal nature of this I didn’t focus as much on
23 provincial and territorial sources in terms of say
24 government websites. However, there were times where it
25 was I think quite relevant to use some examples, and I
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11
1 believe I did so as say the Ontario government and
2 other provinces and for example, with regard to the
3 policies around cases and contact tracing because a lot
4 of the work in public health of that nature is done at
5 the provincial level and although the federal
6 government and the federal provincial territorial
7 organizations like the Chief Medical Officers of Health
8 of every province and territory do set some guidelines

9 or some resources of information that the provinces can
10 use. A lot of these decisions are made at the
11 provincial level, which of course isn’t truthful of
12 federally related travel. So, I don’t know if that
13 answers your question Mr. Drummond, or if you would
14 like me to call you Robert that would be okay too. You
15 could be call me Joel if you want to use Robert, but if
16 we want to go formally, I’m good with that too.
17 14. Q. Thank you, Dr. Kettner, I tend to default to the more
18 formal during such proceedings, so I hope that you’ll
19 be all right with that, but I’m just going to be a
20 little more specific. In preparation for this cross
21 examination today did you review any of the other
22 affidavits or expert reports filed in this matter?
23 A. Yes, I did, I did have a look at, I can’t say I looked
24 at all of them, but I did have a look at some of them,
25 but yeah.
JML TRANSCRIPTION
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12
1 15. Q. Which ones did you look at?
2 A. Well, I think, I’ll just check here. I looked at
3 Waddell, Lisa Waddell’s, Elizabeth Harris and Eleni
4 Galanis, and those are the ones that I sort of looked
5 at more carefully.
6 16. Q. All right. Thank you. Dr. Kettner, where are you
7 located today?
8 A. I’m in my home in Winnipeg.

9 17. Q. Okay. Thank you. Are you in a closed room?
10 A. No, the door is open of my home office.
11 18. Q. Okay. Is there any other person with you?
12 A. Not that I’m aware of.
13 19. Q. Okay, and no person has access to this, to the room
14 during this cross examination?
15 A. I sure hope not.
16 20. Q. Okay. Do you have a copy of your affidavit and all
17 exhibits before you?
18 A. I have a copy of my affidavit. I haven’t printed out
19 all of the exhibits from my affidavit. I don’t think
20 I’ve got those handy. I mean I have them online, but I
21 don’t have them printed out. I’m an old, you know I’m
22 an old guy and a bit old fashioned, I prefer looking at
23 stuff in hard print, but.
24 21. Q. To clarify, Dr. Kettner, I mean do you have before you
25 your CV and your expert report?
JML TRANSCRIPTION
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13
1 A. Yes.
2 22. Q. Okay. Thank you. I don’t mean to suggest do you have
3 all references.
4 A. Okay. I do have that, yeah. I have that with me right
5 now.
6 23. Q. Do you have any other notes before you?
7 A. I think I made a page of notes here. Yeah, I have one
8 page of sort of a list of things just to check. But I

9 think I, depending how you define notes, like in terms
10 of within my reach to sort of look at while we’re
11 talking in terms of handwritten notes, I have very
12 little, just that one page, I think. Is that what
13 you’re asking?
14 24. Q. Yes. I am asking what you have available to you.
15 A. Oh, well that’s a more general question. Do you mean in
16 terms of written notes, or do you mean in terms of
17 anything available to me that might be relevant to this
18 cross examination?
19 25. Q. Well, I am asking what you have before you?
20 A. Okay. Well, there’s more than that because I printed
21 out a few things that I thought I might want to look
22 at. So, I told you I’ve got the affidavits of those
23 three people, I printed off a document that Lisa
24 Waddell referred to called emerging evidence on Covid-
25 19. I have that by my side here. I got something today,
JML TRANSCRIPTION
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14
1 oh not, that was also sent today I think, but I think I
2 had it before, then I have an abstract of an article
3 called Risk of Symptomatic Covid-19 due to aircraft
4 transmission. I have the 2021 May 14 update of the
5 Covid-19 readiness criteria and indicators for easing
6 restrictive public health measures, and that’s a
7 government of Canada document, but that’s available on
8 the website. And I printed off, because this was

9 another document, I think I got this morning,
10 management of cases and contacts of Covid-19 in
11 Ontario. And then, is this, am I, is this what, am I
12 doing what you’re asking me to do, I don’t want to take
13 up unnecessary time, is this what you’re asking me?
14 26. Q. What I’m asking is what materials you have before you.
15 A. Okay. And that’s, I think that’s what I’m telling you,
16 right. Yeah.
17 27. Q. I can’t tell you what your answer is.
18 A. No, but so far what I told you is relevant to what
19 you’re asking, that’s all I’m checking in with you.
20 28. Q. Okay. Mr. Presvelos, I’m going to ask for an
21 undertaking to be provided a copy of Dr. Kettner’s
22 notes that he mentioned.
23 MR. PRESVELOS: I’m going to take it under advisement.
24 29. Q. Okay.
25 A. The only other two documents, or should I keep going
JML TRANSCRIPTION
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15
1 or is…
2 30. Q. You answer as you feel you need to.
3 A. Okay. No, I think the only other two things that I’ve
4 got in front of me, and this isn’t counting stuff that
5 I can search on my computer or other places, which
6 would be I don’t think what you’re asking, but I
7 printed out a breakdown of cases by week and arrival of
8 vaccination status from a public health agency of

9 Canada PowerPoint presentation. I think that covers it,
10 Mr. Drummond.
11 31. Q. Thank you. Mr. Presvelos, I’m going to ask for an
12 undertaking to provide a list of all of the materials
13 before Dr. Kettner. I think I’ve got all of them, but I
14 may have missed something.
15 MR. PRESVELOS: I will provide them to you to the
16 extent that they are not exhibits that appear in the
17 Attorney General, in one of the affidavits of the
18 Attorney General because it sounds some of them are.
19 A. I agree.
20 32. Q. Thank you. Okay. Dr. Kettner, I’m just going to ask
21 that you, for your agreement that you will not access
22 any other documents unless I specifically share them
23 with you.
24 A. I agree to that.
25 33. Q. And I ask you to confirm that you will not discuss any
JML TRANSCRIPTION
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16
1 aspect of this cross examination in any manner with any
2 person until it is concluded, including any breaks we
3 may take with the exception of the discussion with
4 counsel on questions to which an objection is raised.
5 A. All right, I agree to that.
6 34. Q. Thank you. So, Dr. Kettner, we will likely take a break
7 after around 90 minutes, but if you otherwise need one,
8 please let me know, and I’ll do my best to accommodate

9 you.
10 A. And likewise for you, Mr. Drummond.
11 35. Q. Thank you, that’s very kind. And just, just as another
12 matter, almost all my questions will be in respect of
13 your expert report, and I will try and be accurate to
14 identify the page number of that report, but if for
15 some reason I’m silent on the document to which I’m
16 taking you, you can expect that it will be in respect
17 of your expert report, is that a fair way to proceed?
18 A. So, if you don’t specifically say this question is in
19 regards to my expert report, I should just assume that
20 your question is related to the expert report.
21 36. Q. That’s correct. Is that a fair way to proceed?
22 A. Yes, I think I can follow those principles.
23 37. Q. Okay, thank you, Dr. Kettner. Now just before we
24 proceed, are there any corrections or changes you need
25 to make to your affidavit and its attachments, most
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1 specifically your expert report since it was sworn on
2 March 11th?
3 A. Not that I’m aware of.
4 38. Q. Okay, thank you. All right. I’m just going to ask you
5 some questions about your background and experience,
6 and are you currently a practicing physician?
7 A. Well, it depends how you define practicing physician,
8 but the short answer is yes, I, my, you know, my

9 licence is current to practice medicine in the province
10 of Manitoba and I do that in a variety of ways, but I
11 consider myself an active practicing physician.
12 39. Q. Okay. Thank you. So, I note you have a, you have a
13 Master of Science in epidemiology in 1985, and you
14 obtained a specialist certification in community
15 medicine in 1991, and that’s correct?
16 A. Yes, that specialty is now called public health and
17 preventive medicine, but it is the same specialty, it
18 just changed its name after I got my certification.
19 40. Q. Okay. And I note you formerly, the title was Chief
20 Medical Officer of health for Manitoba from 1999 until
21 2008, and then the Chief Provincial Public health
22 officer of Manitoba from 2008 to 2012. I note that one
23 position started right after the other. Were these
24 different positions or was it the result of a
25 reclassification and renaming of position?
JML TRANSCRIPTION
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18
1 A. So, what happened at that point in time is a new public
2 health act was implemented in Manitoba and although the
3 position of Chief Medical Officer actually was not
4 deleted from the act, there was a new title added in
5 called the Chief Provincial Public Health Officer. So,
6 I continued as the Chief Medical Officer of health and
7 assumed that position of the Chief Provincial Public
8 Health officer. There was some implications of the, of

9 the new title, but I would be happy to talk about it,
10 but in general I’m going to say it was at least the
11 same job and most people would say it was a broader
12 scope of responsibilities.
13 41. Q. And so, your training and experience indicates you
14 generally focused your medical career on issues of
15 public health and epidemiology, is that a fair way to
16 characterize it?
17 A. I think so.
18 42. Q. Thank you. Just to clarify, so your position as Chief
19 Provincial Public Health Officer concluded in 2012, and
20 I read your CV and you are not currently a Medical
21 Officer of Health or a similar position for any
22 jurisdiction, are you?
23 A. I am not.
24 43. Q. Okay. And just a few questions; you have never worked
25 in respect of public health measures in respect of
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1 civil aviation, have you?
2 A. No, I don’t think I, not specifically.
3 44. Q. Okay. And you do not have any specific training in
4 aviation medicine, do you?
5 A. I don’t have specific training in aviation medicine. I
6 just should clarify, when you talk about aviation
7 medicine, you’re talking about clinical medicine, I
8 believe. I believe you’re talking about for example,

9 the diagnosis, treatment and care of the people who
10 work in the aviation industry or people maybe
11 travelling, matters related to that, not public health.
12 And my, is that what you mean by aviation medicine?
13 45. Q. Well, okay let me ask you, ask you something else. You
14 haven’t received a diploma or some specialization in
15 aviation medicine, have you?
16 A. No, but the reason I’m asking for clarification Mr.
17 Drummond, is I think it’s quite important to have a
18 clear understanding of the scope and depth of public
19 health medicine. And the reason I want to talk about
20 this briefly, or as long as you would like to, is that
21 I actually as any medical officer of health or more
22 broadly, any public health physician would include in
23 their scope of expertise the assessment of prevention
24 and preventative measures and public health measures
25 relating to travel in general, and that would include
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20
1 air travel. So, that same breadth of application
2 applies to schools, workplaces, any setting in, any
3 social setting in the built environment or in the
4 natural environment in which there is a relevance for
5 the prevention for diseases and injury. Aviation
6 medicine depending on how its defined, and someone who
7 is going to get a diploma in aviation medicine is not,
8 is not primarily learning about public health related

9 to aviation medicine. Yeah, I’m sure prevention is part
10 of it, but mostly what their learning is the clinical
11 medicine of the, of the impact of you know,
12 pressurization, just a few examples, or confinement in
13 a flight when urgent care needs to be given, and there
14 is a whole bunch of clinical aspects of aviation
15 medicine. I am not trained or an expert or have had
16 special training in the clinical aspects of aviation
17 medicine, but I do consider myself, and it’s critically
18 important I would say for any public health physician,
19 especially one working in government, to be familiar
20 with all relevant matters of travel including air
21 travel that are relevant to the public health including
22 the prevention and control of infectious diseases.
23 46. Q. All right. Dr. Kettner, that, I’m just going to be more
24 specific. Have you ever provided advise to the civil
25 aviation medicine branch of transport Canada in terms
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21
1 of aircraft passenger health, either in terms of the
2 prevention of disease or the prevention of other public
3 health measures with an aircraft?
4 A. Not directly I don’t think. Yeah, I don’t think I have
5 done it directly.
6 47. Q. All right. Have you, have you provided any advice to
7 the Government of Canada in respect of public health
8 measures during the Covid-19 pandemic?

9 A. No. Not directly.
10 48. Q. And have you been involved in the crafting or issuing
11 of public health measures in any jurisdiction in
12 respect of the Covid-19 pandemic?
13 A. Not formally, and not directly. And I’ll just clarify
14 this. I mean, I have, I have many colleagues in public
15 health, I’ve been involved in university events of
16 education, of seminars and various other things, I have
17 had other opportunities to ask questions that would
18 lead to the ears of decision makers in public health.
19 So, to what degree I have provided you know,
20 information that has been used or would be considered
21 as advisory, I can’t really measure, but I have not had
22 any formal direct role in that capacity.
23 49. Q. Okay. All right. Thank you, Dr. Kettner. I’m going to
24 shift gears, if you’ll accept that. I’m going to take
25 you to page two of your expert report if you can go
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1 there, and when I say page two, if you look at the top
2 right-hand corner of your report there is some numbers
3 that are right on top of your address, so they’re not
4 the clearest to read.
5 A. Okay. So, I think I’m going to need more help from you
6 here because I probably don’t have a printout of the
7 document that you are referring to that has page
8 numbers, so if you can just help me to navigate this in

9 other ways that would be very helpful.
10 50. Q. Certainly. It’s a page that says part one terminology
11 concepts and scientific foundations for the answers to
12 the questions in part two.
13 A. Yeah, got it.
14 51. Q. Okay. I’m, and it’s on the second last paragraph you
15 have a statement there, but a person can have a
16 positive test result from a sample taken as long as
17 three months after their symptoms or infection.
18 A. Okay. Sorry, I don’t think I’m with you here yet. Just
19 say where that is again on the.
20 52. Q. It’s the end of the second last paragraph.
21 A. Okay. So, can you just tell me the heading of it, is
22 this the…
23 53. Q. It’s infected versus infectious.
24 A. There’s the infectious right, okay. So, the one that
25 starts these concepts and definitions?
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1 54. Q. No, the paragraph I’m referring to says the presence of
2 virus material.
3 MR. PRESVELOS: The page it says part one,
4 terminology concepts and scientific foundations. It’s
5 right at the top center.
6 A. Yes.
7 MR. PRESVELOS: And it’s the second, that part,
8 that page is divided into two, one says caveat, the

9 second says infected versus infectious.
10 A. Right.
11 MR. PRESVELOS: And we’re starting at infected
12 versus infectious, first paragraph first sentence
13 says, the presence of virus materials in the back of
14 one’s nose.
15 A. Got it. Thank you.
16 55. Q. I’m taking you to the end of that paragraph.
17 A. Yes.
18 56. Q. Where you state but a person can have a positive test
19 result from a sample taken as long as three months
20 after their symptoms or infection.
21 A. Yes. Got it.
22 57. Q. And there you have a footnote to document it from a CBC
23 website, do you see that?
24 A. Yeah.
25 58. Q. Okay. I sent this document to you; I’m going to share
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1 my screen again. Dr. Kettner, do you see this on your
2 screen?
3 A. Yes.
4 59. Q. And this is the document you referred to in that
5 footnote?
6 A. I think so.
7 60. Q. Okay. All right. So, you see at the top there it says
8 overview of testing for SARS Covi-2, the virus that

9 causes Covid-19 dated, rather updated February 11,
10 2022?
11 A. Mhm.
12 61. Q. Okay. I’m going to take you down a few pages, bear with
13 me one second. At page six of this document, which I’m
14 about to get to, it’s in a set of columns, and on the
15 left side it says disadvantages, do you see that?
16 A. Yes.
17 62. Q. And there are three points in the middle column let’s
18 call it, it says a positive NAAT diagnostic test should
19 not be repeated within 90 days because people may
20 continue to have detectable RNA after risk of
21 transmission has passed, do you see that?
22 A. Yes.
23 63. Q. And is this the section of this document on which you
24 rely for that statement I just read in your expert
25 report?
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1 A. There might be other parts in it, but I think that’s
2 the one, I even mentioned it in the footnote, I think I
3 even quoted that line so, that must have been the one
4 that I was primarily referring to.
5 64. Q. And you agree that NAAT stands for nucleic acid
6 amplification test?
7 A. I do.
8 65. Q. Okay. And you agree that the Centers for Disease
9 Control and Prevention is an American authority?
10 A. Well, what do you mean by an American authority?
11 65. Q. It is an institution of the United States federal
12 government?
13 A. It is.
14 66. Q. All right. We’re back on the front page. I ask that
15 this be entered as an exhibit, please?
16 A. Sure.
17 COURT REPORTER: Okay, Exhibit 1.
18 EXHIBIT 1: Overview of testing document dated February
19 11, 2022
20 67. Q. Mr. Presvelos, any objection?
21 A. No.
22 68. Q. Thank you. And I’m just going to stop sharing my
23 screen. Thank you. Madam Court Reporter, you did
24 receive all of these documents?
25 COURT REPORTER: Yes, I have it.
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1 69. Q. Okay, thank you very much. And would you agree that the
2 term nucleic acid-based testing is equivalent to
3 nucleic acid amplification test in terms of SARS Covi-
4 2?
5 A. I’m going to have to ask you to repeat that. What’s the
6 first term you used, nucleic acid….
7 70. Q. Nucleic acid-based testing.
8 A. I don’t think I can, I don’t think I can tell you that

9 those are equivalent. I’m not that, I’m not familiar
10 with nucleic acid-based testing as a term. I mean as a
11 generic term I know that these tests are based on the
12 ability to detect sequences of nucleic acids and then
13 amplify that to, to be able to do a PCR test, but I’m
14 not sure I understand maybe the point of your question.
15 71. Q. Okay. So, Dr. Kettner, you used the acronym PCR, you’ll
16 understand me if I use PCR as an acronym for polymerase
17 chain reaction?
18 A. I will.
19 72. Q. Okay. And you, are you aware that the term molecular
20 testing is often used in Canada to refer to the nucleic
21 acid amplification tests?
22 A. I am.
23 73. Q. Okay. And you agree that a polymerase chain reaction
24 test is a form of nucleic acid amplification testing?
25 A. That’s my understanding.
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1 74. Q. Would you agree that a PCR test is a sensitive test to
2 determine the presence of viral RNA in a person?
3 A. Well, here’s where I need to make sure that I
4 understand you and that you understand me because this
5 is a pretty critical issue. I think the way you asked
6 the question my answer would be yes, it’s considered a
7 sensitive test to detect the presence of, of you know,
8 the sequences of nucleic acids. It’s considered quite

9 sensitive for that purpose. Of course, that’s not the
10 same as being sensitive to detect viable or potentially
11 infectious viruses, and that’s why I just want to
12 clarify that which question you’re asking.
13 75. Q. I asked if it was sensitive to detect the presence of
14 viral RNA, and I think you agreed with me.
15 A. Well, yeah I think it’s considered quite sensitive. Of
16 course, I mean sensitivity could be discussed in
17 general qualitative terms, or it can be discussed in
18 very quantitative note terms. Usually when we use the
19 term sensitivity or specificity in epidemiology, we
20 measure it as a sort of percentage against a gold
21 standard. There’s some problems with this because the
22 gold standard is not entirely clear for these tests,
23 but I know that the general thinking here is that the
24 sensitivity approaches 100% for detecting these nucleic
25 acid sequences, so I, that’s my understanding. I’m not
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1 in a position to verify that of course.
2 76. Q. Okay. Dr. Kettner, would you agree that the amount of
3 SARS Covi-2 RNA in an individual tends to decrease
4 post-infection and post-resolution of symptoms?
5 A. Okay, here’s another important need for clarification.
6 You use the term, say what you said again, can you just
7 repeat it, sorry.
8 77. Q. That’s fine. So, Dr. Kettner, would you agree that the
9 amount of SARS Cov-2 RNA in an individual would tend to
10 decrease post-infection and post-resolution of symptoms
11 resulting from infection?
12 A. Yeah, that’s a reasonable thing to think, and I think
13 there’s increasing evidence that that’s true.
14 78. Q. Okay. But given what you put in your report, you agree
15 that the RNA may still be detectable though in lower
16 amounts?
17 A. Yes.
18 79. Q. Okay.
19 A. Now….
20 80. Q. But would you, you would agree that an active infection
21 or recent exposure would also be identified by a
22 positive molecular test?
23 A. I think there’s a high level of confidence that someone
24 who’s got an active infection and has infectious you
25 know, [indiscernible] viable viruses and sufficient
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1 numbers of them are during the active part of the
2 infection and the infectious period. It looks like the
3 PCR test is quite sensitive to pick that up. And
4 probably quite specific also to identify that as a you
5 know, as a, not by, couldn’t be a false positive.
6 81. Q. All right, thank you. Dr. Kettner, are you aware that
7 beginning January 7th, 2021, non-exempt persons
8 entering Canada by air were required to obtain a

9 negative pre-departure molecular test within 72 hours
10 of boarding a flight?
11 A. Yes.
12 82. Q. Okay. Are you aware that as of only February 28th,
13 2022, an antigen test within 24 hours of departure
14 wasn’t accepted as an alternative to molecular testing
15 prior to boarding a flight?
16 A. Yes.
17 83. Q. Okay. And would you agree that a pre-departure
18 molecular test would tend to detect those remnants of
19 viral RNA from up to 90 days previously?
20 A. Well, it could. I mean you know this is, this is a
21 trajectory of probability over time, but certainly
22 consistent with what the CBC statement was that within
23 90 days that test could be, could be positive from
24 somebody who’d had an infection, if that’s what you’re
25 asking.
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1 84. Q. But just to confirm, this accords with your statement
2 that a person can have a positive test result from a
3 sample taken as long as three months after their
4 symptoms or infection?
5 A. Yes.
6 85. Q. Okay. So, would you agree then that the likelihood of a
7 person testing positive in an on-arrival molecular test
8 absent to new exposure to SARS Covi-2 in the interim,

9 that is after the pre-departure test, would be low?
10 A. Okay, I’m going to have to ask you to repeat that,
11 sorry. Sorry.
12 86. Q. All right. Dr. Kettner, given that, would you agree
13 that the likelihood of a person then testing positive
14 in an on-arrival molecular test following a pre-
15 departure molecular test absent a new exposure to SARS
16 Covi-2 in the interim, would be low?
17 A. Okay, I’m sorry, I still, I need to understand the full
18 sequence of this time period that you’re talking about.
19 So, I’m going to have to ask you again. I think I’m
20 going to make a note just as I’m hearing the words.
21 87. Q. That’s fine.
22 A. So, this is someone that has a positive PCR at time,
23 like within three days of departure.
24 88. Q. No. I will clarify.
25 A. Okay.
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1 89. Q. A person who tested negative on a pre-departure
2 negative test.
3 A. Okay.
4 90. Q. This same person then takes an on-arrival test.
5 A. Okay.
6 91. Q. Would you agree that the likelihood of that person
7 testing positive absent a new exposure to SARS Covi-2
8 in that period, would be low?

9 MR. PREVELOS: Sorry. Sorry, sorry, one second
10 counsel, what’s the time difference between the pre-
11 departure test and the arrival test?
12 92. Q. Well, the pre-departure test as I stated, as Dr.
13 Kettner agreed, the pre-departure molecular test had to
14 be taken within 72 hours of boarding a flight.
15 MR. PREVELOS: Oh yes, I understand that, but on-
16 arrival tests assumes the person left the country and
17 came back, and my question is for what duration are we
18 talking about that this individual left the country?
19 93. Q. I’m not mentioning the duration the person left the
20 country, I’m talking….
21 MR. PREVELOS: So, you’re asking whether there’s
22 a reduced chance of viral load after a person, when a
23 person arrives, but we don’t know what time period that
24 person has been out of the country for.
25 94. Q. No, that’s not what I’m asking. I am asking about if a
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1 person took a pre-departure molecular test within 72
2 hours of boarding a flight, and that is a negative.
3 What is the likelihood that a person then would test
4 positive for an on-arrival molecular test absent a new
5 exposure to SARS Covi-2 in that interim?
6 A. Okay, I understand your question now. And I hope you’ll
7 be patient with me because there’s several things in
8 this question that I need to get clarification from

9 you. It’s a very important question, so I just want to
10 make sure that the record has exactly what I’m thinking
11 about the answer.
12 95. Q. Okay.
13 A. But I’m going to read it back to you just to make sure
14 that I do understand it. So, we’re talking about a
15 person that’s say coming back to Canada, they’ve been
16 away for however long it doesn’t necessarily matter,
17 they get their pre-departure test, either a rapid
18 antigen test or a PCR, either or you?
19 96. Q. No, I….
20 A. Just PCR? Just PCR?
21 97. Q. I am talking about before, between January 7th, 2021,
22 and February 28th, 2022, when only a molecular test…
23 A. Okay.
24 98. Q. …was accepted.
25 A. So, they’ve had a PCR test within three days of
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1 departure from wherever they’re coming into Canada and
2 it’s negative. Then they fly into Canada, and then on
3 day one, and maybe day eight, but day one they get
4 another test, another PCR test, and this one’s
5 positive, the previous one was negative, and they on-
6 arrival tested positive, that’s the situation, right?
7 99. Q. That’s correct.
8 A. Okay. And are you asking me, two things you asked me
9 that I need clarification, one was would I agree that
10 the probability of them having a new exposure under
11 this situation is high or low, I forget, you said, you
12 used the word low or high.
13 100. Q. The, my question was, would you agree that the
14 probability of that person testing positive absent a
15 new exposure to SARS Covi-2 would be low?
16 A. Okay.
17 101. Q. Would you agree that the reason for the positive test
18 in the on-arrival molecular test would be, is most
19 likely due to a new exposure?
20 A. Okay, and again, be patient with me. Most likely. So,
21 as an epidemiologist the word most likely is not
22 actually a meaningful measure. I mean likely might
23 distinguish more than 50% probability by the English
24 language definition and usage. Most likely is not
25 quantifiable for me. And so, what do you mean by most
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1 likely? What, are you talking 75%, 90%, what do you
2 mean?
3 102. Q. Well, you started by saying likely, would you agree
4 that….
5 A. No, I didn’t say it was likely, I asked, I said I know
6 it was likely but sorry, okay go ahead.
7 103. Q. So, you used the term likely as a word you could use
8 because it’s more than 50%. Would you agree that it is

9 likely?
10 A. No, not on the minimal information you’ve given me. I
11 would be in no position actually to answer that
12 question from a quantitative point of view. Now why do
13 I say that. Well, because there are many reasons why
14 somebody could have a false negative test on a pre-
15 departure test. And so, you know the first step in this
16 answer is how likely is it that that is a true
17 negative, and I’m in no position to judge that
18 certainly on an individual case because they may not
19 have taken an adequate sample of a nasal Ferens for
20 example, or it may not have been transported properly,
21 or there may have been an error in processing the test,
22 or there may have been an error in reading the results.
23 Now, so then we have a bit of a problem because I might
24 want to make an estimate of the probability of a false
25 negative, and you know that’s something that’s more
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1 doable without knowing the details of that individual
2 one. And then having then take you know, saying what’s
3 their probability that that was a true negative, then I
4 would want to look at some other factors before being
5 too quick to interpret the significance of the arrival
6 positive test. Again, potentially false positives, how
7 it was collected, where was the lab, but you know, et
8 cetera, et cetera. Because you’re asking me about a

9 specific case, all of those things would have to come
10 into play before I could answer your question. The
11 exposure question, you used the word exposure and
12 again, I needed to clarify that because as I tried to
13 explain in my report, there’s a difference between
14 exposure and transition. They have to be understood as
15 two distinct things related, but distinct, and an
16 assessment of one does not equal the assessment of the
17 other. So, I just, that was the other thing. Now, can
18 you have transmission without exposure? I’m going to
19 say no. So, in that sense I think your question is
20 understandable to me that if I was 100% sure that the
21 first test was a true negative, if I was 100% sure that
22 the arrival test was a true positive, then I would say
23 yeah, that would be pretty unlikely and I might even
24 put a percentage on it that that person had, did not
25 have an exposure. And I don’t know if that’s a helpful
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1 answer to you, but maybe it thins out some of the
2 issues relevant to importance of your question.
3 104. Q. Thank you, Dr. Kettner. I thank you for your answer.
4 I’m going to ask you some questions about in flight
5 transmission that are mentioned in your report. As a
6 general question, would you agree that the risk of
7 transmission of any infectious agent is specific to the
8 environment in which the transmission may occur?

9 A. What do you mean? What are you including in
10 environment?
11 105. Q. Well, I’ll just give you just a very broad example. Do
12 you, is the risk of an infection, infectious agent
13 being transmitted the same between two person who are
14 outside 10 meters apart as opposed to 10 people crowded
15 in a broom closet.
16 A. I think there’s….
17 106. Q. Those are different?
18 A. Yeah. There’s a, there’s a difference there yeah, I
19 mean you know, both biological science and
20 epidemiological evidence show pretty good consensus
21 that the risk would be higher in the former than the
22 latter.
23 107. Q. Thank you. Just going to your report, and again, this
24 is on page 17 of your report, and I’ll try and situate
25 you. If you look at the footnotes actually, it would be
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1 the page in which you have footnotes 21 and 22.
2 A. Okay. Thank you, that’s a good way to guide me.
3 Appreciate that.
4 108. Q. Thank you. I note there, and this is at the very bottom
5 of that page to which I said you referenced a report to
6 the standing committee on transport infrastructure and
7 communities trend entitled risk of Covid-19
8 transmission aboard aircraft.

9 A. Yes.
10 109. Q. And there’s a quote from the International Air
11 Transportation Association in respect of risk of a
12 passenger contracting Covid-19 while on board. Do you
13 see that?
14 A. Yes.
15 110. Q. And I looked through your report, and you can confirm
16 this for me, I didn’t note any other information or
17 analysis about the likelihood of transmission of SARS
18 Covi-2 within an aircraft cabin as opposed to any other
19 environment, is that the case, or did you cite some
20 other authority?
21 A. To describe the rate of transmission in an airplane
22 cabin?
23 111. Q. Well, you quoted the IATA about the risk of a passenger
24 contracting Covid-19 while on board appears….
25 A. I didn’t quote the IATA. My understanding was that this
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1 was a report, the asso- yeah. Okay, no I see, yeah, the
2 IATA, the Transport Association I quoted that, and
3 there it states of transmission, and you’re asking me
4 did I quote any other sources of the rate of
5 transmission in airplane cabins. Is that what you’re
6 asking me?
7 112. Q. Well, did you quote, or did you otherwise rely on any
8 sources about the transmission within an aircraft cabin

9 specifically?
10 MR. PRESVELOS: Well, yes. I mean it’s two
11 paragraphs down where it says other data to consider in
12 estimating the probability of transmission is to use
13 the incident rate of cases and location of part
14 implying, as is for example the average daily new cases
15 in Canada and the estimated the rate per person per day
16 [indiscernible] trenches of probability figure there.
17 So, I’m assuming other than that?
18 A. But that’s, that’s not, that’s referring to data that I
19 used to try to estimate the frequency of cases
20 occurring, and that was based on Government of Canada
21 data about the numbers of cases associated with air
22 travel. But so, yes, I think, I don’t know whether
23 that’s an example in answer to your question, but I
24 think you’re asking me did I quote another source that
25 stated an estimated or a belief about the rate of
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1 transmission in an airplane. If that’s your question, I
2 don’t think I did actually.
3 113. Q. Okay.
4 A. And if I didn’t, it’s because I couldn’t find such an
5 estimate on an official government website or an
6 official agency of, of a government organization that
7 came up with their estimate of that probability. So, so
8 that’s yeah, if I had seen such you know, had public

9 [indiscernible] of Canada given its estimate of the
10 probability or the rate of transmission in airplane
11 travel by various parameters, I would definitely have
12 included that in my report. I didn’t find that.
13 114. Q. Okay.
14 A. Now there’s lot of research papers that have made
15 various estimates or done various studies but as I said
16 that the beginning, the method that I used for this
17 report was not to go searching the scientific
18 literature for independent or individual estimates or
19 studies or things like that.
20 115. Q. Thank you, Dr. Kettner.
21 A. And I can explain why I did that with, I can explain
22 why I did that. I would like to but maybe this isn’t
23 the time to do it, but maybe, could I just take a
24 minute to explain why I did that, why that was my
25 approach.
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1 116. Q. Go ahead.
2 A. Because the whole, the whole purpose of my report in my
3 mind and based on the questions I was asked to answer
4 was whether governments and their public health
5 officials had shown the evidence or the data, the
6 information, the analysis and the rationale for this
7 policy. So, really what I was looking for was you know
8 whether they had done that, and that’s what I was

9 looking for. That’s what I, and that’s why I used the
10 method I used.
11 117. Q. Okay.
12 A. I’m not saying the policies are right or wrong, I’m
13 just saying I was looking for their evidence for it.
14 118. Q. Okay. Thank you, Dr. Kettner. Just to clarify, you
15 don’t have any specific knowledge or training about air
16 flow and filtration systems within commercial aircraft,
17 do you?
18 A. You know, the way you worded it probably the, the short
19 is answer is no. But I want to just then make a general
20 point. You know as a general, as a generalist public
21 health practitioner and specialist and expert I
22 suppose, I need to know a little bit about everything
23 that’s relevant to a public health issue, and I need to
24 find out about something that’s relevant if it, if it’s
25 a new problem that I haven’t studied or got advice on
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1 before. So, one of the, one of the most interesting
2 things about being a public health doctor whether
3 you’re a medical officer of health or in any other
4 capacity, is that you need to talk to talk to experts
5 in various area to understand the importance of
6 ventilation for example, like I you know I can’t design
7 the ventilation machine, I don’t really know how to
8 measure airflow, but I do understand the principles of

9 exchanges of air to dilute virus particle properties.
10 119. Q. Fair. But Dr. Kettner, you’ve, you were a provincial
11 chief medical officer of health, that’s correct?
12 A. I was.
13 120. Q. Yes, and during that time you had no jurisdiction with
14 respect to aircraft?
15 A. Well now, okay, since you ask it that way jurisdiction,
16 so two points come to mind. There’s a federal
17 provincial territorial organization of chief medical
18 officers of health, and as many other federal
19 provincial territorial organizations where the
20 provinces and the territories and their officials sit
21 around the table and address issues including things
22 which are just under federal jurisdiction to give
23 advice and to learn about them to gain knowledge about.
24 So, I just want to clarify that. And the other thing is
25 you know, principles of air exchange and dilution of
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1 infectious particles you know, I’m sure there are
2 specificities related to the engineering of that on
3 airplanes, but the principles and much of the
4 mechanisms are the same in other built environment
5 settings that, that might be considered absolutely
6 within the jurisdiction of a provincial public health
7 doctor.
8 121. Q. Okay. But you never set any directions about public
9 health measures on commercial aircraft in Canada, did
10 you?
11 A. I did not.
12 122. Q. Thank you. Okay Dr. Kettner, I’m going to take you up a
13 page, or rather back a page to what’s noted as page 16
14 of your expert report.
15 A. What are the footnotes on this page? What numbers are
16 they?
17 123. Q. 16 through 20, I believe it is.
18 A. Yeah, thank you. I’ve got it in front of me.
19 124. Q. Just one second. So, just one moment, Dr. Kettner. Dr.
20 Kettner, I’m just going to go back briefly, something
21 you mentioned about the federal provincial public
22 health tables, is that the way you described them?
23 A. Yeah, that’s one way to describe it.
24 125. Q. Okay. Thank you. At these, and you’ll understand me if
25 I say FPT for federal provincial territorial, you would
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1 agree that these FPT tables would, would have discussed
2 vaccine mandates and the supporting evidence?
3 A. I would expect so.
4 126. Q. Okay. Okay, thank you. I’m just going to go back to
5 page, the page I took you to, it’s page 16 by the
6 notation. And you have a statement there under point
7 number two, which reads “what factors are the most
8 important to consider in estimating the risk

9 probability of transmission of Covid-19 during an
10 airplane flight” are you situated there, sir?
11 A. Yeah.
12 127. Q. Okay. And you state there the Ontario Ministry of
13 Health consistent with Canada, British Columbia and
14 Quebec uses the following three factors to determine
15 whether a close contact or high-risk exposure to an
16 infectious individual has occurred, and you list three:
17 the duration of the exposure, the distance from the
18 infectious person, and the use of a mask or other
19 barrier, you see that?
20 A. Yes.
21 128. Q. And you cite definitions from British Columbia, Quebec
22 and Ontario which you state are quite consistent, but
23 none of these mentions aircraft as a specific
24 environment for the purposes of close contact or high
25 risk, do they?
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1 A. No, they don’t mention any specific built environment.
2 129. Q. Okay, thank you. I’m going to take you to another
3 document, bear with me. Dr. Kettner, do you see this
4 document I put on the screen?
5 A. Yeah.
6 130. Q. It reads Ministry of Health management of cases of, and
7 context of Covid-19 in Ontario, and it’s dated April
8 19th, 2022, version 14.1, do you see that?

9 A. I do see that, yeah.
10 131. Q. Would you agree that this replaces the document you
11 cited at footnotes 19 and 20 of your report?
12 A. Yeah, I suspect so, same title.
13 132. Q. Okay. And I’m just going to take you to page four of
14 this document just to clarify, and under, do you see on
15 page four under background, it’s under the last
16 paragraph on the page. It states this document
17 replaces, and then it lists some others but then it
18 mentions, and I’ll just, I know this isn’t a highlight,
19 but I’ve identified it, the Covid-19 integrated testing
20 and case conduct in outbreak management interim
21 guidance Omicron search, March 19, 2022. I appreciate
22 this is not the same day as the document you cited in
23 your footnotes at 19 and 20, but you agree that would
24 be, it replaces an updated version of the document you
25 cited?
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1 A. It appears that day I mean, you know I would have to go
2 through the document more to say that it covers exactly
3 the same, but it looks, it looks pretty much like this
4 is the current version, yeah, it’s pretty clear, I
5 think.
6 133. Q. Okay. I’m just going to take you up one paragraph again
7 at the top here. It says this document is intended to
8 provide broad guidelines only and cannot cover every

9 scenario that may be encountered. Therefore, local
10 public health unit PHU decision making is required, do
11 you see that?
12 A. I see that, yeah.
13 134. Q. And you agree that this document does not address the
14 scenario of contacts on an aircraft?
15 A. Well, if the updated version, which I haven’t read,
16 does not include anything specific about the paragraph,
17 then if that’s what you’re asking, yeah. So, that
18 wouldn’t surprise me in a way because most of these
19 guideline documents can’t really cover every specific
20 environment setting so, so it sounds like this one
21 doesn’t have anything specific to airline travel, is
22 that right?
23 135. Q. If you need a moment to look through it, that’s fine.
24 A. Well, that’s what I would be looking for. So.
25 136. Q. Well, let me go back. The document you relied on in
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1 your, as cited in your footnotes, didn’t mention
2 aircraft as a specific environment or scenario, did it?
3 A. It did not. There would be two things I would want to
4 look for I think, of relevance to this examination. One
5 is has, have the other guidelines that I referred to
6 particularly changed, and the other would be is there
7 anything specific to airplane travel.
8 137. Q. Thank you. I’m just going to take you down to page 17
9 of this document, and you can still see this on your
10 screen?
11 A. Yes.
12 138. Q. Okay. And I’m taking you to section 6.1 under six
13 guidelines for close contact, and then in 6.1 this is
14 definition of close contact. Do you see that?
15 A. Yeah.
16 139. Q. Thank you. And you see that it says close, in the
17 second paragraph, close contacts have been in contact
18 with the case/symptomatic person within the 48 hours
19 due to cases symptom onset if symptomatic or 48 hours
20 prior to the specimen collection date, whichever is
21 earlier applicable, and until they have completed their
22 self-isolation period, and, and I’m going to ask you a
23 question of the said report. We’re in close proximity,
24 less than two meters, for at least 50 minutes or for
25 multiple short periods of time without measures such as
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1 masking [indiscernible] and/or use of personal
2 protective equipment, see table one for examples. Do
3 you see that?
4 A. I do. I don’t see table one, but I see that what you
5 just read.
6 140. Q. I can take you to table one if you wish, but I mean is
7 this the basis for your, for your definition in your
8 report that I took you too just earlier?

9 A. You know, I don’t think it’s changed, unless I’m
10 mistaken. So, I think it’s the same reference that I
11 was making that you know this is kind of the usual way
12 as a guideline to decide whether someone has had a
13 close contact or high risk exposure, and so unless I’m
14 missing something, this looks pretty similar.
15 141. Q. Okay, thank you. And then I’m just going to take you to
16 page 20 of this document. Do you see this at the top of
17 the page, it belongs with a bolded close contact
18 followed by a bolded close contact followed by a bolded
19 prolonged contact?
20 A. So, the bold is that physical distancing does not
21 eliminate the risk of transmission, and particularly
22 and certain indoor or poorly ventilated spaces. And
23 then the second one is, got to do with prolonged
24 exposure more than 50 minutes however it does
25 [indiscernible] exposure is [indiscernible] and that
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1 may still be considered close contact depending on the
2 context of the contact or exposure. Yeah, I don’t think
3 that’s changed. I mean I would have to look, but it’s
4 typical to have you know statements that, this isn’t
5 absolute one way or another and that some judgement has
6 to be used by the person interviewing the contact to
7 decide whether they think that an exposure was you
8 know, significant and even if it didn’t necessarily

9 meet the 15 minute time, yeah. So, I don’t think, I
10 mean I don’t think there’s anything there that’s
11 significantly different.
12 142. Q. All right. So, you agree these are the definitions of
13 close contact and prolonged contact that you used and
14 those you agree with as set out in your report?
15 MR. PRESVELOS: Well, so, sorry counsel, come on,
16 right. We’re being silly. The definitions have
17 footnotes in the reports. You’ve now produced a
18 subsequent updated report that could not have been
19 available to Dr. Kettner. Dr. Kettner answered various
20 questions about what he thinks basically the difference
21 is between the definitions and this updated report that
22 wasn’t available, and you’re asking him whether the
23 updated report were the definitions he used in the
24 report that already has citations to the sources which
25 definitions he did pull from. That’s not a fair
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1 question. You’ve asked your questions about what he
2 thinks of the new definitions, you’ve had your answer,
3 let’s move on. I’m going to refuse that question.
4 A. Mr. Drummond, maybe it would help you in the purpose
5 of your question if I said that what I was doing in my
6 report, and I can talk more about this you know if it’s
7 important, was not to confirm or deny whether I agreed
8 with or liked these definitions or would have used the

9 same ones if I was writing this. What I was just
10 referring to was that these are guidelines that they
11 used for close exposure in an operational way i.e. if
12 someone meets the criteria for a high risk or close
13 contact and certain things happen in terms of follow
14 up, in terms of isolation, in terms of [indiscernible]
15 you know et cetera. So, there are operational
16 guidelines. My point in the report, and it is quite
17 possible that thinking has or will change over time,
18 but when I wrote the report, which was referring to a
19 policy that was in place at the time regarding travel
20 requirements for vaccines I, the point I was trying to
21 make was that based on these definitions, sitting
22 beside someone, and certainly sitting two seats away
23 from someone, but even sitting beside someone would not
24 necessarily result in a classification as high risk
25 exposure or a close contact. So, it doesn’t prove
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1 anything one way or another about the probability of
2 transmission happening. I was just trying to make the
3 point that based on those, these guidelines that are
4 accepted by most provinces if not all of them, that
5 these exposures that would happen on an airplane and
6 under the conditions that are observed, might not be
7 considered high risk exposures. I just thought that was
8 something worth being aware of. It doesn’t prove or

9 disprove the rate of transmission, but I would like to
10 think I, like I said, I can’t really, I was operating
11 on the inside of the thinking process was that they
12 used, they developed these guidelines of what kind of
13 probabilities of transmission they’re using as a
14 threshold or a cut off. I’m not privy to that
15 information, especially since they don’t describe, I’ve
16 never seen the criteria described with regard to
17 probability of transmission. But the fact that these
18 were the guidelines in place just seemed relevant to
19 try and figure out how high a risk of high exposure or
20 close contact would be in an airplane, and you know and
21 some of the data that I have been sent you know, and
22 other reports, more recent reports of the government
23 suggest that that might have seemed to be a pretty
24 reasonable approach given the rates of transmission
25 that are being studied. They’re all over the place, so
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1 I’m not in a place to test the validity of all those
2 [indiscernible] from various reports, from you know one
3 in 1.7 million travellers to 46% of travellers in one
4 plane I mean you know, that’s why, that’s why a smart
5 public health official has to pull all this together
6 and make a reasonable estimate, and then tell the
7 public about it.
8 143. Q. Okay, Mr. Presvelos, I’m going to state this, I’m

9 asking Dr. Kettner if he agrees with these two that,
10 these definitions of close contact, prolonged contact
11 and PPE. Actually, I’m not asking about PPE, and I
12 think that’s a fair question. It’s an update to the
13 Ontario directions, which he cited to. So, I’m just
14 going to ask if Dr. Kettner, do you agree with these
15 definitions that Ontario has put forward?
16 MR. PRESVELOS: So, I’m going to refuse the
17 question. It’s irrelevant, and the way Dr. Kettner as
18 he explained was discussing these factors in his report
19 was to make a different point, not to challenge the
20 criteria that you’re asking him to accept, and in fact,
21 it would appear to me that this criteria is actually
22 even more favorable to our case since it would require
23 confirmation of a known Covid-19 exposure. So, in any
24 event, thank you for asking the question. It’s refused.
25 144. Q. I do not understand the basis on which it’s irrelevant.
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1 MR. PRESVELOS: I just told you.
2 145. Q. This is….
3 MR. PRESVELOS: Dr. Kettner was talking about
4 these factors in a different context in his report. Dr.
5 Kettner has explained the manner in which and the
6 purpose for which he discussed these factors. And so,
7 the way you’re asking your questions, asking him to
8 agree or disagree with these factors, it’s irrelevant.

9 146. Q. All right. Dr. Kettner, I’m going to ask you under
10 prolonged contact you’ll note what I’ve highlighted, it
11 says; as part of the individual risk assessment
12 considered a cumulative duration and the nature of a
13 contact, the contacts exposure eg, a longer exposure
14 time, cumulative times of exposures likely increases
15 the risk. An outdoor only exposure likely decreases the
16 risk whereas an exposure in a small closed or poorly
17 ventilated space may increase the risk even if distance
18 or masked, do you see that?
19 A. I see that, yeah, I see that definition of prolonged
20 contact and the things you read from it.
21 147. Q. Okay. And, and you agree that there may be a need for
22 an individual risk assessment in any particular
23 scenario?
24 A. I think I said. I think I said that these are
25 guidelines. You know, the person in front of the
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1 planner is the, whether it’s a public health nurse or
2 whomever, has to make an assessment and a judgement.
3 148. Q. Okay. You agree that many commercial flights will
4 usually be longer than 15 minutes?
5 A. I’ve never been on a flight shorter than 15 minutes. I
6 wish that there were flights that short, frankly.
7 149. Q. And do you agree that an aircraft cabin in flight is a
8 closed space, even if not a small space?

9 A. Well, if by closed space you mean there aren’t any open
10 windows or doors during flight, I can, I’m quite
11 confident that that’s true. If whether there’s any
12 mechanism of drawing in outside air during the flight,
13 I don’t know that. But that would then mean it’s not a
14 closed space I guess, if that’s what a closed space
15 means. But I think there’s filtering and circulation up
16 there that’s in the cabin. I don’t think it’s a good
17 idea to let outside air into the plane. So, I’m going
18 to say, I’m thinking out loud just to make sure that
19 you can understand my interpretation of the answer. So,
20 I think probably it’s a closed space.
21 150. Q. Thank you. I’d ask that this be entered as an exhibit.
22 COURT REPORTER: Exhibit 2.
23 EXHIBIT 2: Article
24 151. Q. Thank you. Dr. Kettner, we’ve been going approximately
25 85 minutes. I wonder if this might be an appropriate
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1 time to say take a 10 minute break, if that works for
2 you?
3 A. I’m okay with that.
4 152. Q. Okay. Madam Court Reporter, can we adjourn for, until I
5 guess it would be 35 minutes past the hour?
6 COURT REPORTER: Sure, I’ll take us off the record.
8 BREAK
9
10 153. Q. All right, Dr. Kettner….
11 A. So, sorry to interrupt. Mr. Drummond, just as a point
12 of order, and this is the, more me as a medical, as a
13 caring medical doctor, when do you have lunch. Like
14 it’s important to have regular meals at regular times
15 for your well-being. I’m just wondering what’s the plan
16 here?
17 154. Q. Dr. Kettner, I think, thank you for your consideration,
18 I appreciate that. I think I will be concluded in
19 fairly short order, and I’m in the mountain time zone,
20 so it’s only about 20 minutes to 11 for me, so. As I
21 say, if you need to take a break, that’s fine, but I
22 hope to be done in short order.
23 A. I’m fine. Thank you.
24 155. Q. Dr. Kettner, before we took a break you mentioned that
25 you had been looking at publicly available information.
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1 I am going to, from the government of Canada, I’m going
2 to share my screen once more with you. Dr. Kettner, do
3 you see this document I have on the screen. It’s from
4 the Public Health Agency of Canada, emerging evidence
5 on Covid-19, evidence brief on the risk of Covid-19
6 transmission in flight update three, and at the top
7 it’s dated November 25, 2021, do you see this document?
8 A. Yes, I see it.

9 156. Q. Thank you. And on the first page at the bottom, I’m
10 going to just read a sentence to you. I’m sorry, I
11 can’t highlight it properly for some reason, try again.
12 This evidence brief summarizes the literature on in
13 flight transmission of SARS Covi-2, the characteristics
14 of these events and the strategies implemented or
15 proposed to mitigate transmission in an airplane or
16 during boarding and disembarkation. This is the third
17 update and includes studies up to November 25, 2021.
18 The first and second update of this review contained
19 literature published up to October 28, 2020, and April
20 26, 2021, respectively. Do you note that?
21 A. I do.
22 157. Q. I’m sorry, Dr. Kettner, I didn’t hear a response from
23 you?
24 A. Oh, I do. Yes, I note that sorry, I said it, but same
25 thing.
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1 158. Q. Thank you. Did you review this evidence brief in
2 preparing your report?
3 A. I did not refer to it. And to be honest, I can’t
4 remember if I reviewed it, and I think that, I think
5 I’ll just add one other thing about why I didn’t use
6 any of it if I did review it. I didn’t find in this
7 document, and looking at it again more recently, any
8 summary estimates on the part of, of the writers of

9 this or the users of this information. In other words,
10 it is a summation of a number, not the summation, in
11 fact it is not a summation, that’s what’s, that’s what
12 the main problem for me was. It’s a collection of
13 various studies and reports, but it’s not, and it
14 doesn’t summarize the findings in terms of sort of, the
15 best estimate of the results from these studies, or how
16 they might be used for policy setting. So, you know
17 when I’ve said many times in the report that I could
18 not find data, evidence, analysis, rationale, or
19 estimates to justify the policies, this is a good place
20 for me to explain what I meant by that because, because
21 although there is data in here, although there is
22 information, although there is the you know somewhat
23 analysis of some of the researchers or writers, what’s
24 missing here is a summation and an interpretation of
25 all this evidence in a quantified way that could
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1 actually guide decision making at a policy level or the
2 rationale for that decision making. So, neither is that
3 contained in this evidence brief, but it’s not
4 contained in any explanations of the policies that have
5 been put in place. And that’s what I’m referring to
6 when I, when that, you know when that kind of recurring
7 verse in my report is that I could not find such things
8 in to explain government policies. Again, not, not that

9 these policies were right or wrong, they just, I’m just
10 looking for justification of them, an explanation of
11 them, and explanation of alternative policies and the
12 pros and cons, and analysis of the harms from these
13 policies, and just looking for that I couldn’t, that’s
14 what I, so I couldn’t find it in this review. I
15 couldn’t find that in this review. Now there’s
16 evidence, or there’s research in these reviews that one
17 could refer to in developing one’s estimates. The way
18 for example, the National Advisory [indiscernible] on
19 immunization has done it, which is to look at many,
20 many papers and then sum it up with their best estimate
21 of the effectiveness of the vaccine, or the rate of
22 adverse affects. That’s the kind of estimates I was
23 looking for that would be used as you know, the sort of
24 summation. That’s what this [indiscernible] just should
25 be able to do, summarize it and then present it either
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1 to the public if they have permission, or to who
2 they’re giving advice to. Sorry, I felt I did need to
3 kind of explain that so you would understand my
4 perspective. Not necessarily an excuse for not having
5 referred to the review, in retrospect, I think it might
6 have been good because there’s a lot of information in
7 this review, which I think sort of would go with the
8 theme of my, of my report that the evidence out there

9 needs to be critically analyzed and thoughtfully
10 applied to Canada. I mean that’s the other issue that
11 you know, that sort of maybe ties back better with what
12 I was saying before about looking for Canadian,
13 official Canadian sources. Very little of the research
14 in this evidence is Canadian. So, you know, one has to
15 be additionally cautious about interpreting it and
16 applying it for Canadian policy.
17 159. Q. Thank you, Dr. Kettner. I’d like to enter this document
18 as an exhibit, please.
19 COURT REPORTER: Okay, Exhibit 3.
20 EXHIBIT 3: Public Health Agency of Canada report
21 emerging evidence on Covid-19, evidence brief on the
22 risk of Covid-19 transmission in flight update three,
23 dated November 25, 2021
24 160. Q. All right. Dr. Kettner, I know we just went on break.
25 I’m just going to ask for five minutes while I check my
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1 notes, and then I’m likely done. If we could go off the
2 record briefly.
3 A. Okay, this is meant as a joke….
5 BREAK
7 161. Q. All right. Thank you, Dr. Kettner. Those are all my
8 questions. You are free to go from my perspective. Your

9 counsel may have some re-direct questions for you.
10 Thank you.
11 A. Thank you, Mr. Drummond.
12 MR. PRESVELOS: Dr. KEttner, have a nice day.
13 A. Thank you, Mr. Presvelos.
14
15
16
17
18 THIS IS TO CERTIFY THAT the foregoing is a true and accurate
19 transcription from the recordings made herein, to the best of
20 my skill and ability.
21
22
23 Angel Hebert 11-June-2022

24 ________________________________ ____________________________
25 ANGEL HEBERT DATE
26 Court Reporter / A.C.T
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51'l9122.5:o5PM Overview of Testing for SARS-O>V-2.
r;'iTil Centers for Disease

lliiiflii.Control and Prevention
COVID-19
Overview of Testing for SARS-CoV-2, the virus that causes

COVID-J 9
Updaced Feb. 11, 2022
- - -- -- - - - - - - - - -
Note: This document provides guidance on the different types of viral tests for SARS--CoV-2 available in the United States
and their intended uses. It does not address issues regarding payment for or insurance coverage of such testing.
Summary of Recent Changes

Updates as ofJanuary 21, 2022
• Revised to align with CDCs updated recommendations on isolation and quarantine.

• Revised to align with CDC recommendations for people who are up to date with their vaccines.
View Previous Updates
Key Points
• People who have symptoms of COVI D-19 or who have had known close contact to someone with COVID-19 should be
tested for COVID-19.
• Point-of care serial screening testing can provide rapid r esults and is critical to identifying people with COVID-19 who do
not have symptoms and slowing the spread of SARS-CoV-2. This is especially important when the COVID-19 Community
Level is high.
• When selecting which SARS--CoV-2 test to use and interpreting results, healthcare providers, public health professionals,
and those organizing and implementing testing should consider the context in which they are being used, including the
prevalence of SARS--CoV-2 in the population being tested and the status (signs, symptoms, close contacts) of the person
being tested.
• A person's vaccination status does not affect the results of their viral test for SARS--CoV-2.
• This guidance has been developed based on what is currently known about SARS-CoV-2 infection and COVID-19 and is
subject to change as additional information becomes available.
A robust and responsive testing infrastructure is essential to the success of stopping the spread of SARS--CoV-2, the virus that
causes COVID-19. This overview describes current information on the types of tests used to detect SARS--CoV-2 infection and
t heir intended uses. including to diagnose infection, screening testing to reduce the virus's spread by people who do not have
symptoms, and to monitor trends in infection. This guidance also includes considerations for.
• Health equity in testing
• Choosing a test
• Interpreting test results in vaccinated persons
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• Testing in specific settings (e.g., K-12 schools, businesses, non-healthcare workplaces, correctional and detention
facilities)
• Other considerations when deciding to test
This information is intended for use by healthcare providers, public health professionals, and those organizing and
implementing testing in non-healthcare settings, such as schools, workplaces, and congregate housing. Information for the
general public on SARS-CoV-2 testing is also available.
Science at CDC
Scientific evidence and studies behind specific COVID-19 guidance and recommendations
Science Briefs MMWR COVID-19 Reports
Considerations When Testing

SARS-CoV-2 testing may be incorporated into a comprehensive approach to reducing transmission that also includes
screening for symptoms and contact tracing. When combined, these strategies can identify people infected with SARS-CoV-2
so that actions can be taken to slow and stop the spread of the virus.
People undergoing testing should receive clear information on
• The manufacturer and name of the test, the type of test, the purpose of the test, the performance specifications of the
test, any limitations associated with the test, who will pay for the test, how the test will be performed, how and when
people will receive test results, and;
• How to understand what the results mean, what actions need to happen after someone has negative or positive results,
the difference between testing for workplace screening versus for medical diagnosis, who will receive the results, how
the results may be used, and any consequences for declining to be tested.
Individuals tested are required to receive patient fact sheets as part of the test’s Emergency Use Authorization (EUA).
Vaccination and SARS-CoV-2 Testing

If a person has received a COVID-19 vaccine, it does not affect the results of their SARS-CoV-2 viral tests (nucleic acid
amplification tests [NAAT] or antigen). Because the Pfizer-BioNTech, Moderna, and Johnson & Johnson COVID-19 vaccines use
the SARS-CoV-2 spike protein to generate an immune response, a positive serologic (antibody) test for spike protein IgM/IgG
could indicate either previous infection or vaccination. Antibody testing is not currently recommended to assess for immunity
to SARS-CoV-2 infection following COVID-19 vaccination or to assess the need for vaccination in an unvaccinated person. To
evaluate for evidence of previous infection in a vaccinated individual, an antibody test specifically evaluating IgM/IgG to the
nucleocapsid protein should be used (e.g., for public health surveillance or the diagnosis of Multisystem Inflammatory
Syndrome in Children (MIS-C) or Multisystem Inflammatory Syndrome in Adults (MIS-A)). For guidance on quarantine and
testing of people who are up to date with their vaccines, please visit COVID-19 Quarantine and Isolation.
Testing for SARS-CoV-2 Infection

Many types of tests are used to detect SARS-CoV-2,1 and their performance characteristics vary.
• Some tests provide results rapidly (within minutes); others require time for processing.
• Some must be performed in a laboratory by trained personnel, some can be performed at the point of care, and others
can be performed at home or anywhere.
• Some tests are very sensitive (i.e., few false-negative results or few missed detections of SARS-CoV-2); others are very
specific (i.e., few false-positive results or few tests incorrectly identifying SARS-CoV-2 when the virus is not present); and
some are both sensitive and specific.
https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html 2/12
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• Some tests can be performed frequently because they are less expensive and easier to use than other tests, and
supplies are readily available.
When selecting which SARS-CoV-2 test to use healthcare providers, public health professionals, and those organizing and
implementing testing should consider the context in which they are being used, including the prevalence of SARS-CoV-2 in the
population being tested (See Table 1) and the status (signs, symptoms, close contacts) of the person being tested.
Test Types
Viral tests, including Nucleic Acid Amplification Tests (NAATs, such as Reverse Transcription – Polymerase Chain Reaction) and
antigen tests, are used as diagnostic tests to detect current infection with SARS-CoV-2 and to inform an individual’s medical
care. Viral tests can also be used as screening tests to reduce the transmission of SARS-CoV-2 by identifying infected persons
who need to isolate from others. See FDA’s list of In Vitro Diagnostics Emergency Use Authorizations  for more information
about the performance of specific authorized tests.
• NAATs are high-sensitivity, high-specificity tests for diagnosing SARS-CoV-2 infection. NAATs detect one or more viral
ribonucleic acid (RNA) genes and indicate a current infection, or can indicate a recent infection due to prolonged viral
RNA detection. NAAT results are not always direct evidence for the presence of virus capable of replicating or being
transmitted to others. Most NAATs need to be performed in a laboratory, however some are point-of-care tests, and a
few are self-tests. Time to results can vary by laboratory test (~1–3 days), but point-of-care or self-tests NAATs can
produce results in about 15–60 minutes. Most NAATs produce qualitative results. NAATs can be performed on upper
respiratory specimens, such as nasopharyngeal, nasal mid-turbinate, anterior nasal, or saliva.
• Antigen tests are immunoassays that detect the presence of a specific viral antigen. Antigen tests generally have similar
specificity, but are less sensitive than most NAATs. Most are less expensive than NAATs and can provide results in
minutes, making them useful in screening programs to quickly identify persons who are likely to have COVID-19. There
are antigen tests available for at-home testing (self-testing), at the point of care, or in a laboratory. Because of the
performance characteristics of antigen tests, it may be necessary to confirm some antigen test results (a negative test in
persons with symptoms or a positive test in persons without symptoms) with a laboratory-based NAAT. Some point-of-
care NAATs that provide presumptive results cannot be used for confirmatory testing. Use of the Antigen Testing
Algorithm  is recommended to determine when confirmatory testing is needed.
Correct interpretation of results from both antigen tests and confirmatory NAATs, when indicated, is important.
Positive test results allow for identification and isolation of infected persons, as well as a case interview to identify and notify
the case’s close contact(s) of exposure and the need to quarantine.
Negative test results in persons with known SARS-CoV-2 exposure suggest no current evidence of infection. These results
represent a snapshot of the time around specimen collection and could change if the same test was performed again in one
or more days. For guidance on quarantine after a negative test, visit COVID-19 Quarantine and Isolation. In healthcare
facilities with an outbreak of SARS-CoV-2, recommendations for viral testing of healthcare providers, residents, and patients
(regardless of their vaccination status) remain unchanged.
Negative test results in persons who have no symptoms and no known exposure suggest no infection. All persons being
tested, regardless of their results, should talk to their healthcare provider about risk reduction behaviors that help prevent
the transmission of SARS-CoV-2 (e.g., wearing a well-fitting mask, physical distancing, avoiding crowds and poorly ventilated
spaces).
Antibody (or serology) tests are used to detect previous infection with SARS-CoV-2 and can aid in the diagnosis of multisystem
inflammatory syndrome in children (MIS-C)  and in adults (MIS-A)2. CDC does not recommend using antibody testing to
diagnose current infection. Depending on the time when someone was infected and the timing of the test, the test might not
detect antibodies in someone with a current infection. In addition, it is not currently known whether a positive antibody test
result indicates immunity against SARS-CoV-2; therefore, at this time, antibody tests should not be used to determine if an
individual is immune against reinfection. Antibody testing is being used for public health surveillance and epidemiologic
purposes. Because antibody tests can have different targets on the virus, specific tests might be needed to assess for
antibodies originating from past infection versus those from vaccination. For more information about COVID-19 vaccines and
antibody test results, refer to Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines Currently Authorized in the
United States.
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Overview of Testing Scenarios

Diagnostic testing is intended to identify current infection in individuals and is performed when a person has signs or
symptoms consistent with COVID-19, or is asymptomatic, but has recent known or suspected close contact exposure to SARS-
CoV-2.
Examples of diagnostic testing include:
• Testing persons with symptoms consistent with COVID-19, whether or not they are up to date on their vaccinations.
• Testing persons as a result of contact tracing efforts.
• Testing persons who indicate that they had close contact exposure with someone suspected or confirmed as having
COVID-19.
Screening tests are recommended for those who have no symptoms and no known, suspected, or reported close contact
exposure to SARS-CoV-2. Screening helps to identify unknown cases so that measures can be taken to prevent further
transmission.
Examples of screening include:
• Testing employees in a workplace setting
• Testing students, faculty, and staff in a school or university setting
• Testing a person before or after travel
• Testing at home for someone who does not have symptoms associated with COVID-19 and no known exposures to
someone with COVID-19
Public health surveillance is intended to monitor population-level burden of disease, or to characterize the incidence and
prevalence of disease. Surveillance testing is primarily used to gain information at a population level, rather than an individual
level, and generally involves testing of de-identified specimens. Surveillance testing results are not reported back to the
individual. As such, surveillance testing cannot be used for an individual’s healthcare decision making or individual public
health actions, such as isolation or quarantine.
An example of surveillance testing is wastewater surveillance.
Choosing a Test
When choosing which test to use, it is important to understand the purpose of the testing (diagnostic or screening),
performance of the test within the context of the COVID-19 Community Level, need for rapid results, and other considerations
(See Table 1). For example, even a highly specific antigen test may have a poor positive predictive value (high number of false
positives) when used in a community where prevalence of infection is low. As an additional example, use of a laboratory-
based NAAT in areas where COVID-19 Community Level is high and increased test demand may result in diagnostic delays
due to processing time and time to return results. Positive and negative predictive values of NAAT and antigen tests vary
depending upon the pretest probability. Pretest probability considers both the COVID-19 Community Level as well as the
clinical context of the individual being tested. Additional information is available on sensitivity, specificity, positive and
negative predictive values for antigen tests and antibody tests, and the relationship between pretest probability and the
likelihood of positive and negative predictive values[458 KB, 1 Page]. Also see FDA’s letters to clinical laboratory staff and
healthcare providers on the potential for false-positive results with antigen tests and the potential for false-negative results
with molecular tests if a genetic variant of SARS-CoV-2 is found in the part of the viral genome assessed by the test.
Table 1 summarizes some characteristics of NAATs and antigen tests to consider for a testing program. Given the risk of
transmission of SARS-CoV-2 from asymptomatic and presymptomatic persons with SARS-CoV-2 infection, use of antigen tests
in asymptomatic and presymptomatic persons can be considered. FDA has provided a list of FAQs for healthcare providers
who are using diagnostic tests in screening asymptomatic individuals, and the Centers for Medicare & Medicaid Services will
temporarily exercise enforcement discretion  to enable the use of antigen tests that are not currently authorized for use in
asymptomatic individuals for the duration of the COVID-19 public health emergency under the Clinical Laboratory
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Improvement Amendments of 1988 (CLIA). Laboratories that perform screening or diagnostic testing for SARS-CoV-2 must
have a CLIA certificate and meet regulatory requirements. Tests that have received an EUA from FDA for point-of-care (POC)
use can be performed with a CLIA certificate of waiver.
COVID-19 Viral Testing Tool

 A tool to help you understand COVID-19 testing options.
Get Started
About the Tool
Table 1. NAAT and Antigen Test Differences to Consider When Planning for Diagnostic
or Screening Use
NAATs Antigen Tests
Intended Use Diagnose current infection Diagnose current infection
Analyte Detected Viral Ribonucleic Acid (RNA) Viral Antigens
Specimen Type(s) Nasal, Nasopharyngeal, Nasal, Nasopharyngeal

Oropharyngeal, Sputum, Saliva
Sensitivity Varies by test, but generally high for Varies depending on the course of
laboratory-based tests and infection, but generally moderate-to-
moderate-to-high for POC tests high at times of peak viral load*
Specificity High High
Test Complexity Varies by test Relatively easy to use
Authorized for Use at the Point-of- Most are not, some are Most are, some are not
Care
Turnaround Time Most 1-3 days. Some could be rapid Ranges from 15 minutes to 30
in 15 minutes minutes
Cost/Test^ Moderate (~$75-$100/test) Low (~$5-$50/test)
Advantages Most sensitive test method available Short turnaround time

(approximately 15 minutes)+
Short turnaround time for NAAT POC
tests, but few available When performed at or near POC,
allows for rapid identification of
Usually does not need to be infected people, thus preventing
repeated to confirm results further virus transmission in the
community, workplace, etc.
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Comparable performance to NAATs

for diagnosis in symptomatic
persons and/or if culturable virus
present
Disadvantages Longer turnaround time for lab- May need confirmatory testing
based tests (1–3 days)
Less sensitive (more false negative
Higher cost per test results) compared to NAATs,
especially among asymptomatic
A positive NAAT diagnostic test people and with some variants
should not be repeated within 90
days, because people may continue
to have detectable RNA after risk of
transmission has passed
*The decreased sensitivity of antigen tests might be offset if the POC antigen tests are repeated more frequently (i.e., serial
testing at least weekly).
^ Costs for: NAATs 
+Refers to point-of-care antigen tests only.
Health Equity in SARS-CoV-2 Testing

CDC’s COVID-19 Response Health Equity Strategy outlines a plan to reduce the disproportionate burden of COVID-19 among
racial and ethnic minority populations and other population groups (e.g., essential and frontline workers, people living in rural
or frontier areas) who have experienced a disproportionate burden of COVID-19. One component to move towards greater
health equity and to stop transmission of SARS-CoV-2 is ensuring availability of resources, including access to testing for
populations who have experienced longstanding, systemic health and social inequities. All population groups, including racial
and ethnic minority groups, should have equal access to affordable, quality and timely SARS-CoV-2 testing – with fast
turnaround time for results — for diagnosis and screening to reduce the COVID-19 Community Level. Efforts should be made
to address barriers that might overtly or inadvertently create inequalities in testing.
In addition, completeness of race and ethnicity data is an important factor in understanding the impact the virus has on racial
and ethnic minority populations. The U.S. Department of Health and Human Services has required laboratories and testing
facilities to report  race and ethnicity data to health departments, in addition to other data elements, for individuals tested
for SARS-CoV-2 or diagnosed with COVID-19. Healthcare providers and public health professionals need to ask and record
race and ethnicity for anyone receiving a reportable test result and ensure these data are reported with the person’s test
results in order to facilitate understanding the impact of COVID-19 on racial and ethnic minority populations.
In communities with a higher proportion of racial and ethnic minority populations and other populations disproportionately
affected by COVID-19, health departments should ensure there is timely and equitable access to and availability of testing
with fast result return, especially in areas where the COVID-19 Community Level is high.
Some strategies to achieve this goal include:
• Use a social vulnerability index to assist in selecting testing sites.
• Assess the capacity of these sites to expand diagnostic and screening testing to meet the demand for impacted areas.
This includes assessing the availability of free testing, wait times for testing and for results, and categories of available
test (NAAT vs. antigen), as well as identifying and removing barriers to testing (e.g., alternatives to drive-through testing
for a community where many do not have cars; availability of testing on evenings and weekends).
• Increase the availability of free testing sites in communities. Employers, community-based, and faith-based organizations
can be important partners to increase the number of free, community-based testing sites. This expansion ensures that
wait times both for testing and reporting of results are decreased, helping limit the spread of SARS-CoV-2.
• Increase public messaging about the importance of testing and communicate these messages in multiple languages and
venues, particularly in communities at higher risk and disproportionately impacted by the virus.
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Considerations for testing in different scenarios
Diagnostic testing
Testing persons with signs or symptoms consistent with COVID-19

Positive test results using a viral test (NAAT or antigen) in persons with signs or symptoms consistent with COVID-19 indicate
that the person has COVID-19, independent of vaccination status of the person. A negative antigen test in persons with signs
or symptoms of COVID-19 should be confirmed by NAAT, a more sensitive test. For more information, see the Antigen Test
Algorithm.
All persons (independent of vaccination status) with positive results should isolate at home or, if in a healthcare setting, be
placed on appropriate precautions  . Most people with COVID-19 have mild illness and can recover at home without medical
care. For more information, see CDC’s COVID-19 quarantine and isolation guidance.
NAATs have detected SARS-CoV-2 RNA in some people’s respiratory specimens long after they have recovered from COVID-19
(>3 months). Studies have not found evidence that clinically recovered adults with persistence of viral RNA have transmitted
SARS-CoV-2 to others. These findings support the recommendation for a symptom-based, rather than test-based, strategy for
ending isolation of most people, so that individuals who are no longer infectious are not kept unnecessarily isolated and
excluded from work or other responsibilities.
Some adults with severe illness may produce replication-competent virus beyond 10 days that may warrant extending
duration of isolation and precautions. A test-based strategy may be considered in consultation with infectious disease experts
for persons with severe illness or who are severely immunocompromised. For more information, including on retesting
persons previously infected with SARS-CoV-2, visit Duration of Isolation and Precautions for Adults with COVID-19.
Testing asymptomatic persons who have had recent known or suspected close contact
exposure to SARS-CoV-2
Identifying close contacts (people who have been within 6 feet for a combined total of 15 minutes or more during a 24-hour
period) of persons with COVID-19 can help reduce the spread of SARS-CoV-2 in communities, workplaces, and schools when
these close contacts quarantine themselves. Viral testing is recommended for individuals who are close contacts of persons
with COVID-19. Regardless of their vaccination status, people who have had a close contact exposure with someone known or
suspected of having COVID-19 should be tested at least 5 days after the incident, if possible, or earlier if symptoms develop.
Most people with a history of test-confirmed COVID-19 who remain symptom-free after recovery do not need to retest or
quarantine if another exposure occurs within 90 days after their initial infection. For more information, see CDC’s COVID-19
quarantine and isolation guidance.
Negative test results using a viral test (NAAT or antigen) in asymptomatic persons with recent known or suspected close
contact exposure suggest no current evidence of infection. These results represent a snapshot of the time around specimen
collection and could change if tested again in one or more days. In instances of higher pretest probability, such as high
incidence of infection in the community, or a person with household or continuous contact to a person with COVID-19, clinical
judgement should determine if a positive antigen result for an asymptomatic person should be followed by a laboratory-
based confirmatory NAAT. Results from NAATs are considered the definitive result when there is a discrepancy between the
antigen and NAAT test. For more information, see the Antigen Test Algorithm.
Because of the potential for asymptomatic and presymptomatic transmission, it is important that individuals exposed to
people with known or suspected COVID-19 be quarantined (if they are not up to date with their vaccines) or wear a well-fitting
mask in public settings (if they are up to date with their vaccines or if they had confirmed COVID-19 within the past 90 days).
Regardless of their vaccination status, persons with positive results should follow CDC’s guidance for isolation. Those not up
to date with their vaccines with negative results should remain in quarantine  for 5 days unless other guidance is given by
the local, tribal, or territorial public health authority.
Based on local circumstances and resources, CDC has provided options to shorten quarantine, including the use of a test-
based strategy. More information on the scientific foundation behind these recommendations is available in Options to
Reduce Quarantine for Contacts of Persons with SARS-CoV-2 Infection Using Symptom Monitoring and Diagnostic Testing.
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Confidentiality of the individual with COVID-19 should be maintained when informing close contacts of their possible
exposure to SARS-CoV-2. People are encouraged to work with public health departments investigating cases of COVID-19,
including identification of close contacts.
Information to help public health departments and healthcare providers prepare for expanded viral testing in facilities after
known or suspected SARS-CoV-2 exposure or in areas where the COVID-19 Community Level is high (Table 2) is available in
CDC’s Performing Broad-Based Testing for SARS-CoV-2 in Congregate Settings.
Accumulating evidence supports ending isolation and precautions  for persons with COVID-19 using a symptom-based
strategy. Adults with more severe illness or who are immunocompromised may remain infectious up to 20 days or longer
after symptom onset, so a test-based strategy could be considered in consultation with infectious disease experts for these
people. For all others, a test-based strategy is no longer recommended except to discontinue isolation or precautions earlier
than would occur under the symptom-based strategy.
People with immunocompromising conditions or people who take immunosuppressive medications or therapies are at
increased risk for severe COVID-19. Immunocompromised people ages 5 years and older should receive a primary COVID-19
vaccine series as soon as possible. In addition, people who are are moderately or severely immunocompromised may not
mount a protective immune response after initial vaccination, and their protection by primary vaccination may wane over
time. Therefore, ACIP and CDC have made age-specific recommendations for an additional primary dose and a booster dose
for this population including, but not limited to, people receiving chemotherapy for cancer, people with hematologic cancers
such as chronic lymphocytic leukemia, people receiving stem cell or organ transplants, people receiving hemodialysis, and
people using certain medications that may blunt the immune response to vaccination.
People who are immunocompromised should talk to a healthcare provider about the potential for reduced immune
responses to COVID-19 vaccines and the need to continue to follow current prevention measures (including wearing a well-
fitting mask, staying 6 feet apart from others they don’t live with, using self-tests, and avoiding crowds and poorly ventilated
indoor spaces) to protect themselves against COVID-19 until advised otherwise by their healthcare provider. Close contacts of
immunocompromised people should also stay up to date with their COVID-19 vaccinations to help protect these people.
Screening Testing
Testing asymptomatic persons without recent known or suspected exposure to SARS-CoV-2 for early identification, isolation,
and disease prevention
Unvaccinated persons with asymptomatic or presymptomatic infection are frequent contributors to community SARS-CoV-2
transmission and occurrence of COVID-19 illness. Serial testing of unvaccinated persons, regardless of their signs or
symptoms, is a key component to a layered approach to preventing the transmission of SARS-CoV-2. Screening allows early
identification and isolation of persons who are asymptomatic, presymptomatic, or have only mild symptoms and who might
be unknowingly transmitting virus. Screening testing may be most valuable in areas where the COVID-19 Community Level is
high (Table 2), in areas with low vaccination coverage, and in certain settings (see examples below).
Use of POC tests, such as antigen tests, for screening can play an important role in testing as a prevention strategy due to the
short turn-around time for results. Antigen tests are most sensitive in the early stages of infection when viral loads are high
and have decreasing sensitivity as disease progresses and when transmission may be less likely. The decreased sensitivity of
antigen tests might be offset if the POC antigen tests are repeated more frequently (i.e., serial testing at least weekly). Thus,
when screening large numbers of persons (e.g., a well-defined cohort) without known or suspected exposure to SARS-CoV-2,
test sensitivity may be less critical than whether the test can be performed more frequently and provide rapid results with
immediate isolation of infected individuals.3 Outbreak prevention and control are increasingly thought to depend largely on
the frequency of testing and the speed of reporting (an advantage of antigen tests) and is only marginally improved – in the
context of serial tests — by the higher test sensitivity of NAATs. In screening settings where antigen tests are used on
asymptomatic people, laboratory-based confirmatory NAAT testing may be needed for certain individuals who test positive.
For interpretation of screening test results, please see the Antigen Test Algorithms.
People without symptoms and without known exposure to COVID-19 do not need to quarantine while awaiting screening test
results. If a person tests positive on a screening test and is referred for a confirmatory test, they should quarantine until they
receive the results of their confirmatory test. For guidance on quarantine and testing of people who are up to date with their
vaccines, please visit COVID-19 Quarantine and Isolation .
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Screening testing as a prevention strategy

• Screening testing can improve detection of SARS-CoV-2.
- Serial testing (within cohorts) with rapid isolation of infected individuals may facilitate re-opening of businesses,
communities, and schools (in-person instruction in K-12 schools4) with less risk of a surge in local cases.
- Frequent testing (1–2 times per week) combined with other risk reduction strategies, contributed to low case rates
in university settings.5
• Frequency of testing could be informed by:

- Current COVID-19 Community Level (Table 2), in addition to other known factors about the epidemiology of
transmission in a particular cohort. If the COVID-19 Community Level is high (Table 2), more frequent screening
might be needed regardless of other indicators.
- Characteristics (e.g., size, proximity of people, duration of interaction) of the school, workplace, residential setting,
or gathering.
- The incubation period for COVID-19. Given that the incubation period can be up to 14 days, CDC recommends
conducting screening testing at least weekly.
• Testing using a tiered approach, analogous to testing described in high-density critical workplace and institutes of higher
education guidance, could be considered and might be particularly important for low incidence areas.
- On some school campuses (e.g., institutes of higher learning), unvaccinated students may be tested upon arrival on
campus or upon return from extended breaks.
• See additional guidance to facilitate implementation of screening in congregate settings.
Examples of groups to prioritize for screening testing

These examples can guide development of local recommendations to prioritize people not up to date with their vaccines for
screening testing, taking into account feasibility and costs. Initial sampling of subgroups for screening testing to evaluate the
need for additional screening testing in a particular group may also be considered. In areas where the COVID-19 Community
Level is high (Table 2), health departments should ensure resources (trained staff and testing supplies) are available to
provide expanded screening testing. These examples are not listed in a priority order.
Racial and ethnic minority groups and other populations disproportionately affected by COVID-19
Teachers and staff in K-12 schools and/or childcare settings
Students, faculty, and staff at institutions of higher education (including community colleges and technical schools)
Workers in high-density worksites or worksites with large numbers of close contact to co-workers or customers
(restaurant workers, transportation workers, grocery store workers)
Government workers with public interactions as part of their duties (post office workers)
First responders (police, fire, emergency medical technician [EMT]) and healthcare personnel
Residents and staff in congregate settings, such as shelters serving the homeless and correctional and detention facilities
or residential settings ,such as nursing homes or those serving persons with disabilities; workplaces that provide
congregate housing (fishing vessels, offshore platforms, farmworker housing or wildland firefighter camps); and military
facilities (barracks)
Persons who recently traveled, either domestically or internationally
Persons who attended large gatherings
Patients in healthcare settings

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Patients in healthcare settings
Specific age groups (e.g., young adults) for whom increases in COVID19 have been documented early as incidence rises,
especially in areas where COVID-19 Community Level is high (Table 2).
COVID-19 Community Levels – Use the Highest Level that Applies to Your Community
New COVID-19 Cases
Indicators Low Medium High

Per 100,000 people in
the past 7 days
New COVID-19 admissions per 100,000

<10.0 10.0-19.9 ≥20.0
population (7-day total)
Fewer than 200

Percent of staffed inpatient beds
occupied by COVID-19 patients (7-day <10.0% 10.0-14.9% ≥15.0%
average)
New COVID-19 admissions per 100,000

NA <10.0 ≥10.0
population (7-day total)
200 or more
Percent of staffed inpatient beds
occupied by COVID-19 patients (7-day NA <10.0% ≥10.0%
average)
Indicators should be calculated for counties or core based statistical areas, although in rural areas with low population
density, multiple jurisdictions might need to be combined to make the indicators more useful for decision-making. The
indicators listed can be found by county on CDC’s COVID Data Tracker Website under “county view”.
* Number of new cases in the county (or other administrative level) in the last 7 days divided by the population in the county
(or other administrative level) and multiplying by 100,000.
†
Number of positive tests in the county (or other administrative level) during the last 7 days divided by the total number of
tests resulted in the county (or other administrative level) during the last 7 days. Calculating Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2) Laboratory Test Percent Positivity: CDC Methods and Considerations for Comparisons
and Interpretation.
Public Health Surveillance Testing for SARS-CoV-2

Public health surveillance is the ongoing, systematic collection, analysis, and interpretation of health-related data essential to
the planning, implementation, and evaluation of public health practice. See CDC’s Introduction to Public Health Surveillance.
Public health surveillance testing is intended to monitor community- or population-level outbreaks of disease or to
characterize the incidence and prevalence of disease. Surveillance testing is performed on de-identified specimens, and, thus,
results are not linked to individual people. Public health surveillance testing results cannot be used for individual decision-
making.
Public health surveillance testing may sample a certain percentage of a specific population to monitor for increasing or
decreasing prevalence or to determine the population effect from community interventions, such as social distancing. An
example of public health surveillance testing is when a state public health department develops a plan to randomly select and
sample a percentage of all people in a city on a rolling basis to assess local infection rates and trends.
“Wastewater,” also referred to as “sewage,” includes water from household/building use (i.e., toilets, showers, sinks) that can
contain human fecal waste, as well as water from non-household sources (e.g., rainwater and industrial use), can be tested for
RNA from SARS-CoV-2. Data from wastewater testing are not meant to replace existing COVID-19 surveillance systems.
Institutes of higher education with the resources to implement wastewater surveillance should develop a wastewater
surveillance strategy in consultation with local public health authorities
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surveillance strategy in consultation with local public health authorities.
CDC is working with state, local, territorial, academic, and commercial partners to conduct surveillance to better understand
COVID-19 in the United States and recently conducted a multistate assessment of SARS-CoV-2 seroprevalence in blood
donors.
• Cases, Data, and Surveillance

- COVID-19-Associated Hospitalization Surveillance Network (COVID-NET)
- COVID-19 Serology Surveillance
- National Wastewater Surveillance System (NWSS)
- FAQ: COVID-19 Data & Surveillance
• Surveillance and Data Analytics
• CDC’s Diagnostic Multiple Assay for Flu and COVID-19 at Public Health Laboratories and Supplies
• Emerging SARS-CoV-2 Variants (SARS-CoV-2 Strain Surveillance)
Setting-specific Testing Guidance

Testing in Healthcare Settings
Nursing Homes
Acute Care Facilities
Infection Prevention and Control Recommendations for Healthcare Personnel
Testing in Communities, Schools and Workplaces
K-12 Schools
Institutes of Higher Education
Healthcare Personnel
Non-Healthcare Workplaces
High-Density Critical Workplaces
Homeless Shelters
Correctional and Detention Facilities
Testing Information for the Public
Testing Guidance for the Public
Testing and International Air Travel
Frequently Asked Questions: Testing
Other Testing Resources
Antigen Testing Algorithm
Interim Guidelines for COVID-19 Antibody Testing
Pooled Procedures for Testing
Laboratory Resources
Performing Facility-Wide Testing in Nursing Homes
Testing in K-12 Settings Playbook 
Antigen Testing for Screening in Non-Healthcare Workplaces
Previous Updates
Updates from Previous Content


As of October 22, 2021
• Based on evolving evidence, CDC recommends fully vaccinated people get tested 5-7 days after close contact with
a person with suspected or confirmed COVID 19
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a person with suspected or confirmed COVID-19.
As of August 2, 2021
• Revised to align with CDC recommendations for fully vaccinated individuals
As of July 1, 2021
• Revised to align with CDC recommendations for fully vaccinated individuals
As of June 14, 2021
• Expansion on the description of categories of tests, choosing a test, and addition of intended uses of testing
• Addition of health equity considerations related to testing, including discussion on ensuring equitable testing
access and availability
• Discussion on expanded availability to, and use of, screening tests to reduce asymptomatic spread
• Discussion on testing of vaccinated individuals and interpretation of test results
• Inclusion of links to setting-specific testing guidance
As of September 18, 2020
• Due to the significance of asymptomatic and pre-symptomatic transmission, this guidance further reinforces the
need to test asymptomatic persons, including close contacts of a person with documented SARS-CoV-2 infection.
As of August 24, 2020
• Diagnostic testing categories have been edited to focus on testing considerations and actions to be taken by
individuals undergoing testing
As of July 17, 2020
• Except for rare situations, a test-based strategy is no longer recommended to determine when an individual with a
SARS-CoV-2 infection is no longer infectious (i.e., to discontinue Transmission-Based Precautions or home
isolation)
As of July 2, 2020
• Added screening to possible testing types
• Removed examples – please refer to setting specific guidance
References
1. Mina MJ, Andersen KG. COVID testing: One size does not fit all. Science 2021;371(6525):126-127.
doi: 10.1126/science.abe9187  .
2. Morris SB, Schwarts NG, Patel P, et al. Case series of Multisystem Inflammatory Syndrome in Adults Associated with
SARS-CoV-2 Infection – United Kingdom and United States, March – August 2020. MMWR. 2020;69(40)1450-1456.
doi: 10.15585/mmwr.mm6940e1  .
3. Paltiel AD, Zheng A, Walensky RP. Assessment of SARS-CoV-2 screening strategies to permit the safe reopening of college
campuses in the United States. JAMA Netw Open. 2020;3(7):e2016818.
4. Larremore DB, Wilder B, Lester E, et al. Test sensitivity is secondary to frequency and turnaround time for COVID-19
screening. Sci Adv. 2020;20(7):eabd5393. doi:10.1126/sciadv.abd5393  .
5. Bracis C, Burns E, Moore M, Swan D, Reeves DB, Schiffer JT, Dimitrov D. Widespread testing, case isolation and contact
tracing may allow safe school reopening with continued moderate physical distancing: A modeling analysis of King
County, WA data. Infect Dis Model. 2020;13(6):24-3 doi: 10.1016/j.idm.2020.11.003  .
Last Updated Feb. 11, 2022
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Ministry of Health
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Table of Contents
1. Background ................................................................................................................................... 4
2. COVID-19 Symptoms ..................................................................................................................5
3. Highest Risk Settings ..................................................................................................................7
4. Public Health Advice for Symptomatic and COVID-19 Positive Individuals ...... 8
You have symptoms and are concerned you may have COVID-19. Now what? .... 12
5. Case and Outbreak Management ...................................................................................... 13
6. Guidelines for Close Contacts ............................................................................................. 17
You’ve been identified as a close contact of someone who has tested positive for
COVID-19 or someone with COVID-19 symptoms. Now what?......................................23
7. Risk of COVID-19 Spread Between People and Animals .........................................25
8. Travellers from Outside of Canada ...................................................................................26
9. Appendix A: Management of Staffing in Highest-Risk Settings........................... 27
10. Additional Resources..........................................................................................................31
11. Document History................................................................................................................. 32
2
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Version 14.1- Significant Updates

Page # Description
9 Workers who are positive or isolated due to symptoms of
COVID-19 are not required to provide proof of a negative test
to return to work
12 & 23 Flow charts for close contacts and people with symptoms of
COVID-19 added
Version 14.0- Significant Updates

Page # Description
Throughout C&CM information from v3.0 of ‘COVID-19 Integrated Testing &
Case, Contact and Outbreak Management Interim Guidance:
Omicron Surge’ incorporated, with no changes to case/contact
isolation recommendations.
Throughout V4.0 COVID-19 Interim Guidance: Omicron Surge Management
of Staffing in Highest-Risk Settings incorporated throughout,
with no changes to recommendations
8 Updated requirements for individual case follow up and
reporting of suspect/confirmed outbreaks
9 Guidance for outdoor exercise for COVID-19 cases/individuals
with COVID-19 symptoms isolating
14 Updated guidance for case reporting for surveillance purposes
15 Clarification for outbreak management in home and
community care settings and paramedic services
27 Information for risk of COVID-19 spread between people and
animals
30 For critical staffing shortages, COVID-19 cases that work in
highest-risk settings who only care for patients/residents who
have recently recovered from COVID-19 infection may return
early.
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Management of Cases and Contacts of

COVID-19 in Ontario
Version 14.1 – April 14, 2022
This guidance document provides basic information only. It is not intended to

provide medical advice, diagnosis or treatment or legal advice.
In the event of any conflict between this guidance document and any orders or
directives issued by the Minister of Health or the Chief Medical Officer of Health
(CMOH), the order or directive prevails.
• Please check the Ministry of Health (MOH) COVID-19 website regularly for
updates to this document, mental health resources, and other information,
• Please check the Directives, Memorandums and Other Resources page regularly
for the most up to date directives.
1. Background
This document provides information for public health management of cases and
contacts in Ontario. The MOH has developed this document with contributions from
Public Health Ontario (PHO) based on currently available scientific evidence and
expert opinion. This document is subject to change as the situation with COVID-19
continues to evolve.
This document is intended to provide broad guidelines only and cannot cover every
scenario that may be encountered; therefore, local public health unit (PHU)
decision-making is required. Nothing in this document is intended to restrict or
affect the discretion of local medical officers of health to exercise their statutory
powers under the Health Protection and Promotion Act.
This document replaces ‘Public Health Management of Cases and Contacts of
COVID-19 in Ontario V 13.0’ (August 11, 2021); ‘COVID-19 Reference Document for
Symptoms’; ‘COVID-19 Integrated Testing & Case, Contact and Outbreak
Management Interim Guidance: Omicron Surge’ (March 9, 2022); ‘COVID-19 Fully
Vaccinated and Previously Positive Individuals: Case, Contact and Outbreak
Management Interim Guidance’ (October 12, 2021); and COVID-19 Interim Guidance:
Omicron Surge Management of Staffing in Highest-Risk Settings (March 31, 2021).
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Guidance provided by the MOH and other relevant Ministries or organizations may
provide additional information about outbreaks and preventative measures in
different settings (e.g., acute care, long-term care homes/retirement homes,
congregate living settings, COVID-19 Provincial Testing Guidance).
Surveillance reporting on variants of concern (VOCs) in Ontario, prevention and
management of COVID-19 as well as information on testing, laboratory results and
their interpretation can be found on the Public Health Ontario webpage.
2. COVID-19 Symptoms
The below symptoms, signs, and clinical features have been most commonly
associated with COVID-19. The common symptoms of COVID-19 may change as
new VOCs emerge.
To prevent community transmission of infectious diseases, all individuals with

symptom(s) of any infectious illness should stay home when they are sick.
Individuals with COVID-19 symptoms should seek assessment from a health care
provider if required and/or if they may be eligible for COVID-19 treatment.
Individuals with severe symptoms requiring emergency care should go to their
nearest emergency department.
When assessing for the symptoms below, the focus should be on evaluating if they
are new, worsening, or different from an individual’s baseline health status (usual
state). Symptoms should not be chronic or related to other known causes or
conditions (see examples below).
One or more of the following most common symptoms of COVID-19 necessitate

immediate self-isolation and, if eligible, COVID-19 testing:
• Fever and/or chills

• Cough
o Not related to other known causes or conditions (e.g., chronic obstructive
pulmonary disease)
• Shortness of breath
o Not related to other known causes or conditions (e.g., chronic heart failure,
asthma, chronic obstructive pulmonary disease)
• Decrease or loss of smell or taste
o Not related to other known causes or conditions (e.g., nasal polyps,
allergies, neurological disorders)
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Two or more of the following symptoms of COVID-19 necessitate immediate self-

isolation and, if eligible, COVID-19 testing:
• Extreme fatigue (general feeling of being unwell, lack of energy, extreme

tiredness)
o Not related to other known causes or conditions (e.g., depression,
insomnia, thyroid dysfunction, anemia, malignancy, receiving a COVID-19
or flu vaccine in the past 48 hours)
• Muscle aches or joint pain
o Not related to other known causes or conditions (e.g., fibromyalgia,
receiving a COVID-19 or flu vaccine in the past 48 hours)
• Gastrointestinal symptoms (i.e. nausea, vomiting and/or diarrhea)
o Not related to other known causes or conditions (e.g. transient vomiting
due to anxiety in children, chronic vestibular dysfunction, irritable bowel
syndrome, inflammatory bowel disease, side effect of medication)
• Sore throat (painful swallowing or difficulty swallowing)
o Not related to other known causes or conditions (e.g., post nasal drip,
gastroesophageal reflux)
• Runny nose or nasal congestion
o Not related to other known causes or conditions (e.g., returning inside from
the cold, chronic sinusitis unchanged from baseline, seasonal allergies)
• Headache
o Not related to other known causes or conditions (e.g., tension-type
headaches, chronic migraines, receiving a COVID-19 or flu vaccine in the
last 48 hours)
Other symptoms that may be associated with COVID-19 and should be

monitored, include:
• Abdominal pain
o Not related to other known causes or conditions (e.g., menstrual cramps,
gastroesophageal reflux disease)
• Conjunctivitis (pink eye)
o Not related to other known causes or conditions (e.g., blepharitis, recurrent
styes)
• Decreased or lack of appetite
o For young children and not related to other known causes or conditions
(e.g., anxiety, constipation)
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3. Highest Risk Settings

Public health units are not expected to provide case and contact isolation guidance
for individual confirmed or probable cases. Public health units must (through case
calls, Virtual Assistant, or other reasonable means) complete case surveillance
requirements by following data entry requirements for individual cases (described in
section 5.1 case reporting, and as per PHO’s data entry guidance). Public health units
should also use calls, Virtual Assistant or other reasonable means to identify cases
that are associated with highest risk settings for surveillance and outbreak
management support. There is no expectation for individual case calling to occur
outside of business hours; however, reports of suspect outbreaks in highest risk
settings should be investigated in a timely manner.
Public health units should make specific considerations for case and contact
management for First Nations, Inuit and Métis communities, in dialogue with the
communities and/or Indigenous health service providers, to support ongoing
surveillance and response that allows for differences in community needs, and
recognizes differential impacts to communities.
Public health units may provide case management, at the discretion of the health
unit, to vulnerable individuals in their region (e.g., individuals who are
homeless/underhoused) to support their isolation.
Public health units must investigate and manage suspect and confirmed outbreaks in
congregate care/living highest risk settings, including:
• Hospitals (including complex continuing care facilities)
• Congregate living settings with medically and socially vulnerable individuals,
including but not limited to long-term care homes, retirement homes, First
Nation elder care lodges, group homes, shelters, hospices, correctional
institutions, and hospital schools
• International Agricultural Workers
Highest risk settings as above should notify their local public health unit when they
have a suspect or confirmed outbreak, as defined by relevant Ministry of Health
guidance for their sector. Highest risk settings that are institutions or public hospitals
must report suspect and confirmed outbreaks to their local public health unit as per
the Health Protection and Promotion Act.
There are no expectations for COVID-19 respiratory outbreaks in institutions that are
not a highest risk setting as above to be entered in the provincial Case and Contact
Management system. If there is strong evidence of a non-COVID-19 aetiology for a
respiratory outbreak, the outbreak should still be managed as per usual by the
health unit. PHUs are still expected to investigate and manage reports of
gastrointestinal outbreaks in institutions as per usual.
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4. Public Health Advice for Symptomatic and

COVID-19 Positive Individuals
4.1 Testing Recommendations
• Individuals with COVID-19 symptoms should seek molecular testing (PCR or
rapid molecular), if eligible. See the COVID-19 Provincial Testing Guidance for
information on eligibility.
o Where there is a high index of suspicion that an individual may be a
COVID-19 case with a possible false-negative PCR or rapid molecular test
result, re-testing as soon as possible is advised, and initiation of case
isolation/outbreak management may be appropriate based on the health
unit’s risk assessment.
• Individuals with COVID-19 symptoms who are not eligible for molecular testing
and have access to rapid antigen tests can use rapid antigen tests to assess the
likelihood that their symptoms are related to COVID-19.
o A single negative rapid antigen test in an individual with COVID-19
symptoms does not mean that they do not have COVID-19 infection, and
the symptomatic individual should not end their isolation on this basis.
o If two consecutive rapid antigen tests, separated by 24-48 hours, are both
negative, the symptomatic individual is less likely to have COVID-19
infection, and they are advised to self-isolate until they have no fever and
symptoms are improving for at least 24 hours (or 48 hours if
gastrointestinal symptoms).
• A positive rapid antigen test in an individual with COVID-19 symptoms is highly
indicative that the individual has COVID-19, and the individual should self-isolate
as per the guidelines below.
• If the individual with COVID-19 symptoms does not have access to testing, they
are advised to self-isolate as per guidelines below.
• Workers who are test-positive cases or isolated due to COVID-19 symptoms are
not required to provide proof of a negative test result or a positive serological
test result to their employers in order to return to work. It is expected that
workers who have tested positive or who have symptoms of COVID-19 abide by
public health direction (and occupational health, where applicable) and advice
on when they would be considered clear to return to work.
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4.2 Isolation Guidelines for Individuals with COVID-19 Symptoms

and/or with a Positive COVID-19 Test
• Self isolation means:
o The case should only leave home if there is a medical emergency or if

they need to get a clinical assessment or test. See the COVID-19 Clinical
Assessments and Testing page for more information.
o If the case must leave the home, they should travel in a private vehicle if
possible. If this is not possible, the case should wear a medical mask, keep
distance from others in the vehicle (e.g., sit in the backseat) and if possible
and weather permitting, open the windows to increase air exchange in the
vehicle.
o As much as possible, the case should stay in a separate room away from
other people in the home and use a separate bathroom if possible. If in the
same room, they should wear a mask (medical mask if available) and
improve ventilation (e.g. windows should be open if possible). Household
members should also wear a mask when in the same room if possible.
Household caregivers should refer to PHO’s fact sheet on Self-Isolation:
Guide for caregivers, family members and close contacts. Anyone who is
at higher risk of severe complications from COVID-19 (e.g.,
immunocompromised and/or elderly) should avoid caring for or coming in
close contact with a case.
o The case may leave their home for independent outdoor exercise (or with
a caregiver, as appropriate), but should maintain physical distance of at
least 2 metres (6 feet) from others at all times. The case should not go to
outdoor fitness classes or personal training sessions and should wear a
mask in common areas when leaving the property if self-isolating in an
apartment building, condo or hotel.
• The duration of self-isolation after the date of specimen collection or symptom
onset (whichever is earlier/applicable) depends on relevant clinical factors such
as setting, severity of infection, and immune status (see Table 1).
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Table 1: Isolation Period for Test-Positive Cases and Individuals with COVID-19
symptoms
Population Isolation Period Additional Precautions after

Self-Isolation Period
• Individuals with severe 20 days (or at N/A
illness 1 (requiring ICU discretion of hospital
level of care) IPAC) after the date of
specimen collection or
symptom onset
(whichever is
earlier/applicable)
• Individuals 12+ who are 10 days (or at discretion For a total of 20 days after the
not fully vaccinated2 of hospital IPAC) after date of specimen collection or
• Individuals residing in a the date of specimen symptom onset (whichever is
highest-risk setting collection or symptom earlier/applicable),
• Individuals hospitalized onset (whichever is immunocompromised
for COVID-19 related earlier/applicable) individuals should follow the
illness (not requiring additional precautions listed in
ICU level of care) the row below.
• Immunocompromised
individuals 3
Severe illness is defined as requiring ICU level of care for COVID-19 illness (e.g., respiratory
1
dysfunction, hypoxia, shock and/or multi-system organ dysfunction).2 Individuals are

considered fully vaccinated if they have received a full series of a Health Canada authorized
vaccine (e.g. two doses of AstraZeneca/Moderna/Pfizer or 1 dose of Janssen) at least 14
days ago.
2
Individuals are considered fully vaccinated if they have received a full series of a Health
Canada authorized vaccine (e.g. two doses of AstraZeneca/Moderna/Pfizer or 1 dose of
Janssen) at least 14 days ago.
3
Examples of immunocompromised include cancer chemotherapy, untreated HIV infection
with CD4 T lymphocyte count <200, combined primary immunodeficiency disorder, taking
prednisone >20 mg/day (or equivalent) for more than 14 days and taking other immune
suppressive medications. Factors such as advanced age, diabetes, and end-stage renal
disease are generally not considered severe immune compromise impacting non-test
based clearance.
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Population Isolation Period Additional Precautions after

Self-Isolation Period
• All other individuals not 5 days after the date of For a total of 10 days after the
listed above, who have specimen collection or date of specimen collection or
COVID-19 symptoms, symptom onset date symptom onset (whichever is
or a positive COVID-19 (whichever is earlier/applicable), individuals
test (PCR, rapid earlier/applicable) should:
molecular or rapid • Continue to wear a well-
antigen test) fitted mask in all public
settings (including schools
and child care, unless
under 2 years old) and
avoid non-essential
activities where mask
removal is necessary (e.g.,
dining out, playing a wind
instrument, high contact
sports where masks
cannot be safely worn). 4
• Not visit anyone who is
immunocompromised or
at higher risk of illness (e.g.,
seniors)
• Avoid non-essential visits
to highest risk settings
such as hospitals and
long-term care homes.
• Employees working in
highest-risk settings
should report their
exposure and follow their
workplace guidance on
return to work.
4
Reasonable exceptions would include temporary removal for essential activities like eating
(e.g., when eating or drinking in shared space at school/child care/work while maintaining
as much distancing from others as possible). Individuals who are unable to mask (e.g.,
children under two years of age) may return to public settings without masking.
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You have symptoms and are concerned you may have COVID-19. Now what?
Do you have any of these symptoms: Fever/chills, cough, shortness of breath, decrease/loss of smell and taste?
No
Yes
Do you have two or more of these symptoms?:
• Sore throat • Extreme fatigue • Muscle aches/joint pain
• Headache • Runny nose/nasal congestion • GI Symptoms (i.e. vomiting or diarrhea)
No Yes
• It is highly likely that you have a COVID-19 infection. You must self-isolate immediately:
• It is less likely that you
o For at least 5 days** (if fully vaccinated or under 12 years old) or 10 days (if not fully vaccinated
have COVID-19
or immunocompromised) after your symptom onset and until you have no fever and your
infection.
symptoms have been improving for 24 hours (or 48 hours if gastrointestinal symptoms),
• Self-isolate until your
whichever is longer in duration
symptoms are
• Household members that do not meet the below criteria must self-isolate while you are self-isolating.
improving for at least
If any of the following apply to your household members, they do not need to isolate:
24 hours (48 hours for
o They have previously tested positive for COVID-19 in the past 90 days,
gastrointestinal
o They are 18 + and boosted
symptoms).
o They are under 18 years old and are fully vaccinated)
• Your household
• If you are eligible, get a PCR test, rapid molecular test or rapid antigen test.
members do not need
• If your symptoms worsen, seek advice from Telehealth or your health care provider.
to self-isolate.
• Notify your workplace.
Note: Symptoms should not be related to any other known causes or conditions.
**For 10 days after symptom onset (or 20 days for immunocompromised individuals): maintain masking in public setting (including schools
and child care, unless under 2 years of age), do not visit or work in any highest risk setting, do not visit vulnerable individuals (e.g.
immunocompromised individuals or seniors).
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5. Case and Outbreak Management

There are no PHU requirements for individual level case follow up for case
management, only for surveillance.
Case management is at the discretion of the PHU and may be conducted as needed
for certain cases in highest risk settings or other vulnerable populations (e.g., to
support isolation).
If case and contact management is initiated, the PHU may determine their
frequency of communications based on a risk assessment and available staffing
resources.
5.1 Case Reporting

For data that is not populated directly into CCM via OLIS (e.g. faxes), PHUs must
enter the minimum set of data elements to create the case in CCM as indicated in
the most recent Enhanced Surveillance Directive for each confirmed case (and
probable cases where feasible).
PHUs must continue to make a best effort to acquire (e.g. using Connecting Ontario),
receive (e.g. information sent directly from hospitals) and enter hospital admissions,
ICU admissions and deaths into CCM for the purpose of COVID-19 surveillance. If
received, PHUs may enter other case information (e.g., underlying medical
condition, symptoms).
In addition, PHUs should continue to identify cases associated with highest risk
settings for surveillance and outbreak management support, and PHUs should
continue to link all COVID-19 cases that are outbreak-associated to the relevant
outbreak in CCM.
Cases that are part of a confirmed COVID-19 outbreak in one of the highest risk
settings should be identified as residents, patients or staff members in accordance
with PHO data entry guidance.
In the event of a future variant of concern, there may be additional time-limited

requirements for additional data entry into CCM in order to gather pertinent initial
surveillance on the emerging VOC, as directed by the Ministry of Health.
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5.2 Considerations for Cases and Outbreak Management in Highest

Risk Settings
Relevant sector-specific guidance for highest risk settings (e.g., LTCHs) should be
followed for those specific settings where conflicting with the below information.
Certain groups, such as home and community care or paramedic services, are
considered highest risk groups for the purposes of molecular testing eligibility, and
access to testing for return to work. However, they are not considered part of
highest risk settings for outbreak management unless they are part of a suspect or
confirmed outbreak in a congregate care/living highest risk setting.
Public health units should make specific considerations for case and contact
management for First Nations, Inuit and Métis communities, in dialogue with the
communities and/or Indigenous health service providers, to support ongoing
surveillance and response that allows for differences in community needs, and
recognized differential impacts to communities.
Highest risk settings should notify their local public health unit of individuals who
test positive on a rapid antigen test and did not receive confirmatory molecular
testing if they are associated with a suspect or confirmed outbreak in the setting.
Close contacts in highest-risk settings that develop symptoms should be managed

as probable cases for outbreak management purposes. Health units should follow
PHO data entry guidance and not enter these contacts as probable cases if test
results are pending.
At the discretion of the PHU, case management of vulnerable individuals or as part

of outbreaks in highest risk settings may be conducted to support those individuals.
This may include:
• Use of clinical assessment centres
• Use of isolation facilities, if applicable
• Use of community supports and agencies
• Psychosocial supports
• Courier, delivery supports for food and necessities
• Emergency financial supports through the provincial government and local
regions
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• Provincial unpaid job-protected infectious disease emergency leave and

federal government financial supports including employment insurance
• Additional resources available to support isolation through the High Priority
Communities strategy
If the case lives in a highest risk setting, they should isolate for at least 10 days after
date of specimen collection or symptom onset (whichever is earlier/applicable)
AND until they are afebrile and symptoms are improving for 24 hours (or 48 hours if
gastrointestinal symptoms), unless otherwise directed by the PHU or as per sector
specific guidance.
If the case works in a highest risk setting, they should speak with their employer and
follow their workplace guidance for return to work.
• For routine operations, COVID-19 positive cases that work in highest-risk settings
may return to work:
o 10 days after symptom onset or date of specimen collection (whichever is
earlier) OR
o After a single negative molecular test (e.g. PCR, rapid molecular) any time
prior to 10 days from the date of symptom onset or specimen collection
(whichever is earlier) OR
o After two consecutive negative rapid antigen tests that are collected at
least 24 hours apart any time prior to 10 days from the date of symptom
onset or specimen collection (whichever is earlier) AND
o Provided they have no fever and other symptoms have been improving for
24 hours (or 48 hours if vomiting/diarrhea).
• See Appendix A for Staffing Options for Highest Risk Settings experiencing
critical staffing shortages. Options listed above for return to work should be
exhausted prior to progressing to options listed in critical staffing shortages
options listed in Appendix A.
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5.3 Detected (Low Level) PCR Target Gene Results

• Some laboratories have added the qualifier “detected (low level)” to positive PCR
results where the cycle threshold (Ct) value is high (meaning the viral load level
is low, e.g., a Ct value between 35 and 37). This result is still a POSITIVE result
and should be interpreted in the clinical and epidemiological context of the case.
It may represent an early stage of infection, a late stage of infection (e.g. residual
non-infectious gene fragments), or a false positive result. This “detected (low
level)” result is distinct from “indeterminate” results where the result cannot be
differentiated between the presence or absence of the target gene. Individuals
with a “detected (low level)” target gene result should still be managed as a case.
However, if the pre-test probability of COVID-19 is low (e.g., asymptomatic
screen testing) and there are no other target genes reported as detected on the
PCR assay at the time, then repeat molecular testing as soon as possible may be
warranted as for any other situations where there is a concern for a false positive
result.
5.4 Management of Previously Cleared Cases with New Positive

Results
• Findings of a new positive test result after completing isolation due to a

COVID-19 infection may represent:
o Persistent positive result from the previously cleared infection episode,
especially likely if the new positive result occurred within 90 days if using
molecular testing or within 30 days if using rapid antigen testing; OR
o Reinfection from a new infection episode, especially likely if the new
positive result occurred beyond 90 days if using molecular testing or
beyond 30 days if using rapid antigen testing.
• If molecular samples from the previously cleared infection and molecular
samples from the new positive result are available and of sufficient viral load
(Ct value <30), VOC screening and/or whole genome sequencing may be
requested to provide further laboratory evidence supporting a reinfection with
a different SARS-CoV-2 variant as opposed to persistent positivity with the
same SARS-CoV-2 variant (see Case Definition – Coronavirus Disease [COVID-
19] Section C. Laboratory-Based Case of Reinfection).
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• Persistent positive: If there is evidence that the new positive result is likely to
be due to ongoing persistent detection from the previously cleared infection,
then no further public health case management is required. Supporting
evidence of a persistent positive include: testing done by molecular methods
within 90 days of the previously cleared infection, the Ct value of the new
positive being equal or higher (suggestive of a lower viral load) than the Ct
values reported during the previous infection, and/or same variant identified
with the new positive result as which was reported during the previous
infection.
• Reinfection: Confirmed reinfections should meet either the lab-based or time-
based Ontario Case Definitions. Cases that do NOT meet the case definition for
confirmed re-infection but where re-infection is suspected should still be
managed as a currently infectious. PHUs can request additional information
from the testing laboratory on specimens tested using molecular methods
from individuals suspected of re-infection (e.g., Ct values, gene targets
detected) to further inform interpretation of the results. See PHO Data Entry
Guidance for entry of new positive results in previously cleared individuals. Do
NOT enter a new case entry for suspected reinfection that do not meet the
case definition. PHO is available for consultation on re-infection cases
(whether confirmed or suspected) via epir@oahpp.ca
6. Guidelines for Close Contacts

6.1 Definition of Close Contacts
A close contact is defined as an individual who has an exposure to a confirmed
positive COVID-19 case, an individual with COVID-19 symptoms, or an
individual with a positive rapid antigen test result.
Close contacts have been in contact with the case/symptomatic person within
the 48 hours prior to the case’s symptom onset if symptomatic or 48 hours prior
to the specimen collection date (whichever is earlier/applicable) and until they
have completed their self-isolation period; AND
Were in close proximity (less than 2 meters) for at least 15 minutes or for multiple
short periods of time without measures such as masking, distancing and/or use
of personal protective equipment (see table 1 for examples).
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Outside of suspect and confirmed outbreaks managed by the PHU, it is the

responsibility of the individual with COVID-19 symptoms or COVID-19 positive
test to determine who their close contacts are and to notify them of their
potential exposure.
Employers must also follow requirements as per the Occupational Health and
Safety Act.
Table 1: Examples of Close Contacts

Exposure Setting Examples of Close Contacts
Household (includes other • Anyone living in the same household, while the
congregate settings) case was self-isolating.
o This may include members of an extended
family, roommates, boarders, etc.
o This may include people who provided care
for the case (e.g., bathing, toileting, dressing,
feeding etc.)
o This EXCLUDES individuals who live in a
completely separate area/unit (e.g. self-
contained basement apartment).
Community/Workplaces/ • Had direct contact with infectious body fluids of

Schools/Child the case (e.g., coughed on or sneezed on)
care/Camps • Were in close proximity (less than 2 meters) 1 for
at least 15 minutes or for multiple short periods
of time without consistent and appropriate use
of personal protective equipment3 such as
masking.
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Exposure Setting Examples of Close Contacts

Health Care and See the relevant sector specific guidance
congregate care/living documents for more information.
highest risk settings (e.g. Patient/resident is the case:
long-term care homes, • Health care worker and/or staff who provided
retirement homes, First direct care for the case, or who had other
Nation Elder Care Lodges, similar close physical contact (i.e., less than 2
group homes, shelters, metres from patient for more than transient
hospices, correctional duration of time)1 without consistent use of
institutions, hospital personal protective equipment (PPE)3 as
schools). recommended by their organization’s IPAC
guidelines or best practice guidance for their
sector.
• Other patients/residents in the same semi-
private/ward room
• Other patients/residents who had close1,
prolonged2 contact with the patient case
Health care worker/staff is the case:
• All patients/residents who had close1
prolonged2 contact to the health care
worker/staff.
• Note: Patients exposed to the HCW where
contact was neither close nor prolonged, AND
the HCW was masked for the entire duration
would generally not be considered high risk
exposures. Consideration may also be given if
the patient was consistently masked during
the interaction.
• All co-workers who had unprotected close1
and/or prolonged2 contact with the case (e.g.,
within 2 metres in an enclosed common area)
• Close contacts as identified by hospital IPAC
For further details see: Focus On: Risk Assessment Approach for COVID-19
Contact Tracing
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1
Close Contact: Maintenance of physical distancing measures (> 2 metres) for
the entire duration of exposure decreases the risk of transmission. However,
physical distancing of 2 metres does not eliminate the risk of transmission,
particularly in confined indoor and poorly ventilated spaces and during exercise,
talking loudly, yelling or singing activities.
2
Prolonged Contact: Prolonged exposure duration may be defined as lasting
cumulatively more than 15 minutes; however, individuals with exposures of <15
minutes may still be considered close contacts depending on the context of the
contact/exposure. As part of the individual risk assessment, consider the
cumulative duration and nature of the contact’s exposure (e.g., a longer exposure
time/cumulative time of exposures likely increases the risk, an outdoor only
exposure likely decreases the risk, whereas exposure in a small, closed, or poorly
ventilated space may increase the risk even if distanced or masked), the case’s
symptoms (coughing or severe illness likely increases exposure risk), physical
interaction ( e.g., hugging, kissing), and whether personal protective equipment
by the contact or source control by the case was used.
3
PPE
Use of PPE, if worn consistently and in accordance with organizational
recommendations for the nature of the interaction and for the entire duration of
exposure, the individual would generally not be considered a close contact;
however, it is important to assess the context of the interactions with the case
and other factors that may increase risk of exposure (e.g., physical touching,
prolonged duration, confined space with poor ventilation). Workers should follow
organizational policies on the use of PPE for suspected and confirmed COVID-19
patients.
6.2 Close Contacts Outside of Highest-Risk Settings

6.2.1 Non-Household Close Contacts
• For a total of 10 days after the last exposure to the COVID-19 positive case or
individual with COVID-19 symptoms, the non-household member notified by a
case should:
o Self-monitor for symptoms and self-isolate if they develop any symptom of
COVID-19;
o Wear a well fitted mask in all public settings;
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 Individuals should maintain masking as much as possible in public

settings (including school and child care, unless under 2 years old).
Reasonable exceptions would include removal for essential activities
like eating, while maintaining as much distancing as possible;
 Participation in activities where masking can be maintained
throughout may be resumed, but individuals should avoid activities
where mask removal would be necessary (e.g. dining out; playing a
wind instrument; high contact sports where masks cannot be safely
worn);
 Individuals who are unable to mask (e.g., children under two years of
age, etc.) may return to public settings without masking
o Not visit anyone who is immunocompromised or at higher risk of illness
(e.g., seniors);
o Avoid non-essential visits to highest risk settings such as hospitals and
o Employees working in highest risk settings should report their exposure
and follow their workplace guidance.
• In some scenarios, close contacts who are part of outbreak investigations may
be contacted by public health and advised of additional recommendations.
6.2.2 Household Close Contacts
• COVID-19 positive cases/individuals with COVID-19 symptoms should isolate

away from household members where possible to avoid ongoing exposures.
o The last day of exposure to the household case is the last day of the case’s
isolation period if there was ongoing exposures.
• Household members of the COVID-19 positive case/individual with COVID-19
symptoms should self-isolate while the case is isolating, with the following
exceptions:
o Household members who are 18 years of age or older and have already
received their booster dose
o Household members who are under 18 year of age and are considered
fully vaccinated 5
5
Individuals are considered fully vaccinated if they have received a full series of a Health
Canada authorized vaccine (e.g. two doses of AstraZeneca/Moderna/Pfizer or 1 dose of
Janssen) at least 14 days ago.
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o Household members who have previously tested positive for COVID-19 in

the last 90 days (based on a positive PCR, molecular or rapid antigen test
result) and have since completed their isolation period. These individuals
may also attend highest risk settings, as long as they are currently
asymptomatic.
• If self-isolation is complete at less than 10 days, or if self-isolation is not
required, for a total of 10 days after the last exposure 6 to the COVID-19 case,
ALL household members should:
o Self-monitor for symptoms and self-isolate if they develop any symptom of
COVID-19;
o Wear a well fitted mask in all public settings;
 Individuals should maintain masking as much as possible in public
settings (including school and child care, unless under 2 years old).
Reasonable exceptions would include removal for essential activities
like eating, while maintaining as much distancing as possible;
 Participation in activities where masking can be maintained
throughout may be resumed, but individuals should avoid activities
where mask removal would be necessary (e.g. dining out; playing a
wind instrument; high contact sports where masks cannot be safely
worn);
 Individuals who are unable to mask (e.g., children under two years of
age, etc.) may return to public settings without masking
o Not visit anyone who is immunocompromised or at higher risk of illness
(e.g., seniors);
o Avoid non-essential visits to highest risk settings such as hospitals and
o Employees working in highest risk settings should report their exposure

and follow their workplace guidance.
6
“Last exposure” refers to last day the contact was exposed to an individual who was still
isolating with either COVID-19 symptoms or a positive test result (e.g., household contacts
would have ongoing exposure until the end of the cases isolation period if unable to
effectively self-isolate in the home. If a child with COVID-19 was self-isolating from Monday
to Saturday, the ‘last exposure’ for the parent who was caring for the COVID-19 positive
child would be the Saturday.
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You’ve been identified as a close contact of someone who has tested positive for COVID-19 or someone with
COVID-19 symptoms. Now what?
Does the COVID-19 positive/symptomatic person live with you?
No Yes
Do you have COVID-19 symptoms? • If you do not meet the below criteria you must self-isolate for the
same amount of time as the positive/symptomatic person. If any
Yes No of the following apply to you, you do not need to self-isolate**:
o You have previously tested positive for COVID-19 in the last
• Self-isolate immediately for at least 5 days 90 days
• Self-monitor for symptoms for
(if fully vaccinated or under 12)** or 10 days o You are 18+ and boosted
10 days after your last
(if not fully vaccinated or o You are under 18 years old and are fully vaccinated
exposure.**
immunocompromised) after symptom • If you develop symptoms, continue/start to self-isolate and get
• Report your exposure to your
onset and until you have no fever and tested if you are eligible. Follow the guidance for cases.
employer and follow any work
other symptoms are improving for 24 • If anyone else in your household develops symptoms, if you are
restrictions.
hours (or 48 hours for gastrointestinal isolating and still have no symptoms then you should extend your
• If you develop symptoms, get
symptoms). self-isolation until the newly symptomatic person has finished
tested if eligible and self-isolate
• Get tested if eligible and follow the isolating.
immediately.
guidance for cases.
**Wear a well-fitted mask in public (including schools and child care, unless under 2 years of age), physical distance and maintain other public health measures for
10 days following your last exposure if leaving home. You should NOT visit or attend work in any highest risk settings and not visit individuals who may be at higher
risk of illness (i.e. seniors or immunocompromised) for 10 days after your last exposure.
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6.3 Close Contacts in Highest-Risk Settings

• Close contacts working/volunteering/attending highest-risk settings who
develop any symptom(s) of COVID-19 should self-isolate and be tested by
molecular testing as soon as possible.
• Close contacts who live in a highest risk setting may need to isolate following
an exposure, based on the sector-specific isolation guidance (e.g. COVID-19
Guidance: Long-Term Care Homes and Retirement Homes for Public Health
Units), direction from local public health unit or direction from the local hospital
infection prevention and control team for hospitalized patients.
• Employees in highest risk settings who have had a COVID-19 exposure should
speak with their employer and follow their workplace guidance for return to
work.
o Employees who are close contacts who have previously tested positive for
COVID-19 in the last 90 days (based on positive rapid antigen test or
molecular test results) can attend work in the highest-risk setting, as long
as they are currently asymptomatic. These individuals are advised to self-
monitor for symptoms for 10 days after last exposure.
o For routine operations, asymptomatic close contacts that work in highest-
risk settings may participate in testing for early return to work:
 Following a negative molecular test (e.g., PCR, rapid molecular)
collected on/after day 5 after last exposure 7 OR
 Following a negative molecular test (e.g., PCR or rapid molecular)
prior to first shift (if collected before day 5) AND perform daily rapid
antigen testing for 10 days after last exposure or until a second
7
“Last exposure” refers to last day the contact was exposed to an individual who was still
isolating with either COVID-19 symptoms or a positive test result (e.g., household contacts
would have ongoing exposure until the end of the cases isolation period if unable to
effectively self-isolate in the home. If a child with COVID-19 was self-isolating from Monday
to Saturday, the ‘last exposure’ for the parent who was caring for the COVID-19 positive
child would be the Saturday).
24
AR07795
negative molecular test is collected on/after day 5 from last

exposure 8
o See Appendix A for Staffing Options for Highest Risk Settings experiencing
critical staffing shortages. Options listed above for return to work should be
exhausted prior to progressing to options listed for critical staffing
shortages in Appendix A.
• Additional workplace measures for individuals returning after a negative
molecular test collected before day 5 of last exposure may include:
o Active screening for symptoms ahead of each shift
o Individuals on early return to work should not remove their mask when in
the presence of other staff to reduce exposure to co-workers (i.e. not
eating meals/drinking in a shared space such as conference room or lunch
room.
o Working in only one facility, where possible;
o Ensuring well-fitting source control masking for the staff on early return to
work to reduce the risk of transmission (e.g. a well fitting medical mask or
fit or non-fit tested N95 respirators or KN95s).
7. Risk of COVID-19 Spread Between People

and Animals
• There have been some infrequent confirmed reports of the SARS-CoV-2 virus
spreading from animals to individuals (e.g., in mink farms)
• Based on available information to date, animal-to-human transmission is likely
very uncommon and the risk to most people in Canada for acquiring COVID-19
from animals appears to be very low.
• See the Government of Canada’s website for more information on the risk of
COVID-19 spreading from animals to people, for information on how to keep
your pets safe when you have COVID-19 or COVID-19 symptoms and
guidelines for individuals who have had contact with farm animals or wild life.
8
If the individual tests positive on a test before day 10, they should not continue testing on
subsequent days and wait until day 10 prior to returning to work. Routine molecular testing
of positive cases is NOT recommended due to the high likelihood of ongoing positivity, but
may be considered if initial test was indeterminate or low level positive.
25
AR07796
8. Travellers from Outside of Canada

PHU follow-up for international flights where travellers are under federal quarantine
is not required, unless the traveller tests positive during their quarantine period and
the case information is forwarded to the PHU.
See the Government of Canada’s website for testing and quarantine requirements
and exemptions for travellers within and outside of Canada. The Government of
Canada’s website also provides quarantine requirements for travellers who have an
exposure or test positive during the federal quarantine period
All individuals permitted to enter Canada should follow the Federal Emergency
Orders and public health and workplace rules, self-monitor for symptoms and
immediately self-isolate should symptoms develop.
Compliance with the orders is managed by the Public Health Agency of Canada
(PHAC) with support from other agencies, including the Canada Border Services
Agency (CBSA), local police, the Ontario Provincial Police (OPP), and the Royal
Canadian Mounted Police (RCMP). In addition, in some regions private security have
been contracted to assist with in-person follow-up. Local PHUs do not have a direct
role in enforcement of the Quarantine Orders but are able to provide support and
information (e.g., requirements of self-isolation) and, if required, refer cases to the
local police. PHUs may also contact the Compliance and Enforcement office at
PHAC : phac.isolation-isolement.aspc@canada.ca to request a quarantine breach
assessment.
Should an individual require essential health care during the 14-day quarantine
period, these individuals may seek service but should be managed as an individual
in isolation. Where possible, travellers should receive healthcare remotely through
services such as Telehealth Ontario.
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AR07797
9. Appendix A: Management of Staffing in Highest-

Risk Settings
It is the responsibility of the organization implementing this guidance to determine what
early return to work option to use under their current circumstances and populations
served. In the event of conflicting guidance, specific direction on which staffing options can
be used for early return to work from other relevant ministries (e.g., Ministry of Long-Term
Care) should be followed.
If staffing shortages are impacting care, routine return to work options listed below should
be exhausted prior to progressing to options for critical staff shortages, which have more
risk of COVID-19 transmission within the setting. The use of options with more risk of
COVID-19 transmission should be commensurate to the risk of insufficient staffing to
patients/residents to provide adequate care.
When available, use of testing options is preferred to other options. Close contacts should
be prioritized for return to work over COVID-19 positive cases.
9.1 Routine Operations Staffing Options

Asymptomatic Close Contacts
• For routine operations, asymptomatic close contacts that work in highest-risk settings
may return to work:
1) Following a negative molecular test (e.g., PCR, rapid molecular) collected
on/after day 5 from last exposure 9 OR
2) Following a negative molecular test (e.g., PCR or rapid molecular) collected
before day 5 after last exposure AND performing daily rapid antigen tests for 10
days after last exposure or until a second negative molecular test is collected
on/after day 5 after last exposure. 10
9
“Last exposure” refers to last day the contact was exposed to an individual who was still isolating
with either COVID-19 symptoms or a positive test result (e.g., household contacts would have
ongoing exposure until the end of the cases isolation period if unable to effectively self-isolate in
the home. If a child with COVID-19 was self-isolating from Monday to Saturday, the ‘last exposure’
for the parent who was caring for the COVID-19 positive child would be the Saturday).
10
If the individual tests positive on a test before day 10, they should not continue testing on
subsequent days and wait until day 10 prior to returning to work. Routine molecular testing of
positive cases is NOT recommended due to the high likelihood of ongoing positivity, but may be
considered if initial test was indeterminate or low level positive.
27
AR07798
• Asymptomatic close contacts who are returning after a negative molecular test
collected before day 5 after last exposure are recommended to follow the Workplace
Measures below for reducing risk of exposure.
COVID-19 Positive Cases
• For routine operations, COVID-19 positive cases that work in highest-risk settings may
return to work:
1) 10 days after symptom onset or date of specimen collection (whichever is
earlier) OR
2) After a single negative molecular test any time prior to 10 days from the date of
specimen collection or symptom onset (whichever is earlier) OR
3) After two consecutive negative rapid antigen tests that are collected at least 24
hours apart any time prior to 10 days from the date of specimen collection or
symptom onset (whichever is earlier) AND
4) Provided they have no fever and other symptoms have been improving for 24
hours (or 48 hours if vomiting/diarrhea).
9.2 Moderate COVID-19 Transmission Risk Staffing Options (For Critical

Staffing Shortages)
• For critical staffing shortages, asymptomatic close contacts that work in highest-risk
settings may return to work under the following conditions:
1) After two negative rapid antigen tests collected 24 hours apart 11 AND
2) Given they perform daily rapid antigen testing for 10 days after last exposure or
until a negative molecular test is collected on/after day 5 from last exposure.9
• If testing is not available, asymptomatic close contacts may return to work 7 days after
last exposure, with workplace measures for reducing risk of exposure until day 10.
• For critical staffing shortages, COVID-19 positive cases that work in highest-risk
settings and ONLY care for COVID-19 positive patients/residents or patients/residents
who have recently recovered from COVID-19 infection, may return to work:
1) 7 days after symptom onset or date of specimen collection (whichever is
earlier/applicable) without testing11 AND
2) Provided they have no fever and symptoms improving for 24 hours (48 hours if
vomiting/diarrhea).
9.3 Higher COVID-19 Transmission Risk Staffing Options (For Critical

Staffing Shortages)
11
Maintain workplace measures for reducing risk of exposure for 10 days after last exposure.
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AR07799
• For critical staffing shortages, asymptomatic close contacts that work in highest-risk
settings may return to work under the following conditions:
1) After a single negative rapid antigen test prior to first shift 12 AND
2) Given they perform daily rapid antigen testing for 10 days after last exposure or
until a negative molecular test (e.g. PCR, rapid molecular) is collected on/after
day 5 from last exposure.9
• If testing is not available, asymptomatic close contacts may return to work 5 days after
last exposure, with workplace measures for reducing risk of exposure until day 10.
• For critical staffing shortages, COVID-19 positive cases that work in highest-risk
settings and ONLY care for COVID-19 positive patients/residents or patients/residents
who have recently recovered from COVID-19 infection, may return to work:
1) Earlier than day 7 (i.e., day 6, preferable to day 5, etc) without testing12 AND
2) Provided they have no fever and symptoms improving for 24 hours (48 hours if
vomiting/diarrhea).
9.4 Workplace Measures for Reducing Risk of Exposure

• Where possible, avoid assigning staff on early return to work to vulnerable
patients/residents (e.g., immunocompromised, unvaccinated, other underlying risks
for severe disease).
• Personal Protective Equipment (PPE) and IPAC practices should be reviewed
(including audits) to ensure meticulous attention to measures for staff on early return
to work.
• Prioritize cohorting of staff who are early returned cases to working with COVID-19
positive patients only, due to their residual risk of transmission.
• Additional workplace measures for individuals on early return to work may include:
o Active screening ahead of each shift
o Individuals on early return to work should not remove their mask when in the
presence of other staff to reduce exposure to co-workers (i.e. not eating
meals/drinking in a shared space such as conference room or lunch room.
o Working in only one facility, where possible;
o Ensuring well-fitting source control masking for the staff on early return to work
to reduce the risk of transmission (e.g. a well fitting medical mask or fit or non-fit
tested N95 respirators or KN95s).
12
Maintain workplace measures for reducing risk of exposure for 10 days after last exposure.
29
AR07800
9.5 Administrative Considerations for Selecting Staff for Return to Work

Under Critical Staff Shortages
• The fewest number of staff who are close contacts or who are COVID-19 cases should
be returned to work early to allow for business continuity and safe operations.
• Staff who are nearest to completion of their self-isolation period should be returned
first.
• Where possible, preferential return to work for those who have received all
recommended doses of the COVID-19 vaccine (including booster doses) should be
considered due to decreased risk of developing symptomatic infection with Omicron
infection compared to those with two doses or those who have not completed a
primary series.
• Those who have an exposure to a COVID-19 case that does not live with them should
be prioritized to return before those who have ongoing exposure to a household
member with COVID-19, because the risk of transmission is higher among those with
ongoing exposures (e.g., providing direct, ongoing care to a COVID-19 positive
household member).
30
AR07801
10.Additional Resources
• Public Health Ontario Public Resources
• Public Health Agency of Canada’s Public Health Management of Cases and

Contacts for COVID-19
• Public Health Agency of Canada’s COVID-19: For Health Professionals website
• Centers for Disease Control and Prevention’s COVID-19 website
• European Centre for Disease Prevention and Control’s COVID-19 website
• Ministry of Health’s COVID-19 website
• Provincial Infectious Diseases Advisory Committee’s Tools for Preparedness:

Triage, Screening and Patient Management of Middle East Respiratory Syndrome
Coronavirus (MERS-CoV) Infections in Acute Care Settings
• Government of Canada’s COVID-19 Affected Areas list
• World Health Organization's Disease Outbreak News website, and COVID-19

website
31
AR07802
11. Document History

Revision Date Document Section Description of Revisions
January 30 2020 Document was created.
February 5 2020 Contact Language included to reflect policy

Management – change: self-isolation of 14 days for
Public Health those returning from Hubei province
Advice and for close contacts of cases.
February 7, 2020 Throughout Updates to reflect changes to case

Document definition and self-isolation
February 12 2020 Case and Contact Updates to language around risk level
Management and corresponding level of self
isolation/ self monitoring
Travellers from
Affected Areas Addition of Table 3
March 3 2020 Updates throughout Updates based on new case definition

document and evolving advice based on travel
history of patient
March 25 2020 Updates throughout Change in Purpose section; guidance

document on testing, explanation on case
definition, assessment and
management of persons suspected of
COVID-19, Information on pets
April 15 2020 Updates throughout Updates on case definition

document description, travellers from outside of
Canada, link to other guidance (e.g.
provincial testing), updates to
streamline language throughout
June 23 2020 Updates throughout Major updates to most sections,

document addition of several reference tables,
moved to 2 risk exposure levels: low
and high risk, moved appendices to
become separate documents.
32
AR07803

September 8 2020 Updates throughout Additional information on
document asymptomatic cases with low pre-test
probability; new appendix 8; new
table: Assessing Scenario Likelihood in
Asymptomatic Cases with Low Pre-
Test Probability; minor update to
travel section; new information on
COVID Alert
October 9 2020 Updates throughout Updates on frequency/nature of
document contact with low/high risk contacts
Updated messaging to align with new
guidance on case clearance timelines.
December 1 2020 Updates throughout New section on Re-Infection; updates
document to case isolation for asymptomatic
cases; updates to contact follow-up;
further detail on risk assessment for
contact tracing; removal of Non-
Medical Mask section; addition of
Appendix 9; updated section on
Travellers from Outside of Canada
January 12 2021 Updates throughout Specify collection of vaccine
document information, clarify that vaccination
does not change case & contact
management at this time, updates to
informing PHO of flight notifications,
updates to federal quarantine
guidance, clarification to extension of
POC of some asymptomatic cases,
clarify guidance on PPE for HCW
exposures, clarify guidance on patient
exposures to HCW cases
33
AR07804

May 6 2021 Updates throughout New section on preliminary positive
document results from point-of-care assays; new
section for testing of previously
cleared cases (re-positive, re-
infection) and self-isolation of
previous positives with new high-risk
exposures; new section on enhanced
case management for VOC screen
positive cases; new section on testing
of asymptomatic high-risk contacts;
updates to contact management in
the context of VOC emergence (lower
threshold for classifying contacts as
HR exposure and requiring self-
isolation); travellers from outside of
Canada update.
August 11 2021 Updates throughout Incorporation of fully
the document immunized/previously positive
individuals; New section on
notification of individuals identified
through Backward Contact Tracing;
Updated section: self-isolation of
previous positives with new high-risk
exposures (10 day self isolation);
Updated section: Testing and Self-
Isolation of Asymptomatic High-Risk
Contacts; Follow up for high risk
contacts is now day 5 and 10 of self-
isolation; Section 5.2 update;
Updated table 4 and modified
footnote 4 on PPE and eye protection.
;Updated section: Travellers from
Outside of Canada; New section:
Contact tracing for train/bus/cruise
ship passengers.
34
AR07805

April 6 2022 Updates throughout Incorporation of COVID-19 Integrated
document Testing & Case, Contact and Outbreak
Management Interim Guidance:
Omicron Surge; Incorporation of COVID-
19 Interim Guidance: Omicron Surge
Management of Staffing in Highest-Risk
Settings; Incorporation of COVID-19
reference document for symptoms;
PHUs not expected to conduct case
management for individual confirmed
or probable cases, but must complete
case surveillance requirements by
following data entry requirements for
individual cases, PHUs must investigate
and manage suspect and confirmed
outbreaks in congregate care/living
highest risk settings
35
AR07806
•••
Public Health Agence de la sante
Agency of Canada pubtique du Canada November 25, 2021
Emerging Evidence on COVID-19
Evidence Brief on the Risk of- COVID-19 Transmission in

Flight: update 3 ,
November 2021
Table"of contents
Introduction............................................................................................................................ 1
What's new............................................................................................................................. 2
Key points............................................................................................................................... 2
Overview of the evidence........................................................................................................ 4
Investigations of in-flight transmission events..............................•..•................................ 5

Risk of sars-cov-2 transmission on airplanes .................................................................... 7
Indirect analyses of sars-cov-2 infection transmission risk and mitigation strategies on airplanes 8
Methods .......................................................................................................•.................•..... 10
Acknowledgements ............ .. ...... ................. ........... .........•.................... . ...........9
Evidence tables ................................................................................................•.................... 11
Table 1: investigations of in-flight transmission events (n=37) ....................................... 11

Table 2: reviews, reports, passengers surveys, and risk assessments related to sars-cov-2 transmission on
airplanes (n=22) ............................................................................................................. 29
Table 3: studies and reviews that examined the aerodynamics of respiratory droplets on airplanes and
mitigation strategies for respiratory infections on planes (n=26) .................................... 41
Appendix 1 ........................................................................................................................... 56
References ........................................ ,········........................................................................... 57
Introduction
What is the evidence on in-flight transmission of COVID- 19, assessments of risk. and mitigation
strategies related to air travel?
Many changes have been implemented by airlines and national government during the pandemic to reduce
the risk of SARS-CoV-2 transmission during air travel. This evidence b rief summarizes the literature on in-
flight transmission of SARS-CoV-2, the characteristics of these events, and the strategies implemented or
proposed to mitigate transmission in an airplane or during boarding and disembarkation. This is the third
update and includes studies up to November 25, 2021. The first and second update of this review contained
literature published up to October 28, 2020 and April 26, 2021, respectively.
PHAC EMERGING SCIENCE SUMMARIES
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COVID-19 Summary of Flight Transmission Risk
AR07807 November 25, 2021
What’s new
Highlights from the current literature include:
 Twenty-five additional studies were added in this update; twelve flight investigations (Table 1), five
reviews, one passenger/crew survey on infection and prevention measures, two risk assessments
(Table 2), and five simulation studies on reduction of respiratory virus spread and the relative impact
of mitigation strategies during air travel (Table 3). These new studies bring the total number of studies
included in this review to 84.
 Overall, attack rates (AR) were low (0-10%) except for two new reports of super-spreading events
caused by variants of concern (VOCs) or former variants of interest (VOIs) (AR: 16-40%).
 The findings from the new studies further substantiate results from the previous updates.
Key points
From a total of 37 flight investigations of transmission events during air travel, 13 reported no evidence of in-
flight transmission (eight on repatriation and five on commercial flights) and 24 reported likely transmission
from in-flight exposure. Whole genome sequencing results from eight investigations aided in linking cases to
an on-flight single exposure 1, 2, 3, 4, 5, 6, 7, 8. Emerging VOCs were reported in two of the studies 4, 5.
 Overall, most studies reported attack rates between 0-10%; the two studies with the highest attack
rates, 16% and 40%, coincided with exponential growth of SARS-CoV-2 in their respective countries of
departure (South Africa, Jun 2021 and India, Apr 2021) and reported transmission of VOCs onboard,
with large clusters of Delta and Kappa 4, 5.
 Multiple reports of in-flight transmission events involved flights without mandatory face masks 1, 2, 7, 9,
. There were several studies, with transmission events occurring early in the pandemic Jan-Mar
10, 11, 12, 13
2020, that did not mention mask usage on board 8, 14, 15, 16, 17, 18, 19, 20. There were also instances where
transmission events occurred even though face masks were mandatory 3, 4, 5, 21, 22, 23, 24; however, studies
have indicated some instances of low-compliance with mask wearing/incorrect mask use (e.g., not
covering the nose) 4, 22, the removal of masks for eating/drinking 4, 21, 22, as well as cases involving
children who were likely exempt from masking requirements 5, 6. One study found that wearing a face-
mask is protective against SARS-CoV-2 on flights (odds ratio=0.21) 7.
 Symptom and temperature checks prior to boarding were reported by some studies 5, 11, 21, 25, 26. Failure
of passengers to report symptoms led to transmission on at least one flight 11.
 Proximity to an index case (two-row radius) was a risk factor in investigations where seating charts
were available (odds ratio: 4.8; risk ratio: 7.3; attack rate 3.8-30.9%) 4, 7, 9, 10, 11, 12, 19, 24.
PHAC EMERGING SCIENCE SUMMARIES 2

 Most reports of in-flight transmission events occurred prior to widespread vaccination roll-out. One
study found that vaccinated passengers were 74% less likely to be infected compared with those who
were not vaccinated 4.
 The most commonly implemented public health measures were in-flight physical distancing, enhanced
cleaning, mandatory face masks, hand hygiene, physical distancing during boarding and
disembarking, designated crew only areas, and quarantine areas for unwell passengers 3, 4, 5, 21, 22, 25, 26, 27,
28, 29, 30, 31, 32
. One survey of passengers and crew indicated that both the passengers and crew felt safer
after implementation of enhanced safety measures to curb transmission and felt that most measures
were feasible to implement, apart from physical distancing of 1.5-2m while in-flight 33.
The risk of SARS-CoV-2 transmission during air travel was addressed directly in 22 reviews, reports, and risk
assessments (Table 2), and indirectly in 26 reviews, predictive models, simulation experiments, environmental
monitoring studies, and in silico studies (Table 3).
 The key finding of the SARS-CoV-2 literature on transmission during flights is that multiple
interventions are needed to maximally reduce the risk of transmission (Table 2); this is summarized
well in the Appendix 1 figure from the Aviation Public Health Initiative report led by Harvard 34.
o Across reviews, the risk of infection during a flight is low 35, 36, 37, 38, 39. A meta-analysis found
that from January–June 2020, the risk of being infected with SARS-CoV-2 in an airplane cabin
was estimated to be 1 case for every 1.7 million travelers 35.
o The longer the duration of the flight, the higher the infection risk 40. On average, the attack
rate increased from 0.7% (95% CI: 0.5% - 1.0%) to 1.2% (95% CI: 0.4% - 3.3%) when the travel
time increased from 2.0 to 3.3 hours 40. Removing masks for meal service led to increased risk
41
.
o Public health measures such as maintaining physical distancing during boarding,

disembarkation, and in-flight, enhanced cleaning, hand hygiene, and universal mask use for
duration of flight implemented in a layered approach significantly reduce the risk of
transmission 34, 37, 38, 39, 42, 43.
o Airplane ventilation systems are designed to quickly refresh cabin air and this level of
ventilation substantially reduces the time particles remain in the cabin compared to other
indoor environments and thus reduces the opportunity for transmission, particularly when
coupled with other public health measures (Table 2 & Table 3).
o Adherence to public health measures by passengers and crew are a critical factor to the impact
of these measures to reduce the risk of transmission, such as symptom screening guidelines
and on-board procedures 33.
 Indirect studies on risk assessment and mitigation strategies used aerodynamics of droplets and
aerosols to characterize high risk situations, or simulated boarding and in-flight movements to

suggest strategies for minimizing interaction of people and maximizing the distance between people
in flight (Table 3).
o In‐flight particle numbers in the air in airplanes are lower than that of retail/grocery stores,
restaurants, office spaces, homes, and other forms of transport 44.
o Passengers who sneeze or cough while standing or moving about the cabin spread their
respiratory droplets considerably further than those seated 45.
o Wearing a face mask significantly decreased the spread of respiratory aerosols (>90%).
N95/FFP2 masks were more effective at reducing infections compared to cloth masks 46, 47.
o Boarding an airplane by groups of related individuals, those seated in back of plane and
window seats first as well as other more complicated algorithms such as the reverse pyramid
scheme were shown to reduce the interaction with other people 48, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57.
Decreasing the amount of carry-on luggage was also found to reduce interactions on-board.
Although some strategies such as increasing the number of boarding groups or social
distancing may sacrifice efficiency (i.e., longer total boarding/disembarkation time), they can
significantly reduce the risk of infection.
o Grouping families and strategically spacing passengers on flights that are not at capacity
improves physical distance between passengers. Algorithms developed by researchers were
presented to maximize this concept and demonstrated the potential performance of these
algorithms compared to middle seat empty or aisle seat empty strategies 40, 46, 58, 59. Across all
of these strategies, their effectiveness decreased on fuller airplanes 40, 46, 58, 59.
Overview of the evidence

The in-flight transmission events recorded across studies were investigated through contact tracing
investigations and cohorts. The cluster/outbreak investigations are at high risk of bias due to their
retrospective and descriptive nature. Cohorts were available for repatriation flights and are at lower risk of
bias because the passengers and crew were followed-up in a uniform manner for a specific time period.
Review literature ranged from good quality systematic reviews to narrative literature reviews. There was good
agreement in the information and recommendations across the different review literature.
Quantitative risk assessments, predictive models, simulation experiments, and other in silico studies were
highly variable in their objectives and approaches. No attempt to assess the validity of these studies was
conducted. These studies aim to mimic a real world scenario usually to explore options for different
interventions. Their results should be interpreted with caution as they may not reflect what would happen in a
field setting.
There were only a small number of flights for which epidemiological investigations of possible transmission
events had been undertaken. These events are likely under-reported and/or under-investigated due to the
logistics and available resources for contact tracing. It is also difficult to classify instances of in-flight

transmission as acquisition of SARS-CoV-2 may occur prior to departure, at various points during travel, or
during quarantine/upon arrival. Whole genome sequencing may help in linking cases to an on-flight single
exposure. Future investigations, risk assessments, and predictive models should also address whether optimal
public health measures are the same for small aircrafts, the implication that current VOCs, and emerging
SARS-CoV-2 variants and their attributes (e.g., increased transmissibility) may have on in-flight transmission
risk, as well as the impact of vaccination status of both travellers and airline staff in mitigating risk.
Investigations of in-flight transmission events
The full extent of COVID-19 exposure associated with airplanes is not known. Thirty-seven studies (13 are new
since the last review update) were identified where the possibility of in-flight SARS-CoV-2 transmission was
investigated. Twenty-four studies report transmission occurred and 13 report no transmission occurred
during the flights. Transmission was primarily passenger to passenger, although six studies reported
transmission event(s) from passenger to crew 7, 8, 11, 17, 19, 20. Several studies of repatriation flights where many
precautions were taken report no transmission to the crew 27, 28, 29, 30, 31, 32. Overall, in-flight transmission attack
rates ranged from 0-40%, but flights varied by a number of factors including public health measures
implemented, capacity, presence of VOCs, and flight-time length. High level points are listed below and
details on individual studies can be found in Table 1.
Public health measures enhanced during in-flight travel included a combination of physical distancing,
enhanced cleaning, mandatory face masks, hand hygiene, physical distancing during boarding and
disembarking, designated crew only areas, and quarantine areas for unwell passengers 3, 4, 5, 21, 22, 25, 26, 27, 28, 29, 30,
.
31, 32
 Symptom and temperature screening at the airport were mentioned in a few investigations 5, 11, 21, 25, 26.
The failure of individuals to adhere to the screening guidelines and report symptoms demonstrate
that screening was not an effective control measure on its own and it needs to be used in conjunction
with other precautions 11.
 Many of the larger transmission events occurred before the mandatory use of face masks on flights 1, 2,
7, 9, 10, 11, 12, 13
or other risk reduction strategies had been implemented. There were several studies, with
transmission events occurring early in the pandemic Jan-Mar 2020, that did not specify mask usage on
board 8, 14, 15, 16, 17, 18, 19, 20.
 There are also instances where transmission events occurred despite mandatory face mask
requirements 3, 4, 5, 21, 22, 23, 24. One study found that wearing a mask inappropriately (OR 2.46, 95% CI:
0.75-8.09) or not at all (OR 4.6, 95% CI: 1.28-16.6) were associated with SARS-CoV-2 positivity 7.
Incorrect use of the mask (e.g., not covering the nose) was considered an important factor of
transmission in at least one other study 22. Three studies noted that masks were removed during the
flight to eat or drink 4, 21, 22. Two cluster investigations reported positive cases detected in children,
who were likely exempt from masking requirements 5, 6.

Seating arrangements and proximity to an infected case were important risk factors for in-flight
transmission.
 Cluster investigations that had access to seating charts showed those seated within two to three rows
of the index case were at higher risk of acquiring COVID-19 compared to those sitting further away
(odds ratio: 4.8; risk ratio: 7.3; attack rate 3.8-30.9%) 4, 7, 9, 10, 11, 12, 19, 24. One study found that passengers
seated in the two rows ahead a confirmed case were at a slightly higher risk of being infected
compared to passengers in the same row or two rows behind 24.
 However, there were several cases across the cluster investigations that were seated much further
away and the mode or circumstance of transmission was not obvious (could have been from
movement in cabin, shared restrooms, or fomite transmission) and could not be confirmed 1, 6, 11, 18.
One investigation of three international flights to China found that the majority of confirmed cases
were seated in the middle of the economy section or near restrooms and galleys 24. It is not clear
whether any particular seats are associated with a higher risk of contracting infection. While some
studies suggest that sitting in the middle seat may be the most risky due to contacts on both sides,
the prevalence of COVID-19 was not found to differ significantly between passengers sitting in
window, aisle, or middle seats 10, 24.
 Across cluster investigations it was frequently postulated that the window seat should be a safer seat
as there are fewer contacts with other people compared to the aisle seats, however one investigation
found that being in a window seat was a higher risk than the aisle seat 1. This was an unexpected
finding that the authors could not explain. Table 3 describes modelling and simulation studies that
look at the potential differences in risk of sitting in different areas and seats on an airplane.
Length of flight time was an outcome of an investigation into transmission on domestic flights in China
early in the pandemic (January 2020) that reported increased risk with longer travel time 10. The estimated
attack rate (upper-bound estimate) increased from 0.7% (95% CI: 0.5%-1.0%) to 1.2% (95% CI: 0.4%-3.3%)
when travel time increased from 2 hours to 3.3 hours 10.
Impact of vaccination was estimated to reduce the likelihood of a passenger being infected by 74% in one
study 4. The impact of vaccine mandates on risk of in-flight transmission was not reported or estimated in any
study and most of the research included in the review occurred prior to widespread vaccination roll-out.
Variants of concern (VOCs) were implicated in two studies that identified multiple VOCs or VOIs present on-
board including Delta, Alpha, Beta, and Kappa.
 Phylogenetic analysis of genome sequence from 30 cases linked to a flight from South Africa to China
in June 2021 found that 27 were caused by Delta and 3 were caused by Alpha, Beta and C.1.2 4. A
single index case on that flight was associated with secondary transmission to 33 passengers.
 WGS conducted on 46 cases linked to a single flight from New Delhi to Hong Kong in April 2021,
reported likely transmission of three variants on-board, with Kappa causing the largest cluster (37

cases), onward transmission of Alpha occurring from 1 of 3 primary cases to 2 others onboard, and at
least one onboard transmission of Delta 5.
Whole genome sequencing (WGS) was undertaken in eight investigations. In all cases it helped to identify
cases linked to the same source and added a layer of information that the epidemiological investigation
would have missed 1, 2, 3, 4, 5, 6, 7, 8.
Several limitations are observed across these investigations mainly related to limitations in the data obtained.
For example, pre/post flight contacts between index case and secondary contacts could not be excluded 1, 11,
12, 14, 15, 16, 17, 18, 22
, and for some investigations, seating location was not known 11, 21.
Risk of SARS-CoV-2 transmission on airplanes
Twenty-two citations provide evidence on the transmission risk of SARS-CoV-2 on airplanes (Table 2). These
are a mixed group of review literature (n=10), reports (n=2), passenger/crew surveys (n=2), and quantitative
risk assessments (n=8) that examine the risk of SARS-CoV-2 transmission while flying. High level points are
listed below and details on individual studies can be found in Table 2.
 Reviews and reports had similar conclusions and recommendations 37, 38, 39, 42, 43. The report released
by the Aviation Public Health Initiative (APHI) on October 27, 2020 remains the most comprehensive
risk assessment of SARS-CoV-2 transmission from gate-to-gate 34. It evaluated the available evidence
and considered expert opinion and simulation results in its evaluation of reducing risk transmission of
SARS-CoV-2 on flights 34. They outline why a layered risk mitigation strategy is necessary and the
importance of compliance from passengers and the airlines, which was also suggested in the other
reviews.
 In agreement with findings from Table 1, three systematic reviews and two literature reviews
concluded that the risk of infection during a flight is low but may be highest for individuals seated
within two rows of the index cases 35, 36, 37, 38, 39.
 A meta-analysis of studies from January–June 2020 found the risk of being infected with SARS-CoV-2
in an airplane cabin was estimated to be 1 case for every 1.7 million travelers (95% CI: 712,000 to 8
million) 35. The risk was substantially decreased with implemented mitigation measures where the risk
in March 2020 was 1:425,062 and from April-September 2020, the risk was 1:7.1 million. Quantitative
risk assessments outlined in Table 2 also provide risk estimates of SARS-CoV-2 on airplanes and in
many cases they estimate the risk of transmission is higher than the meta-analysis. While we know in-
flight transmission has been under-reported, the risk of in-flight transmission varies depending on
many factors, including the parameters used in the models and the variation in the analysis across
studies.
Passenger and crew surveys examined the impact and perception of enhanced safety measures to reduce
the risk of SARS-CoV-2 transmission gate-to-gate 33 and infection and prevention performance and
awareness 60.

 In April 2020, passengers and crew from a flight from Auckland to Bangkok reported positive feedback
about implemented changes such as crew only restrooms, frequent cleaning of restrooms, designated
quarantine areas on the plane, masking everyone, use of face shields, frequent hand hygiene, and
symptom and temperature checks 33. Passengers reported physical distancing of 1.5-2m could be
maintained at check-in, pre-boarding and boarding, but not in-flight 33.
 Using a five-point Likert scale, the average infection prevention score among cabin crew in South
Korea was good with a mean score (SD) of 4.56 (± 0.44) on a five point scale, this was lower than their
awareness scores 4.75 (± 0.28) 60. The difference between awareness and performance was only
significant for hand hygiene and not mask wearing or handling COVID-19 cases 60. Infection
prevention performance was significantly associated with awareness (p < 0.05) and simulation-based
personal protective equipment (PPE) training experience (p < 0.05) 60.
Risk assessments explored the impact of different public health measures and implementation of a variety of
strategies on the risk of transmission during a flight.
 The combination of masks, social distancing among passengers, and improved ventilation can reduce
infection risk to <1% 61, 62, 63.
 One study reported the risk of per-person infection during a 13 hour air travel in economy class where
the majority of passengers were masked was 0.56% (95% CI: 0.41%–0.72%), equivalent to 0.17 infected
individuals 23. If all the passengers were not masked, the estimated number of infections increased to
17 for a 13 hour flight 23. Another study reported that infection probabilities for a 2 hour flight without
face masks was comparable to a 12 hour flight where all passengers wore high efficiency facemasks 41.
This study also found that removing mask for meal service increased risk 41.
 The longer the duration of the flight, the higher the SARS-CoV-2 infection risk 40. On average, the
attack rate increased from 0.7% (95% CI: 0.5% - 1.0%) to 1.2% (95% CI: 0.4% - 3.3%) when the travel
time increased from 2.0 to 3.3 hours 40.
 Removing roughly one-third of the passengers by keeping the middle seats empty and increasing
social distancing while boarding significantly reduced the infection risk (by 35-50%) compared to a full
airplane 64, 65. One risk assessment, based on data from late Sep 2020, estimated that a traveller on a
flight in the US had a risk of contracting SARS-CoV-2 of 1/3900 on a full flight and 1/6400 if the
middle seat empty policy was in place (these numbers depend on the disease activity in the
population) 66.
Indirect analyses of SARS-CoV-2 infection transmission risk and mitigation strategies on airplanes
Several simulation and in silico models have been developed to explore ways to minimize the risk of
transmitting an infectious disease on an airplane or during embarkation and disembarkation. There were
eleven studies on boarding/disembarking an airplane, six on optimal seating patterns to minimize in-flight
transmission, one that analyzed both boarding/disembarking an airplane, masking, and optimal seating
patterns, and seven on the aerodynamics of respiratory aerosols in an airplane when coughing and sneezing.

A single review of these aerodynamic studies up to June 2020 was also identified. These studies looked at
strategies for boarding to minimize passenger interactions and seating plans to maximize distance and
minimize interaction with other people. The studies that look at ventilation on the airplane and how coughing
or sneezing impacts airflow describe the distance and range of droplets and aerosols from various seats (e.g.,
window, middle, aisle) and when standing or walking about the cabin. High level summary points are listed
below and details on each individual study can be found in Table 3.
Public health measures such as the impact of masking and physical distancing on minimizing the risk of
inhaling respiratory aerosols from other passengers were examined.
 When surgical masks were used in simulations, there was a >90% reduction in droplets released
during the cough simulation compared to no mask 46.
 A predictive model demonstrated that N95/FFP2 masks were more effective at reducing infections
compared to cloth masks (95-100% vs 40-80%, respectively) 47.
 Physical distancing can be improved by grouping families and strategically spacing passengers on
flights that are not at capacity 52, 67.
Boarding/disembarking an airplane strategies to minimize contact while maintaining some level of

efficiency were explored in several simulations.
 Increasing the number of boarding groups, decreasing carry-on luggage, and avoiding interaction with
other passengers (i.e., boarding back of plane and window seats first) was found to decrease risk of
infection significantly, albeit with a sacrifice in overall efficiency (i.e., lengthier
boarding/disembarkation time) in some scenarios 48, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57.
 One predictive model estimated that the boarding/deplaning process contributed more to infection
risk than inflight movement (total secondary infections: 4.4 vs 0.7) 47.
 Two predictive models demonstrated the reverse pyramid boarding scheme, where passengers are
divided into boarding groups depending on their seats’ positions and boarded in a diagonal fashion,
was effective in reducing infection risk 55, 56. Back to front boarding of the plane was also shown to
decrease risk in another predictive model 53.
Optimal seating arrangements to minimize the risk of in-flight exposure was conflicting across simulations.
 The seats immediately adjacent to the index cases have the highest infection risk, followed by the row
directly behind and in front 40, 46, 58, 59. There is conflicting evidence on what seats (aisle, middle, or
window) have a higher infection risk 46, 68, 69. Differences in risk between different airplanes as well as
business and economy seats are also discussed in two studies 68, 70.
 Vacant middle seat occupancy was shown to reduce infection risk in two studies 47, 65.
Studies of in-flight respiratory aerosol dynamics were demonstrated in several simulations and
experiments to show both the superior ventilation within an airplane and activities that may be higher risk
than others.

 The travel distance of cough particles is heavily influenced by the direction and type of cough 69, 71.
Standing or walking about the cabin can lead to much further spread of respiratory droplets and
aerosols 45.
 In‐flight particle concentrations in the air in airplanes are lower than that of retail/grocery stores,
restaurants, office spaces, homes, and other forms of transport 44, 46. Further, simulation experiments of
in-flight aerosol transmission and surface contamination find that air in the cabin is rapidly renewed 58.
Methods
A daily scan of the literature (published and pre-published) is conducted by the Emerging Sciences Group,
PHAC. The scan has compiled COVID-19 literature since the beginning of the outbreak and is updated daily.
Searches to retrieve relevant COVID-19 literature are conducted in Pubmed, Scopus, BioRxiv, MedRxiv, ArXiv,
SSRN, Research Square and cross-referenced with the COVID-19 information centers run by Lancet, BMJ,
Elsevier, Nature and Wiley. The daily summary and full scan results are maintained in a refworks database and
an excel list that can be searched. Targeted keyword searching is conducted within these databases to
identify relevant citations on COVID-19 and SARS-COV-2. Search terms used included: flight, airplane, aircraft,
plane, airline travel, and air travel. The search netted 849 citations (507 from initial search up to October 28,
2020, 147 from second search conducted April 26, 2021, and 195 from updated search conducted on
November 25, 2021), which were screened for relevance to the review. Additional references to relevant
synthesis research not related to SARS-CoV-2 or the current pandemic were identified through citations in
articles on the current pandemic and an additional google search was executed May 4, 2021 to identify any
new non-indexed reports using (COVID-19 or SARS-CoV-2) AND (flight OR plane). Potentially relevant
citations were examined to confirm it had relevant data and relevant data is extracted into the review.
This review contains research published up to November 25, 2021.
Acknowledgments:
Prepared by: Kaitlin Young, Tricia Corrin, and Lisa Waddell, National Microbiology Laboratory Emerging
Science Group, Public Health Agency of Canada.
Editorial review, science to policy review, peer-review by a subject matter expert and knowledge mobilization
of this document was coordinated by the Office of the Chief Science Officer: ocsoevidence-
bcscdonneesprobantes@phac-aspc.gc.ca

Evidence tables
Table 1: investigations of in-flight transmission events (n=37)
STUDY METHOD KEY OUTCOMES
Flights with secondary cases identified (n=24)
Lv (2021) 4 This study investigates a flight of  During the quarantine period, 39 passengers
203 passengers which took off tested positive for SARS-CoV-2. Phylogenetic
new
from South Africa on June 9, 2021 analysis of genome sequences from 30 cases
and arrived at Shenzhen, China, found that 27 were caused by Delta and 3
Cohort study on June 10, 2021. All passengers were caused by Alpha, Beta and C.1.2.
had negative PCR and IgM assays
 Six PCR-positive cases were identified to be
within 48 h before boarding. It
the primary cases, who were likely to be
China was mandatory for inbound
infected in South Africa.
Jun 2021 passengers to wear masks
throughout the entire flight and  Transmission to secondary cases was linked to
on the way to the quarantine 1 index case.
hotel. An online questionnaire  197 passengers were considered exposed to
survey was conducted among all the index case, and 33 flight-associated cases
passengers. Upon landing, were reported during the quarantine.
passengers underwent a 14-day
 Passengers sitting within three rows of the
quarantine period. Multivariate
index case had a higher attack rate (30.9%,
logistic regression was conducted
17/55), compared with that of those located
to identify risk factors for
three rows away from the index case (11.3%,
infection.
16/142) (RR 4.22, 95% CI: 1.55–11.50).
 Use of hand sanitizer showed significant

protection (RR 0.24, 95% CI: 0.09–0.66).
 Vaccinated passengers were 74% less likely to

be infected compared with those without
vaccination (RR 0.33, 95% CI: 0.08–1.43) but
this was not statistically significant.
 87.3% (172/197) of travellers reported having

taken off their masks during the flight (reason
and length of time not reported).

Blomquist (2021) Identified infections among  The investigation determined 5 cases to be

9
passengers 18 England‐bound linked to potential aircraft transmission, 55
flights with infectious cases using infectious passengers and 2313 co‐passengers,
national case management with 2221 flight‐only contacts. The overall
Cohort study datasets. Passengers were SARS-CoV-2 transmission on short to medium‐
considered to be infectious haul flights was estimated to be low.
during the flight if lab results
UK  The following attack rates were estimated:
were positive 7 days before or 2
Dec 2020 days after the flight. o 0.2% (95% CI 0.1‐0.5) among all
flight‐only contacts.
o 3.8% (95% CI 1.3‐10.6) among

Note: whole genome sequencing
contact‐traced flight‐only contacts
could not be applied as this data
who sat within a two‐seat radius.
was not available for index and
secondary cases from the same o 13.0% (95% CI 7.6%‐21.4%) among
flight. co‐travellers with multiple non‐
flight exposures to infectious cases.
 Passengers were likely not wearing masks

during the flight as it was still early in the
pandemic before mask wearing was
widespread/mandatory.
Zhang (2021) 23 Enrolled all passengers and crew  Of 4492 passengers and crew with suspected
suspected of being infected with COVID-19 infection, 161 cases were confirmed
new
SARS-CoV-2 that were on during quarantine.
international flights bound for
 The number of confirmed cases on the 30
Cohort study Beijing on international flights in
flights investigated ranged from 2 to 11 per
March 2020. They provided the
flight. After investigation, only 2 (1.2%)
characteristics of all confirmed
confirmed cases were suspected of being
China cases of COVID-19 infection and
infected during flight.
March-Aug 2020 utilised Wells-Riley equation to
estimate the infectivity of COVID-  Taking masking and ventilation into account,
19 during air travel. The infectivity the effective infectivity was estimated to be
is quantified with infectious only 4 quanta/h (range 2–5). This value was
quanta released by one source used to calculate risk of per-person infection.
case per hour. Passengers were The risk of per-person infection during a 13 h
screened upon arrival. Health air travel in economy class where the majority
passengers underwent 14 days of of passengers were masked was 0.56% (95% CI
isolation for medical evaluation 0.41%–0.72%), or 0.17 infections.
and those suspected of having

COVID-19 were transferred to  If all the passengers were not masked, the
hospital. Clinical outcomes were number of infected individuals could be
followed up until August 1, 2020. roughly 6 for a 5 h flight, and 17 for a 13 h
flight in economy class.
 The per-person risk of individuals in first class

was ~4 times higher than travel in the
economy class.
Toyokawa (2021) 7 This study investigated  There were 148 passengers: the index patient,
passengers and flight attendants 141 other passengers (seat occupancy: 80.2%),
new
exposed to COVID-19 on March four flight attendants, and two pilots. The
23, 2020, on board a 2-hour flight authors were able to interview/follow-up on
Cohort study (Boeing 737-800) in Japan. 126 passengers.
Whole-genome sequencing of
 Of the 146 passengers (excluding the pilots),
SARS-CoV-2 was used to identify
there were 14 confirmed cases and 6 probable
Japan the infectious linkage between
(symptomatic but did not undergo RT-PCR
Mar-Apr 2020 confirmed cases. The association
testing) identified. The secondary attack rate
between confirmed COVID-19
was 9.7% for confirmed cases only and 13.8%
and proximity of passengers'
if probable cases were included.
seats to the index case and/or the
use of face masks was estimated  The genome sequence of the virus in 12 of the
using logistic regression. 14 confirmed cases were all either identical or
differed only by 1 nucleotide to that of the
index case.
 92 passengers wore a mask at all times, 20

most of the time, and 11 did not wear a mask
at all. Wearing a mask inappropriately (OR
2.46, 95% CI 0.75-8.09) or not at all (OR 4.6,
95% CI 1.28-16.6) were associated with SARS-
CoV-2 positivity.
 Passengers seated within two rows of the

index patient were at higher risk of infection
(OR 4.8, 95% CI 1.46-15.8).
Bae (2020) 21 299 passengers were on an  Based on RT-PCR testing and no development
evacuation flight from Milan, Italy of symptoms, 6 evacuees had asymptomatic
to South Korea (duration 11 h) COVID-19.
Cohort study March 31, 2020. Medical checks
 One evacuee, who self quarantined for 3 weeks
were conducted before the flight,
before the flight and then 2 weeks after the

South Korea everyone wore N95 respirators flight, had an RT-PCR positive test on day 14 of
except when eating and social quarantine in South Korea. The authors
Mar 2020
distancing was observed on suggest her exposure must have been on the
embarkation and disembarkation. flight where she was 3 rows from an
asymptomatic case and they shared the same
All evacuees were under medical
washroom.
observation during a 14 day
quarantine with RT-PCR testing
on day 1 and day 14.
Guo (2021) 24 Obtained data on all international  There were three international flights during
flights to Lanzhou, China, from the study period, from Riyadh (MU7792),
preprint
June 1 to August 1, 2020, through Jeddah (MU7790), and Moscow (CA608). The
new the Gansu Province National flights had a total of 700 passengers, of which
Health Information Platform and 27 (3.9%) passengers were confirmed to have
the official website of the Gansu COVID-19.
Surveillance study
Provincial Center for Disease
 Flight 1: Prevalence of COVID-19 was 7.9%.
Control and Prevention. They
The prevalence rates were 4.8% (95% CI 0.7-
China calculated the period prevalence
10.3%) among passengers seated on the
rate of COVID-19 among the
Jun-Aug 2020 window seats, 15.5% (5.9-25.1%) on the middle
passengers of all flights during
seats, and 5.6% (1.5-9.8%) on the aisle seats
the 14-day period following the
(P=0.054). The prevalence rates were 16.7%
flight, and stratified the
(9.5-27.2%) in the two rows ahead of each
prevalence by the seat positions.
confirmed case, 14.0% (5.8-28.6%) in the same
Passengers were required to wear
row with a confirmed case, and 10.7% (6.0-
masks during the flight.
17.9%) in the two rows behind each confirmed
case (P=0.465).
 Flight 2: Prevalence was 1.6%. The prevalence

for the window seats was 0%, for the middle
seats was 3.4% (1.4-8.1%), and for the aisle
seats was 1.6% (0.6-3.8%) (P=0.268). In the two
rows ahead of each confirmed case, the
prevalence was 4.5% (0.2-24.9%)], in the same
row 0%, and in the two rows behind 4.2% (0.2-
23.1%) (P=1.000).
 Flight 3: Prevalence was 1.6%. The prevalence

rates were 2.3% (2.3-6.9%) in the window
seats, 1.6% (1.6-4.8%) in the middle group, and
1.1% (1.1- 3.4%) in the aisle group (P=1.000).

There were no other confirmed cases around

the seats of the confirmed cases.
 Conclusions: The majority of confirmed cases

were seated in the middle rows of the
economy class, or near restrooms and galleys.
The prevalence of COVID-19 did not differ
between passengers sitting on window, aisle or
middle seats. Passengers seated in the two
rows ahead of a confirmed case were at a
slightly higher risk of being infected compared
to passengers in the same row or two rows
behind.
Dhanasekaran This study reports on a large  The attack rate of passengers was 40%, 12/59
(2021) 5
cluster (n=59 cases) linked to a cases were symptomatic.
single flight with 146 passengers
new  WGS, conducted for 46 cases, identified
from New Delhi to Hong Kong in
infections on board were caused by three
April 2021. The airline used
different variants: Alpha (n = 5/46, 10.9%),
Cluster thermal screening and social
Delta (n = 2/46, 4.3%) and Kappa (n = 39/46,
investigation distancing during check-in and
84.8%).
boarding. Passengers were tested
at arrival and during a 21-day  37 of the Kappa sequences clustered together
China very closely suggesting a single transmission
quarantine period.
Feb-Apr 2021 Epidemiological information was cluster (i.e., a superspreading event onboard).
collected from passengers of the  Onward transmission of Alpha likely occurred
flight. Whole genome sequencing from 1 of 3 primary cases to 2 others onboard.
was conducted to compare
 Evidence was suggestive that there was at least
sequences from this flight.
one onboard transmission of Delta.
 8 of the positive cases were detected in

children under the age of two, who were likely
exempt from masking requirements.
 Using the time from arrival-to-detection as a

proxy for SARS-CoV-2 incubation, they
estimated that at least 7 individual cases were
likely infected prior to travel and 41 were
infected during transit. 11 cases were detected
>14 days after arrival.

 Limitations of this study were that not all cases

could be sequenced and possible confounding
due to lack of detailed information on
passenger movements during airport check-in,
pre-flight boarding, onboard the flight and
during ground transportation to designated
quarantine hotels.
Hu (2021) 10 Used the itinerary and  A total of 5,797 airline passengers on 177
epidemiological data of COVID- planes were included in this study. 209 airline
new
19 cases and close contacts on travellers were confirmed to have COVID-19.
domestic airplanes departing
 175 individuals were identified as index cases.
Cluster from Wuhan city in China
The attack rates of a seat were 0.3% (lower-
investigation between Jan 4- January 23, 2020,
bound estimate, 18/5400, 95% CI 0.2-0.5%) to
to estimate transmission risk of
0.6% (upper-bound estimate, 34/5622, 95% CI
COVID-19 among travellers. Data
China 0.4-0.8%). Each index case infected 0.2 (SD 0.5)
from the National Health
to 0.1 (SD 0.3) individuals.
Jan 2021 Commission of China was used to
identify cases who had a travel  The seats immediately adjacent to the index
history of domestic flight during case had an AR of 9.2% (95% CI 5.7-14.4%) and
illness or within 14 days before a relative risk of 27.8 (95% CI 14.4-53.7)
symptom onset. Passenger lists compared to other seats.
who seated within three rows to  The middle seat had the highest AR (0.7%, 95%
the confirmed cases were CI 0.4-1.2%). The window and aisle seats had
supplied by airlines. A passenger the same AR (0.6%, 95% CI 0.3-1.0%).
was defined as an index cases if
 There was no significant difference in AR
they had confirmed infection after
between airplanes (Boeing vs. Airbus).
the travel, had symptom onset
within 14 days before travel or  Risk increased with longer travel time. The
within 2 days after, and had the upper-bound AR increased from 0.7% (95% CI
earliest date of symptom onset 0.5%-1.0%) to 1.2% (95% CI 0.4%-3.3%) when
among other cases within 3 rows. the co-travel time increased from 2 hours to
Passengers were considered close 3.3 hours.
contacts when they were within 3  There was a lack of detailed information on
rows of an index case. Secondary passenger movements during airport check-in,
cases were defined as close pre-flight boarding, and onboard the flight.
contacts who had symptom onset Further, asymptomatic cases would not have
later than the index case and been included in the analysis.
within 2-14 days after travel. The
attack rate (AR) of a seat= the

number of confirmed cases/the  Note: This study took place before the
total number of close contacts implementation of stringent public health
that used the same seat location measures in China. Masks would not have
apart from index cases. been mandatory during the flight.
Swadi (2021) 2 A comprehensive investigation  During the required 14-day managed isolation
into the potential source of and quarantine period, 7 passengers who had
COVID-19 infections among 7 traveled on the flight received positive SARS-
Cluster travelers that were on a flight CoV-2 test results.
investigation from Dubai, UAB on Sept 29 th
 The 7 passengers had begun their journeys
2020, with a stop in Kuala
from 5 different countries before a layover in
Lumpur, Malaysia, and landed in
New Zealand Dubai; pre-departure SARS-CoV-2 test results
Auckland, New Zealand (18 hour
prior to boarding were negative for 5. None of
Sep 2020 duration). These 7 passengers had
the passengers reported close contact at the
been seated within 4 rows of each
Dubai airport.
other. The lineage of the
genomes obtained from the 7  Among the 7 passengers, 2 were probably
passengers was determined. Mask index case-patients infected before the flight,
use was not mandatory. Post 4 were probably infected during the flight, and
aircraft transportation to the remaining passenger was probably
quarantine facilities was physically infected while in isolation.
distanced where possible, and  5/7 cases wore masks and gloves while on the
mask use was mandated. flight, including the two index cases, while the
other two cases did not.
 Genomic analysis found that the sequences

obtained from all 7 cases were assigned to
lineage B.1 and were genetically identical.
Eichler (2021) 3 Investigated the origin of multiple  Genomic sequence and epidemiological
COVID-19 cases identified after analysis identified a multi-branched chain of
14 days in post travel quarantine. transmission that included international and
Cluster domestic air travel and probable aerosol
investigation transmission in the quarantine hotel (not
summarized below).
 The index case was identified to be a

repatriated citizen returning to New Zealand
New Zealand
from India.
Aug 2020
 Three secondary cases from the index case’s
18 hour (35% occupancy) international flight

on a Boeing 747 were identified by whole

genome analysis. All three cases sat within 2
rows from each other, and were required to
wear facemasks.
 In-flight infection transmission also occurred

from one of the secondary cases, who was
unknowingly exposed during quarantine and
released from quarantine before they were
positive, to three passengers during an 85
minute domestic flight (50% capacity) on a
Boeing 737. The three cases sat near one
another (in front of each other) while the
infectious case sat at a distance.
 Note: All flight passengers wore masks during

the flights.
Murphy (2020) 6 An outbreak investigation into  13 cases were linked to a single international
COVID-19 cases linked to an flight (duration 7.5h). The cases had come
international flight into Ireland in from three different continents.
Cluster the summer, 2020.
 Only 49 passengers and 12 crew were on the
investigation
Masks were worn by 9 cases, not flight. No data on the crew or 11 passengers.
worn by 1 child case and was
 Whole genome sequencing showed 5 strains
Ireland unknown for 3.
from passengers matched suggesting a single
Jun-Aug 2020 point source of infection. The index case(s) was
not identified through the epidemiological
investigation, but plausible theories suggest a
proportion of cases acquired COVID-19 in-
flight.
 4 of the flight cases were not seated near a

positive case, had no contact in transit, wore
face masks in-flight and would not have been
considered a close contact.
 A social network is shown to demonstrate how

the flight cases spread SARS-CoV-2 to 46
secondary contacts in the community.

Speake (2020) 1 The flight, an Airbus A330-200, on  29 passengers on the flight had SARS-CoV-2,
Mar 19, 2020 from New South and an additional 35 had compatible
Wales to Perth (duration 5h) had symptoms by tested negative. 18 from cruise
Cluster 28 business class and 213 ships and 10 domestic/international travellers.
investigation economy passengers.
 Based on WGS 18 cases were considered
An epidemiologic and whole- primary: 13 Ruby Princess, 4 Ovation of the
Australia genome sequencing investigation Seas and 1 traveller from the US.
were undertaken.
Mar 2020  11 secondary cases, 3 did not have WGS and
Mask use was rare on this flight were classified as possible, 8 are considered to
and inconsistent. have occurred in-flight. The 8 did not know
each other, 4 from US and 4 Australians.
 Among the 11 secondary cases, 8 were within

2 rows of an infected case and 3 were more
distant. All secondary cases were from the mid
section despite 5 infectious cases in the aft
cabin.
 64% in were in a window seat, risk ratio 5.2

(95% CI 1.6-15.4).
 WGS allowed proper attribution of cases to in-

flight transmission.
Khanh (2020) 11 Flight from London, UK to Hanoi,  There were 16 crew and 201 passengers. The
Vietnam on March 2, 2020 index case started to experience symptoms the
(duration 10h). All successfully day before the flight, she was seated in
Cluster traced passengers and crew were business class.
investigation interviewed, tested and
 14 passengers and 1 crew were identified as
quarantined.
positive during the contact tracing
Vietnam At arrival, there were temperature investigation.
checks and symptom screening
Mar 2020  12 were in business class and 92% were seated
and some countries (not UK) had
within 2 meters of the index case and 1 was
to undergo SARS-CoV-2 testing.
more than 2 meters, risk ratio 7.3 (95% CI 1.2-
Facemasks were not mandatory
46.2).
on airplanes.
 Three other contacts (2 passengers and 1 flight
attendant) did not have a close encounter with
the index case as they were in economy class.

Choi (2020) 8 A study examining confirmed  The cluster included 2 passengers (a married
COVID-19 cases in Hong Kong couple) in business class and 2 crew.
and travel history identified 4
 The couple both had symptom onset on March
Cluster people that shared a flight from
10, so they were already infected during travel.
investigation Boston, US to Hong Kong, China
March 9, 2020. The airplane was a  The flight attendants developed symptoms
Boeing 700-300ER (duration March 16 and 18. One of 2 flight attendants
Hong Kong spent 5 days in Boston, the other could not be
>15h), with 294 passengers.
Mar 2020 confirmed.
Not all passengers were tested.
 Their viral sequences all matched 100% and
No mandatory quarantine or
were not sequences that had been seen in
airport screening was in place.
Hong Kong. However, close matches were
Use of facemasks was not
identified from Toronto, New York and Boston.
mentioned.
 Based on this analysis the authors conclude it
is likely that the couple transmitted SARS-CoV-
2 to the flight attendants during the flight.
Hoehl (2020) 12 102 passengers of a flight from  The tourist group was tested for SARS-CoV-2
Tel Aviv, Israel to Frankfurt, on arrival, 7 of 24 were positive. On the flight
Germany March 9, 2020. 24 the 7 positive from the tourist group were
Cluster members were from a tourist symptomatic (n=4), presymptomatic (n=2) and
investigation group that unknowingly at the asymptomatic (n=1).
time had had contact with an
 1 of 71 other passengers with follow-up data
infected hotel manager 7 days
Germany reported having a positive RT-PCR test 4 days
prior.
after the flight. 7 of 71 reported symptoms of
Mar 2020
No preventative measures were COVID-19 within 14 days of the flight; one was
taken on the flight. confirmed with IgG serology and PRNT test.
Crew were not followed-up.  Both confirmed cases are considered likely on-
board transmission events, they were sitting
Antibody tests were offered,
within 2 rows of an index case.
however many passengers did not
get tested, so additional
transmission events may not have
been detected.
Quach (2021) 20 This is an in-depth analysis of the  183 primary, 1000 secondary, and 311 third
epidemiological characteristics of generation contacts all of which were tested
new
a flight-associated COVID-19 and quarantined.
outbreak and subsequent contact
tracing, systematic testing, and

Cluster strict quarantine to prevent  In addition to the index case, 15/183 primary
investigation further transmission. contacts tested positive for COVID-19, of
which 14 were passengers and 1 was a crew
Flight VN54 (10hr) consisted of 16
member.
crew members and 201
Vietnam
passengers.  5 secondary cases emerged among secondary
Mar 2020 contacts of 4 primary cases.
 The attack rate among secondary contacts was

0.3%.
 Public health measures were not mentioned.
Pavli (2020) 19 Contact tracing activities of  18 flights with 21 index cases and 891
international passengers arriving passengers and 90 crew were traced.
or departing from Greece Feb 26-
 Of the 21 index cases, 6 were symptomatic, 12
Cluster Mar 9, 2020.
were pre-symptomatic and 2 developed
investigation
No public health measures were symptoms 5-7 days after the flight.
noted.
 5 secondary cases were identified that many
Greece have been in-flight transmission from one
Feb-Mar 2020 flight (Israel to Greece, duration 2h) with two
COVID-19 cases. The secondary cases were
seated within 2 seats of an index case.
Wang (2021) 18 Contact tracing activities of a  The source of infection in this cluster was a
family cluster of COVID-19. The family member’s girlfriend who travelled via
reported cluster involved 3 plane from Guizhou province. This case had
Cluster confirmed cases, 2 asymptomatic close contact with a confirmed case on the
investigation infections, and a total of 34 close plane while waiting in line for the bathroom as
contacts within the family, of well as getting on and off the plane.
which 8 were visiting relatives
China
from other provinces, and 1 was
Feb 2020 on the same flight as a confirmed
case.
Yang (2020) 13 A flight from Singapore to  The index case developed a fever on the flight
Hangzhou (duration 5h) carrying and did not wear a mask, he was identified
325 people on January 23, 2020. during disembarkation and tested positive. All
Cluster passengers were quarantined for 14 days. 11
Seat assignments were not
investigation other passengers developed symptoms and
obtained, so physical proximity of
tested positive for an AR=3.4%.

China the index and other cases is not

known.
Jan-Feb 2020
Masks were worn by flight
attendants, but not by most
passengers.
Chen (2020) 22 A flight from Singapore to  16/335 COVID-19 cases were diagnosed
Hangzhou (duration 5h) carrying among passengers, attack rate 4.8%. None of
335 people on January 24, 2020. the crew were infected.
Cluster
The flight was strictly managed  Only one passenger did not have a plausible
investigation
because 100 people on the flight epidemiological history of exposure prior to
were from Wuhan. the flight. On the flight, he was seated near 4
China infected passengers from Wuhan for
All passengers were quarantined
approximately 1 hour and did not wear his
Jan-Feb 2020 for 14 days.
facemask properly (not tight and nose not
Facemasks were worn on the covered).
flight except when eating and
drinking.
Zhang (2020) 16 Reported two case clusters of  Public health investigation and contact tracing
COVID-19 who were identified led to the identification of 12 confirmed cases
new
through inbound screening when of PCR-confirmed SARS-CoV-2 infection
returning to China from related to 2 tour groups. For the majority of
Cluster Singapore/Malaysia. cases, the exact route of transmission was
investigation unclear as the cases could have gotten SARS-
CoV-2 infection in Wuhan/Hubei before travel,
or from each other during their 5-day tour in
China
Singapore/Malaysia, or during the 5-h flight.
Jan 2020 However, one of the documented cases was
not actually part of the tours, but had close
contact with the other COVID-19 patients on
one of the flights. Considering the incubation
period of SARS-CoV-2, the most likely
exposure for this case was the flight.
Kong (2020) 15 This paper details the travel and  Transmission within the tour group (group A)
potential transmission of SARS- resulted in 13 confirmed or suspected
CoV-2 from an index case in tour infections and could have occurred on flights,
Cluster group A to 3 other tour groups bus or during tours. The first case was
investigation that were in Europe Jan 16-28.

Shared flights and lodging were hospitalized Jan 22, and others in the group
considered in the epidemiological fell ill starting Jan 26.
China
investigation. Face mask use or
 It seems unlikely that transmission from Group
Jan 2020 other precautions were not
A to Group B tour group occurred on a
mentioned.
January 16 flight as the 3 cases in Group B
were not identified until January 29.
 It is plausible that transmission from Group A

to two others and a tour guide from group C
and- an independent traveller,-occurred on a
Jan 28 flight.
 It is also plausible that transmission from

Group A to 3 people in Group D occurred at
lodging shared by both groups Jan 22.
Mun (2021) 17 This case series describes two  The first case became ill on Feb 21, 2020 and
flight attendants diagnosed with was diagnosed on Feb 25, 2020. Thorough
COVID-19 who shared the crew's epidemiologic investigations suggested in-
Case series resting area and ground flight disease transmission as the source of
transportation, and discusses the infection as the flight attendant had worked
risks experienced by flight during a flight on February 15th, 2020 which
South Korea
attendants. had on-board 39 Korean Catholic pilgrims
Feb-Mar 2020 coming from Tel Aviv, Israel. Soon after their
return to South Korea, 30 pilgrims were
diagnosed with COVID-19. There were no
other identified sources for this case. After the
flight, she continued to work between
February 19 and February 22, 2020.
 After the first flight attendant was diagnosed

with COVID-19, a 2-week self-quarantine
period was imposed on all crew members
(n=30). Only one crew member was diagnosed
with COVID-19 during this quarantine on Mar
6, 2020. While the two flight attendants
worked on different decks of the plane, they
had shared the crew's resting area and ground
transportation after the first flight attendant
had developed symptoms.

Eldin (2020) 14 A case investigation of a French  This investigation suggests that transmission
national who developed COVID- occurred on the flight from Bangui to Yaoundé
19 shortly after returning to where French nationals were on the same
Case report France. He had left France plane as the first case of COVID-19 diagnosed
February 13 for Bangui, Central in Cameroon after the February 24th flight.
African Republic and returned to
France  The case developed symptoms shortly after
Marseille, France with his partner
returning to Marseille France. The flight is the
Feb 2020 on February 24th via Yaoundé,
most plausible point of exposure.
Cameroon.
Flights with no secondary cases identified (n=13)
Lee (2020) 25 Describes a repatriation flight  No cases of COVID-19 were detected among
from China to Taiwan. All the the evacuees.
new
medical staff were equipped with
personal protective gear
Cohort study (protective coveralls, face shield,
N95 mask, gloves) and these
remained donned throughout the
Taiwan mission. At Wuhan airport before
Mar 2020 boarding the passengers
underwent temperature
screening. People boarded based
on colored labels. Green: free of
fever and respiratory symptoms
for the preceding 14 days; Red:
well on examination but had
declared that they had fever or
respiratory symptoms in the past
14 days; Black: afebrile but
experienced any kind of
respiratory symptoms at the point
of examination). Two seats were
left vacant between each
passenger. Passengers were asked
not to talk to each other during
the flight, not to consume
Food/drinks, and to avoid going

to the toilet. All evacuees

underwent 14 day quarantine

upon arrival and RT-PCR testing.
Kim (2020) 27 Describes a repatriation flight of  One passenger was identified as a PUI during
80 Koreans from Iran to Korea, the first leg of the flight but tested negative
with a direct transfer of upon arrival and one additional passenger was
Cohort study passengers between airplanes in categorized as a PUI during the second leg of
Dubai. Strict infection prevention the flight upon developing a fever tested
precautions were implemented positive upon arrival. No additional
South Korea
(i.e., vinyl curtains to separate passengers, aircrew, medical staff, or others
Mar 2020 clean and contaminated zones, involved in the evacuation, developed signs of
PPE, face masks, and social infection during the 14-day observation
distancing). Passengers with period.
symptoms in the last two weeks
were designated as ‘patients
under investigation’ (PUI).
Everyone aboard the flight was
screened for SARS-CoV-2 upon
arrival into Korea and completed
a mandatory 14-day medical
quarantine.
Suzuki (2021) 28 Measured serum antibody titers  Median compliance with PPE was 90% (range
for SARS-CoV-2 in 10 healthcare 70-100%, n=8).
workers who were engaged in the
 The number of positive cases on each of the
Cohort study operation of charter flights for the
five flights was 3, 2, 2, 1, and 0, respectively.
evacuation of Japanese residents
from Hubei Province. All  All samples from all healthcare workers were
Japan seronegative, indicating that PPE was effective
participants wore PPE. Blood
Feb-Mar 2020 samples were collected at in protecting staff during repatriation flights.
enrollment (after February 14th)
and at every 2 weeks after
enrollment until 4 weeks after the
final participation in the
evacuation operation.
Nir-Paz (2020) 29 This article describes the  Two of the repatriated citizens (a couple), were
repatriation of 11 citizens from SARS-CoV-2 positive upon arrival. Thus, it is
the Diamond Princess cruise ship. assumed that they were infectious on the
Cohort study airplane.

Before boarding a 13.5 hour flight  No secondary cases were identified among the
Feb 20, 2020 all 11 citizens had a other repatriated citizens or 4 crew members.
Israel
negative SARS-CoV-2 RT-PCR test
 Everyone on the flight were observed to wear
Feb 2020 result.
their facemask except for eating and drinking.
Precautions were taken, everyone
wore surgical or FFP2 masks and
crew had minimal interaction with
passengers.
Ng (2020) 26 Followed up on 94 persons who  Two passengers tested positive for COVID-19
boarded an evacuation flight from on arrival. The son of one of these cases also
new
Wuhan to Singapore. tested positive during day 3 of quarantine.
Temperature checks were
 Although individuals on-board tested positive,
Cohort study conducted at check-in. Surgical
it was not confirmed whether any cases
masks were provided to
occurred in-flight.
passengers. At arrival they
Singapore underwent temperature screening
Jan 2020 again and then underwent 14 day
quarantine, where they were
checked for symptoms 3 times
daily. Any persons reporting
symptoms underwent RT-PCR
testing.
Jia (2021) 72 During a second outbreak in  Travelers on the same flight carried different
Guangzhou, China in Mar-Apr viral variants whereas travelers who lived
new
2020, near real-time genomic together shared the same viral variants.
surveillance was conducted on
 Flight ET606 departing from Ethiopia had 12
Cluster 109 confirmed imported cases to
infected passengers from 6 different African
investigation elucidate the source and spread
countries. Viral genomes were obtained for 10
of SARS-CoV-2. The cases were
of them, and the viral variants were assigned
from travelers returning from 25
to 4 different haplotypes.
China different countries in Asia (n =
26), Africa (n = 28), Europe (n =  Flight TG668 departing from Thailand included
Mar-Apr 2020
36), and North and South America 6 infected passengers from Pakistan who were
(n = 19). The phylogenetic previously unacquainted but were traveling
analyses aimed to determine how together on a tour. Viral genomes were
the virus was transmitted among obtained for 5 of them and 4 viral haplotypes
were identified.

passengers on the same flights  The findings suggest that SARS-CoV-2 was not
and among family members. transmitted during air travel, and the travelers
were likely infected before the flight.
Draper (2020) 73 Two flights with an infected crew  Due to a delay in getting manifests, it was
member were identified in almost a week before the flight passengers
Northern Territory, Australia. All were notified (n=195 people to quarantine).
Cluster 555 passengers were considered
 326 air passengers from other flights were also
investigation close contacts necessitating
monitored with 131 quarantined for being in
contact tracing and quarantining
the same row or within 2 rows of an infected
activities. There were 28 cases and
Australia case.
527 close contacts over the two
Mar-Apr 2020 months. 94% follow-up rate was  No secondary cases (0%, 95% CI 0-1.1%) from
achieved. flights were identified.
No public health measures or

mask wearing noted.
Qian (2020) 74 12 cases had taken a flight  Eleven of these cases were linked to the
Ningbo to Zhejiang, China temple; the exposure of one case was
following a super spreading event unknown, but not considered to have occurred
Cluster at a temple in Ningbo. on the flight. No secondary cases are known to
investigation have occurred from the flight.
mask wearing noted.  The results of contact-tracing investigations
China identified 88 cases of COVID-19 admitted to
five hospitals in Zhejiang province, China.
Jan 2020
Ruonan (2021) 75 Analyzed Guangzhou imported  Out of 34 flights, 10 (29.4%) had more than 3
case data from The National cases on-board. There is no clear evidence of
Information Management System the spread of COVID-19 on any of the flights.
Surveillance for Infectious Diseases Reports of
analysis the China Disease Control and
Prevention Information System.
China
Jan-Apr 2020
Chen (2020) 32 Describes repatriation of people  Flight personnel were tested three times, no
back to China. Does not provide COVID-19 cases were identified.
new
any details on number of flights
investigated. The cabin area was

Descriptive study divided various zones (a clean

area, buffer zone, passenger
sitting area and quarantine area).
China Each passenger was provided with
Jul 2020 (est) two N95 masks and could take
them off only to eat/drink during
meal times. Crew members and
medical staff could choose to
wear medical disposable caps,
gloves, goggles, protective suits,
or gowns. All flight attendants
performed hand hygiene
frequently.
Karim (2020) 30 This article summarizes the  There were 82 positive cases detected among
repatriation of Malaysian citizens the repatriated citizens. Secondary
using chartered commercial transmission among repatriated citizens during
Descriptive study aircraft. The mission objectives the flight was not investigated.
were to repatriate as many
 There was a single positive case of a healthcare
citizens based on aircraft capacity
Malaysia worker involved in the mission, based on the
and prevent onboard
sample taken on arrival of the flight. This
Feb-Apr 2020 transmission of the disease to
worker was asymptomatic and did not test
flight personnel. All flight team
positive again upon repeat testing (potential
personnel underwent briefing on
false positive or sampling error). No
in-flight safety procedures and
investigation into how the worker may have
use of personal protective
acquired infection was described. There were
equipment (PPE). All repatriates
no infections involving flight team members
were required to wear face masks
who worked with the case.
and sanitise their hands upon
boarding the flight.
Cornelius (2020) This article summarizes the  The study included 39 flights with > 2000
31
repatriation of US citizens by US individuals.
Department of health and human
 The article describes in depth the precautions
services air medical evacuation
taken to transport many potentially infected
Descriptive study crews.
individuals. Best practices for IPC during air
transport are described in the paper. No cases
US were identified of emergency workers
acquiring COVID-19 during evacuation flights.
Jan-Mar 2020

Schwartz (2020) 76 Reports on the index case who  No secondary COVID-19 cases were identified
arrived in Toronto on Jan 22, after despite public health follow-up.
taking a 15hr flight from China
Case reports with 350 people onboard.

Canada mask wearing noted.
Jan 2020
Est= Date the study took place is estimated from the publication date or the country the study was
conducted was based on author affiliations. AR = attack rate
Table 2: Reviews, reports, passengers surveys, and risk assessments related to SARS-CoV-2
transmission on airplanes (n=22)
Reviews (n=10)
Moon (2021) 77 This systematic review and meta-  Of the 147 included studies, 14 were on SARS-
analyzes aimed to analyze CoV-2. These included risk of transmission in
new
different transmission risks of the following confined spaces: airplane (n=1),
respiratory infectious diseases home (n=7), hospital (n=3), restaurant/bar
Systematic review (including SARS-CoV-2) according (n=2), and navy ship (n=1).
to the type of confined space
 In the sub-group analysis for SARS-CoV-2,
(e.g., home, residential space,
residential space (combined RR 8:30, 95% CI:
Korea (est) school, work, airplane etc.).
3.30-20.90) and airplanes were the riskiest
Nov 2021 (est) The systematic review is high spaces for transmission (RR 7.30, 95% CI: 1.15–
quality and includes studies up to 46.20).
Dec 2020.
Pang (2021) 35 Systematic review of COVID-19  As of August 2020, there were at least 2866
cases related to air travel up to index cases that were documented air
Sept 2020. The review was limited passengers.
Systematic review to flights with passenger index
 Fewer than 50 documented potential
cases and did not include
secondary cases associated with air travel
transmissions amongst air crew,
US (est) during the pandemic were reported.
ground crews, or airport staff.
Apr 2021 (est)  Mask use on reviewed flights ranged from use
A quantitative approach was used
unknown to mandatory N95 use.
to estimate the risk of air travel

transmission. Correction factors  From January–June 2020, the risk of being

were used in risk estimates for infected with SARS-CoV-2 in an airplane cabin
asymptomatic transmission and is estimated to be 5.927x10-7 or 1:1.7 million.
underreporting. Transmission risk Uncertainty in the correction factors and a 95%
was calculated for three time CI indicate risk ranges from 1 case for every
periods of interest: (1) January– 712,000 travelers to 1 case for every 8 million
June 2020 the period covered by travelers.
the literature, (2) the month of
 For the month of March 2020, the risk is
March 2020 when the global
estimated to be 2.353x10-6 or 1:425,062.
spread of COVID-19 was
occurring, and (3) April–  From April-September 2020, the risk is
September 2020 to account for estimated to be 1.413 x10-7 or 1:7.1 million.
the sharp drop in worldwide air
travel and increased use of
COVID-19 testing.
Arora (2021) 78 This review was based on articles  Factors that affect the transmission risk on
that have studied or analyzed the flights include duration of the flight, number of
new
impact of international travel by infected persons (passengers) on board and
air or sea. A search was carried their stage of illness, size of the aircraft, and
Narrative review out in PubMed with the terms type of air-ventilation system used.
“coronavirus, COVID19,
international travel, transmission,
Apr 2021 (est) screening, airports, aircrafts,
Germany (est) maritime, ship.”
Rosca (2021) 36 Four electronic databases were  18 studies on in-flight SARS-CoV-2

searched for studies published 1 transmission (130 unique flights) and 2 studies
new
February 2020–27 January 2021 on wastewater from aircraft were included.
on SARS-CoV-2 transmission
 The quality of evidence from most published
Systematic review aboard aircraft. Assessed study
studies was low.
quality (QUADAS-2) and reported
important findings.  The proportion of contacts traced ranged from
Romania (est) 0.68 to 100% across studies.
Feb 2020-Jan 2021  In total, 273 index cases were reported, with 64
secondary cases. Secondary attack rate among
studies that followed up on >80% of
passengers and crew (n=10 flights) varied
between 0 and 8.2%.

 Genomic evidence was used to investigate on-

board transmission on 4 flights.
 Conclusions: SARS-CoV-2 can be transmitted

during aircraft travel, but is relatively rare. Risk
of infection could be highest for individuals
seated within two rows of the index cases. The
heterogeneity in design and methodology
restricts the comparison of results across
studies.
Khatib (2021) 38 Narrative review of the literature  In-flight transmission risk is low, but a layered
assessing safety of air travel multipronged approach (onboard masking,
new
relating to coronavirus disease distancing during boarding and deplaning,
2019 (COVID-19) transmission disinfection protocols and preflight screening
Literature review from January 2020 to May 2021. and testing measures) is necessary to reduce
the risk and establish a threshold for safety.
Canada1
Jan 2020-May
2021
Sun (2021) 79 Narrative review of publications  A summary of literature on airport screening

related to the COVID-19 operations and boarding strategies.
pandemic and air transportation
 Summarizes the existing (2020) literature
Literature review published in 2020.
regarding in-flight operations in the presence
of COVID-19 and in-flight transmission events.
China (est)  Conclude that widely available, robust data for
Apr 2021 (est) whether there are transmission occurs despite
proper mask use on airplanes would yield
more valuable insights.
Bielecki (2021) 37 Narrative review of topics related  Air travel numbers have significantly declined
to air-travel in the pandemic (51.6% decrease compared to 2019).
period. Topics included traveller
 Infection risk during flights is low: 1 infection
Literature review numbers, peri-flight prevention,
per 54 h of flight and zero infections during a
and testing recommendations
12-h flight.
and in-flight SARS-CoV-2
Switzerland (est)  Flying will be safer by optimizing screening
transmission, photo-
Feb 2021 (est) epidemiology of mask use, the procedures, minimizing the risk of allowing
pausing of air travel to mass pre- or asymptomatic cases to board (i.e.,

gathering events, and quarantine testing), and implementation of/adherence to

measures and their effectiveness. simple hygiene measures and physical
distancing that prevent the spread of diseases.
Passenger screening is inadequate to detect all
infectious cases.
 Models predict minimal risk of in-flight

transmission but these do not consider human
behavior and variations between airline
procedures.
 High airflow and use of HEPA filters onboard

planes make it unlikely to catch the virus from
someone who is not seated close by. There is
some evidence that passengers within two
rows of an index case are at higher risk.
Khatib (2020) 42 Narrative review of literature on  Air quality aboard modern aircraft is very safe
SARS-CoV-2 transmission risks (HEPA filters are 99.97% effective in removing
and infection prevention particles between 0.1 and 0.3 μm in diameter
Literature review strategies used by commercial air and 100% of larger particles).
travel. Authors provide
 Further study is needed to examine the
recommendations and propose
Canada (est) interaction between airflow and resulting
strategies to mitigate the spread
particle dispersion, but authors recommend
Dec 2020 (est) of COVID-19.
turning on the personal airflow (gasper) above
each passenger to improve travel comfort, air
quality and reduce person-to-person
transmission of exhaled contaminants.
 Risk is highest during boarding and

disembarkation.
 A window seat is thought to be the safest

option-though recent real-world outbreak
studies are questioning this.
 Recommendations included: masks should be

used, frequent hand sanitization promoted
and physical distancing ensured when feasible
from boarding to disembarkation. High-
frequency touchpoints should be disinfected
between flights and in-flight. Pre-screening

and pre-testing measures should be used in

addition to the preventive measures enforced
onboard. The implementation of a
standardized digital health pass for COVID-19
and more robust contact tracing may be key
factors to allow for a gradual safe return to air
travel.
Kelly (2021) 39 A literature review was conducted  Captured 11 studies that reported possible
on in-flight transmission of SARS- evidence of in-flight transmission of SARS-
new
CoV-2. Articles published January CoV-2, with attack rates ranging from 0-6.9%
1 to December 1, 2020 were among the exposed passenger and cabin crew.
Literature review included.
 Flights with the highest attack rates did not
have mandatory masking.
Ireland (est)
Jan-Dec 2020
Freedman (2020) Narrative review of all  Describe 4 well documented flights, three
43
publications of possible in-flight included in Table 1 1, 8, 11 and the forth is an
SARS-CoV-2 up to Sep 21, 2020. online inventory of flights to Hong Kong that
reported transmission to 2 passengers, 1
This review summarized
Literature review seated with 5 index cases, masks were used
transmission events by attributes
on-board (duration 8 h).
such as mask wearing on the
US (est) flight in an attempt to describe  3 single transmission events have been
and quantify the risk under reported, 2 were published 12, 22.
Sep 2020 (est)
different scenarios and
 6 high risk flights with no transmission are
considerations such as differing
listed, 1 is published 76. The inventory of flights
incidence rates of SARS-Co-V-2 at
from Hong Kong lists many flights with
origin and destination, intensity of
positive passengers and no secondary
viral load in index cases, flight
transmission attributable to the flight.
duration, masking practices
onboard, pre-flight screening and  5 evacuation flights of which 3 are published 21,
passenger spacing.
29
are listed with one possible transmission
event. The review states >1.7 million
There were not enough data
passengers were repatriated by their
points to quantify the risk.
government or a cruise ship company during
the pandemic, few have been documented in
the literature.

 Flights lists with known COVID-19 cases were

identified from Canada and Australia. These
lists are for other passengers to self identify
and isolate. US CDC is also collecting data, but
has not published any findings.
 Clear clustering of cases was identified where

seat plans were available, but some
transmission occurred to people > 2 rows from
the index case. The flights with large
transmission clusters occurred before face
masks were mandated on flights and several
high-risk flights with no transmission had
mandatory masks.
Reports (n=2)
Marcus (2020) 34 This excellent quality APHI Report  Layered non-pharmaceutical interventions
Aviation Public includes data up to September 28, (NPIs) significantly reduce the risk of disease
Health Initiative 2020. transmission and includes: optimal ventilation,
Report from the disinfection of surfaces, wearing face masks,
This research-led guidance report
Harvard TH Chan procedures to encourage social distancing
reflects a mixture of literature
School of Public particularly during embarkation and
review, in silico models and expert
Health disembarkation, but also during flight (e.g. no
engagement to assess the
queuing for the restrooms or walking about
following question: “In the midst
the plane and minimizing interaction with
of this complex, novel coronavirus
Risk assessment crew.)
crisis, how can aviation leaders
advance an independent  Airplane ventilation is highly sophisticated and
US (est) evidence-based program to delivers high amounts of clean air to the cabin
reduce the risks of SARS-CoV-2 which rapidly disperses exhaled air.
Sep 2020 (est)
disease transmission and with
 Crew and Passenger Behavior: Public safety on
that, enhance the safety and
board and airplane depends a lot on individual
confidence of its workforce and
behaviours: first health attestations and
passengers?”
screening pre-boarding, mandatory facemasks,
social distancing and orderly conduct to avoid
congestion combined with hand washing and
cleaning. This is encouraged via the penalty of
being on a “no-fly” list for non-compliance.
 Overall, there is limited data on in-flight

transmission, however it appears that a very

low number of infections could be attributed

to in-flight transmission and there is evidence
that NPIs, particularly mask use, resulted in no
transmission despite infectious passengers
onboard. They describe 13 manuscripts (also
included in Table 1) of studying in-flight
transmission. Of note, no crew from
repatriation flights acquired SARS-Cov-2, a
demonstration that adherence to NPIs is
effective.
 Layered risk mitigation strategies can

significantly reduce the risk of transmission,
but require compliance from passengers and
the airlines.
Shaimoldina A public dataset of international  Flight infections have decreased and air travel
(2020) 80
flight infection information was has been significantly reduced.
used to analyze the trend in flight
 Preventing SARS-CoV-2 infected individuals
traffic and infections during the
from boarding flights is challenging due to
Surveillance data pandemic. Based on existing
testing accuracy, asymptomatic cases and
analysis and literature, the authors then
many other factors including the inability to
literature review describe challenges of prevention
maintain physical distance and density of
of SARS-CoV-2 infected
passengers on a plane.
individuals from boarding flights
Kazakhstan (est)  Solutions may include hotel quarantine for
and solutions for flight
Dec 2020(est) resumption. arriving passengers, mandatory PPE, airport
diagnosis, and rapid imaging/biomarker
diagnosis by advanced high-technology.
Passenger and crew surveys (n=2)
Pongpirul (2020) This study targeted passengers  Response rate for the online questionnaire was
33
and crew of two repatriation low: 22.5%
flights operated by Thai Airways
 Several risk reduction measures were
(TG476 from Sydney 9.25h and
implemented and well received. These
Cross-sectional TG492 from Auckland to Bangkok
included crew only restrooms, frequent
study 11.5h), total 335 passengers and
cleaning of restrooms, designated quarantine
35 crew.
areas on the plane, masking everyone, use of
Thailand An online questionnaire was face shields, frequent hand hygiene (alcohol
administered to get individual
Apr 2020

feedback about social distancing, gel provided to all passengers), symptom and
mask wearing, and other temp checks.
procedures put in place to reduce
 Physical distancing of 1.5-2m could be
the risk of SARS-CoV-2
maintained at checking, pre-boarding and
transmission. In depth interviews
boarding, but not in-flight.
were conducted with crew.
 Crew found that handing passengers surgical
masks, face shields and alcohol gel prior to the
flight was impractical as passengers often had
their hands full already with multiple pieces of
carry-on luggage.
Ryu (2021) An online survey was conducted  The level of IP performance (4.56 ± 0.44) was
60 to assess the level of infection significantly lower (p < 0.05) than that of IP
prevention (IP) and factors awareness (4.75 ± 0.28), however the
new affecting IP performance among difference was not significant for wearing a
aircraft cabin crew (n=177) during mask or handling confirmed or suspected
the COVID-19 pandemic. COVID-19 passengers. Hand hygiene had
Cross-sectional
significantly lower performance (4.47 ± 0.56)
study Infection prevention (IP)
compared to awareness (4.61 ± 0.08).
performance and IP awareness
was evaluated using a five-point  IP performance was significantly associated
South Korea Likert scale. Mean and SD are with IP awareness (p < 0.05) and simulation-
Aug-Sep 2020 provided as outcomes. based PPE training experience (p < 0.05).
Simulation-based personal
protective equipment (PPE)
training experience and
organizational culture was also
evaluated.
Risk assessments (n=8)
Horstman (2021) Applied computer fluid dynamic  In a 3-hour flight, infection risk of an airborne
61
results of virus transport and infection influenza was approximately 50% for
concentration, past data on passengers sitting in the vicinity (i.e., a single
Influenza transmission in row) of infected cases (positioned at the 12th
Risk assessment airplanes, and the Wells Riley row aisle seats), estimated as 2-3 infections per
quanta estimation, to estimate 131 passengers.
infections risk of an arbitrary
US (est)  When the analysis was compared to field data
airborne viral infection on Boeing
where 4 symptomatic infected cases led to 2
Mar 2021 (est) 737-600 airplanes. The
secondary infections, SARS-CoV-2 was found
parameters and data in the

analysis were then compared to to be less infectious and lie mid-range of the
field data on SARS-CoV-2 on an applied Influenza infectious dose data.
airplane.
 Masks, social distancing among passengers by
Note: Field data based on the 2.9 feet, vacant middle seat at 66% capacity,
transmission event described by reduced the risk of transmission by more than
Hoehl (2020) in Table 1. 48%. The use of N95 masks and surgical masks
(ASTM 3) reduced the number of secondary
Investigators assumed the virus
infections to 0.
emission rate was 1.6 ± 1.2 x 105
genome copies/m3h that
corresponded to 1267
viruses/minute released, and an
Influenza human 50% infectious
dose (HID50) of 2554
copies/quanta.
Wilson (2021) 63 Using a stochastic SEIR model, the  Although this study was mainly about
study aimed to model the risk of importation risk, the authors provided an
new
COVID-19 outbreaks associated estimate of infection risk in their methods as a
with international air travel from parameter for the larger model.
Risk assessment Australia to New Zealand, along
 Estimated 2 in-flight infections arising from
with the likely impact of various
933 exposure-hours, giving an estimated risk
control measures that could be
of transmission per hour of flying in a plane
New Zealand used to minimise the risk of such
containing an infectious person of 0.00214.
May 2021 (est) outbreaks. In-flight transmission
risk was a parameter used in the
model. Using previously
published literature, the authors
estimated the number of hours of
exposure to infected cases for a
flight with mandatory mask use
(number of infected people on
the flights x flight hours).
Wang (2021) 41 Estimate inflight SARS-CoV-2  Infection probabilities for a 2 hour flight
infection probability for a range without face masks were comparable to a 12
of scenarios using experimental hour flight where all passengers wore high
Quantitative risk aerosol dispersion data and a efficiency facemasks. Overall, infection
assessment modified Wells-Riley equation. probabilities were higher in the economy class
Scenarios were varied based on

UK (est) quanta generation rates and face cabins (MID-AFT) compared to the business
mask efficiencies, and specified class (FWD) sections.
Feb 2021(est)
for a B777-200 aircraft.
 Individual infection probabilities during a 2
hour unmasked flight ranged from 4.5%-
60.2%. The average infection probabilities
based on the number of infected passengers
on the flight ranged from 0.1%-2.5% in the
same scenario. For a 12 hour unmasked flight
individual infection probabilities ranged from
24.1%-99.6%, average infection probability
0.8%-10.8%.
 The use of high/low efficiency masks by

passengers during a 12 hour flight except
during 1 hour meal service increased average
infection probabilities by ~59% to ~8%,
compared to when masks were worn for the
entire flight.
McCarthy (2021) This mechanistic transmission The relative benefits of different mitigation
64
model assumes that the strategies on the airplane can be explored:
probability of SARS-CoV-2
 Time spent seated was the most important
infection is additive over sub-
factor in total risk score.
Quantitative risk activities. Sub-activities that
assessment together make up the air travel  Mask-wearing, making masks mandatory,
activity include boarding the given what we currently know, could be a
plane, moving to and entering (cost-) effective strategy for risk reduction.
NA (est)
one’s seat, sitting on the plane for  Keeping the middle seat vacant unless there is
Jan 2021 (est) the duration of the flight, and a party of three travelling together at least
finally leaving ones seat and halves the risk, under a very wide range of
disembarking the plane. decay assumptions.
The model also assumes a three-  Managing boarding is less costly than leaving
hour long flight and that there is seats empty, but the analysis found that the
no direct physical contact total impact will be lower.
between participants and that all
surfaces are disinfected. It also
assumes that all passengers are
compliant with the boarding and
masking policies.

This is a risk-cost-benefit decision

analysis framework that can be
applied to many settings,
including airplanes. The analysis
can produce relative risks.
Dai (2021) 62 Estimated the association  If people wear masks in an aircraft cabin, then
between the infection probability natural ventilation or normal mechanical
new
and ventilation rates with the ventilation can provide a sufficient ventilation
Wells-Riley equation, where the rate to ensure that the infection probability is
Risk assessment quantum generation rate (q) by a less than 1%.
COVID-19 infector was obtained
using a reproductive number-
China (est) based fitting approach. The
Aug 2020 (est) model was applied to multiple
confined space scenarios (offices,
classrooms, buses, and aircraft
cabins).
Zhang (2021) 23 Enrolled all passengers and crew  Of 4492 passengers and crew with suspected
suspected of being infected with COVID-19 infection, 161 were confirmed
new
SARS-CoV-2 that were on during quarantine.
international flights bound for
 The number of confirmed cases on the 30
Risk assessment Beijing on international flights in
flights investigated ranged from 2 to 11 per
March 2020. They provided the
flight. After investigation, only 2 (1.2%)
characteristics of all confirmed
confirmed cases were suspected of being
China cases of COVID-19 infection and
infected during flight.
March-Aug 2020 utilised Wells-Riley equation to
estimate the infectivity of COVID-  Taking masking and ventilation into account,
19 during air travel. The infectivity the effective infectivity was estimated to be
is quantified with infectious only 4 quanta/h (range 2–5). This value was
quanta released by one source used to calculate risk of per-person infection.
case per hour. Passengers were The risk of per-person infection during a 13 h
screened upon arrival. Health air travel in economy class where the majority
passengers underwent 14 days of of passengers were masked was 0.56% (95% CI
isolation for medical evaluation 0.41%–0.72%), or 0.17 infections.
and those suspected of having  If all the passengers were not masked, the
COVID-19 were transferred to number of infected individuals could be
hospital. Clinical outcomes were roughly 6 for a 5 h flight, and 17 for a 13 h
followed up until August 1, 2020. flight in economy class.

 The per-person risk of individuals in first class

was ~4 times higher than travel in the
economy class.
Hu (2020) 40 This risk assessment applies  The overall risk of SARS-CoV-2 transmission on
epidemiological data from planes with high efficiency air filtration devices
airplane passengers (n= 9,265 was reported to be relatively low. The
Quantitative risk passengers and 175 index cases, estimated AR upper bound was 0.60% (95% CI:
assessment on 291 airplanes) and close 0.43%-0.84%), and R0 ranged from 0.12 to
contacts to estimated attack rates 0.19.
(AR) and reproduction number
China  Transmission risk was variable by seat distance
(R0) prior to the lockdown in
from infected case(s) and duration of the trip.
Dec 2019- Mar Wuhan. Relative risk among seats
2020 by proximity to the index case  The seats immediately adjacent to the index
was also estimated. cases were the highest risk, AR of 9.2% (95%
CI: 5.7% - 14.4%), relative risk (RR) of these
AR upper bound was estimated,
seats compared to others seats on the airplane
based on the assumption 34 and
was 27.8 (95% CI: 14.4 - 53.7). The middle seats
69 close contacts were infected
had the highest AR (0.7%, 95% CI 0.4% - 1.2%),
on the flight departing Wuhan.
followed by the window seats (0.6%, 95% CI
0.3% - 1.0%) and the aisle seats (0.6%, 95% CI
0.3% - 1.0%).
 Lower bounds of AR estimates linked to air

travel increased from 0.0% (95% CI 0.0% -
0.6%) to 0.4% (95% CI 0.02% - 2.2%), and
upper bounds from 0.7% (95% CI 0.5%-1.0%)
to 1.2% (95% CI 0.4% 3.3%) when trip duration
increased from 1.5 hours to 3.3 hours.
However these results were not significant due
to limited data on secondary cases based on
flight times.
Barnett (2020) 66 This risk assessment calculates the  Based on the assumptions, the risk of
risk of SARS-CoV-2 infection contracting COVID-19 from a nearby
Preprint
resulting from exposure on an passenger on a flight in the US was about 1 in
airplane using data from late 3,900 on a full flight.
Quantitative risk September 2020 and earlier
 Under the “middle seat empty” policy, that risk
assessment research findings. It did not
falls to in 6,400, a factor of 1.64 lower.
account for loading/unloading,
going to the bathroom, length of

US the flight, and made some  The point estimate for death risk was
assumptions about the approximately one death per 800,000
Sep 2020
“protection” afforded by the seat passengers.
backs as a barrier between rows.
 Transmission risk was lowest when the
It is based on economy class in
contagious passenger is in a window seat and
airplanes with 6 seats in a row.
highest when in an aisle seat.
Est= Date the study took place is estimated from the publication date or the country the study was
conducted was based on author affiliations.
Table 3: Studies and reviews that examined the aerodynamics of respiratory droplets on airplanes and
mitigation strategies for respiratory infections on planes (n=26)
Boarding/Disembarkation (n=11)
Milne (2021) 56 Used an agent-based model to  The reverse pyramid boarding method
determine the number of passengers divides passengers into boarding
new
to include in each boarding group groups depending on their seats’
when using the Reverse Pyramid positions, using a ‘diagonal loading’
Predictive model method. They investigated the effect scheme.
of carry-on luggage, the social
 Health risks decrease as the number of
distance maintained between
Reverse Pyramid boarding groups
Romania (est) passengers walking down the aisle,
increase.
Aug 2021 (est) and the number of boarding groups.
The model assumed a 30 row single-  In a scenario with the most carry-on
aisle airplane with three seats on each luggage and 1m aisle social distance,
side of the aisle, with each middle seat using 6 boarding groups vs. 3 groups
empty (due to seat social distancing), reduced the average risk to aisle and
for a total of 120 passengers boarding window seat passengers by 58%
the airplane. and 81% respectively while increasing
the average boarding time by 1.2%.
 In a scenario with no carry-on luggage,

using 6 boarding groups vs. 3 groups
reduced the risk to aisle and window
seat passengers by 62% and 96%
respectively while increasing boarding
time by 3.2%.

 Changing the aisle social distance from

1m to 2m brings provided negligible
health value to seated passengers.
Islam (2021) 57 Simulated new boarding processes  Back-to-front boarding doubled the
enacted by airlines in response to infection exposure compared with
new
COVID-19 using pedestrian dynamic random boarding and increased
models to determine whether they exposure by around 50% compared to
Predictive model lead to an increased or decreased risk a typical boarding process prior to the
of infection spread compared to outbreak of COVID-19. Increased
alternatives. exposure arises from the proximity
US (est) between passengers moving in the
Apr 2021 (est) aisle and while seated. Prohibiting the
use of overhead bins to stow luggage
and boarding the window seat before
the aisle seat can ameliorate this
increase in exposure risk.
 Keeping middle seats empty also

resulted in a substantial reduction in
exposure.
Cotfas (2021) 54 Use an agent-based model and  When minimizing the health risk to
stochastic simulation approach to passengers was the primary objective
investigate the impacts of the Reverse the optimal solution was to assign an
Predictive model Pyramid method on average boarding equal number of window seat
time and health risk to aisle and passengers to 1 and 2 boarding
window seat passengers. Assessments groups, and an equal number of aisle
Romania (est)
were based on social distancing by seat passengers to boarding groups 2
Mar 2021 (est) maintaining distances of 1-2 meters and 3. This option was robust to
between passengers when walking changes in luggage volume and aisle
down the aisle, keeping the middle social distance. The option reduced
seat empty, and different carry on health risk among aisle seat passengers
luggage policies. by 22.76%-35.31%, when compared to
other simulations which minimized
boarding time.
 Scenarios that reduce boarding time,

and health risks to a lesser degree, are
also discussed.

Milne (2021) 49 In these stochastic simulation  Increased luggage = increased

experiments and agent-based models, boarding time.
the authors assess six boarding
 In a scenario where there is 1 m aisle
Predictive model methods and compare their
distancing, the back-to-front by row –
performance with that of the two best
WilMA method has shorter boarding
boarding methods used to date with
US (est) times, fewer seat interferences, and less
social distancing according to four
aisle seat risk than the baseline back-
Feb 2021 (est) performance metrics. Three of the
to-front method for each luggage
metrics are related to the risk of the
scenario. The baseline back-to-front by
virus spreading to passengers during
row method has less window seat risk
boarding. The fourth metric is the time
for the higher volumes of luggage
to complete boarding.
scenarios.
The two “best” baseline boarding
 In a scenario where there is 2 m aisle
methods are back-to-front by row and
distancing, the back-to-front by row –
modified reverse pyramid half zone
WilMA – offset 3 method is superior to
(see figures for description). The back-
the baseline modified reverse pyramid
to-front by row – WilMA method
half zone method because its boarding
boards the passengers one row at a
time is about the same and it has less
time starting from the rear of the
significantly less aisle seat risk and
airplane. The five other boarding
window seat risk. The back-to-front by
methods are created by adjusting the
row – WilMA method has the lowest
back-to-front by row – WilMA method
window seat risk.
so that some of the window seat
passengers board earlier. In particular,
k rows of window seat passengers will
board the airplane before any aisle
seat passengers. In the five new
methods, the value of k ranges
between 2 and 6.
Xie (2021) 50 Quantitatively compare the  The number of high-risk passengers

disembarkation process of a Boeing decreased by 72% after adopting
737-300 before and after adopting Strategy I.
Predictive model disembarkation management
 After adopting Strategy II, the number
strategies.
of high-risk passengers again
China (est) Two strategies are investigated: decreased by 27%.
Jan 2021 (est) Strategy I: Where there is one infected  Although both strategies sacrifice
passenger, ground crews first disinfect efficiency (i.e., longer total

cabin aisles before the disembarkation disembarkation time), they also

process begins, then passengers in significantly reduce the risk of infection.
front of the infected patient
disembark from the front door while
passengers in the rear of the case
disembark from the rear door. The
patient and his or her “close contacts”
disembark only after all passengers
have left the cabin.
Strategy II: Where there are multiple

infected passengers, passengers are
evacuated from the front door or rear
door from traversed columns that do
not contain patients or close contacts.
After the passengers have left the
cabin, the cases and “close-contacts”
leave from the front or back door
without picking up their luggage.
After the cases have left, the ground
crews perform a second disinfection
of the cabin. After disinfection, the
remaining passengers leave through
the front or rear door.
Milne (2020) 48 In these stochastic simulation  As the number of boarding groups

experiments and agent-based models, increases from two to four, average
the authors adapt the Reverse boarding times decrease.
Predictive model Pyramid method for social distancing
 When the number of boarding groups
when an airplane is boarded using a
increases from 3 to 6, the aisle seat risk
jet bridge that connects the terminal
US (est) decreases significantly from 44% to
the airplane’s front door. They assess
21%.
Nov 2020 (est) the impact of number of boarding
groups (2 vs. 6) to show the resulting  As the volume of luggage carried
impact on four performance aboard the airplane decreases, the risk
evaluation metrics. The first duration decreases significantly.
performance metric is the average  Doubling the aisle social distance from
boarding time. The second 1 m to 2 m increases the average
performance metric is the number of boarding time and decreases both aisle
type-3 seat interferences during the and window seat risks.

boarding (i.e., switching seats, moving

out into aisle to allow window
passenger access to seat). The third
and the fourth performance metrics
pertain to seated passengers’ health
while later boarding passengers pass
them.
Schwarzbach (2020) Evaluate the applicability of  The authors demonstrate that

81
technology-based social distancing commonly utilized Receiver Signal
methods while boarding in an aircraft Strength Indicator (RSSI) measurements
cabin environment using a radio can lead to false-positive and false-
Simulation propagation simulation based on a negative encounter classification,
experiment three-dimensional aircraft model. They depending on the path-loss model
perform a ray tracing propagation tuning, lowering the reliability and user
simulation in a section of a modeled acceptance of technology-aided social
Germany (est)
Airbus A321 aircraft cabin. distancing options.
Oct 2020 (est)
 From an application point of view, a
possible implementation of the
proposed technological approaches
could look at the following: Real-time
proximity warning, Post-processing
contact tracing, Boarding/deboarding
scheduling.
Delcea (2021) 55 Estimate the number of passengers for  If the objective is to minimize health
each boarding group assuming risk among passengers, then reverse
reverse pyramid boarding with the pyramid boarding first group should be
Predictive model middle seats unoccupied. Apply those with window seats in the rear half
agent-based modeling and a of the airplane, the third group should
stochastic simulation to evaluate be passengers with aisle seats in the
Romania (est)
impacts on boarding time and health front half of the airplane, with the
May 2020 (est) risk to passengers in each scenario. second boarding group being the
remaining passengers. This
arrangement was found to be the most
ideal as it reduced health risk to aisle
seat passengers by 25% and by 22% for
window seat passengers, while
increasing boarding time by 2%.

Milne (2020) 51 In these stochastic simulation  Average boarding time is the

experiments, the authors assess nine comparable measurement between
adaptations of boarding methods several scenarios.
Predictive model according to four performance
 Increased social distance (1m to 2m) =
metrics. Three of the metrics are
increased boarding time.
related to the risk of the virus
US (est)  Increased proportion of people with
spreading to passengers during
Aug 2020 (est) boarding. The fourth metric is the time luggage = increased boarding time.
to complete boarding of the two-door  Seating the window seat passengers
airplane when apron buses transport before aisle seat passengers decreases
passengers to the airplane. the risk of seat interference (where the
aisle seat has to get up to let the
window seat in).
 Aisle seat risk is higher when social

distance is lower (1m), luggage is
carried, when boarding is random.
 The author indicates that window seat

risk is less than aisle seat risk during
boarding, but does not estimate what
the difference may be.
Schultz (2020) 52 A cellular automata model that  The model shows that compared to
models the movement of passengers random boarding of people, boarding
during the boarding process. They do groups (e.g., families) together
Predictive model not consider facemasks. They model individually will result in the shortest
distance to index case and contact boarding time 41% of the random
time to estimate transmission risk. scenario and least transmission risk
UK (est)
0.09 compared to 0.57-0.62 for any of
Jul 2020 (est) the random scenarios when the plane is
half-full. These boarding times were
relatively stable at 75% and 100%
capacity; however, transmission risk
increased to 0.31 and 0.66 for the
boarding in groups, individually
scenario.
Cotfas (2020) 53 An agent-based model is used to  Back to Front boarding of the plane
simulate the passenger boarding took the longest time, but had the
process, mainly interactions with lowest health risk in the simulation.

Predictive model agents and other people. (used  The risk is similarly low if a 2-meter
NetLogo platform). social distance is maintained when
boarding.
They model the length of time to
Romania (est)
board the plane under a number of  Boarding is more efficient and less risky
May 2020 (est) scenarios and considering hand when passengers do not have luggage
luggage storage times. to store.
The outcome is about length of time

already seated passengers come into
contact with other people either as
they pass by down the aisle or due to
having to get up to let a person into
the window or middle seat.
In-flight transmission and seating (n=6)
Dietrich (2021) 65 Used bacteriophage MS2 virus  Compared with exposures in full
dispersion data as a surrogate for occupancy scenarios, relative exposure
SARS-CoV-2 and modeled the risk to an individual passenger in
Environmental relationship between SARS-CoV-2 vacant middle seat scenarios was
monitoring and exposure and aircraft seating reduced by 23% to 57%.
predictive model proximity. Both full occupancy and
 The 23% exposure reduction was
study vacant middle seat occupancy
observed for a single passenger who
scenarios were considered.
was in the same row and two seats
US (est) away from the SARS-CoV-2 source,
empty middle seat between.
Apr 2021 (est)
 A 57% exposure reduction was
observed in a scenario involving a
three-row section that contained a mix
of SARS-CoV-2 sources and other
passengers.
 Overall exposure risk reduction in a full

120-passenger cabin with vacant
middle seats ranged from 35.0% to
39.4%.
Saretzki (2021) 82 This study investigated the  The visualized airstream in the cockpit
distribution of exhaled air between demonstrated no crossflows, indicating
new
crew members and passengers on a no, or minimal, aerosol transport
small aircraft (4-seater Morane between the two pilots.

Simulation Saulnier MS893E). An externally  There was negligible air flow towards
experiment connected ventilation system was the passengers who received
used to simulate the cockpit in-flight ventilation from the additional nozzles
airflow. The airstream was marked just in front of their seats.
Germany (est) with smoke for visualization and the
 In small planes, the air will leave the
Oct 2021 (est) airflow velocity was measured with a
cockpit either via leakages of the side
thermal anemometer.
windows and doors, discharge valves or
systems in the side windows or doors
or discharge valves in the cockpit’s
floor. For this reason, individuals on
board should be instructed to sneeze
or cough towards the side wall of the
cockpit or inside the crook of their arm.
 Conclusion: The risk of transmission

from a strong ventilated airstream in a
small plane is insignificant.
Zhang (2021) 83 A cabin model of a seven-row Airbus  The virus spreads to the ceiling of the
A320 aircraft is constructed for cabin within 50 s of the infected
new
simulating the SARS-CoV-2 spread in passenger normal breathing.
the cabin with a virus carrier using the
 When the infected passenger breathes
In silico study Computational Fluid Dynamics (CFD)
normally, the virus can spread to the
modeling tool. The passengers’
seats in the front row, the same row
infection risk is also quantified with
China (est) and to the back two rows.
the susceptible exposure index (SEI)
Sep 2021 (est) method. N2O is used as a tracer gas to  When the infected passenger coughs,
establish a continuous system, and the virus can spread to the front three
Euler’s method is applied in the CFD rows, the same row, and the two rows
tool to simulate the SARS-CoV-2 behind that an SEI>1, which indicated
concentration and distribution in this the risk for infection.
study. The virus distribution changes  While the high mass fraction areas stay
in the cabin under the carrier’s normal on the same side of the aisle as the
breathing and coughing are compared infected passenger.
based on the simulation data.
 Simulations investigating the effects of
mask wearing were not done.
Desai (2021) 68 Modeled the airflow, transport of oral  Seat ranking across aircrafts were
and nasal expired particles (e.g. CO2 highly variable.
and coronavirus) at different seat

In silico study positions inside Airbus Airbus 380 and  In the first class section: The Airbus
Boeing B747 aircraft. Simulations best ranked seat was warmer than the
considered First, Business and Boeing best ranked seat, but has worse
US (est) Economy class sections in each circulation.
Feb 2021 (est) aircraft. Seat positions were ranked
 In business class: Airbus best ranked
based on CO2 mass fraction,
seat was colder, but offered better
temperature, and velocity
circulation than the Boeing best ranked
corresponding to passenger nose
seat. The Airbus seat was located in the
positions at each seat location.
side bank of the seats on the aisle side
and the Boeing seat was is located next
to the window.
 In economy class: The best ranked seat

for the Airbus was located next to the
window while the best ranked seat for
the Boeing was the middle seat in the
side bank of the seats. The Airbus seat
had a higher temperature, lower CO2
concentration, and lower air velocity,
the trade-off for a warmer seat was
worse circulation.
 Overall, airbus economy best ranked

seat was both warm and with good
circulation; the Boeing seat performed
worse in all these areas.
Ghorbani (2020) 84 The model, Monte Carlo Simulations,  The figures in the paper depict optimal
optimizes the number of passengers arrangement of passengers in an
preprint
and their arrangements under a social airplane. Key to safely increasing the
distancing measure for the airline number of passengers is to group
In silico study industry for single aisle and double families closely together.
aisle scenarios.
US (est)
Oct 2020 (est)
Salari (2020) 67 A mixed integer programming (MIP)  If social distance is completely adhered
model to properly assign passengers to, no aisle seat use and no one within
to seats on an airplane while 3.3ft, the max load is 20 passengers in a
In silico study effectively preserving two types of 120-seat plane.

social distancing: keeping the  If passengers can sit in the aisle seat,
passengers seated far enough away this increases to 30 passengers socially
Canada (est)
from each other and providing a safe distanced 3.3ft+. Sitting in the aisle
Jun 2020 (est) distance between seat assignments should include strategies to limit
and the aisle. They use an airbus A320 movement / possible exposure of
with 20 row, single aisle and three people moving around the plane.
seats on each side.
 Middle seat blocking policy lead to less
The MIP model ran a number of multiple people within 3.3.ft compared
scenarios: to the leave the aisle seat open policy.
 Middle seat empty  The more people on the plane, the

more people were seated close to each
 Social distance of 3.3 ft when
other and thus considered to be in
seated
increasingly higher risk situations with
 Aisle seat empty 1, 2 or 3+ people within 3.3.ft. See
 Hybrid figures for illustration.
Boarding to disembarkation (n=1)
Namilae (2021) An infection spread model was  Simulation results for secondary
47 developed using pedestrian infection by passenger status during
dynamics to model the movement the London flight indicate that the
preprint of passengers during boarding and boarding/deplaning processes
new deplaning and the passenger contribute more to infection risk than
trajectories and seating inflight movement does (4.4 vs 0.7).
arrangements. This model
 Using the data from the Singapore
Predictive model accounted for varying infection
flight as an example, the simulation
dose by distance to an infective
demonstrated that if everyone had
person and then included a
US (est) used FFP2 or N95 masks for the entire
standard exponential dose-
duration of the flight, there would be
Jun 2021 (est) response relationship for infection
2.3 secondary infections compared to
risk. The model was then calibrated
55 with no mask usage.
against a different super spreading
event and modified to account for  Over 50 simulations revealed that the
public health measures such as type of mask impacted secondary
mask wearing. infections. With the middle seat vacant,
the mean secondary infections were
Data from three flights was to
29.75 with no masks, 5.72 with cloth
inform the model. Specifically, they
masks, and 0.99 with N95/FFP2. This
used: 1) London to Hanoi on Mar 1,
increased by all mask types when the
2020, 201 passengers with 1 index
middle seat was not vacant (55.03 no

passenger resulting in 13 masks, 10.46 cloth masks, and 2.32

secondary infections; 2) Singapore N95/FFP2 masks).
to China on Jan 24, 2020, 321
 Overall, N95/FFP2 and cloth mask
passengers with 2 index cases and
usage would have reduced infections
12-14 secondary infections; 3)
by 95-100% and 40-80%, respectively.
Japan to Israel on Feb 20, 2020, 9
passengers with no secondary
infections.
Aerosol studies in an airplane (n=7)
Talaat (2021) 58 Studies in-flight aerosol transmission  Particles take 2–3 min to deposit or
and surface contamination using a leave the system as air in the cabin is
computational model of a cabin zone rapidly renewed.
Simulation of a Boeing 737. The investigation
 Aerosol in the 1 μm–20 μm size range is
experiment aims to understand the effect of
concentrated within one row of the
reducing passenger capacity (from 60
index patient, and virtually, no particles
to 40) and to compare to alternative
US (est) make it past two rows from the index
intervention measures such as using
patient. Larger particles such as 50 μm
Feb 2021 (est) sneeze shields (sneeze guards)
particles are only present in the row of
between passengers on a full capacity
the index patient.
flight. The investigation considers a
wide range of particle sizes (1–50 μm).  A relatively small fraction (21–26%) of
exhaled particles are directly removed
This study does not take into account
by the ventilation system. The majority
more than one infection on board,
of the particles deposit on surfaces in
human behaviour e.g. talking, eating,
the cabin, with more 1 μm particles
drinking, adherence to mask wearing,
depositing on the walls than on the
or moving down the aisles.
ground (10–14% vs 3%–6%).
 The most contaminated surfaces in the

full capacity model (60 passengers)
with no sneeze guards are the
passengers (including the index
patient) at 31% deposition fraction
followed by the seats at 27%. In the
reduced capacity model with no sneeze
guards and the full capacity model with
sneeze guards, total deposition on
passengers is reduced to 21% and 15%,
respectively.

 The total inhalable fraction is the lowest

in the full capacity model with sneeze
guards (0.5%) followed by the reduced
passenger capacity model without
sneeze guards (0.7%) and then the full
capacity model without sneeze guards
(1.7%). However, reduction in
passenger capacity and use of sneeze
guards eliminates the direct
transmission of 50 μm particles.
Although these particles deliver a much
smaller inhalable fraction compared to
1 μm particles, they contain
substantially more virions than 1 μm
particles due to their volume.
Kinahan (2021) 59 Aerosol dispersion and deposition in  The maximum exposure, 0.0947-
two wide-body aircraft (Boeing 767- 0.4614%, occurs in a seat next to a
300 and Boeing 777-200 at 30,000 ft) source, with the next highest risk of
Simulation was measured using fluorescent and inhalation typically occurring in the
experiment DNA-tagged microspheres. seats in front and behind the simulated
Experimental data included over 300 infected passenger. This maximum
releases from a simulated SARS-CoV- exposure risk equates to a minimum
US (est)
2-infected passenger in seats while in- reduction of 99.54% of 1 µm aerosols
Jan 2021 (est) flight. The tests were designed to from the index source to the breathing
measure the aerosol concentration zone of a typical passenger seated
within passenger breathing zones in directly next to the source.
neighboring seats and rows from the
 Less than 0.03% of tracer particles
simulated infected passenger. The
settle out on solid surfaces during
breathing releases included a mix of
testing, with the highest concentration
tests with the mannequin not wearing
on the surfaces closest to each release
a mask and tests with a mask.
location. Notably horizontal surfaces,
This study does not take into account such as arm rests were typically higher
more than one infection on board, or than vertical surfaces such as seatbacks
human behaviour (e.g., talking, eating, and inflight entertainment (IFE)
drinking, or adherence to mask systems.
wearing).
The average reduction with a mask in total
particles counted was 15.6%.

Rivero-Rios (2021) 44 Particulate matter (PM) concentrations  In‐flight particle concentration in the air
were measured in a variety of indoor in aircraft was lower than that of
spaces including 19 flights, retail/grocery stores, restaurants, office
Biological retail/grocery stores, restaurants, spaces, homes, and other transport
monitoring study office spaces, homes, and other tested.
transport (private cars, buses, trains).
 Particles with diameters smaller than 1
Flights were chosen to cover a range
US µm dominate the total particle number
of flight durations/destinations and
concentrations (because they are the
July 2020 aircraft models and including the
most difficult to remove by filtration).
following stages of air travel: Terminal
(departure), Boarding, Taxiing (out),  PM concentrations exhibited a V‐shape
Climbing, Cruising, Descending, pattern, with high levels at boarding
Taxiing (in), Disembarkation, and and a continued decrease and stable
Terminal (arrival). minimum concentration during
cruising. Slight increases in particle
mass concentration during food service
were observed. When the plane began
descending, particle concentrations
started increasing and an abrupt
increase was typically observed once
the cabin door was opened and the
disembarkation process began.
 Air exchange rates in the cabin are

rapid during flight, reducing the
number of particles in the cabin
significantly. Ambient air at altitude
contains fewer particles than air at the
surface, contributing to low cruising
particle number and mass
concentrations and also explains the
decrease and increase observed during
climbing and descending.
Kotb (2020) 45 In this computational fluid dynamic  The airflow of coughing and sneezing
(CFD) modeling simulation to examine droplets produced from the moving
what happens to respiratory droplets passengers could reach seated
In silico study when expelled by a sneeze or cough passengers several rows from the
by a person moving around an source compared to when standing
airplane cabin.
Egypt (est)

Sep 2020 (est) still. Cough distance 1.1m, sneeze went

further when standing still.
 Comparing the droplets spread range

resulting from the moving passenger
and stand-still one, the quicker the
passenger moves, the further the
droplets spread.
 Figures illustrate coughing/sneezing

during standing and in motion in an
economy class airplane cabin.
Silcott (2020) 46 The simulations used 767-300 and  High air exchange rates 1.8 x 108 on
777-200 aircrafts/models to study aircraft. Cumulative particle exposure
Unpublished
aerosol penetrations by an infected was 10x less on the airplane compared
COVID-19 passenger into the area to a residential house.
Simulation around them. 300 replications were
 Particles were in the cabin less than 6
experiment conducted including terminal loading
minutes (vs. 1.5h in a house). Air
and unloading. Inflight simulations
particulate removal was 15x faster than
conducted in the hanger and at 35
in a house and 5x faster than in a
US 000ft.
modern hospital isolation room.
Aug 2020 This study does not take into account
 Surgical masks were used in
human behaviour e.g. talking, eating,
simulations, there was a >90%
drinking, adherence to mask wearing
reduction in droplets released during
or other modes of transmission e.g.
the cough simulation compared to no
fomite.
mask.
 Sharing a row with a COVID-19 case is

the highest risk, the row behind and in
front are the next highest risk. There
was little practical difference in risk
between seats. See figures in paper.
 The individual air nozzle did not make a

difference to the risk.
 During embarking and disembarking,

keeping the air circulating, loading in
small groups may reduce risk. There
was low risk of jet wave exposure from

an infected person already sitting on

the plane.
Yan (2020) 71 This study developed a computational  The cough flow was found to have a
model to mimic a Boeing 737 long and effective impact on
economy section with three rows and contaminants transport, up to 4 s (or 8x
Simulation 9 manikins. longer than the cough).
experiment
 A wide range of sizes of droplets was
dispersed in the direction of the cough
Australia (est) due to the strong jet-effects of
coughing compared to what occurs
Aug 2020 (est)
with ventilated flow. (see figures in
paper).
Yang (2018) 69 Using computational fluid dynamics,  The travel distance of cough particles
this study investigated the effect of was heavily influenced by the direction
cough-jet on local airflow and and type of cough. The aisle seat
In silico study containment transport in a typical person coughing resulted in longer
airplane cabin. The particle dispersion particle travel distance than the middle
from a cough in a three-seat airplane and window seat. The middle seat was
Australia (est)
row was simulated. considered the most at risk of exposure
Dec 2017 (est) seat.
Reviews (n=1)
Jayaweera (2020) 85 Literature Review on aerodynamics of  They describe the flow of air in the
SARS-CoV-2 in droplets and aerosols cabin and reports a complete air
– in an Airplane Cabin (see Appendix exchange within 2-3 minutes, which
Literature review 1). The section of the review that should be good for quickly dissipating
focuses on airplane cabins. virus-laden droplets. They also indicate
the air is passed through a HEPA filter,
Sri Lanka (est)
which can remove particles >0.3 µm.
Jun 2020 (est) Cough-jet trajectories with no mask,
surgical mask and N95 mask are
described in the paper.
Est= Country of study based on author affiliations and date of study based on publication date.

Appendix 1
NPI table from Marcus (2020) 34 highlights the interventions that can be used together to help minimize the
risk of SARS-CoV-2 transmission when flying.

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AR07867
TAB 55
AR07868

FEDERAL COURT
BETWEEN:
NABIL BEN NAOUM
Demandeur
et
Défendeur

AND BETWEEN:
Demandeur
et
Défendeur

AND BETWEEN:
AND AEDAN MACDONALD
Applicants
and
Respondent
JML TRANSCRIPTION
AR07869
2

AND BETWEEN:
Applicants
and
Respondent
_________________________________________________________________
CROSS-EXAMINATION OF DR. PETER McCULLOUGH

May 11, 2022
_________________________________________________________________
Sharlene Telles-Langdon For the Respondent

Keith Wilson For Dr. McCullough
JML TRANSCRIPTION
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3
INDEX
PAGE
Exhibits ................................................... 4
Undertakings ............................................... 5
DR. PETER McCULLOUGH

Cross-Examination by Ms. Telles-Langdon .............. 6
Redirect Examination by Mr. Wilson .................... 50
JML TRANSCRIPTION
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4
EXHIBITS
PAGE
1. Capture of screenshot of The America Out Loud Story for
Identification ......................................... 18
2. The article Myocarditis with Covid-19 mRNA Vaccines by
Bozkurt et al, published in Circulation on August 10,
2021 ................................................... 32
3. Article from Morbidity and Mortality Weekly Report on
April 1st of 2022, titled Cardiac complications After
SARS CoV 2 Infection and mRNA Covid-19 Vaccination
PCORnet United States, January 2021 to January 2022 ... 37
4. Notice of withdrawal from Elsevier for the article
entitled “A Report on Myocarditis Adverse Events”...... 41
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5
UNDERTAKINGS
PAGE
1. Ask that Dr. McCullough after this cross-examination
take his time to read this story and the words that
are on the website and confirm that they are the same... 18
2. Mr. Wilson confirms that the comparisons of the
webpages will be done immediately after the cross-
examination is completed................................ 20
JML TRANSCRIPTION
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6
1 MAY 11, 2022
2 DISCOVERY COMMENCED
4 DR. PETER McCULLOUGH, affirmed, testified:
5 COURT REPORTER: Can you please just state and then
6 spell your name for the record?
7 DR. McCULLOUGH: Peter Andrew McCullough, P-e-t-e-
8 r, middle name Andrew, A-n-d-r-e-w, last name M-c-C-u-
9 l-l-o-u-g-h.
10 COURT REPORTER: Perfect. Thank you. Counsel, we’re on
11 the record whenever you’re ready.
12
13 CROSS-EXAMINATON BY MS. TELLES-LANGDON
14
15 1 MS. TELLES-LANGDON: Thank you, and good afternoon, Dr.
16 McCullough. Thank you for joining us this afternoon.
17 A. Thank you.
18 2 Q. To begin with, Dr. McCullough, I would just like to

19 confirm that you are the Peter McCullough of the City
20 of Dallas in the State of Texas in the United States
21 who swore an affidavit dated March 11, 2022 in the
22 Brian Peckford v. Canada proceedings in the Federal
23 Court of Canada?
25 3 Q. I know that was a mouthful but that was the
26 description of your affidavit. Thank you. This
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7
1 afternoon I am going to have some questions for you
2 based on the affidavit that you swore in this matter
3 on March 11th, okay?
4 A. Yes.
5 4 Q. First I have a few housekeeping matters. When I am
6 referring to your affidavit during this cross... well,
7 I will be referring to your affidavit during this
8 cross-examination, so do you have it there available

9 and ready for your reference?
10 A. Yes.
11 5 Q. And, Dr. McCullough, where are you physically located
12 right now?
13 A. I’m in my home.
14 6 Q. So, in a - in a room in your home in, I guess
15 presumably in Dallas, Texas?
16 A. Yes.
17 7 Q. Is there anyone else in the room with you, Dr.
18 McCullough?
19 A. No.
20 8 Q. Can you please also confirm that when you’re in breaks
21 in this cross-examination you’ll not communicate with
22 any party outside of this virtual meeting on this
23 platform? Or take instructions from anyone other than
24 properly framed objections from your legal counsel?
25 A. Yes.
26 9 Q. Would you please confirm for me that during the cross-
27 examination you’ll be not - you will not be viewing or
JML TRANSCRIPTION
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8
1 referring to any notes or documents other than -either
2 on paper or electronically - other than your affidavit
3 or as requested documents that are presented to you
4 during the cross-examination?
5 A. Yes.
6 10 Q. Can you confirm that you have no other notes or
7 documents beside you - besides your affidavit either
8 on your desk physically or electronically?

9 A. Yes.
10 11 Q. And for the sake of clarity, Dr. McCullough, whenever
11 I refer you to a page number in your affidavit, it
12 will be the page number that is in the upper right
13 hand corner of your affidavit, okay?
14 A. Yes.
15 12 Q. At any point you’re not with me on the same page,
16 literally, please don’t hesitate to ask and seek
17 clarification. As a final housekeeping matter, Dr.
18 McCullough, would you please tell me what documents
19 you reviewed in preparation for this cross-
20 examination.
21 A. I reviewed my report, my af...my - what you would call
22 my affidavit, and the report of Dr. Liu.
23 13 Q. Okay, thank you. Moving on to your qualifications,
24 Dr. McCullough, at paragraph 2 of your affidavit,
25 which is on page 2, you have indicated that you are a
26 practicing cardiologist and an internal medicine
27 specialist. Prior to the pandemic, Dr. McCullough,
JML TRANSCRIPTION
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9
1 would it be fair to say that you were particularly
2 expertise with respect to - or you had a particular
3 area of expertise with respect to cardiovenal effects
4 or the connection with the heart and kidney disease?
5 A. Yes.
6 14 Q. I gather from reviewing the publications in your CV
7 that renal disease is another name for kidney disease?
8 A. Yes.
9 15 Q. And just - this is partly for my clarification,
10 nephrology, as I understand it, it’s the subspecialty
11 of internal medicine that focuses on kidney disease,
12 right?
13 A. Yes.
14 16 Q. And then I guess cardiology is a subspecialty of
15 internal medicine that focuses on heart disease,
16 correct?
17 A. Yes.
18 17 Q. But you’re not an immunologist, correct?
20 18 Q. In your CV, starting at page 14 of your affidavit, you
21 set out that you’re on a number of editorial boards.
22 Some of those boards, I guess such as the Journal of
23 Kidney Disease and Advances in Chronic Kidney Disease
24 would presumably relate to kidney disease, correct?
26 19 Q. And from the titles, some of the other editorial
27 boards are for journals that clearly relate to
JML TRANSCRIPTION
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10
1 cardiovascular disease, or cardiology, correct?
3 20 Q. Yeah. One of the journals that you’ve identified in
4 the list on page 14 of your CV is Circulation for
5 which you state you have been on the editorial board
6 since 2016, right?
7 A. That needs to be updated, and I have come off the
8 editorial board of Circulation, and it was Circulation

9 and Heart Failure, and as I generally recall I’ve come
10 off the board in the last few years.
11 21 Q. Okay. I noted - so then what if the corrections - the
12 date would be 2016 until when were you on the
13 editorial board for Circulation?
14 A. I’m so sorry, what page are you on? What PDF page are
15 you on?
16 22 Q. Page 14.
17 A. Okay.
18 23 Q. And it’s item number 11 in your editorial
19 responsibilities. Circulation, editorial board. Your
20 CV says 2016 to present.
21 A. And which exhibit of my report is that? A, B, C, or
22 D?
23 24 Q. That would Exhibit A.
24 A. Okay.
25 25 Q. Which is your CV.
26 A. Right. So, it’s Exhibit A and you’re on page 14 of...
27 26 Q. Page 14 of the - it’s the page 14 - I - of the PDF.
JML TRANSCRIPTION
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11
1 It’s the top - the number in the top right hand
2 corner.
3 A. Is 14...
4 26 Q. Is 14...
5 A. Okay.
6 27 Q. ...and then under the heading Editorial
7 Responsibilities. Item number 11 is Circulation,
8 editorial board, 2016 to present is what it states in

9 your CV.
10 A. Right. Yeah, I’m going - I’d have to check my files
11 on that, but as you can see I have numerous editorial
12 board responsibilities so I update my curriculum vitae
13 roughly every quarter and I have to go back and update
14 some of these. So, there are some end dates to these
15 that aren’t indicated, but as I’ve testified already
16 it’s been within the last few years.
17 28 Q. Did you have anything more precise than the last few
18 years as to when you came off the Circulation
19 editorial board?
20 A. No.
21 29 Q. Regardless, can you tell me, is Circulation a journal
22 that relates to cardiology or nephrology?
23 A. Cardiology.
24 30 Q. I - on page 16 of your affidavit it states that you
25 are a manuscript reviewer for Circulation since 1998.
26 Do you see that at page 16? It’s item number 40.
27 Circulation, 1998 to present. Are you still a
JML TRANSCRIPTION
AR07879
12
1 manuscript reviewer for Circulation?
2 A. Yes.
3 31 Q. And I see from your published abstracts and peer
4 reviewed published manuscripts that you have a - you,
5 yourself, have in fact repeatedly published in the
6 journal Circulation, correct?
7 A. Yes.
8 32 Q. But in reviewing your CV, in all of your clinical

9 trial and study responsibilities, your grant awards,
10 your published abstracts, and your peer reviewed
11 manuscript - published manuscripts, prior to Covid-19
12 none of your body of work specifically relates to
13 myocarditis or viral induced myocarditis, correct?
15 33 Q. At paragraph 8 of your affidavit, which is page 4, you
16 state that in 2021 you started publishing a weekly
17 contribution on America Out Loud called the McCullough
18 Report. If you give me a minute I’m going to share my
19 screen, Dr. McCullough, and hopefully show you what is
20 the webpage for America Out Loud. Okay, Dr.
21 McCullough, what I am showing you is, I hope, is the
22 webpage for the America Out Loud website with the URL
23 www.americaoutloud.com. Are you seeing that on your
24 screen, Dr. McCullough?
25 A. Yes.
26 34 Q. I’m going to use - navigate on that website to the Who
27 We Are subpage. Do you see that occur, Dr.
JML TRANSCRIPTION
AR07880
13
1 McCullough?
2 A. Yes.
3 35 Q. Would you please - so, this is what we’re looking at
4 is The America Out Loud Story which was under the Who
5 We Are tab. Dr. McCullough, would you please read the
6 first paragraph of that story out loud, starting with
7 “The America Out Loud Story”?
8 A. And - and what’s the purpose of me reading that?

9 36 Q. I’m asking that you read it into the record, please,
10 Mr... Dr. McCullough.
11 A. I - I decline that. If you want to read information
12 into the record, please - please feel free to do so.
13 37 Q. Dr. McCullough, you have indicated that you publish a
14 weekly report called The McCullough Report for America
15 Out Loud, correct?
16 A. Yes.
17 38 Q. I’m just asking that you acknowledge at least that
18 this is the story of the - or this is the Who We Are
19 page on the America Out Loud Story. That is the
20 webpage from the America Out Loud Story? What’s
21 your...
22 MR. WILSON: Sharlene, I’m...I’m...
23 MS. TELLES-LANGDON: Yes.
24 MR. WILSON ...Keith Wilson here. I have a
25 concern. I’m unclear. It seems like two things are
26 being conflated, and perhaps you could assist in being
27 precise. One is your simultaneously asking about
JML TRANSCRIPTION
AR07881
14
1 texts that appears on the Who We Are subpage of a
2 website in conjunction with a question about Dr.
3 McCullough participating in some publishing with
4 respect to the website. So, which is it?
5 MS. TELLES-LANGDON: Well, Dr. McCullough has stated at page
6 - at paragraph 8 of his affidavit that starting in
7 2021 he published a weekly contribution on America Out
8 Loud called The McCullough Report. I am just

9 establishing what that site is for the record.
10 MR. WILSON: Thank you. I thought you were
11 suggesting that the words you were asking him to read
12 were words that you believe he published.
13 MS. TELLES-LANGDON: I am not asking him to read words that
14 I believe he published. I was asking him to read
15 words that belong to The America...that are from The
16 America Out Loud Story page where Dr. McCullough is a
17 regular contributor.
18 MR. WILSON: That’s fair.
19 39 MS. TELLES-LANGDON: Well, perhaps we’ll do this. Dr.
20 McCullough, I’m going to pull down, please watch the
21 screen, I’m going to pull down on the screen the tabs
22 again, go to Shows. Are you seeing that?
23 A. Yes.
24 40 Q. We’re now on the Shows website, and you would agree,
25 Dr. McCullough, that there is a link to The McCullough
26 Report...
27 A. Yes.
JML TRANSCRIPTION
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15
1 41 Q. ...directly on this website? And having followed that
2 link, Dr. McCullough, would you agree that this link
3 takes the viewer to the collection of your weekly
4 contributions to the America Out Loud website?
5 A. Yes.
6 42 Q. I’m now going to return to the Who We Are tab of the
7 America Out Loud website. You’re still declining to
8 read anything into the record here, Dr. McCullough?

9 A. I’m declining because I - I didn’t write that or make
10 that contribution on the platform. I don’t control
11 the content of it and I’ve offered to you if you have
12 a desire to read it into the record, for you to read
13 it into the record yourself.
14 43 Q. That’s fine, Doctor...
15 MR. WILSON: And, Sharlene, just so I’m - I’m clear,
16 that would be my objection too. Dr. McCullough was
17 quicker at the switch. I mean having witnesses go to
18 websites and read things that other people may or may
19 not have written, in my view has - is firstly,
20 irrelevant; secondly, has no evidentiary value and is
21 verging on improper.
22 44 MS. TELLES-LANGDON: And, Keith, and would I would like...
23 Sorry, Mr. Wilson, and what I would like to do, Dr.
24 McCullough, is I’m going to... I had a paralegal
25 capture a screen download of the contents of The
26 America Out Loud Story, and I am going to stop
27 sharing my screen for a moment and navigate to that
JML TRANSCRIPTION
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16
1 screen capture document, if I can. Dr. McCullough,
2 can you see that document on the screen?
3 A. Yes.
4 45 Q. You agree or accept that that is a capture of what we
5 just looked at on the America Out Loud website?
6 A. Yeah, I can’t agree with that. It’s not dated and I -
7 I couldn’t verify what - what your paralegal did,
8 so...
9 46 Q. Well, I just, Dr. McCullough, showed you the website.
10 Should I pull them up side by side? Would you like to
11 take a moment to compare them line for line?
12 A. It’s your time, counsel. It could take a quite a long
13 time if you want me to do clerical work in - in
14 identifying line by line to multiple paragraphs, but
15 it’s your time. If you want to spend it that way,
16 feel free.
17 MS. TELLES-LANGDON: Mr. Wilson, I’m going to ask that this
18 get - be admitted as an exhibit for identification,
19 and I’m going to ask that Dr. McCullough after this
20 cross-examination take his time to read this story and
21 the words that are on the website and confirm that
22 they are the same, and then I will ask that this
23 document be entered as an exhibit.
24 MR. WILSON: Can you help me understand the
25 relevance of what a third party wrote on a website
26 that Dr. McCullough doesn’t control has to anything
27 here?
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1 MS. TELLES-LANGDON: It’s a reflection of a - of the - it
2 represents the publication to which he is a regular
3 contributor to the platform to which he chooses to be
4 a regular contributor.
5 MR. WILSON: Okay.
7 EXHIBIT 1: Capture of screenshot of The America Out Loud
8 Story for identification.

9
10 UNDERTAKING 1: Ask that Dr. McCullough after this cross-
11 examination take his time to read this story and the
12 words that are on the website and confirm that they
13 are the same.
14
15 MS. TELLES-LANGDON: Thank you. Madam Court Reporter, would
16 you please have that entered for now as exhibit for
17 identification, and Mr. Wilson, can you please confirm
18 that Dr. McCullough will undertake - that you will
19 undertake on Dr. McCullough’s behalf that he will
20 confirm the contents of this document are consistent
21 with the contents of the webpage, at which point we
22 will then enter it as an exhibit.
23 MR. WILSON: And do we know the date upon which the
24 - this was retrieved, was captured, the screen capture
25 occurred?
26 MS. TELLES-LANGDON: Yes, we do. It was captured yesterday.
27 MR. WILSON: Okay, and so that would be for the
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1 purposes of the record, May 10, 2022.
3 MR. WILSON: And can you confirm, counsel, that the
4 earlier image that you had was a live shot - a live
5 feed to the website as of May 11...
7 MR. WILSON: ...2022? Thank you.
8 MS. TELLES-LANGDON: I - I confirm that. I followed a link

9 to bring up the live website.
10 MR. WILSON: And the undertaking is to confirm that
11 the wording on the PDF document matches the wording
12 that we viewed on the website under the Who’s Who -
13 Who We Are subtab of this website, correct?
14 MS. TELLES-LANGDON: Under the America Out Loud, Who We Are
15 tab, yes, correct.
16 MR. WILSON: And, counsel, you’re clear, I take it,
17 in Dr. McCullough’s answer that he did not write this?
18 MS. TELLES-LANGDON: I am clear in Dr. McCullough’s answer
19 that he did not write this.
20 MR. WILSON: Thank you.
21 MS. TELLES-LANGDON: And, Mr. Wilson, may I have your
22 undertaking that you will do that immediately after
23 the cross in given that webpages of course can change.
24 MR. WILSON: Yes.
25 MS. TELLES-LANGDON: Thank you.
26
27 UNDERTAKING 2: Mr. Wilson confirms that the comparisons of
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1 the webpages will be done immediately after the cross-
2 examination is completed.
4 47 Q. Returning to your CV, Dr. McCullough, if I can stop
5 sharing the screen, under - at page 10 of your
6 affidavit under professional experience, you set out
7 various positions that you held with Baylor University
8 Medical Center from February 3, 2014 until February

9 25, 2021. I understand, Dr. McCullough, that Baylor
10 Medical University Center terminated your positions
11 with them because you promoted the use of therapies
12 seen as unproven for the Covid...for the treatment of
13 Covid-19 and because you questioned the efficacy of
14 the Covid-19 vaccines, is that correct, Dr.
15 McCullough?
16 A. No.
17 48 Q. Well, then, Dr. McCullough, how is it that your
18 termination with Baylor came about?
19 A. I wasn’t terminated from Baylor. I was never employed
20 by Baylor University Medical Center. I was employed
21 by the Health Texas Provider Network.
22 49 Q. All right, Dr. McCullough, I put it to you that Baylor
23 cut ties with you then because Baylor disagreed with
24 your continued promotion of the use of treatments,
25 including zinc hydroxychloroquine, erythromycin, and
26 ivermectin as Covid-19 treatments, correct?
27 A. No.
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1 50 Q. I understand you entered into a severance agreement
2 with Baylor that as a term...as - as part of the terms
3 of your severance with - of your relationship with
4 Baylor that you would not hold yourself out as being
5 affiliated with Baylor or its related institutions, is
6 that correct?
7 A. I was faced with a contract non-renewal, and I
8 negotiated a separation agreement that had terms with

9 it which are customary that I have obeyed with prior
10 employers when I’m moving from employer to employer.
11 So, not unlike this agreement as with others once I
12 stopped my employment with Health Texas Provider
13 Network, I abided by the terms of my separation
14 agreement and have not violated them.
15 51 Q. I understand, Dr. McCullough, that in September of
16 2021 the 191st District Court in Dallas, Texas, granted
17 Baylor a temporary restraining order against you to
18 stop what they alleged to be your continuing
19 mentioning of your positions with Baylor. Is that
20 correct?
21 A. That’s incorrect. The temporary restraining order
22 restrained me to the separation agreement with which I
23 was already compliant with.
24 52 Q. But it is correct that the District Court of Dallas
25 County, Texas, 191st District Court in Dallas County,
26 Texas, granted Baylor a temporary restraining order
27 against you?
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1 A. The restraining order was, according to my separation
2 agreement, so it fundamentally made mo change in - in
3 my professional activities.
4 53 Q. Is it correct, Dr. McCullough, that Baylor University
5 is suing you for violation of that separation
6 agreement?
8 54 Q. In June of 2021 in an interview with Reiner Fuellmich

9 in regard to the Covid-19 pandemic, you stated, and I
10 quote, “Were under the application of a form of
11 bioterrorism that’s worldwide that appears to have
12 many - been many years in the planning,” correct?
13 A. Correct.
14 55 Q. In that same interview did you also state the first
15 wave...I’m sorry, and I quote, “The first wave of the
16 bioterrorism is a respiratory virus that’s spread
17 across the world and affected relatively few people,
18 about 1% of the population, but generated great fear,”
19 correct?
20 A. Yeah, I - I haven’t reviewed that video in - in a long
21 time, but as I generally recall that - that is - is
22 correct.
23 56 Q. I could play that video for you, Dr. McCullough, if
24 you wish.
25 A. It’s your time.
26 57 Q. In that same interview did you state that, “That fear
27 was used very quickly and I think surprisingly to
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1 generate tremendous influence in human life,
2 lockdowns, all the things you know about, and every
3 single thing that was done in the public health
4 response to the pandemic made it worse”?
5 A. As I generally recall, that’s correct.
6 58 Q. In that same interview did you also state, “So, what
7 we have discovered is that the suppression of early
8 treatment was tightly linked to the development of a

9 vaccine, and the entire program, and this in a sense
10 bioterrorism phase 1 was rolled out, really was all
11 about keeping the population in fear and in isolation
12 and preparing them to accept the vaccine, which
13 appears to be phase 2 of a bioterrorism event.” Do
14 you agree that that would represent something that you
15 had said in that interview?
16 A. As I generally recall, that’s correct.
17 59 Q. In January 11th of 2022 you were interviewed by Anthony
18 Pompliano in which, among other things, you discussed
19 profits and sales of Covid-19 vaccines by Pfizer and
20 Moderna. In that interview you stated, “There seems
21 to be also a plan from the beginning to suppress early
22 treatment for Covid-19 in the developed nations,
23 including the United States, Canada, some South
24 American countries, Britain, the EU, South Africa, and
25 Australia, those of the - are the countries that had
26 been starved of early treatment and those markets, if
27 you will, have been prepped for mass vaccination.”
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1 Did you state that, Dr. McCullough?
2 A. Yeah, I can’t specifically recall that interview but
3 those statements are in line with my views at the
4 time.
5 60 Q. In that same interviews, I put it to you, that you
6 also stated that you are, “Calling for the vaccine
7 mandates to be dropped,” and that you, “Think these
8 products ought to be paused completely,” and

9 “...pulled off the market.” Does that sound like
10 something that you would have said in that interview?
11 A. I can’t specifically recall that interview, but those
12 statements are in line with my views at the time.
13 61 Q. Just give me a moment. Dr. McCullough, I’d like to go
14 to your report now. I’m just trying to find it on my
15 screen. There we go. At paragraph 4 of your report,
16 which is page 189 of your affidavit. In that
17 paragraph you have referenced two articles. The
18 second article is a 2020 article from the Morbidity
19 and Mortality Weekly Report published by the United
20 States Centres for Disease Control and Prevention. I
21 take it you would generally consider the CDC to be a
22 credible source of information, correct?
23 A. Yeah, I’m so sorry, I’m in my report in paragraph 4,
24 paragraph number 4, starts with “I’ve led clinical
25 education and research,” so are you on a different
26 paragraph or...
27 62 Q. Paragraph number 4 of your report, which is at page
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1 189 of your affidavit. It’s page 189 of the PDF. I’m
2 not in the affidavit, we’re in Exhibit B to your
3 affidavit now, Dr. McCullough.
4 A. Okay. And - and you’re on what PDF page?
5 63 Q. 189.
6 A. Okay.
7 64 Q. I believe the PDF pages and the pages in the top right
8 corner of your affidavit should match. Can you

9 confirm that at your end so I don’t mislead you on a
10 PDF pages?
11 MR. WILSON: They do not.
12 A. I’m on - I’m on Exhibit B...
13 65 Q. Oh...
14 A. ...and it starts at 184 at the top, but Exhibit B only
15 has 20 pages.
16 66 Q. That’s fine. Okay, so it is Exhibit...I’m sorry, I’m
17 - for some reason on my PDF the page numbers on the
18 affidavit and the PDF page numbers match, so I can
19 only give you the page number in the top right hand
20 corner of the affidavit.
21 A. Okay.
22 67 Q. So, the page number is 189 in the top right hand
23 corner of the affidavit, and the paragraph number is
24 paragraph 4.
25 A. Okay.
26 68 Q. And in footnote 3 to paragraph 4 you have cited -
27 you’ve referenced two - two different articles, one
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1 that’s a 2012 article, and then the second one, see
2 also Morbidity and Mortality Weekly Report, and it’s
3 an article about allergic reactions after the first
4 dose of Pfizer. My question, Dr. McCullough, is I
5 take it that you generally consider the CDC could be a
6 credible source of information given that you’re
7 citing to CDC.
8 A. No, I disagree with that.

9 69 Q. Well, Dr. McCullough, I note that you’ve also relied
10 on information from the CDC at paragraphs 3 and
11 footnote 1, paragraph 6, 21, and 25 of your report.
12 Are you saying that you’re relying on sources that in
13 your report that you don’t consider to be credible?
14 A. Oh, I disagree with your statement, and here’s the
15 reason why. The CDC makes statements and has made
16 statements and put information on the website that may
17 or may not be credible. It depends on each specific
18 content. The MMWR is the non-externally peer reviewed
19 journal of the CDC, and while I may not agree with
20 authors conclusions or statements, I am relying on the
21 MMWR for the data presented in those publications.
22 70 Q. Okay, so you do rely on the MMWR for the data that
23 they publish.
25 71 Q. Going to the conclusion at paragraph 30 of your
26 affidavit... All right, so, Dr. McCullough, your
27 conclusion in your affidavit, “In my professional
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1 opinion, younger males without comorbidities should
2 not receive the Covid-19 vaccine because the benefit
3 of the Covid vaccine for young males does not outweigh
4 the risks of permanent heart injury to young males
5 from the Covid vaccine.” In reaching your opinion,
6 Dr. McCullough, did you consider the article
7 Myocarditis with Covid-19 mRNA Vaccines by Bozkurt et
8 al, published in Circulation on August 10, 2021?

9 A. No, I’d have review that - that paper to - to answer
10 that question.
11 72 Q. About whether or not you considered it? I’m going to
12 share my screen, Dr. McCullough, again, and show you
13 that paper. Perhaps that’ll... Are you seeing that
14 paper, Dr. McCullough?
15 A. Yes, I am.
16 73 Q. Did you review this paper in preparing your report?
17 A. Now, I can’t recall if I’ve reviewed it in preparing
18 my report, but I have reviewed it generally in my
19 review of the literature on this topic. There’s -
20 this paper and over 200 papers in the literature on
21 myocarditis caused by the Covid-19 vaccines.
22 74 Q. Would you like to take a minute, Dr. McCullough, to
23 read the abstract for yourself to refamiliarize
24 yourself with this paper before I ask you any further
25 questions?
26 A. Okay.
27 75 Q. You’ve had a chance to read the abstract?
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1 A. Yes.
2 76 Q. I’m just going to scroll down to the second page just
3 before we get into any questions on the content of
4 this affidavit. I note that on the second page of
5 this article, and then you can see it’s in the margin,
6 on other pages as well, that the words “State of the
7 Art” are written vertically in the margin in a blue
8 tab. I’m wondering is as I guess a former member of

9 the editorial board for Circulation, Dr. McCullough,
10 could you tell me what this State of the Art
11 designation indicates?
12 A. It’s a category.
13 77 Q. Okay. The first paragraph of this affidavit, Dr.
14 McCullough, states - actually, category of what, Dr.
15 McCullough?
16 A. Of articles.
17 78 Q. Does it indicate a particular level of importance?
18 A. No.
19 79 Q. Paragraph 1 of this report states, “There is now
20 increasing evidence for myocarditis and
21 myopericarditis as rare complications of coronaviral
22 disease 2019 for the mRNA vaccinations, especially in
23 young adults and adult males. Here we provide further
24 details about this phenomenon and its potentially
25 underlying mechanisms. We also discuss the balance,
26 the risk of myocarditis vaccination versus cardiac and
27 other risks from Covid-19 viral infections.” Do you
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1 agree, Dr. McCullough, that this paper is directly
2 relevant to the subject of your report?
3 A. You know, I think it could be helpful. I wouldn’t
4 characterize it as directly relevant only because of
5 its bias. Its senior author is a well known vaccine
6 proponent who him and his institution have a direct
7 conflict of interest in promoting mass vaccination,
8 and it’s well recognized that Dr. Hotez is promoting

9 mass vaccination in the major media on a frequent
10 basis.
11 80 Q. The author of this - the lead author is Biykem, B-i-
12 y-k-e-m, Bose...I would’ve read it Bozkurt, B-o-z-k-u-
13 r-t. Is that the same person to whom you just
14 referenced?
15 A. No, I’m referencing the senior author Peter Hotez.
16 81 Q. I see. The last - the third author listed. I am
17 scrolling through to the - I’d like to go to the
18 assessing the risk portion of this document, and under
19 the Assessing the Risk heading of this document at
20 page 480 of the - on the publication, which is the
21 tenth page of the PDF - the authors conclude, “Despite
22 these rare cases of myocarditis, the benefit/risk
23 assessment for Covid-19 vaccination shows a favourable
24 balance for all age and sex groups.” And there’s a
25 reference at figure 2 and 3 in the document. “Given
26 the known potential risk of complications with Covid-
27 19 infection, including hospitalization and death even
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1 in younger adults, mortality remains .1 to 1 per
2 100,000 per person for 12 to 29 years of age. The
3 benefit decision remains overwhelmingly favourable for
4 vaccination, therefore Covid-19 vaccination is
5 currently recommended for everyone greater than 12
6 years of age. Covid-19 vaccination not only prevents
7 Covid-19 related hospitalization and death, but also
8 Covid-19 related complications such as myocarditis,

9 multisystem inflammatory syndrome, and a post-acute
10 sequelae of SARS CoV 2 infection or Long Covid.” Do
11 you agree, Dr. McCullough, that that risk assessment
12 is directly relevant to the opinion that you provided?
13 A. It’s irrelevant, and I strongly disagree with that. I
14 think it’s completely incorrect.
15 82 Q. Do you agree, Dr. McCullough that this would’ve been a
16 peer reviewed paper to be published in Circulation?
17 A. Yes.
18 83 Q. Dr. McCullough, you did not reference this in your
19 report, correct?
21 84 Q. Those are all the questions I have on this document.
22 I would like to mark it as Exhibit 2 to this cross-
23 examination, please.
24 MR. WILSON: No objection.
25
26 EXHIBIT 2: The article Myocarditis with Covid-19 mRNA
27 Vaccines by Bozkurt et al, published in Circulation on
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1 August 10, 2021.
3 MR. WILSON: Ms. Telles-Langdon, is it possible for
4 you to have one of the lawyers or paralegal on your
5 team email to my team the PDF document that you wanted
6 us to do the comparison on so that we can get that to
7 teed up for when the questioning concludes?
8 MS. TELLES-LANGDON: Yes, if we just off the record for a

9 moment for that discussion or...
10 MR. WILSON: Sure.
11
12 OFF RECORD
13
14 85 MS. TELLES-LANGDON: Dr. McCullough, as a cardiologist and
15 as a professional, would you agree that it’s your
16 responsibility to evaluate emerging evidence?
17 A. You know, in a relevant activity, yes.
18 86 Q. Would it - specific to your report would it be - would
19 you agree that it would be your responsibility to
20 evaluate emerging cardiology evidence and myocarditis
21 evidence with respect to the vaccinations and Covid-
22 19?
23 A. Yes, I provided, you know, they were published within
24 the time frame of - of producing the report.
25 87 Q. Would you also agree that it is important to keep an
26 open mind, Dr. McCullough?
27 A. Yes.
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1 88 Q. Even to the point of changing your opinion on the best
2 recommended course of action for your patients if new
3 or more comprehensive evidence supports a different
4 course of action?
5 A. If it’s my interpretation and my recommendation, then
6 yes, I’m always open because of the - the data come in
7 and continue to shape and form opinions.
8 89 Q. Give me just a moment. I’m going to share my screen

9 again, Dr. McCullough. What I’m showing to you is a
10 Block et al article - I’ll make it a little smaller so
11 it’s all on the screen - published in the Morbility
12 (sic) - Morbidity and Mortality Weekly Report, the MMR
13 (sic) weekly report. This was published on April 1st
14 of 2022, titled Cardiac Complications After SARS CoV
15 2 Infection and mRNA Covid-19 Vaccination - PCORnet
16 United States, January 2021 to January 2022. Do you
17 see that clearly on that - on the screen, Dr.
18 McCullough?
19 A. Yes.
20 90 Q. You indicated prior - at the outset of this cross-
21 examination that you reviewed Dr. Peter Liu’s
22 affidavit. Dr. Peter Liu refers to this article. Did
23 you also review this article as a result of reviewing
24 Dr. Liu’s affidavit?
25 A. No, I didn’t.
26 91 Q. Well, then if you’d like to take a moment, Dr.
27 McCullough, read the first paragraph of this article
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1 to familiarize yourself with its contents and subject.
2 A. Okay.
3 92 Q. So, Dr. McCullough, just for the record this is a
4 paper that compares the relative risk of cardiac
5 complications, particularly myocarditis and
6 pericarditis associated with Covid-19 infection, and
7 it comments about multisystem inflammatory syndrome is
8 also a rare complication of SARS CoV 2, but ultimately

9 the article is specifically and largely looking at the
10 relative risks of myocarditis complications from Covid
11 infection versus the rel... versus the risks of
12 infection - or sorry, myocarditis from Covid
13 vaccination. And I’m going to scroll down, Doctor...
14 Well, first of all, Dr. McCullough, would you agree...
15 I realize that you could not have considered this
16 report, or this article in your report because it
17 postdates your report, but would you agree, Dr.
18 McCullough, that this article is directly relevant to
19 the opinion that you provided to the court in the
20 conclusion of your report - sorry, to the court in a
21 conclusion of your report?
22 A. No, it wouldn’t be relevant in terms of - in terms of
23 agreement because this paper appears to be un...
24 invalid for many reasons.
25 93 Q. The subject matter, though, is directly relevant to
26 the same subject matter on which you opine in your
27 report, correct?
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1 A. Partially.
2 94 Q. I’m going to scroll down to the summary of this report
3 on page 6, and I’m going to read it into the record.
4 “Summary: What is already known about this topic?
5 Studies have shown...” Sorry.
6 “Studies have found an increased risk for cardiac
7 complications after SARS CoV 2 infection and mRNA
8 Covid-19 vaccination, but few have compared the risk.

9 What is added by the report? Data from 40 health care
10 systems participating in a large network found that
11 the risk for cardiac complications was significantly
12 higher after SARS CoV 2 infection than after mRNA
13 Covid-19 vaccination for both males and females in all
14 age groups. What is the implications for public
15 health practice? These findings support continued use
16 of recommended mRNA Covid-19 vaccines among all
17 eligible persons aged five or older.”
18 You’d obviously accept, Dr. McCullough, that I’ve just
19 accurately - accurately read that summary into the
20 record?
21 A. Yeah, I disagree with that, the conclusions. You’ve
22 read it into the record but I - I disagree with those
23 conclusions.
24 95 Q. Fine. I would like to have this document marked as
25 Exhibit 3, please.
26 MR. WILSON: What was the exhibit number again?
27 Three?
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1 MS. TELLES-LANGDON: Three.
2 MR. WILSON: Thank you. No objection.
4 EXHIBIT 3: Article from Morbidity and Mortality Weekly
5 Report on April 1st of 2022, titled Cardiac
6 complications After SARS CoV 2 Infection and mRNS
7 Covid-19 Vaccination - PCORnet United States, January
8 2021 to January 2022.

9
10 96 MS. TELLES-LANGDON: Turning to your affidavit, Dr.
11 McCullough, your report at paragraph 9 of your report,
12 Exhibit B to your affidavit, do you have it Dr.
13 McCullough?
14 A. Yes.
15 97 Q. At paragraph 9 of your report, Dr. McCullough, you
16 reference here what you have described as your own
17 peer reviewed publish research titled A Report on
18 Myocarditis Adverse Events in the U.S. Vaccine Adverse
19 Event Reporting Systems, Theirs, in Association with
20 Covid-19 Injectable Biological Products, which you
21 cite at footnote 9. You do not state in either
22 footnote 9 or at paragraph 9 that this paper was
23 withdrawn by the publisher, correct?
24 A. I don’t state it because it was fully published and
25 accepted after peer review and the publisher in
26 violation of the contract in committing tortious
27 interference when publishing now is under a letter of
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1 intent for a suit for violation of the publication
2 agreement, so in my view it is a valid publication.
3 The reasons for retraction are not acceptable and -
4 and the publisher’s indicated that they have retracted
5 it because they didn’t sufficiently invite it to begin
6 with, although allowed full peer reviewed process. It
7 was not retracted for any issues of scientific
8 integrity or invalidity.
9 98 Q. So, I’m just going to click on the - I’m going to
10 share my - yes, I’m going to share my screen first
11 again so you can see what I’m doing, Dr. McCullough.
12 And so your counsel can also see what I’m doing. In
13 your report, Dr. McCullough, I am going to click on
14 the link that you have included as the citation for
15 your report, and I hope the share screen follows the
16 link. So, you would agree, Dr. McCullough, that when
17 I clicked on the link beside the citation in footnote
18 9 in your report - in paragraph 9 of your report - the
19 link... Well, the screen did not follow. Well, now,
20 what... Okay, so I did click on the link in footnote
21 9 to paragraph 9, and this is what came up. Dr.
22 McCullough, are you surprised at what came up is a
23 notice from Elsevier that says “Withdrawn” in front of
24 - in capital letters in front of your name, “A Report
25 on Myocarditis Adverse Events”?
26 A. No, I have explained the illegal nature of their
27 withdrawal. This was fully published and available to
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1 the public for weeks before this illegal action.
2 99 Q. So, this notice says, “The article has been withdrawn
3 at the request of the authors and/or editor.” I take
4 it, Dr. McCullough, that it was not withdrawn at the
5 request of either of the authors, yourself or Dr. Rose
6 given your comments here today.
7 A. Neither Dr. Rose nor myself requested the withdrawal.
8 We were asked by Elsevier multiple times to request

9 that withdrawal and we declined.
10 100 Q. All right. I’m going to stop sharing this, and I’m
11 going to tell you what... You see here that there in
12 on the screen first before I stop sharing, there is a
13 PDF version available of this withdrawal notice. If
14 you’re looking at the screen, Dr. McCullough, I’m
15 scrolling through that PDF version of the withdrawal
16 notice which is a three page document. I’m going to
17 stop sharing the screen, and then go to that PDF
18 document. I think I shared it on the screen. Hang on
19 just a moment, please. Okay, Dr. McCullough, are you
20 seeing on the screen now what would be the PDF version
21 of the withdrawal notice? It’s a three page document.
22 I’m just going to scroll down. The second page has
23 almost nothing on it, and then the last page has the
24 same - the same point here, “Article has been
25 withdrawn at the request of the authors and/or
26 editors.” Do you accept that is the withdrawal
27 notice for your paper, Dr. McCullough?
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1 A. You know, I disagree with that. It’s not a notice to
2 me that it was - was withdrawn. It’s - it’s
3 indicating when this article is searched for that it’s
4 title is presented it’s date of issue is presented
5 and, you know, it’s a three page document that’s
6 forward facing to the public.
7 101 Q. To notify the public that the article has been
8 withdrawn.
9 A. It - it doesn’t indicate the intent of the article.
10 102 Q. This document says “Withdrawn”, and then has the title
11 of your article.
12 A. Yeah, but - but a paragraph down it says, “Please cite
13 this article as Jessica Rose, Peter McCullough, M.D.”,
14 so it just reads as it reads, counsel.
15 MS. TELLES-LANGDON: Mr. Wilson, I’m going to ask that this
16 be entered into the record - entered as Exhibit 4.
18
19 EXHIBIT 4: Notice of withdrawal from Elsevier for the
20 article entitled “A Report on Myocarditis Adverse
21 Events”.
22
23 103 MS. TELLES-LANGDON: I take it, Dr. McCullough, this article
24 was not published elsewhere then?
25 A. No.
26 104 Q. And I understand, as you’ve already indicated, that
27 you’re suing Elsevier for refusing to publish this
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1 study?
2 A. The article was fully peer reviewed and published.
3 So, this was a published article. Five days before
4 the USFDA pediatric meetings on vaccination it was
5 with...withdrawn for the publisher illegally.
6 105 Q. Can you please turn to paragraph 15 of your report,
7 Dr. McCullough? It starts on page 191 and carries
8 over onto page 192 of your affidavit. At paragraph 15

9 of your report, Dr. McCullough, you present findings
10 by Tschope - T-s-c-h-o-p-e - et al from a May 2019
11 paper titled “Management of Myocarditis Related
12 Cardiomyopathy in Adults,” which was published in
13 Circulation Research. Would you agree - would you
14 agree, Dr. McCullough, that as this paper predates
15 Covid-19 it relates to patients diagnosed with acute
16 myocarditis generally, not either Covid-19 vaccine-
17 induced myocarditis or even Covid-19 induced
18 myocarditis?
19 A. I agree with that.
20 106 Q. Would you also agree, Dr. McCullough, that the
21 information presented in this study was based on cases
22 of myocarditis referred to a major cardiovascular
23 investigation centre in Europe that conducts trials in
24 patients who have failed to recover from their
25 myocarditis?
26 A. I agree with that.
27 107 Q. Going to page 193 of your affidavit, it is the brief
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1 summary that you present following paragraph 16. In
2 this brief summary you state the opinion that
3 approximately - or you make note that approximately
4 13% of those with vaccine-induced myocarditis have
5 permanent heart injury, but that percentage is
6 extrapolated from the Tschope paper that you discuss
7 at paragraph 13, correct?
8 A. I disagree with the statement you just made.

9 108 Q. Well, if we go back to paragraph - paragraph 15, you
10 state in your affidavit, “According to Tschope et al,
11 in a paper in Circulation Research, 13% of individuals
12 with myocarditis will have a permanent injury.” You
13 state that in your affidavit at paragraph 15. Yes,
14 correct?
15 A. You know, I was referring to on page 193 the brief
16 summary, first bullet, says, “Peer reviewed research
17 shows that 13% of people who get myocarditis will
18 likely have permanent injury,” and so the statement is
19 as I read it in the report. Do you have a specific
20 question on that first statement I just read?
21 109 Q. That first statement in your summary is based on that
22 Tschope - I’m sorry I’m sure I’m mispronouncing the
23 Doctor’s name - but it’s based on that Tschope paper
24 that you reviewed in paragraph 15, correct?
25 A. Well, it’s based on that and the totality of evidence
26 in myocarditis in the Tschope paper as shown in the
27 figure of 210 individuals, 13% are impaired, but in
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1 grey 34% are improved but not recovered to normal.
2 So, at least 13% - it could be a greater percentage.
3 110 Q. But as you’ve already agreed, Dr. McCullough, that is
4 in a group of patients who failed to recover from
5 their myocarditis and were being investigated for
6 myocarditis prior to the emergence of Covid-19,
7 correct?
8 A. No, you’ve stated incorrectly in the figure, paragraph

9 15 and 210 individuals. Twenty-six percent had
10 recovered.
11 111 Q. I didn’t say anything about recovered, Dr. McCullough.
12 A. Look in the figure - figure 1...
13 112 Q. Yes. No, I see the figure 1, Dr. McCullough. The
14 question, you state at paragraph 15, according to the
15 Tschope paper in Circulation, 13% of individuals with
16 myocarditis will have a permanent injury. You state
17 that, correct? Yes?
18 A. Yes, I state it but you’ve indicated, and it’s in the
19 record now, that figure 1 does not indicate a
20 proportion recovered, and I’m stating it simply says
21 “recover” and it’s 26%. That means recovered. So, I
22 disagree with your reading of my report.
23 113 Q. I’m sorry, Dr. McCullough, I don’t recall saying
24 anything about recover or recovered.
25 A. Well, let’s go ahead and read back the transcript.
26 114 Q. That’s not a thing we can do, Dr. McCullough. My
27 question for you, Dr. McCullough, was you make that
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1 statement, 13% of individuals with myocarditis will
2 have permanent injury at paragraph 15. And then when
3 you make your summary at page 193, you make the same
4 statement, 13% of people who get myocarditis will
5 likely have permanent heart injury. I’m saying to
6 you, Dr. McCullough, I am - am I making the correct
7 assumption that that 13% number that you put in your
8 summary is based on the Tschope study that you discuss

9 at paragraph 15?
10 A. As I’ve already testified, according to the Tschope
11 study, and others support that, that it could be
12 greater than 13%.
13 115 Q. So, when you say at the end of this summary that the
14 research shows it is likely that people - and it’s
15 likely that approximately 13% of those with vaccine-
16 induced myocarditis will have permanent heart injury,
17 that statement “likely 13% will have the same - will
18 have for vaccine-induced myocarditis will have
19 permanent heart injury”, that’s based on an
20 extrapolation of the Tschope article, correct?
21 A. It’s based on my sum total of knowledge and skill as a
22 medical doctor, as well as seeing and examining
23 patients with vaccine-induced myocarditis. It could
24 be 13%, or it could certainly be greater with that
25 form of myocarditis.
26 116 Q. Based on the MMWR Report, Dr. McCullough, that I put
27 to you earlier, Dr. Peter Liu in his affidavit
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1 reproduced some of the data from that MMWR Report.
2 You indicated that you reviewed Dr. Liu’s report. Do
3 you have it there available for you?
4 A. Yes.
5 117 Q. Just give me a minute and I’ll give you a page number.
6 It is - at least on the version in front of me, page
7 80 of the PDF document in Dr. Liu’s report in his
8 Exhibit B. Taking you to - he has in the bottom right

9 hand corner page numbered at page 6 of his - of his
10 report.
11 A. Okay.
12 118 Q. Six and carrying on to page 7. Do you have that there
13 in front of you?
14 A. Yeah, his report doesn’t have any page numbers at the
15 top.
16 119 Q. No, it does not. This is true, but in the bottom
17 right hand corner there’s page numbers.
18 A. Okay. So, what page number at the bottom right hand
19 corner?
20 120 Q. Page number at the bottom right hand corner is page 6.
21 A. Okay.
22 121 Q. And it is his discussion of results from the MMWR
23 article that we discussed earlier, their April 20...
24 1st, 2022 article.
25 A. Yes.
26 122 Q. Dr. McCullough, I - I put it to you that, as Dr. Liu
27 reports, based on the MMWR article, “For patients aged
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1 12 to 17 years, the incidence of Covid-19 related
2 myocarditis was between 50.1 to 64.9 out of 100,000,
3 versus myocarditis seen after the first dose of an
4 mRNA vaccination at 2.2 to 3.3 out of 100,000, and
5 22.0 to 35.9 out of 100,000 after the second dose.”
6 Do you accept this statement, Dr. McCullough?
7 A. No.
8 123 Q. Based on the MMWR report as reflected in Dr. Liu’s

9 report, I put it to you, Dr. McCullough, that for
10 patients aged 18 to 29 years, the incidence of Covid-
11 19 related myocarditis was 55.3 to 100.6 out of
12 100,000 versus myocarditis seen after the first dose
13 of mRNA vaccine at 0.9 to 8.1 out of 100,000, and 6.5
14 to 15.0 out of 100,000 after the second dose. That
15 the great differences of incidents between Covid-19
16 induced myocarditis versus that following mRNA
17 vaccines are statistically significant. Do you agree
18 with that statement, Dr. McCullough?
19 A. No, and it’s - it’s completely incorrect for the
20 following reasons, that patients admitted with Covid-
21 19 of the hospital routinely have blood testing for
22 troponin like they do for all other critical
23 illnesses, and troponin can be elevated without any
24 clinical evidence of myocarditis, and that’s what’s
25 being reported in the Covid-19 respiratory illness
26 statistics. The vaccine-induced myocarditis is a
27 representation of only those sick enough to receive
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1 the vaccine at home and then come to an ER hospital
2 and generate an electronic health code record. Those
3 cases invariably had history, physical, EKG, imaging,
4 and a diagnosis of myocarditis made. So, they’re two
5 completely different sets of reporting that can’t be
6 compared, and Dr. Liu here, in my view, is not
7 credible or reliable in making these comparisons.
8 124 Q. Dr. McCullough, as I understand it, both patient

9 groups - the groups that had Covid-19 induced by...
10 I’m sorry, myocarditis induced by Covid-19, and then
11 had myocarditis induced by vaccine-related
12 myocarditis, come from the same body of data, those
13 hospitalized. I need to pull that report back up for
14 you, Dr. McCullough. I’ll share my screen for a
15 moment, Dr. McCullough. You see there on page 1 of
16 the MMWR report, Dr. McCullough, “This study used EHR
17 data from 40 health care systems participating in the
18 PCORnet, the National Patient Center Clinical Research
19 Network. It is a network of - a National Network of
20 networks that facilitate use of health care data and
21 inoperability through use of common data...” I’m not
22 going to begin to tell that I understand what that
23 means. I’m sure you do, but my understanding as a lay
24 person is that this was all based on individuals who
25 went to seek out medical care for their symptoms.
26 A. My interpretation of this, and the reason why its
27 invalid, is patients being hospitalized for Covid-19
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1 respiratory illness in my experience and in my
2 anticipation here in this network, which I’m familiar
3 with, is that they are all ill with Covid-19 and it’s
4 well described that approximately half have an
5 elevation in cardiac troponin without clinical
6 evidence of myocarditis. That elevation in troponin
7 triggers an ICD code that’s being relied upon here and
8 incorrectly diagnosing those with Covid-19 respiratory

9 illness with myocarditis. That’s very different than
10 people taking a vaccine who should never generate
11 codes. They should never come to the hospital for
12 medical problems, but in fact they’re coming to the
13 hospital in large numbers, and in fact they indeed
14 will almost certainly meet criteria for myocarditis
15 because its under consideration as the diagnosis.
16 125 Q. Well, thank you, Dr. McCullough. Well, there’s no
17 dispute between you and Dr. Liu that Covid-19 vaccines
18 can cause myocarditis. I put it to you, Dr.
19 McCullough, that despite some exceptions which you
20 have discussed in your paper, in - in generally
21 speaking, in contrast to Covid-19 induced myocarditis
22 or traditional viral myocarditis prior to the
23 pandemic, the natural history associated with mRNA
24 vaccine-induced myocarditis appears to have a
25 relatively good outcome. Do you accept this
26 statement, Dr. McCullough?
27 A. No, I don’t.
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1 126 Q. Right.
2 MS. TELLES-LANGDON: Can you give me a moment, Mr. Wilson,
3 perhaps we’ll go off the record. Maybe this is a good
4 time for a - for a 15 minute break
5 MR. WILSON: Certainly.
7 OFF RECORD
9 127 MS. TELLES-LANGDON: Thank you, and Dr. McCullough, I don’t
10 have any further questions for you.
11 128 MR. WILSON: Counsel, I do have three matters in
12 redirect. May I proceed?
13 MS. TELLES-LANGDON: Yes, of course.
14
15 REDIRECT EXAMINATION BY MR. WILSON
16
17 129 MR. WILSON: Okay, thank you. Dr. McCullough,
18 welcome back. With respect to the - the MMWR report,
19 that’s a form of newsletter that comes from the CDC,
20 is that correct? Or is that the case?
22 130 Q. And is this a peer reviewed publication?
23 A. My understanding is that the CDC has an internal peer
24 reviewed - peer review process, but that is not fully
25 externally peer reviewed, and the great concern on any
26 of the MMW reports concerning the vaccine is the CDC
27 is a vaccine stakeholder. They are co-administrating
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1 the U.S. vaccine program with the FDA, so they can’t
2 be considered unbiased or a credible source of
3 opinions on vaccines.
4 131 Q. And when you were asked a question by my friend
5 regarding its relevance to the conclusions of your
6 paper and your report recognizing that this particular
7 article from the MMWR report is post - postdates your
8 writing of your report, you had answered in response

9 to a question of the relevance of this CDC document
10 and you felt that it wasn’t, as I am understanding
11 your testimony, because it was invalid, can you
12 explain why you believe its invalid?
13 A. It’s invalid because individuals who are sick with
14 Covid-19 in the hospital we routinely check troponin
15 values, just like we would for pneumococcal
16 respiratory failure, other cause of respiratory
17 failure and the troponin value which is a blood test
18 for heart injury is commonly above the upper limit in
19 normal. That’s triggering the ICD codes in the
20 electronic health record. That - that paper is
21 relying upon to declare myocarditis in Covid-19
22 respiratory illnesses, and that paper does not
23 indicate the cases were reviewed. So, there’s no
24 indication that the patients had EKG evidence -
25 echocardiography evidence, MRI, or had a clinical
26 diagnosis of myocarditis. So, the declaration of
27 myocarditis existing in the Covid-19 respiratory cases
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1 has to be completely discounted. Now, on the side the
2 vaccine they do indicate people are taking the vaccine
3 and actually showing up to hospitals and triggering
4 electronic health record codes for myocarditis, and I
5 can tell you a person coming from the outpatient world
6 triggering a troponin elevation, or EKG echo, or
7 imaging, that contextually is far more likely to be
8 real myocarditis, not a misrepresentation from ICD

9 codes and inpatients. So, there are apples and
10 oranges. I am worried that in fact in this large
11 Pecory (ph) net network that people are taking the
12 vaccine and generating any electronic health records.
13 The vaccine should be safe and people should not be
14 driven to the hospital for evaluation of any problems
15 let alone heart damage.
16 132 Q. So, when you say they’re not reviewed, does that mean
17 the patient is not seen by a physician to conduct a
18 physical assessment in a clinical setting?
19 A. No, it means there’s no adjudication of whether or not
20 they’ve had myocarditis on the in-patient encounter
21 for Covid-19. I can tell you every patient in the ICU
22 does have blood troponin values entered as a matter of
23 routine, just like they had CBCs and blood
24 chemistries. And in my experience in this is that
25 that’s what’s triggering the ICD code that is cropping
26 cross walked to myocarditis, and this false
27 declaration that patients with Covid-19 respiratory
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1 illness have myocarditis, and certainly even a greater
2 falsehood that is more common than in those with the
3 vaccine because the large numbers of people taking the
4 vaccine, those individuals should not be generating
5 any health care encounters. The vaccine should be
6 safe when in fact it’s driving people to seek medical
7 care.
8 133 Q. In your medical professional view what steps are

9 required clinically to confirm that a person with the
10 elevated blood test result that’s presented actually
11 has myocarditis?
12 MS. TELLES-LANGDON: So, Mr. Wilson, I’m going to object
13 here. I think we’re going a little bit beyond. I
14 didn’t object when there was some amount of
15 speculation as to what was and was not done in the
16 background in the MMWR report on Mr. McCullough - Dr.
17 McCullough’s part, but it seems now we’re going beyond
18 the area of redirect here.
19 MR. WILSON: Well, I’ve asked him to illuminate his
20 - to - to expand his no answer, which is why its
21 invalid, and he’s just explained that there's
22 differences in the review process leading to the data
23 collection from the two groups, and I’m asking him
24 just to be more clear about this because I’m not a
25 medical doctor, the judge is not a medical doctor, and
26 it goes to the heart of your question which is are -
27 is this reliable data comparison that you read from
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1 Dr. Liu’s report, so I don't think I’m going into a
2 new area.
3 MS. TELLES-LANGDON: I - I asked - I asked Dr. McCullough if
4 he agreed with that statement, and he said no, from
5 Dr. McCullough’s report that I didn’t ask him to weigh
6 in on the credibility and reliability of Dr. Liu.
7 That is for you to address with Dr. Liu in cross-
8 examination.
9 MR. WILSON: Well, I don't agree but I am prepared
10 to move on because I think we might have enough
11 already that I can piece together for later.
12 134 Q. My last question relates to - and of course we don’t
13 have a live transcript so I can’t go back to it, but
14 Dr. McCullough, counsel had asked - my notes indicate
15 that counsel had asked you a question relating to
16 myocarditis caused by the Covid-19 vaccine has a
17 positive or good outcome, and you indicated no. Can
18 you elaborate why did you say no?
19 A. The Covid-19 vaccines are new and in fact younger
20 people have just started to receive them in the last
21 several months. So, we can’t know the long term
22 outcome, the long term outcome of myocarditis. The
23 serious events are to the development of symptomatic
24 heart failure and cardiovascular death. We can’t know
25 what those outcomes are until many years have passed,
26 probably five to ten years. What we know now is that
27 there are fatal cases of myocarditis reported in the
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1 medical literature. This is very disturbing because
2 this represents the tip of the iceberg, and as
3 individuals die in the community, very few undergo
4 autopsies or investigation. So, my concern is the
5 immediate death and injury rate is - is far higher and
6 whatever is being reported is simply the tip of the
7 iceberg because it’s spontaneous reporting and not
8 everyone is checked for this problem.

9 Secondly, there are now two papers - a baseline and
10 follow up paper by Jenna Shower published in
11 Pediatrics showing that the heart damage occurring in
12 children does not resolve, and it certainly doesn’t
13 resolve over the course of several months by cardiac
14 MRI. This is greatly concerning as more
15 administrations of the vaccine and conceivably more
16 vaccine-induced myocarditis occurs. A child at
17 baseline is - who is healthy cannot be made healthier
18 by the injection of the genetic code for the spike
19 protein which is proven to cause heart damage.
20 135 Q. And my final question is, you’ve used the acronym ICD.
21 Can you explain that an ICD code is?
22 A. An ICD code is the - it stands for the International
23 Classification of Diseases. It’s generated from
24 hospital encounters. So, hospital encounters, once
25 somebody is hospitalized they can generate many ICD
26 codes. In fact they can generate them every day, and
27 then they get organized into various constellations.
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1 So, someone admitted with Covid-19, the respiratory
2 illness, has a much greater opportunity because of
3 blood testing and other measures to generate ICD
4 codes. That’s a very different from an outpatient, an
5 outpatient who takes a vaccine should generate no ICD
6 codes because they shouldn’t go to the hospital. And
7 so for those reasons those with Covid-19 respiratory
8 illness generate ICD codes for neurologic problems,

9 cardiovascular, immunologic, and hematologic as a
10 general reflection of being ill in the hospital as a
11 patient would with other forms of respiratory failure.
12 MR. WILSON: Thank you very much. Those conclude my
13 redirect questions.
14 MS. TELLES-LANGDON: Thank you. Then I think we are
15 complete for the day.
16
17
18 DISCOVERY ENDS
19
20
21
22
23
24
25
26
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Court Transcriber
ACT ID: 2887221650
May 13, 2022
JML TRANSCRIPTION
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AR07922
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AR07923 JML TRANSCRIPTION
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PRIMER
Myocarditis With COVID-19 mRNA Vaccines
Biykem Bozkurt~ , MD, PhD; lshan Kama~ MD; Peter J. Hotez, MD, PhD
ABSTRACT: Myocarditis has been recognized as a rare complication of coronavirus disease 20 19 (COVID- 19) mRNA
vaccinations, especially in young adult and adolescent males. According to the US Centers for Disease Control and Prevention,
myocarditis/pericarditis rates are ... 12.6 cases per million doses of second-dose mRNA vaccine among individuals 12 to
39 years of age. In reported cases, patients with myocarditis invariably presented with chest pain, usually 2 to 3 days after
a second dose of mRNA vaccination, and had elevated cardiac troponin levels. ECG was abnormal with ST elevations in
most, and cardiac MRI was suggestive of myocarditis in all tested patients. There was no evidence of acute COVID- 19 or
other viral infections. In 1 case, a cardiomyopathy gene panel was negative, but autoantibody levels against certain self-
antigens and frequency of natural killer cells were increased. Although the mechanisms for development of myocarditis are
not clear, molecular mimicry between the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)
and self-antigens, trigger of preexisting dysregulated immune pathways in certain individuals, immune response to mRNA,
and activation of immunologic pathways, and dysregulated cytokine expression have been proposed. The reasons for male
predominance in myocarditis cases are unknown, but possible explanations relate to sex hormone differences in immune
response and myocarditis, and also underdiagnosis of cardiac disease in women. Almost all patients had resolution of
symptoms and signs and improvement in diagnostic markers and imaging with or without treatment Despite rare cases of
myocarditis, the benefit-risk assessment for COVID-19 vaccination shows a favorable balance for all age and sex groups;
therefore, COVI D-19 vaccination is recommended for everyone ~ 12 years of age.
Key Words: COVID-19 ■ COVID-1 9 vaccines ■ mRNA vaccine ■ myocarditis ■ pericarditis ■ SARS-CoV-2 ■ vaccination
here is now increasing evidence for myocarditis nosed in approximately 10 to 20 individuals per 100 000
T and myopericarditis as rare complications of coro-

navirus disease 2019 (COVID-19) mRNA vacci-
nations, especially in young adult and adolescent males.
per year,2 and occurs more commonly and at younger
ages in males compared with females.3
In the pre-COYID-19 era, among 620195 reports
Here we provide further details about this phenomenon filed at the Vaccine Adverse Event Reporting System
and its potential underlying mechanisms. We also discuss (VAERS) between 1990 and 2018, 0.1% were attribut-
the balance of risk of myocarditis with vaccination versus able to myopericarditis.1 Of those myopericarditis reports,
cardiac and other risks from COVID-19 viral infection. 79% were in males.1 However, VAERS is primarily a
safety signal detection and hypothesis-generating system
and cannot be used to determine if a vaccine caused an
EPIDEMIOLOGY AND CLINICAL adverse event4 Through this passive reporting, the Cen-
ters for Disease Control and Prevention (CDC) and the
PRESENTATION OF MYOCARDITIS AFTER US Food and Drug Administration conduct postlicensure
COVID-19 VACCINATION vaccine safety monitoring.4 This approach is not specific,
Historically, postvaccination myocarditis has been report- and most VAERS events are typically not actually linked to
ed as a rare adverse event after vaccinations, especially vaccinations. Instead, various methods and statistical tech-
smallpox vaccination, influenza, hepatitis B, or other vac- niques are used to analyze VAERS data, which the CDC
cinations.1 In the general population, myocarditis is diag- and Food and Drug Administration use to guide further
The opinions expressed in this arlide are not necessarily those of the editors or of the American Heart Association.
Correspondence to: Biykem Bozkurt, MD, PhD, MEDVAMC, 2002 Holcombe Blvd, Houston, TX 77030. Email bbozkurt@bcm.edu
The podcast and transcript are available as a Data Supplement at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA121.056135.
For Sources of Funding and Disclosures, see page 482.
C 2021 American Heart Association, Inc.
Cirwlation is available at wwwahajournals.org/joumal/circ
Orr:ulation. 2021 ; 144:471-484. DOI: 10.1161 /Cl RCU LATIONAHA 121.056135 August 10, 2021 471
AR07924
Bozkurt et al Myocarditis Wrth CCVI D-19 mRNA Vaccines
mRNA COVID- 19 vaccines compared with unvaccinated

Nonstandard Abbreviations and Acronyms individuals or individuals vaccinated with non-mRNA
COVI 0-19 vaccines on the same calendar days (rate
COVID-19 coronavirus disease 2019 ratio of 10.8 [95% Cl, 3.2-49.0], adjusted for site, age,
CDC Centers for Disease Control and sex, race/ethnicity, and calendar date).5 The estimated
Prevention myocarditis/pericarditis chart-confirmed rate was 12.6
IL interleukin cases per million doses with second-dose mRNA vac-
SARS severe acute respiratory syndrome cine among individuals 12 to 39 years of age.5 The rates
SARS•CoV-2 severe acute respiratory syndrome based on lntemational Classification of Diseases, 10th
coronavirus 2 Revision-coded cases were also higher in males than in
VAERS Vaccine Adverse Event Reporting females 5 (Table 3). All chart-confirmed cases with follow-
System up had resolution of symptoms; and among those who
had follow-up ECG/echocardiography and laboratory
testing, most had returned to normal or baseline.5 On this
safety evaluations, such as Vaccine Safety Datalink, and basis, the Food and Drug Administration will add a warn-
inform decisions around vaccine recommendations and ing to the product label of both mRNA vaccines regard-
regulatory action. Therefore, VAERS data must be inter- ing the risk of myocarditis.7
preted with caution because of the inherent limitations of Several myocarditis cases after COVI D-19 vaccina-
passive surveillance.4 VAERS is subject to reporting bias, tion have been published in peer-reviewed journals,s--19
including both under- and overreporting of adverse events with reports predominantly after the second dose of
or stimulated reporting that might occur in response to mRNA COVID-19 vaccines (BNT162b2 mRNA-Pfizer-
intense media attention and increased public awareness.4 BioNTech and the mRNA-1273-Moderna; Table 4).
Recently, a CDC Advisory Committee on Immuniza- Patients in these reports invariably presented with chest
tion Practices identified a likely association between pain, usually 2 to 3 days after a second dose of mRNA
the 2 COVID-19 mRNA vaccines from Pfizer-BioNTech vaccination, some preceded with fever and myalgia 1
and Moderna and cases of myocarditis and pericarditis.5 day after vaccination. These were predominantly young
Patient reports in VAERS were categorized according males requiring hospitalization for myocarditis and with-
to CDC work case definitions as probable myocarditis, out a history of COVID-19 or comorbidities. All tested
confirmed myocarditis, or acute pericarditis5 (Figure 1). negative for current COVID-19 by polymerase chain
According to the Advisory Committee on Immunization reaction testing. A majority had spike antibody levels
Practices, after ::::300 million COVID- 19 mRNA vaccine for severe acute respiratory syndrome coronavirus-2
doses administered through June 11, 2021, there were (SARS-CoV- 2) suggesting effective immunization. All
1226 reports of probable myocarditis/pericarditis cases had elevated cardiac troponin, the highest level peak-
in VAERS, 67% of which followed the second dose.5 Sev- ing usually 3 days after vaccination (Table 4). ECG was
enty-nine percent were in males, with the majority in indi- abnormal with ST elevations in most presentations. An
viduals <30 years of age with a median age of 24. Time echocardiogram was abnormal in only 40%, with only a
to onset of symptoms was a median of 3 days, with the small percentage having a left ventricular ejection frac-
highest rate at day 2 after vaccination and among patients tion<50% on presentation. Cardiac MRI was abnormal in
16 to 18 years of age. In 484 probable myocarditis/ all tested patients, with findings suggestive of myocardi-
pericarditis cases among patients ~29 years of age that tis such as late gadolinium enhancement and myocardial
were reviewed and characterized by the CDC,5 86% had edema 8-type natriuretic peptide or N-terminal pro-B-
reports of chest pain on presentation, 61 % had reports type natriuretic peptide levels were only mildly elevated
of ST- or T-wave changes on ECG, 64% had reports of in approximately two-thirds of the patients when mea-
elevated cardiac enzymes, and 17% had reports of abnor- sured. C-reactive protein levels were elevated in most
mal cardiac imaging.5 .ln 323 of the reports that met the and decreased along with troponin through the hospital
CDC definition of confirmed myocarditis/pericarditis, stay. Almost all patients had resolution of symptoms and
96% were hospitalized, but most were discharged with signs and improvement in diagnostic markers and imag-
a resolution of symptoms.5 The observed myocarditis/ ing with or without treatment (Table 4).
pericarditis reports were higher than expected case rates The Israeli Ministry of Health also reported 148 myo-
for males compared with females, and higher at younger carditis cases among 10.4 million vaccinated individuals
ages compared with older ages (Tables 1 and 2).5 occurring within 30 days of mRNA vaccination, a major-
Additional analyses of CDC Vaccine Safety Datalink ity after a second dose, mostly in males 16 to 30 years
with data from 9 participating integrated health care of age.20 Most cases required hospitalization up to 4
organizations revealed an increased risk of myocarditis/ days but were considered mild. The report suggested a
pericarditis events among individuals 12 to 39 years probable link between the second-dose mRNA vaccine
of age in the 7-day risk interval after vaccination with and myocarditis among men 16 to 30 years of age,20
47'2 August 10, '20'21 Circulation. '20'21;144:471 - 484. DOI: 10.1161/CIRCULATIONAHAl '21.056135
AR07925
Bozkurt et al Myocarditis Wrth COVID-19 mRNA Vaccines
CDC Working Case Definitions
Acute Myocardltis Acute Pericarditis
Probable Case Confirmed Case Probable Case
• Presence of~ 1 new or worsening of the • Presence of~ 2 new or worsening

• Presence of~ 1 new or worsening of the
of the followlng cllnlcal symptoms
following clinical symptoms following clinical symptoms
• chest pain/ pressure/ discomfort • acute chest pain (typically
• chest pain/ pressure/ discomfort
described as pain made worse by
• dyspnea/shortness of breath • dyspnea/shortness of breath
lying down, deep inspiration,
• palpitations • palpitations cough, and relieved by sitting up
• syncope • syncope or leaning forward, although
• AND~ 1 new finding of • AND other types of chest pain may
• elevated troponin above upper limit of • histopathologic confirmation of occur) t
normal myocarditis * • pericarditis rub on exam
• abnormal ECG or rhythm monitoring • OR • new ST-elevation or PR-
findings consistent with myocarditis" • elevated troponln above upper limit of depression on ECG
• abnormal cardiac function or wall normal AND cardiac MRI findings • new or worsening pericardia!
motion abnormalities on consistent with rnvocarditis• effusion on echocardiogram or
echocardiogram • AND no other ldentlfiable cause of the MRI
• cardiac MRI findings consistent with symptoms and findings • Autopsy cases may be classlfled as
myocardltis • pericarditis on basis of meeting
• AND no other identifiable cause of the hlstopathologic criteria of the
symptoms and findings pericardium
Figure 1. Centers for Disease Control and Prevention working case definitions for acute myocardltls and acute perfcanlltls.
Adapted from Centers for Disease Control and Prevention5 with permission. Copyright 0 2021, Centers for Disease Control and Prevention.
with a stronger link for age 16 to 19, and decreasing COVID-19 vaccination, reflecting higher than expected
association with older age. 16•20 The prevalence of myo- numbers of myocarditis cases. 18
carditis was 1/20000 for the 16- to 30-year group
compared with 1/100000 in the general population
receiving the same vaccine. Similarly, the US Depart-
COVID-19-ASSOCIATED MYOCARDITIS
ment of Defense reported 23 male military personnel Wrth the emergence of COVID-19 in Hubei Province,
diagnosed with myocarditis after 2.8 million doses of China, there was an expectation that the SARS-CoV-2
COVID-19 vaccinations administered in the Military would cause predominantly respiratory illness, similar to
Health System, mostly after the second dose of mRNA that seen with severe acute respiratory syndrome (SARS)
Table 1. Expected Versus Observed Number of Myocarditis/Pericanlltls Cases In 7-Day Risk Window After
Dose 2 of mRNA Covld·19 Vaccination•
ferMles Males
Age groups Doses administered Elrpec:ted",t Observed" Doses adrnlnlstmed Expec:tad",t Observed"
12-17 y 2189726 0-2 19 2039871 0-4 128
18-24y 6237262 1-6 23 4337287 1-8 219
26-29y 4161976 0-5 7 3625674 1-7 69
30-39y 9356296 2-18 11 8311 301 2-16 61
40-49y 9927773 2-19 18 8677766 2-16 34
60-64y 18696450 4-36 18 16266927 3-31 18
65+y 21708976 4-42 10 18041647 3- 36 11
COVID-19 indicates coronavirus disease 2019.

*Preliminary myocarditis/pericard~is reports to US Vaccine Adverse Event Reporting System after dose-2 mRNA vaccination, expected
vs observed number of cases using 7-day risk window with data through June 11, 2021. Includes total pn!limina,y reports identified by Cen-
ters for D isease Control and Prevention Advisory Committee on Immunization Practices through Vaccile Adverse Event Reporting System
database s earches for reports with myocard~is/pericarditis codes and prescreened Vaccine Adverse Event Reporting System reports with
signs and symptoms consistent with myocard~is/pericarditis. Obse,ved cases may include probable and confirmed cases by Centers for
Disease Control and Prevention. Adapted from Centers for Disease Control and Prevention• with permission. Copyright C 2021, Centers
for Disease Control and Prevention.
tBased on US population-based background incidence rates of medical cond~ions for use in safety assessment of COVID-19 vaccines
and expected counts among females 12 to 29 yeara of age adjusted for lower prevalence relative to males by factor of 1.73.1 Adapted from
Centers for Disease Control and Prevention• with permission. Copyright C 2021, Centers for Disease Control and Prevention.
Circulation. 2021 ; 144:471-484. DOI: 10.1161 /Cl RCULATIONAHA 121.056135 August 10, 2021 473
AR07926
Table 2. Crude Reporting Rates of Myccardltfs/Perfcardltls Cases per MIiiion Doses After
mRNA COVID-19 Vaccination
Female rates par mlllon closes Male rates ps mlllon closes
Age groups Al closes Dose1 Dose2 Al closes Dose1 Dose2

12-17 y 4.2 1.1 9.1 32.4 9.8 66.7
18-24 y 3.6 1.6 6.6 30.7 8.7 66.3
26-29 y 2.0 0.8 2.6 12.2 4.6 20.4
30-39y 1.8 1.4 1.8 6.9 2.0 10.0
40-49y 2.0 0.9 2.8 3.6 1.0 6.1
60-64y 1.6 1.0 1.8 1.9 1.0 2.3
66+y 1.1 0.6 1.2 1.2 0.7 1.4
Prelimina,y rnyocarditis/pericardiis crude reporting rates per milion mRNA vaccine doses administered by sex and dose
nt.mber to US Vaccine Adverae Event Reporting System following mRNA COVID-19 vac:cinalion with no restrictions on post-
vaccination observation time, data through June 11, 2021. Adapted from Centera for Disease Control and Prevention" with
permission. Copyright C 2021, Centers for Disease Control and Prevention COVID-19 indicates coronavius d isease 2019.
in 2002 to 2003.21 However, with the next phase of the rious condition is defined by an excessive hyperinflamma-
COVID-19 epidemic in Southern Europe and later New tory response that can affect muttiple organs including the
York City, it became apparent that there were cardiovas- lungs, kidneys, brain, skin, eyes, the gastrointestinal sys-
cular involvement and thromboembolic complications.22 tem, and the cardiovascular system, resulting in ventricular
Therefore, COVID-19 emerged as a virus pathogen af- dysfunction, coronary aneurysms, and shock33,34
fecting the vasculature and resutting in myocardial injury, Although some investigators have proposed direct
requiring far different therapeutic approaches compared virus invasion as the most likely mechanism, others focus
with SARS.22.23 Historically, pre-COVID-19, coronaviruses more on host inflammatory cell responses. Emerging
have not been commonly associated with significant myo- data indicate that a maladaptive host immune response
cardial damage. SARS infected >8000 individuals without fueled by excessive activation of innate immune path-
significant incidence of myocarditis. In 1 autopsy series, ways along with proinflammatory cytokine surge, deregu-
SARS-CoV-1 was polymerase chain reaction amplifiable lated thromboinflammation, thrombotic microangiopathy,
in 7 of 20 (35%) hearts, but was not associated with lym- and endothelial dysfunction may play a role in patho-
phocytic myocarditis, the hallmark of classic viral myocar- genesis of cardiac injury related to COVID-19.35.36 Other
ditis.24Similarly, Middle East respiratory syndrome corona- hypothesized mechanisms include demand ischemia, and
virus infected >2000 individuals, with only 1 case report stress- and hypoxia-induced myocardial injury.23 Baseline
of MRI-diagnosed Middle East respiratory syndrome coro- comorbidities including metabolic syndrome, hyperten-
navirus myocarditis.25 On the other hand, epidemiological sion, and cardiovascular disease likely also play a role.
·data suggest that :.:12% to 20% of hospitalized patients Although SARS-CoV-2 can enter the cardiomyocyte
with COVID-19 have evidence of cardiac injury as indicat- through an angiotensin-converting enzyme 2- mediated
ed by elevated levels of cardiac troponin.23.26 Furthermore entry and SARS-CoV-2 copies have been detected in heart
in young athletes recovering from COVID-19 infection,27 tissue,37-39 cardiac histopathology studies have reported
cardiac MRI abnormalities consistent with myocarditis the absence of diffuse lymphocytic myocarditis tradition-
have been reported at a higher prevalence than expected, ally seen in viral myocarditis or confluent myocyte necrosis
in :.:1 % to 3% of the athletes.2&-32 It was also recognized expected in fulminant myocarditis.38.40--43 Hearts of patients
that COVID-19 can result in a muttisystem inflammatory who died of COVID-19 have revealed a greater number and
syndrome in children and younger adults. This rare but se- diffuse distribution of CD68+ cells compared with matched
Table 3. Myocardltls/Perlcardltls Rates Based on lntemaUonal ClasslflcaUon ofDiseases, 1oth

Revision Codes
Fsnale rates par mlllon llale ratas par mlllon

Age group 12-39 y Femalec:asa closes (95'11, Cl) Male cases doses (95'11, Cl)
Any mRNA both doses 6 3.2 (1 .2-6.9) 26 16.9 (11.0-24.B)
Any mRNA dose 1 2 1.9 (0.2-7.0) 4 4.7 (1.3-12.0)
Any mRNA dose 2 4 4.7 (1.3-12.0) 22 32.0 (20.1-48.6)
Myocard~is/pericarditis rates based on lntemationaJ Oassification of Diseases, 10th Revisioo-coded cases in Centers for Disease
Control and Prevention Vaccine Safety Datalink in 21-day risk interval, 12 to 39 years of age, data through June 5, 2021. Adapted
from Centers for Disease Control and Prevention" with permission. Copyright C 2021, Centers for Disease Control and Prevention.
COVID-19 indicates coronavirus disease 2019.
474 August 10, 2021 Circulation. 2021;144:471-484. DOI: 10.1161 / Cl RCULATIONAHA 121.056135
AR07927
control or other myocarditis hearts, indicating that cells of ing cells exposed to RNA may still have the capacity to
monocyte/macrophage lineage rather than lymphocytes express cytokines and activation markers in certain indi-
may be dominant in this setting.35 Other studies revealed viduals, although this may be markedly less when exposed
that interstitial cells, pericytes, and macrophages in the myo- to mRNA with nucleoside modifications than when treated
cardium contain SARS-COV-2 RNA by in situ hybridization, with unmodified RNA45The immune system may therefore
and that pericytes infected by SARS-CoV-2 may play a role detect the mRNA in the vaccine as an antigen, resulting in
in capillary endothelial cell or microvascular dysfunction and activation of proinflammatory cascades and immunologic
individual cell necrosis.39,42,44 It is important to note that mac- pathways that may play a role in the development of myo-
rophages can mediate both local and systemic responses carditis as part of a systemic reaction in certain individu-
to viral infection, are also capable of fixing complemen\ and als.45.48 It will be important to monitor the possibility of such
therefore could cause the direct death of nearby myocytes complications because the revolutionary use of mRNA is
through the activation of apoptotic attack complexes.35 being considered for other vaccinations and therapies.
These findings suggest that COVID- 19 may incite a form In published reports of myocarditis after COVI D-19 vac-
of myocarditis that is different from the typical lymphocytic cination, cardiac biopsy was reported in only 2 cases and
myocarditis associated with other viral myocarditis presen- did not demonstrate myocardial infiltrate11 or any evidence
tations and may instead be associated with diffusely infiltra- of myocarditis.9 This could be attributable to a sampling
tive cells of monocyte/macrophage lineage.35•41•44 error in these few cases, or a different mechanism causing
myocardial injury detected by cardiac biomarkers and MRI
not manifest as traditional lymphocytic or eosinophilic myo-
- carditis or myonecrosis on cardiac histopathology. SARS-
POTENTIAL MECHANISMS OF COVID-19 COV-2 polymerase chain reaction and viral serology for
VACCINE MYOCARDITIS other causes including hepatitis, Epstein-Barr virus, cyto-
SARS-CoV-2 mRNA vaccines contain nucleoside-mod- megalovirus, parvovirus, mycoplasma, H Iv, influenza A/8,
ified mRNA, encoding the viral spike glycoprotein of respiratory syncytial virus, rhinovirus, enterovirus (Cox-
SARS-CoV-2, but not live virus or DNA They are encap- sackie A, Coxsackie 8), adenovirus, and other causes were
sulated in lipid nanoparticles that act as delivery vehicles negative for acute or active infection, when tested, arguing
to transport mRNA into the cells and may include inactive against myocarditis caused by COVID-19 or other infec-
ingredients such as buffer and salts. Once inside the host tions.10,14-18 Serology for autoimmune disorders with anti-
cells, the vaccine's mRNA causes the cells to build the nuclear antibodies and rheumatoid factor were negative,
spike protein which then stimulates an adaptive immune with no evidence of predilection to individuals with preex-
response to identify and destroy a virus expressing spike isting autoimmune disorders.10 There was also no evidence
protein. Vaccine-induced spike protein lgG antibodies of leukocytosis, eosinophilia, anemia, thrombocytopenia, or
prevent attachment of SARS- COV-2 to its host cell via transaminase elevation.19·12 D-Dimer was slightly elevated
spike protein binding to the angiotensin-converting en- in 2 patients without evidence of pulmonary embolus or
zyme 2 receptor, and thereby neutralizes the virus. venous thromboembolic events,12.14 and erythrocyte sedi-
Selected RNA molecules can be immunogenic and mentation rate was mildly elevated in some cases. 14 In
stimulate the mammalian innate immune system, destroy- 1 case repo~ a panel testing for variants in 121 genes
ing the mRNA before it reaches target cells, preventing potentially linked to cardiomyopathy was negative,17 argu-
the spike protein and neutralizing antibody production. ing against an existing predisposition to cardiomyopathy
Nucleoside modifications of mRNA have been ground- attributable to known gene variants in that case.
breaking, shown to reduce innate immunogenicity, and By 1 case repo~ SARS-CoV-2 spike lgM and lgG neu-
result in less activation of cytokines, paving the path for tralizing antibody levels were not significantly different in the
mRNA vaccine development45 COVID-19 mRNA vac- patient with myocarditis than in individuals without myocar-
cines have been shown to be highly effective and safe in ditis post-COVID-19 mRNA vaccination,17 arguing against
large-scale trials.46.47 Systemic reactions to the vaccine, a hyperimmune response.17 In the same repo~ the patient
which are usually mild and transien\ were reported more with myocarditis had elevated levels of IL-1 (interleukin 1)
commonly among the younger population and more often receptor antagonis\ IL-5, IL-16, but not proinflammatory
after the second dose. Adverse cardiovascular effects in cytokines such as IL-6, tumor necrosis factor, IL-18, IL-2,
these trials were isolated, with incidences <0.05%, and or interferon-y levels. However, the patient had diminished
did not include myocarditis.46.47 levels of leukemia inhibitory factor, varying bidirectional
Although nucleoside modifications of mRNA have been profiles for IL-10, macrophage migration inhibitory factor,
shown to reduce their innate immunogenicity,45 in cer- and vascular endothelial growth factor relative to an unvac-
tain individuals with genetic predisposition,48 the immune cinated individual or a vaccinated individual without myo-
response to mRNA may not be turned down and may drive carditis.17 This patient also had higher levels of antibodies
the activation of an aberrant innate and acquired immune against some self-antigens such as aquaporin 4, endothe-
response. The dendritic cells or Toll-like receptor express- lial cell antigen, and proteolipid protein 1.17 Historically, cir-
Circulation. 202 1; 144:471--484. DOI: 10.1161/ CIRCULATIONAHA121.0561 3 5 August 10, 2021 475
BozkurtAR07928
et al Myocarditis Wrth COVID-19 mRNA Vaccines
Table 4. Case Reports and Case Serles of Myocardltls after COVID-19 Vaccination
Montgomet,
Cases«les Marshall et al' R-etal' larsoo at aJfl Abuetar• KJm etal 11 etar•
Cases, n 7 7 8 6 4 23
Case source Hospitalized pa- Hospitalized Hospitalized pa- Hospitalized patients Hospitalized Case series from
tients in different patients in 2 US tielrts in Italy and in Israel patielrts in 1 us US Miitary Health
centers in USA centers USA center System
Male sex, 'lb 100 100 100 100 76 100
Median age (range), y 17(14-19) 24 (19-30) 29 (21-66) 22 (16-46) 30 (23-70) 26 (20-61)
Vaccine type All BNT 162b2 6 BNT162b2 (Pfiz- 6BNT 162b2 BNT 162b2 (Pfizsr) 2BNT162b2 7 BNT162b2
(Pfizer) er),1 mRNA-1273 (Pfizer), 3 mRNA- (Pfizer), 2 mRNA- (Pfizer), 16 mRNA-
(Modems), 1 J&J 1 273 (Moderna) 1273 (Modema) 1273 (Modems)
'lb Patients presenting after 100 71 88 83 100 87

second vaccination
'lb Patients with prior CO- 0 14 26 0 0 13

VI D-19 history
'lb Patients COVI D-19 poly- 0 (all tested) 0 (6/7 tested) 0 (all tested) 0 (all 6 tested) 0 0 (19/ 23 tested)
merase chain reaction positive
'lb Patients with COVID nu- 0 (6 tested, all 0 (4/7 patients N/R 0 (6 tested, all nega- N/R N/ R
cloocapsid antibody present negative) tested, aD negative) live)
('lb of tested)
'lb Patient s with SARS-CoV-2 100 fr, (4/6 tested pe- N/R 1 00 (all 6 tested) N/ R N/ R
spike antibody tims, 2 presented
aAa- Im vaccinalion)
Presentation
runebetween last vaccine 2 (2-4) 3 (2- 7) 3 (1-4) 2.6 (1 - 16), (6 pts 1-3 2.6 (1 - 6) 2 (1 - 4)
and symptom onset, me- days, 1 patient 16
dian days, (range) days post first dose)
'lb Patielrts with chest pain 100 100 100 100 100 100
on presentation
'lb Patients with other 86 42 63 33 76 N/R

symptoms (eg, myalgia,
fatigue, fever)
Diagnostic evaluation
'lb Patients with lropOnin 100 100 100 100 (6/ 6) 100 100 (23/ 23)
elevation (of tested)
Median time to troponin 3 N/R 3 N/ R N/R N/ R
peskafter V8CCWlalion, days
'lb Patients with BNP or NT- 83 (6/ 6 tasted) 60% (6 tested) N/R N/R 6 0 (2/4 tested) N/R
proBNP elevation (among
tested)
'lb Patients with CRP eleva- 86 (6/7 tested) 71 88 100 1 00 (3/3 tested) N/ R
lion (among tested)
'lb patients with oosinophiia N/ R N/ R 0 0 N/ R N/ R

(among t ested)
'lb Patients w ith abnormal 1 00 abnormal 71 (4 patients 88 (6 patients with 1 00 (all 6 with ST 1 00 (all with ST 83 (19/23 with
ECG (among tested) (86% with ST with ST elevations, ST elevation, 1 elevation) elevation, 2 with ST-segment el-
elevation, 1 with 1 patient with patient peaked T PR depression) evations, T-wave
atrioventricular nonspecific ST/T waves, 1 patient inversions, and
d issociation and changes) normal) nonspecilic ST
junctional rhythm) changes)
'lb Patielrts with abno,- 100 (all with myo- 1 00 (all with LGE, 100 (a.II with LGE, 100 (all with mild 1 00 (all with 1 00 (8/8 with
mat cardiac M RJ (among cardial edema, 1 with waD motion 6 with edema) subepicardial ederna LG E, increased subepicardial
tested) LGE, hyperemia) abnormality, 3 with endLGE) Tl end T2 inten- late gadolinium
myocardial ederna sity) enhancement or
in T2) focal myocardial
ederna)
(Conmuedl
476 August 10, 2 02 1 Circulation. 202 1;144:471-484. DOI: 10.11 61/CIRCULATIONAHA121.056135

AR07929
Table 4. Continued
Summary of
Bautista Gan:la Mclean et al Muttua.mar c:uesslesand
Case report Ammirati et al" et ar• (US) 1• D~geloetal" ~-ar• et af'1 cue reports
Case, n 1 1 1 1 1 1 61 patients
Case source Hospitalized pa- Hospitalized pa- Hospitalized pa- Hospitalized pa- Hospitalized pa- Hospitalized pa- AD hospitalized
tient in Italy tient in Spain tient in USA tient in Italy tient in USA tient in USA patients
Sex Male Male Male Male Male Male 98%males
Age,y 66 39 16 30 24 62 Mean age 26y
Vaccine type BNT162b2 BNT162b2 BNT162b2 BNT162b2 mRNA-1273 mRNA-1273 ABmRNAvac-

(Pfizer) (Pfizer) (Pfizer) (Pfizer) (Modema) (Modema) cines except for
one
Presentation after 2nd Yes Yes Yes Yes Yes Yes 69'1b
vaccine
History of Covid-19? Yes, 9 rno ago No No No No No 11%
Is the patient Covid-19 No No No No No No 0

polymerase chain reac-
lion positive?
Does the patient have a Yes No N/R No N/R No 6%

nucleocapsid antibody?
Does the patient have Yes Yes N/R Yes N/R Yes 91%
SARS-CoV-2 spike
antibody?
Presentation
Tome between last vac- 3 1 1 3 4 1 24 days
cination and symptom
onset, days
Did the patient have Yes Yes Yes Yes Yes Yes 100%
chest pain?
Did the patient have No Yes Yes Yes Yes Yes 63%
other symptoms (eg,
myalgia, fatigue, fever)
Diagnostic evaluation
Did the patient have Yes Yes Yes Yes Yes Yes 100
troponin elevation?
Median days to tro- 4 2 3 3 4 4 3
ponin peak after vac-
cination
Did the patient have N/R N/R Yes N/R N/R No 61%
a BNP or NT-proBNP
elevation?
Did the patient have Yes N/R Yes Yes Yes Yes 89'11,
CRP elevation?
Did the patient have No N/R No M~d No No 0

eosinophilia?
Did the patient have an Yes (ST eleva- Yes (ST eleva- Yes (ST eleva- Yes (ST eleva- Noischemic Yes (incomplete 87%
abnormal ECG? tion) tion) tion) tion) changes right bundle-
branch block
and left axis
deviation)
Did the patient have an Yes (lG E end Yes (subepicar- Yes (signs of Yes (subepicar- Yes (patchy mid- Yes (mid myo- 100%
abnormal caroiac MRI? myocardial dial enhance- myocardial fbo- dial LG E of the myocardial and cardial end sub-
edema in T2 im- ment) sis, myocardial myoca,dium) epicardial LGE epicardial linear
aging) hyperemia, and a with edema) and nodular
smal pericardial LGEMdmild
effusion) hypokinesis)
( Continued)
Drr:ulalion. 2021 ;144:471-484. DOI: 10.1161 /CIRCULATIONAHA 121.056135 August 10, 2021 477
AR07930
Bozkurt et al Myocarditis With COVID-19 mRNA Vaccines
Table 4. Continued
Montgomery
caseser1es Marshall et ... Rosner et al' Larson et al" Abu et ..,. Kim et al" etal'•
'lb Patients with abnormal Abnormal in 29'lb, Abnormal in 67'lb Wall motion abnor- 33 (216 with hypoki- N /R LVEF <50'lb in
echocard iogram (among nonnal in 71'lb (mild hypokinesis mality with regional netic segments but 17% (4/23), no
tested) (6/7) in 3, 1 low IYEF, or generalized prese,ved EF), 67% structural abnor-
1 mild LV enlarg&- hypokinesis in all nonnal (4/6) mality in any
ment), nonnal in (100%)
43'lb
% Patients with IYEF<50% 14 (1/7 with IYEF 14 (1 patient with 26 (1 patient with 0 26 (1 patient with 17% (4/23)
(among tested) 47%) LVEF 36'1b-40%) LVEF 36%, an- LVEF 40%)
other 47%)
Outcome
% Patients with symptoms 100 100 100 100 100 70'lb (16/ 23 pa-
resolved t ier'lts)
Median hospitalization 4 (2-6) 3(2-4) N/R (aD reported 6 (4-8) 3(2-4) N/ R

length of stay, days (range) as stable)
'lb Patients treated with 86% with NSAIDs, 43%with 38% with NSAID, 100% with NSAID 60'lb with N/ R
medications for myocsrditis 67'lb with steroids, NSAl DS, 43'lb 26% with colchi- and colchicine NSAIDS, 76%
67'lb with intra- with colchic ine, cine, 13% with with colchicine,
venous imfflt.l'le 43% with fsmoti- steroids 26'lb with st&-
globulin, 43'lb with dine, 14'lb with roids
famotidine, 14'lb steroids
with colchicine
(Continued)
culating heart-reactive autoantibodies have been reported Another important potential mechanism for myocar-
at a higher frequency in patients with myocarditis and have ditis is molecular mimicry between the spike protein of
been implicated in pathogenesis.49 These autoantibod- SARS-CoV-2 and self-antigens.50 Antibodies against
ies are usually directed against multiple antigens, some of SARS-CoV-2 spike glycoproteins have been experimen-
which may have functional effects on cardiac myocytes.49 tally shown to cross-react with structurally similar human
Thus, autoantibody generation could be one of the mecha- peptide protein sequences, including a-myosin.50 How-
nisms whereby myocarditis may develop in susceptible indi- ever, severe adverse events or autoimmune reactions
viduals after vaccination. However, it should be noted that have been very rare.46•47 Although COVID-19 vaccination
in the patient studied, autoantibody levels peaked on day 2 does not appear to provoke de novo immune-mediated
along with symptoms, but they did not recede as expected, adverse events, it is possible that it may trigger preex-
as the clinical condition improved, although the follow-up isting dysregulated pathways in certain individuals with
was rather short Autoantibodies are found more frequently predisposition, resulting in a polyclonal B-cell expansion,
in first-degree relatives of patients with cardiomyopathy immune complex formation, and inflammation.48
than in the healthy population, raising the possibility that Earlier animal studies of vaccines for SARS-CoV- 1 and
myocarditis may develop in a subgroup of patients with the Middle East respiratory syndrome coronavirus had raised
appropriate genetic background. Also, the autoantibodies concerns for enhanced disease with reexposure to wild-
may not be paihogenic and could also be seen as a result type virus after vaccination.51.52 These were triggered by dif-
of myocardial inflammation. In addition, this case patient ferent mechanisms, including neutrophilic and eosinophilic
had a 2-fold increase in ihe frequency of natural killer (N K) cellular infiltrates, possibly linked to Th 17 responses, or
cells, which are the classical population of innate lymphoid nonneutralizing antibodies resulting in enhancement of anti-
cells, expressing a heterogeneous repertoire of germline- body-induced cellular cytotoxicity, complement-dependent
encoded receptors that allows them to destroy cells that are pathways, and aberrant activation of the innate and acquired
infected by viruses, cancer cells, or cells that are rejected. immune system.53-56 Antibody-dependent enhancement of
The surge in NK cells may have either contributed to ihe immunity was initially observed in ihe 1960s with respiratory
paihology or ihe disease resolution process. It is not clear syncytial virus and measles vaccines.57 It was characterized
whether the differences seen in ihis patient regarding rela- by nonneutralizing antibodies generated by past infection or
tive increases in NK cells, autoantibodies, and a dysregu- vaccination failing to shut down the paihogen on reexpo-
lated cytokine profile reflect a causal pathological immune sure and acting as a gateway by allowing the virus to gain
response or reactive adaptive responses to myocardial entry, replicate, and lead to wider dissemination of illness
inflammation, and await validation by further studies. and overreactive immune responses causing more severe
478 August 10, 2021 Circulation. 2021;144:471-484. DOI: 10.1161 / CIRCULATIONAHA l 21.056135
AR07931
Bozkurt et al Myocarditis Wrth COVI D-19 mRNA Vaccines
Table 4. Continued
Summary of
Bautista Gan:la Mc:wanetel Mulhula.mer cae..tesend
Ceserepo,t Ammirati et er• et er• (US)'• D'Angelo et .,,. Albert et er• et er• cue,.ports
Did the patient have an N/R No abnonnality Nonnal Abnormal, wall normal No wall motion 39%
abnonnal echocardio· noted motion abnor· abnormal~ies,
gram? matily and mild EF preserved
pericardia! effu-
sion, NL LVEF
Did the patient have No (NL LVEF) No (NL LVEF) No(NLLVEF) No (NL LVEF) No (NLLVEF) No (NL LVEF) 16%
LVEF<60'lb?
Outcome
Did the patient's syrnp· Yes Yes Yes Yes Yes Yes 89'1b
toms resolve?
Hosp~ization length 7 6 7 7 N/R 4 Mean 4.6 days

of stay, days
Treabnent of myocar· None "Anti-inflammato- Treated with Bisoprolol ace- ll·Blocke< Lisinopril, Varying treat·
d~is ry• medications intravenous im- tylsalicylic acid, carvedilol ment strategies
mune globulin, steroid
NSAID
BNP elevation: B N ~ pg/ml; NT-proBNP elevation: NT-proBN~126 pg/ml; CRP elevation: C ~ BNP indicates B-type natriunltic peptide; CO·
VID-19, coronavirus disease 2019; CRP, Creactive protein; LGE, late gadolinium enhancement, LVEF, left ventricular ejection fraction; NL, normal; N/R, not reported,
NSAID, nonsteroidal anti·inflammalory drugs; and NT-proBNP, N·terminal-pro-BNP.
illness. However, no evidence of either cellular immune endomyocardial biopsy samples arguing against hypersen-
enhancement or antibody-dependent enhancement of sitivity, allergic or eosinophilic myocarditis.s-17 Lipid nanopar-
immunity was observed in non-human primate studies iicles or adjuvants used in mRNA vaccines have not been
after SARS-CoV-2 virus challenge, either after vaccina- shown to result in an immune or inflammatory response and
tion or previous infection.58 These findings led an National have not been associated with myocarditis either.
Institutes of Health ACTIV study (Accelerating COVID-19 Rare occurrences of vaccine-induced immune throm-
Therapeutic Interventions and Vaccines) panel to conclude botic thrombocytopenia have been reported after vacci-
that the risk of immune enhancement after COVI D-19 nation with the recombinant adenoviral vector encoding
immunizations was low, but required ongoing pharmacovigi- the spike protein antigen of SARS-COV-2.60 Although
lance and monitoring.58 To date, neither COVI D-19 disease very rare thrombotic complications have been reported
nor the new COVID-19 vaccines have shown evidence of after mRNA COVID-19 vaccinations, these patients did
causing antibody-dependent enhancement of immunity not have thrombocytopenia or antiplatelet antibodies.61,62
or other forms of immune enhancement with reexposure. None of the myocarditis cases reported after mRNA vac-
People infected with SARS-CoV-2 have not been reported cination had evidence of thrombotic events, thrombocyto-
to develop antibody-dependent enhancement of immunity penia, or disseminated intravascular coagulation (Table 4).
on repeat exposure, and vaccine breakthrough COVI D-19 These patients also did not have persistent fever beyond
cases are rare and mild. Furthermore, there is no evidence the first few days, lymphadenopathy, hepatosplenomeg-
of acute COVID-19 infection during presentation with myo- aly, cytopenias (anemia, leukopenia, and thrombocytope-
carditis cases after COVID-19 vaccination, arguing against nia), hypofibrinogenemia, transaminitis, extreme elevation
a breakthrough infection as a cause (fable 4). in ferritin or multiorgan impairment to suggest a cytokine
Reports to date also do not suggest a delayed hyper- storm, hemophagocytic lymphohistiocytosis, or macro-
sensitivity reaction, such as serum sickness-like reaction phage activation syndrome that results from overactiva-
or eosinophilic myocarditis as a cause for myocarditis after tion of T lymphocytes and macrophages.63.64
mRNA COVID-19 vaccination.15 Atthough rare, delayed Male predominance in myocarditis/pericarditis cases
localized skin hypersensitivity reactions have been described has been described in clinical and experimental studies
with mR NA COVI D-19 vaccination with a median latency of before, and the reasons are unknown. An important pos-
7 days,59 unlike myocarditis emerging earlier within 3 to 4 sible explanation relates to sex hormone differences.3,65,66
days after vaccination. None of the case reports published Testosterone is thought to play a role, by a combined
to date had evidence of eosinophilia in peripheral blood or mechanism of inhibition of anti-inflammatory cells3.65-67
immune complex deposition or eosinophilic infiltrates in and commitment to a Th1 -type immune response.68
Orr:ulation. 2021;144:471-484. DOI: 10.11 6 1/Cl RCULATIONAHA 121.056135 August 10, 2021 479
BozkurtAR07932
et al Myocarditis With COVID-19 mRNA Vaccines
Estrogen has inhibitory effects on proinflammatory T efit decision remains overwhelmingly favorable for vacci-
cells, resulting in a decrease in cell-mediated immune nation. Therefore, COVID-19 vaccination is currently rec-
responses; and pericarditis incidence is higher in women ommended for everyone ~12 years of age5 (Figure 3).
during the postmenopausal period.69 Another contributing COVID-19 vaccination not only prevents COVID-19-re-
factor could be underdiagnosis in women. By our analy- lated hospitalizations and death, but also COVI D-19-
sis of the VAERS database, as of June 6, 2021, there related complications such as myocarditis, multisystem
were 6235 reported cases of chest pain, 690/o of which inflammatory syndrome,33 and post-acute sequelae of
were in women, versus 30% in men.7° Despite a higher SARS-CoV-2 infection or long COVID-19.74
prevalence of chest pain in women, diagnostic evaluation,
including ECG, laboratory biomarkers, echocardiography,
and MRI, was performed and reported more often in male MANAGEMENT STRATEGIES
than in female patients presenting with chest pain after Although rare, clinicians should be aware of the myocar-
COVID vaccination (Bozkurt, unpublished data, 2021 ). ditis and pericarditis risk, which should be considered in
individuals presenting with chest pain within a week af-
ter vaccination, especially in the younger population. For
ASSESSING THE RISK initial evaluation, ECG and cardiac troponin level should
Despite these rare cases of myocarditis, the benefit-risk be obtained, and inflammatory markers such as C-reactive
assessment for COVID-19 vaccination shows a favor- protein and erythrocyte sedimentation rate can be helpful.5
able balance for all age and sex groups5 (Figures 2 and For suspected cases, cardiology consultation and evalu-
3). Given the known potential risk of complications with ation with echocardiography and cardiac MRI should be
COVI D-19 infection, including hospitalizations and death considered. An evaluation for acute COVI D- 19 infection
even in younger adults (mortality remains 0.1- 1 per (via polymerase chain reaction of respiratory tract sample)
100 000 for persons 12-29 years of age), the risk-ben- and past disease (via SARS- CoV-2 nucleocapsid and
Potential Prevention of COVlD-19,

Potential Risk of Myocardftfs with Hospitllizations, ICU admissions and
COVlD-19 Vaccination Death with COVlD-19 Vaccination
~
!
0
t§'
9
O"
.ff
~
~
ra
....
....
,:.
....
r
+s;;w +m+a
S-10 myocanlitis<35eS 51;69myocarditiscases
C, •
~l
~
ra
~
....
....
,:.
....
M&iiM
8500 Qwl6-19casos
183 llosj>itallzatlons
38 ICU admlsslons
1 Death
Nbii◄
8500 Cov~19 cas,s
183 Hospltallzallons
38 IOI admissions
1 Death
l
0
C:
~
ra
~ 4-5 myocanlitis cases 45-56 myac:anlltls cases ~
,.~ 14,000 Covi6-19 cases
1127 HospltallzaUons
93 ICU admissions
12,000 Covid·l9 cases
530~
127 ICU admissions
!3 ~ ~ 13 Deaths 3 Deaths
~ co co
....
b ....
oil
a"
'< ~
ra
,.~ 15,000 Qwl6-19cases 15.000 Qwld-19 cases
936 Hospltaballons
0
::, ~ 2 myocardltls cases 15-18 myocanlltls cases ~ 1459 Hospltalllatlons
215 IOI admissions
a, a, 87 ICU admissions
3:: N N
4Deaths 13 Deaths
..i-
~ .i-
N N
;I"
~ Pull!nt!al P"""'nlfon of CIJVll)..19 r,.latJ!d myocardial lnju~
MIS-(, post-<1CUU! sequelae SARS-CoV-2 Infection
N
N
for every million second dose COVID-19 mRNA vaccinations
Figure 2. Predicted benefits of reduction In COVID-19-related hospttallzatfons and death and rtsks of myocardltis after second
dose of mRNA COVID-19 vac:dnatlon by age group.
Adapted from Centers for Disease Control and Prevention5 with permission. Copyright 02021 , Centers for Disease Control and Prevention
('COVlD-19 mRNA vaccines in adolescents and young adults: Benefit-risk presentation'). Predictions for hospitalization and myocarditis
rates were calculated for eNery million doses of mRNA vaccine based on hospitalization rates from Coronavirus Disease 2019 (COVID-19}-
Associated Hospitalization Surveillance Network (COVID-NET) as of May 22.71 BenefiVrisk were calculated over 120 days. To meet the ECG
or rhythm-monitoring criterion, at least 1 of the following must be included: ST-segment or T-wave abnormalities, paroxysmal or sustained atrial,
supraventricular, or ventricular arrhythmias, atrioventricular nodal conduction delays or intraventricular conduction defects. COVJD-19 indicates
coronavirus disease 2019; ICU, intensive care unit; MIS-C, multisystem inflammatory syndrome in children; and SARS-CoV-2, severe acute
respiratory syndrome coronavirus-2. tUsing either the original or revised Lake Louise criteria72 *Using the Dallas criteria73 §Autopsy cases may
be dassified as pericarditis on the basis of meeting histopathologic criteria of the pericardium.
480 August 10, 2021 Cirr:ulation. 2021;144:471 - 484. DOI: 10.1161/CIRCULATIONAHA121.056135

AR07933
Bozkurt et al Myocarditis With COVlD-19 mRNA Vaccines
Predicted Prevented COVID-19 Predicted cases of

Associated Hospitalizations Myocardltis
Age Groups
- 12-11 1
18-24 I
25-29 I
30-39 I
40 - 49 I
3145 50-64 I
9027 65+ I
2000 1500 1000 SOO 0 500 1000 1500 2000
Number of Cases
Rgure 3. Potential rtsk of myocardltls with COVID-19 mRNA vaccination In the 120 days after vaccination and predicted
prevention of COVID-19 cases, COVID-19-related hospltallzatfons, lnt&nslve care unit admissions, and deaths according to age
groups and sex.
Adapted from Centers for Disease Control and Prevention5 with permission. Copyright 02021, Centers for Disease Control and Prevention
(•COVID-1 g mRNA vaccines in adolescents and young adults: Benefit-risk presentation"). Predictions for hospitalization and myocarditis rates
were calculated for every million doses of mRNA vaccine based on hospitalization rates from Coronavirus Disease 2019 (COVID-19)-Associated
Hospitalization Surveillance Network (COVID-NET) as of May 22, 2021. BenefiVrisk was calculated over 120 days.
spike protein antibodies) would be helpful. Evaluation and tolic dysfunction, guideline-directed therapy including
management may vary depending on the patient's age, !3-blockers and angiotensin-converting enzyme inhibitors
clinical presentation, potential other causes and comor- should be initiated. Management should include a cardi-
bidities, hemodynamic and rhythm stability, and clinical ologist for initial assessment, evaluation, treatment, and
course. Patients with chest pain, evidence of myocardial follow-up, and an infection disease specialist for guid-
injury, ECG changes, cardiac imaging abnormality, arrhyth- ance on subsequent immunization strategies.
mia, hemodynamic instability after COVID-19 vaccination Although the clinical course appears mild with likely res-
likely will require hospitalization and close follow-up. olution of symptoms and signs, it is reasonable to restrict
In published case reports, in addition to supportive or defer strenuous physical activity and competitive sports
care, nonsteroidal anti-inflammatory drugs, steroids, and until after complete resolution of symptoms, signs, hemo-
colchicine were used for management of some of the dynamic, rhythm, diagnostic, and biomarker abnormalities. If
patients with myocarditis after COVID-19 vaccination. A a person develops myocarditis or pericarditis after the first
few patients were treated with intravenous immunoglob- dose of an mRNA vaccine, CDC recommends that their
ulin and aspirin, and some were initiated on !3-blocker second dose be delayed and that the second dose could
and angiotensin-converting enzyme inhibitor therapy be reconsidered on resolution of symptoms, signs, and
because of left ventricular systolic dysfunction. Although findings, under certain circumstances.75 There is evolving
there are no prospective or randomized studies, it is rea- evidence that a single-dose mRNA vaccine does not offer
sonable to consider these therapies, especially in patients adequate protection in the general population against new
with significant symptoms and findings. Among patients SARS-COV-2 variants, and further studies are needed to
with rapid resolution of symptoms, with preserved car- determine efficacy of a single versus 2 doses of mRNA
diac function and normal biomarkers or resolving car- vaccination in different age groups.75 CDC recommends
diac biomarker abnormality, therapy may be deferred. In that all cases of myocarditis and pericarditis post-COVID-
patients with persistent mild symptoms without hemo- 19 vaccination be reported to VAERS.5
dynamic instability, arrhythmia, significant left ventricu-
lar dysfunction or heart failure, colchicine, nonsteroidal
anti-inflammatory drugs, and steroids may be considered.
In patients with left ventricular dysfunction, heart failure,
FUTURE DIRECTIONS AND RESEARCH
new-onset arrhythmia, or hemodynamic instability, intra- PRIORITIES
venous steroids and intravenous immunoglobulin along Studies are needed to elucidate the incidence, risk fac-
with other cardiac or circulatory supportive measures tors including genetic predisposition, prognosis, potential
can be considered. In patients with left ventricular sys- mechanisms, reasons for sex differences, clinical course,
Orculation. 2021 ;144:471-484. DOI: 10.1161/CIRCULATIONAHA121.056135 August 1O, 2021 481

AR07934
Bozkurt et al Myocarditis Wrth COVI D-19 mRNA Vaccines
treatment strategies, and the long-term impact of myo- for any health problems including rare cases of myocardi-
carditis after COVI D-1 9 vaccination.5 tis after vaccination.75 Despite rare cases of self-limited
Future research studies should be designed and sup- myocarditis, the benefit-risk assessment for COVl 0-19
ported specifically: ( 1) to characterize the role of specific vaccination shows a favorable balance for all age and sex
immune cell populations, their similarities and differences in groups; therefore, COVID-19 vaccination is currently rec-
the development of COVID-19, immunity post-COVID-19 ommended for everyone 12 years of age and older.
vaccinations, myocardial injury and multisystem inflamma-
tory syndrome in children related to COVlD-19, and myo-
ARTICLE INFORMATION
carditis related to COVlD-19 vaccines; (2) to characterize
histopathology, immunohistochemistry, ultrastructura~ and Affiliations
Winters Center for Heart Failure Research, Cardiovascular Research Institute
functional changes of the myocardium in the setting of myo- (B.B.), Department of Medicine (I.K), and Department of Pedialrics and Molecular
cardial injury related to COVID-19, and myocarditis related Virology & Microbiology, National School of Tropical Medicine (PJ.H.), Baylor Col-
to COVID-19 vaccines, and their correlation with cardiac lege of Medicine, DeBakey VA Medical Center, Houston, TX.
imaging and cardiac biomarkerfindings; (3) to prospectively Sources of Funding

screen for the development of myocarditis and myocardial None.
injury after COVlD-19 vaccinations in different populations
Disclosures
with specific emphasis on sex- and age-related differences; Dr Bozkurt Consultation for Bayer and scPharmaceuticals, Clinical Events Com-
(4) to explore predisposing factors for the development mittee for Guide-HF Trial Abbott Pharmaceuticals, and Data Safety Monitoring
of myocardial injury with COVlD-19 or myocarditis with Board for Anthem Trial by Liva Nova Pharmaceuticals. Dr Hotez: Inventor on a
COVID-19 vaccine technology owned by Baylor College of Medicine that was
COVlD-19 vaccines (eg, genetic factors, comorbidities, licensed nonexdusively to vaccine companies in India (Biological E) and else-
immunity or autoimmunity profile); (5) to explore the mecha- where. Dr Kamat reports no conflicts.
nisms for development of myocarditis related to COVID-19
mRNA vaccination, including but not limited to molecular
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484 August 10, 2021 Circulation. 2021;144:471-484. DOI: 10.1161 /Cl RCULATIONAHA121.056135
JML TRANSCRIPTION
AR07937
1-888-288-6817
Centers for Disease Control and Prevention DATE: 'K?j I\ -~ ~
EX # : CJ INITIALS: :A: ,p
Morbidity and Mortality Weekly Report

Early Release /Vol. 71 April 1, 2022
Cardiac Complications After SARS-CoV-2 Infection and mRNA COVID-19

Vaccination - PCORnet, United States, January 2021-January 2022
Jason P. Block, MD1; Tegan IC. Boehmer, Ph.02; Christopher B. Forrest. MD, PhD3; Thomas W. Carton, PhD4; Grace M. Lee, MIY;
Umed A. Ajani, MBBS2; Dimitri A. Christakis, MD6 ; Lindsay G. Cowcll, PhD7 ; Christine Draper1; Nidhi Ghildayal, PhD1; Aaron M. Harris, MD2;
Michael D. Kappelman, MD8; Jean Y. Ko, PhD2; Kenneth H. Mayer, MD9; Kshema Nagavcdu, MPH1; Matthew E. Oster, MD2• 10;
Anuradha Paranjape, MD 11;Jon Puro, MPA12; Matthew D. Ritcher; David IC. Shay, .MD2; Deepika Thacker, MD13; Adi V. Gundlapalli, MD, PhD
2
Cardiac complications, particularly myocarditis and This study used EHR data from 40 health care systems"' par-
pericarditis, have been associated with SARS-CoV-2 (the ticipating in PCORnet, the National Patient-Centered Clinical
virus that causes COVID-19) infection (J-3) and mRNA Research Network (7), during January 1, 2021-January 31,
COVID-19 vaccination (2-5). Multisystem inflamma- 2022. PCORnet is a national network of networks that facili-
tory syndrome (MIS) is a rare but serious complication of tates access to health care data and interoperability through
SARS-CoV-2 infection with frequent cardiac involvement use of a common data model across participating health care
(6). Using electronic health record (EHR) data from 40 U.S. systems (https://pcomet.org/data). The PCORnet Common
health care systems during January 1, 2021-January 31, Data Model contains information captured from EHRs and
2022, investigators calculated incidences of cardiac outcomes other health care data sources (e.g., health insurance claims),
(myocarditis; myocarditis or pericarditis; and myocarditis, including demographic characteristics, diagnoses, prescrip-
pericarditis, or MIS) among persons aged ~5 years who had tions, procedures, and laboratory test results, among other
SARS-CoV-2 infection, stratified by sex (male or female) and elements. The study population included persons with docu-
age group (5-11, 12- 17, 18-29, and ~30 years). Incidences of mented SARS-CoV-2 testing, viral illness diagnostic codes,
myocarditis and myocarditis or pericarditis were calculated after or COVID-19 vaccination during the study period. Data
first, second, unspecified, or any (first, second, or unspecified) were obtained through a single query that was executed by
dose of mRNA COVID-19 (BNT162b2 [Pfu.er-BioNTech] participating health care systems to generate aggregated results.
or mRNA-1273 [Moderna]) vaccines, stratified by sex and Five cohorts were created using coded EHR data among
age group. Risk ratios (RR) were calculated to compare risk persons aged ~5 years: 1) an infection cohort (persons who
for cardiac outcomes after SARS-CoV-2 infection to that after
* The 40 PCORnet siteswcreAdventHealth, Allina Health, Children's Hospital
mRNA COVID-19 vaccination. The incidence of cardiac Colorulo, Cincinnati Children's Hospital, Columbia Health, Duke University,
outcomes after mRNA COVID-19 vaccination was highest for Fenway Health, Health Choice Network, Johns Hopkins University, Lurie
males aged 12- 17 years after the second vaccine dose; however, Oilldrcn's Hospital, Medical Collcge ofWISCOnsin, Medical University ofSouth
Carolina, Montc:fiore Medical Center, Mount Sinai Health System, Nationwide
within this demographic group, the risk for cardiac outcomes Children's Hospital, Nemours Child.ten's Hospital, New York University
was 1.8-5.6 times as high after SARS-CoV-2 infection than Langone Medical Center, Nonhwestcm University, OCHIN, Inc., Ochsner
after the second vaccine dose. The risk for cardiac outcomes was Health System, Ohio State University, Orlando Health System, Penn State
College ofMedicine and Penn State Health Miltnn S. Hershey Medical Center,
likewise significantly higher after SARS-CoV-2 infection than Seattle Children's Hospital, Temple University, University of Florida Health,
after first, second, or unspecified dose of mRNA COVID-19 Universityoflowa Healthcare, University ofl<ansas, University Medical Center
New Orleans, University of Miami, University of Michigan, University of
vaccination for all other groups by sex and age (RR 2.2-115.2). Missouri Health Care, University of Nebraska, University of North Carolina,
These findings suppon continued use of mRNA COVID-19 University of Pittsburgh Medical Center, University off= Southwest Medical
vaccines among all eligible persons aged ~5 years. Center, University ofUtah, Vandabilt University Medical Center, w.akc Forest
Baptist Health, and Weill Cornell Medicine. These sires represent a.cademic
and oommunity hospiws that serve patients who arc self-pay or have public or
private insurance.
U.S. Department of Health and Human Services

Centers for Disease Control and Prevention
AR07938
Early Release
received ~1 positive SARS-CoV-2 molecular or antigen test vaccioarinn typically had evidence of previous SARS-C.OV-2
result); 2) afust dose mhort {petsons who received a fust dose infection (8); a 42-day risk window also was used for this
of an mRNA COVID-19 vaccine); 3) a second dose mhort outcome to allow fora pomble long latency between infection
(persons who received a second dose ofan mRNA COVID-19 and diagnosis of MIS (6).1 Because persons with MIS who
vaccine); 4) an unspecified dose cohort (persons who received have cardiac involvement might only receive an ICD-10-CM
an mRNA COVID-19 vaccine dose not specifted as a first or code for MIS, rather than myocarditis or pericarditis, this
semnd dose); and 5) an any dose cohort (persons who received combined outcome allowed for a mmpreheosive capture of
any mRNA COVID-19 vaccine dose). The any dosemhort is potential cardiac complications after infuction. Nearly 80%
a combination of the other three vaccination cohorts; persons of cases of MIS have cardiac involvement (9). Cohorts were
who received 2 doses were induded twice in this mhon, once stratified by sex and age group.
for each dose.t Vaccine doses speciftcally mded as booster or The sex- and age-sttatified incidences of the cardiac out-
emadoseswere exduded. Petsonswith a positive SARS-CoV-2 mmes (cases per 100,000 pem>ns) were calculated within 7-,
test result ~O days before receipt of an mRNA COVID-19 21-, or 42-day risk windows. Unadjusted RRs and 95% Cis
vaccine were excluded from the vaccine mhorts; persons who were calculated as the incidences of the outcomes within the
had received an mRNA COVID-19 vaccine dose ~30 days infection cohort divided by the incidences in the fust, second,
before a positive SARS-CoV-2 test result were excluded from unspecified, and any dose mhorts separately for each sex and
the infuction mhort. In the infuction cohort, there were no age sttatum. RRs whose Cis did not include 1.0 were mnsid-
other cxcl.usions based on vaccination status. The follow- ered statistically significant; RRs were not mmpared ~
ing indct dates were used for mhort entrance: fust po.wve outcomes, risk windows, vaccine dose, or sex and agesttatum.
SARS-CoV-2 test result for the infuction mhort; first vac- This activity was reviewed by CDC and was amducted con-
cination for the first dose mhort; second vaccination for the sistent with applicable federal law and CDC policy.)101c
second dose mhort; the single vaccioation for the unspecific The study population mnsisted of 15,215,178 persons aged
dose mhort; and the first, second, and unspecified vaccination ~5 yeus, including 814,524 in the infuction mhort; 2,548,334
for the any dose cohort. Persons could be represented twice in in the first dose mhort; 2,483,597 in the second dose mhort;
the any dose mhort if they received a first and ~nd dose; 1,681,169 in the unspecified dose cohort; and 6,713,100 in
they would have a different index date for each of the doses. the any dose mhort (Table 1).tt Among the four COVID-19
Incidence of three cardiac outcomes (myocuditis; myocar- vaaioarionmhorts, 77%-79% ofpersons were aged ~O years;
ditis or pericarditis; and myoc:arditis, peric:arditis, or MIS) within the SARS-CoV-2 infection mhort, 63% were aged
were defined using lntemlltiontd Clllssification of Diseases, ~Oyears.
Tmth Revision, CliniazlModijiaztion (ICD-10-CM) diagnostic Among males aged 5-11 years, the incidences of myocar-
codes§ within 7-day or 21-day risk windows after the index: ditis and myocu:ditis or perlcarditis were 12.6-17.6 cases per
date; persons who had received any of these diagnoses during 100,000 after infuction, 0-4 after the first vaa:ine dose, and
the year preceding the index date were exduded. The outcome 0 after the second dose; incidences ofmyocardi~ pericarditis,
induding MIS was only assessed for the infection cohort or MIS were 93.0-133.2 after infection (Table 2). Because
because the rare reports of MIS after mRNA COVID-19 there were no or few cases of myocarditis or pericarditis after
vaccination, the RRs for several mmparisons could not be
tThe 6m dose cohon included persons who had either the first of 2 doses
~0 days before a scmnd dose or a spcci6c mdc for a 6rst dose; thesemnd dose
calculated or were not statistically significant. The RRs were
cohort inc:ludcd persons who had either the second of2 doses ~ days after a significant when comparing myocarditis, pericarditis, or
6m close or a spcci6c mdc for a semnd dose. The umpccific:d dose cohon MIS in the 42 days after infection (133.2 cases per 100,000)
inc:ludcd pmonswhohad onlyonemde for an mRNA COVID-19vaa:ination
that was not spccificd as a first or second dose. The any dose cohon was the with myocarditis or peric:arditis after the first (4.0 cases per
combination of the first, sccx,ml, and unspcci&cd close mhorts; this cohon 100,000; RR33.3) or second (4.7 cases per 100,000; RR28.2)
included all doses capam:d. with duplication ofpersons who rccem:d 2 doses. vaccine dose.
Vaccination and infection co:lusions were provided before but not after
exposures; thus, pcnons who had an infection soon after a vaccination would
still be included in the wcrinarion cohort or vice vma. The cohorts were not ! MIS oftm oa:ws in the abscncc of prior positive SARS-C.oV-2 test results;
muwallycax:lusivc; pcaonsvaa:inatcdand infectr.d could bcin both waioarion these cases were not capmml in the infection cohorts.
and infection cohorts. However, because the outcomes were assessed in shon - 45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. Sect. 241 (d); 5 U.S.C. Sect.
time periods after inda dates, overlap in outmmcs was unlikdJ; unless an 552a; 44 u.s.c. Sect. Sea. 3501 et seq.
outcome was ClpCricnccd mon: than once. tt In the fhstandscamd dmcv.m:incmhorts, 27% ofpcrsonsm:cm:dModcma
§Myoc:arditiswas ddinal as prcsc:nce ofICD-10-CM codes B33.22, 140, 140.0, and 73% rccem:d Pmc:r-BioNTc:ch. In the uaspcdficd close cohort, 36%
140.1, 140.8, 140.9, or 151.4. PericarditiswasdcfmcdaspffSt.llCCofICD-10-CM rca:ivcd Modana and 64% Pm.cr-BioNfccb., and in the any close mhon,
codes B33.23, 130, 130.0, l30.1, 130.8, 130.9, or 131.9. MIS was dc6ncd as 29% rca:m:d Modcrna and 71% P&zcr-BioNTc:ch.
presence ofICD-10-CM code M35.81.
2 MMWR / April 1, ~022 / Vol. 71

AR07939
Early Release
TABLE 1. Demographic characteristics of penons who were Infected with SARS-C.oV-2 or received a first. second, unspecified, or any dose of
an mRNA COVID-19 vaccine* -National Patlent-Centered Olnkal Research Network, United States.January 1, 2021-Jarwary 31, 2022
No.(96)
mRNA COVID-19vaufnatlon mhort
SARS-CoV-2
Characterfstlc Infection mhortf Rrst dose•,§ Seamd c1ose•.S Unspedfted dose*•' Anydose*,..
Cohort total 814,524 (100) 2.548,334 (100) 2.483,597 (100) 1,e81,169(100) 6,713,100 (100)
Age group, yrs
5-11 76,960(9) 48,986(2) 41.742(2) 3().199(2) 120/J27(2)
12-17 70,336(9) 190,810(7) 179.612(7) 113,775(7) 484,197(7)
18-29 151,950 (19) 308,892 (12) 297,560 (12) 241,787 (14) 848,239 (13)
30-50 255,103 (31) 665,876 (26) 652,947 (26) 490,808 (29) 1,809,631 (27)
51-65 152,243 (19) 601,615 (24) 588,873 (24) 404,445 (24) 1,594,933 (24)
~ 107,932 (13) 732,155 (29) 722,863 (29) 400,155 (24) 1,855,173 (28)
Sex
Female 457,506 (56) 1,497,984 (59) 1,463,746 (59) 997,741 (59) 3,959,471 (59)
Male 357,018 (44) 1,0S0,350 (41) 1,019,851 (41) 683,428 (41) 2,753,629 (41)
RaceJEthnldtytt
Hispanic 133,784 (16) 309,468 (12) 298,270 (12) 169,688 (1 O) 777,426 (12)
Asian 23,684(3) 133,445 (5) 131,205 (5) 83,937(5) 348,587(5)
Black or African American 162,434 (20) 408,657(16) 395,283 (16) 283,534 (17) 1,087,474(16)
Other 34,473(4) 93,100(4) 90,122(4) 54,305(3) 237,527(4)
White 408,152 (50) 1,441,573 (57) 1,407,974 (57) 1,001,686 (60) 3,851,233 (57)
Missing§§ 58,980(7) 205,834(8) 204,224(8) 98,299(6) 508,357(8)
* In the first and second dose cohorts, 2796 of persons received mRNA-1273 (Modema) vaccine and 739' received BNT162b2 (Pflzer-BfoNTech) vacdne. ln the
unspecifted dose cohort. 36116 received Modema and 6496 PRzer-BfoNTech. In the any dose cohort. 29J6 received Moderna and 7196 Pflzer-BloNTech.
t Persons In the Infection cohort lnduded those who received cl?1 positive SARS-CoV-2 molecular or antigen test result.
Slheflrstdose cohort Included persons who had either the fhst of 2 doses cl?20 days before a second dose or a spedflc code for a first dose;the second dose cohort
Included persons who had either the second of 2 doses :!!20 days after a first dose or a spedflc code for a second dose.
•lheunspedfleddosecohortlncludedpersonswhohadaslngledosethatwasnotspedfledasaflrstorseconddose;dosesspeclfledasboosterdoseswereexduded.
"The any dose cohort Is the first, second, and unspedfled dose cohorts combined; persons who had 2 doses are represented twice In the cohort but had different
Index dates forthefrflrst and second doses.
tt Persons of Hispanic origin could be ofany race; Asian, Black or African American, White, or other (which lndudes American Indian or Alaska Native, Native HawaDan
or Other Paclflc Islander, multiple race, and other race) persons are not Hispanic.
§§ Missing race category lndudes no Information, refused to answer, unknown, or missing.
Among males aged 12-17 years, the incidences of myocar- for cardiac outcomes among infected persons compared
ditis and myocmlitis or pericmlitis were 50.1-64.9 cases per with first dose recipients were 10.7-Gl.2, and compared
100,000 after infection, 2.2-3.3 after the 6rst vaa:ine dose, with second dose recipients, were 10.8-115.2; all RRs were
and 22.0-35.9 after the second dose; incidences ofmyocuditm, statistically signiflcant.
pericarditis, or MIS were 150.5-180.0 after infection. RRs for Among females aged 5-11 years, incidences of myocmlitis
cardiac outcomes mmparing infucted persons with first dose andmyocmlitis or pericatditiswere 5.4-10.8 cases per 100,000
recipients were 4.9-69.0, and with second dose recipients, were after infection, and incidences of myocarditis, pericarditis, or
1.8-5.6; all RRs were statistically signiflcant. MIS were 67.3-94.2 after infection (Table 3). No cases of
Among males aged 18-29 years, the incidences of myocar- myocmlitis or perlcarditis after vaccination were identified.
ditis and myocarditis or pericmlitiswere 55.3-100.6 cases per The incidences ofcardiac outcomes did notwry by age among
100,000 after infection, 0.9-8.1 after the first vaa:ine dooe, females aged ~12 years. In this group, the incidences of myo-
and 6.5-15.0 after the second dose; incidences ofmyocmlitis, carditis and myocarditis or perlcmlitis were 11.9-61.7 cases
pericarditis, or MIS were 97.2-140.8 after infection. RRs for per 100,000 after infection, 0.5--6.2 after the first vaccine dose,
cardiac outcomes mmparing infucted persons with first dose and 0.5-5.4 after the second dme; incidences of myocmlitis,
recipients were 7 .2-61.8, and with semnd dose recipients, were pericarditis, or MIS were 27.1-93.3 after infection. Among
6.7-8.5; all RRs were statistically signiflcant. females aged ~12 years, RRs for cardiac outmmes mmparing
Among males aged ~O yeais, the incidences ofmyocarditis infected persons with first dose recipients were 7 .4-42.6,
and myocarditis or perlcarditis were 57.2-114.0 cases per and with second dose recipients, were 6.4-62.9; all RRs were
100,000 after infection, 0.9-7.3 after the first vaccine dose, statistically signiflcant.
and 0.5-7.3 after the semnd dose; incidences of myocmlitis,
perlcarditis, or MIS were 109.1-136.8 after infection. RRs
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TABLE 2. lnddenceof cardiacoutmmesamong males aged ~yearsafterSARS-CoV-2 Infection ormRNA COVID-19vacdnatlon and rlskratios.
by age group and rlstwlndow-Natlonal Patient-centered Olnlcal Researdl Networlr. United States. January 1, 2021-January 31, 2022
lnddelsc:e9 among males Risk ratio (95Ct6 0) SARS-CoV-2 lnfedlon versus mRNA COVID-19vacdnatlon
mRNA COVID-19vacdnatlon cohort mRNA COVID-19vacdnatlon cohort
Agegroup,yrs/SARS<oV-2 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
OUtcome/ Infection Rrst Seamd Unspecified Any Rrst Second Unspedfted Arry
Rlskwlndow mhortt tJosei dosel c1oset dose.. dose' dosei c1oset dose-
. s-11tt
MJocardltls
7-day 12.6 0 0 0 0 NC NC NC NC
21-day 17.6 4.0 0 6.5 3.2 4.4 (05-35.7) NC 2.7 (03-22.1) 5.4(1.1-26.1)
Myocardltls or perlcardltls
7-day 12.6 0 0 0 0 NC NC NC NC
21-day 17.6 4.0 0 6.5 3.2 4.4 (0.5-35.7) NC 2.7 (03-22.1) 5.4(1.1-26.1)
Myocardltls, pertcardltls, or MJ5H
7-day 93.0 -" NC NC NC NC
21-day 103.0 25:, (3.5-187.0) NC 16.0 (2.2-116.0) 31.7 (7:J-131.2)
42-day 133.2 333 (4..6-240.5) 28.2 (3.9-203.9) 103 (25-42.3) 205 (7.4-56.7)
12-1:,tt
Myocardltis
7-day 50.1 2.2 22.0 16.7 12.9 23.0 (53-99.5) 2.3(1.2-4A) 3.0(1.3~ 3.9 (2.1-7.0)
21-day 59.0 3.3 26.7 20.4 16.0 18.0 (5.4-60.6) 2.2 (1.2-4.0) 2.9 (1.4-6.0) 3.7 (2.1-6A)
7-day 56.0 2.2 26.7 22.3 16.0 25:, (6.0-1103) 2.1 (1.1-3.9) 2.5 (1.2-5.2) 3.5 (2.0-6.1)
21-day 64.9 3.3 35.9 29.7 21.6 19.8 (5.9-66.2) 1.8(1.0-3.1) 2.2 (1.1-4.2) 3.0 (1.8-5.0)
Myocarditls, perlcardltls, or MJ5H
7-day 1505 69.0 (16.8-283.2) 5.6 (3.5-9.2) 6.8 (3.6-12.7) 9A (6.2-14A)
21-day 1593 48.7 (15.2-155.7) 4.4 (2.9-6.9) SA (3.1--9.4) 7.4 (5.0-10.8)
42-day 180.0 4.9 (3.2-7.4) 4.6 (3.0-6.9) SA (3.2--9.1) 4.9 (3.5-6.7)
18-29
Myocardltts
7-day 55.3 0.9 6.5 7.0 4.6 61.8 (8.5-451.8) 8.5 (3.7-19.1) 7.9(33-19.0) 12.0 (6.4-22.5)
21-day 63.7 3.6 8.4 11.6 75 17.8 (6.4-49.8) 7.6 (3.7-15.7) 55 (2.7-11.0) 8.4 (5.0-14.2)
Myocardltts or perfcarditls
7-day 855 2.7 12.1 22.0 115 31.8 (9.9-102.0) 7.0 (3.8-12.9) 3.9 (23-6.6) 7A(4.8-115)
21-day 100.6 8.1 15.0 27.8 16.1 12.5 (6.2-25.2) 6.7 (3.9-11.7) 3.6 (2.3-5.8) 6.3 (4.3--9.1)
Myocardltls, perlcardltls, or MlsH
7-day 9'1.2 36.2 (11.3-115.5) 8.0 (4.4-14.6) 4A(2.6-7A) 8.5 (5.6-12.9)
21-day 112.3 13.9 (7.0-28.0) 75 (4.4-13.o) 4.0 (2.5-6.4) 7.0(4.8-10.1)
42-day 140.8 7.2 (4.5-11.4) 8.4 (5.o-13.9) 4.5 (2.9-6.9) 6.4 (4.6-8.8)
~o
Myucardltls
7-day 57.2 0.9 05 3.0 13 67.2 (31.4-143.8) 115.2 (42.6-311.7) 18.9 (11.2-31.7) 45.7 (30.2-69.2)
21-day 63.0 1.9 1.2 4.2 2.2 32A (19.3-543) 50.8 (26.7-96.4) 15.1 (9:J-23.7) 28.3 (20.4-393)
Myocardllls or perlcardltls
7-day 100.2 3.8 3.1 1S.O 6.3 26.6 (18.2-38.7) 32.3 (21.3-48.8) 6.7 (5.2-8.6) 16.0 (12.9-19.8)
21-day 114.0 73 73 20.1 10A 15.6 (11.8-20.7) 15.6 (11.7-20.7) 5.7 (4.5-7.1) 18.9 (9.1-13.1)
Myoc:ardltls, perlcardltls, or MJSIS
7-day 109.1 28.9 (19.9-42.0) 35.1 (23.3-53.0) 7 3 (5.7-9.4) 17.4 (14.1-215)
21-day 123.0 16.8 (12.7-22.3) 16.8 (12.7-22.2) 6.1 (4.9-7.7) 11.8 (9.9-14.0)
42-day 136.8 10.7 (8.6-13.4) 10.8 (8.6-13.5) SA (4.4-6.7) 8.7 (7.4-10.1)
Abbmvlatlons: MIS= multtsystem Inflammatory syndrome; NC = not calculated.
• Cases per 100,000 persons.
t Persons In the Infection cohort Included those who received ~1 positive SAAS-CoV-2 molecular or antigen test result.
§ Theflrst dose cohort lnduded persons who had either the first of 2 doses :i!:20 days before a second dose or a spedffc code for a first dose;the second dose cohort
Included persons who had either the second of 2 doses :i!:20 days after a first dose or a spedflc code for a second dose.
1 Theunspedfleddosecohortlncluded persons who had aslngledosethatwas not specified asaftrstorsecond dose;dosesspedfled as booster doses were excluded.
"The any dose cohort Is the first, second., and unspedfled dose cohorts combined; persons who had 2 doses are represented twice In the cohort but had different
Index datesforthelrflrst and second doses.
tt BNT162b2 tpffzer-81oNTech) Is the only mRNA COVID-19 vacdne approved for persons aged 5-17)'eill'S.
§§ Diagnoses of rnyocardltk, perlcard~ or MIS after a poslthle SARS-CoV-2 test result compared with diagnoses of rnyocardltfs or pertcarditfs after vaccination. The
42-day risk ratios were only calculated for this outa>me and comparison. The fnddence of myocardltls or perlcardltls In this risk window was 4.0, 37.1, 19.7, and
12.8 cases per 100,000 for males aged 5-11, 12-17, 18-29, and 2!-30 yea,s after a first dose of an mRNA COVID-19 vaccine; 4.7, 39.4, 16.8, and 12.7 cases per 100,000
after a second dose; 12.9, 33.4, 313, and 253 cases per 100,000 after an unspecffled dose; and 6.5, 37.1, 22.0, and 15.8 cases per 100,000 after any dose.
" Dashes Indicate the Incidence for vaccination cohorts was not applicable because the comparison for Incidence of myocardftls. perlcardltls, or MIS after Infection
was to myocardltls or perkardftls after vaccination.
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TABLE 3. Incidence of cardiac outcomes among females aged ~5 years after SARS-0,V-2 Infection or 111RNA COVID-19 vaccination and risk
ratlos,byagegroupandrlskwlnclcM-NatlonalPatient-centeredClnicalResearchNetwork,UnltedStates,January1,2021-January31,2022
. Incidence• among females Risk ratio (,sew, CQ SARS-CoV-2 lnfedlon versus mRNA COVID-19vacdnatlon
Age group. yrs/ SARS-CoV-2 mRNA CDVID-19 vac:dnatlon a,hort mRNA CDVID-19vacdnatlon G>hol't
OUtmme/ Infection Rrst Second Unspecified Any

Rlskwlndow mhortt dos,e§ dose' c1oset dose" Flrstdosei Seconddosei Unspecified c1oset
s-ntt
Myocardltls
7-day 5.4 0 0 0 0 NC NC NC NC
21-day 8.1 0 0 0 0 NC NC NC NC
Myocardltls or pertcardltls
7-day 8.1 0 0 0 0 NC NC NC NC
21-day 10.8 0 0 0 0 NC NC NC NC
Myocanlltls, penmrdltls, or MISff
7-day fil3 -" NC NC NC NC
21-day 80:J NC NC NC NC
42-day 942 NC NC NC NC
12-1711'
Myocardltls
7-day 24:J 1.0 1.1 0 0.8 245 (3.1-193.3) 23.1 (2.9-182.0) NC 31.2 (6:1-1443)
21-day 35.7 1.0 3.2 1.7 2.G 35.4 (4.6-270.5) 11.1 (3.2-39.o) 21.4 (2.8-163.4) 18.0 (6.4-50.5)
Myocardltls or perfcardftls
7-day 24:J 2.0 2.1 0 1.6 12.2 (2.6-56.7) 115(25-53.4) NC 15.6 (4.8-50.6)
21-day 35.7 2.0 5.4 3.3 3.6 17.7 (4.0-78.4) 6.7 (2.4-18.7) 10.7 (2.4-47.4) 10.0 (4.3-23.4)
Myocardltls, penmrdltls, or MJSIS
7-day 63.1 313 (7.4-132.7) 295 (6.9-125.0) NC 39.8 (13.8-115.2)
21-day 79.6 395 (9.4-165.4) 14.9 (5.7-383) 23.8 (5.7-99.9) 223 (1 o.6-47.2)
42-day 933 11.6 (5.4-25.0) 12.4 (55-28.1) 14.0 (5.0-39.4) 12.4(7.1-21.7)
18-29
Myocarditls
7-day 11.9 05 1.6 3.9 1.8 235 (3.0-182.0) 7.6(2.1-27.1) 3.1 (1.1-8.4) 65 (28-15.2)
21-day 195 1.0 2.1 5.8 2.8 19.2 (4.5-82.9) 93 (3.1-275) 3.4 (1.5-7.5) 7.1 (3.6-14.0)
7-day 23.8 25 3.1 7.1 4.0 9.4 (3.6-24.8) 7.6(3.1-18.7) 3.4 (1.6-7.0) 5.9 (3.3-10.6)
21-day 33.6 4.6 5.2 10.9 6.6 7.4 (3.5-1 S.5) 6.4(3.1-13.1) 3.1 (1.7-5.6) 5.1 (3.1-8.2)
Myocardltls, perlcardltls, or Masff
7-day 27.1 10:J (4.f-27.9) 8.6 (3.5-21.0) 3.8 (1.9-7.8) 6.7 (3.8-11.9)
21-day 40.1 8.8 (4.2-18.2) 7.6 (3.8-15.4) 3:, (2.1-6.5) 6.1 (3.8-9.6)
42-day 672 83 (4.8-14.3) 11.6(6.1-22.1) 5.2 (3.2-8.7) 7.8 (53-113)
~
Myocardltls
7-day 32.6 O.S o.s 1.0 0.7 42.6 (21.5-84.4) 62.9 (27.6-143.6) 313 (15.2-643) 44.0 (27.9-693)
21-day 363 1.4 0.9 1.6 13 25.2 (15.1-42.0) 383 (20.6-713) 23.2 (12.8-42.2) 28.2 (19.6-40.6)
Myocarditls or penmrdltls
7-day 53.8 3.1 1.7 8.2 3.9 17.1 (12.G-24.5) 31.2 (19.6-49.7) 6.6 (4.9-8.8) 13.9 (11.0-17.7)
21-day 61.7 6.2 4.1 10.7 65 10.0 (7.6-13.1) 14.9 (10.S-20.5) 5.8 (4.5-7.5) 9.4(7.7-11.5)
M:,ocardltls. perlcardltis. or MisH
7-day 58.6 18.7 (13.1-26.6) 34.0 (21.4-54.0) 7.1 (5.4-9.5) 15.2 (12.D-19.2)
21-day 68.2 11.0 (8.4-14.4) 165 (12.G-22.6) 6.4(4.9-8.3) 10.4 (8.6-12.7)
42-day 79.6 8.4 (6.7-10.5) 10.0 (7.9-12.8) 5.6 (4.5-7.0) 7.9 (6.7-9.4)
Abbreviations: MIS= multlsystem Inflammatory syndrome; NC = not calculated.
• Cases per 100,000 persons.
t Persons In the Infection cohort Included those w"9 received ~1 positive SARS-CoV-2 molecular or antigen test result.
§ Theflrstdose cohort Included persons who had efthertheftrstof 2 doses~ days before a second dose or a spedffc code fora ftrstdose;the second dose cohort
Included persons who had either the second of 2 doses :t20 days after a first dose or a spedflc code for a second dose.
1 The unspedfted dose cohort Included persons who had a single dose that was notspedfled as a first or second~ doses specified as booster dosesweree-=luded.
"The any dose cohort Is the first, second, and unspecified dose cohorts combined; persons who had 2 doses are represented twice In the cohort but had different
Index dates for thelrflrst and second doses.
tt BNT162b2 (Pftzer-BloNrech) Is the only mRNA COVID-19 vaccine approved for pessons aged 5-17 years.
§§ Diagnoses of myocardltls. perlcardltfs. or MIS after a positive SARS-CoV-2 test result compared with diagnoses of rnyocardltis or perfcardltis aftervacdnatlon. The
42-day risk ratios were only calculated for this outcome and comparison.1he Incidence of myocardltis or pericardltis fn this risk window was o. e.1. 8.1, 95 cases
per 100.000 for females 5-11, 12-11. 18-29, and ~o years after a first dose of an mRNA COVID-19 vacdne; o, 75, 5.8, and ao cases per 100,000 after a second dose;
0, 6.7, 12.9, and 14.2 cases per 100,000 after an unspedfled dose; and 0, 7 5, 8.7, and 10.1 cases per 100,000 after any dose.
" Dashes Indicate the Incidence for vaccination cohorts was not applicable because the comparison for Incidence of "¥)Cllrdltis, perlcardltls, or MIS after lnfectfon
was to myocardltls or perfcan:lltis after vaccination.
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Discussion
Summary
Analysis ofEHR data from 40 U.S. health care systems found What is already known about this topic?
that the incidenc.es ofcardiac complications after SARS-CoV-2 Studies have found an increased risk for cardiac complications
infection or mRNA COVID-19 vaccination were low overall after SARS-CoV-2 infection and mRNA COVID-19 vaccination,
but were higher after infection than after vaccination for both but few have compared these risks.
males and females in all age groups. Two studies from Israel (2) What is added by this report?
and the United Kingdom (3) have found similar higher risk Data from 40 health care systems participating in a large
for myocarditis after SARS-CoV-2 infection compared with network found that the risk for cardiac complications was
that after mRNA COVID-19 vaccination. significantly higher after SARS-CoV-2 infection than after mRNA
Myocarditis or pericarditis incidence after mRNA COVID-19 COVID-19 vaccination for both males and females In all
vaccination in the current study (0-35.9 per 100,000 for males age groups.
and 0-10.9 for females across age groups and vaccine cohorts) What are the implications for public health practice?
was similar to estimates found in a study from eight U.S. These findings support continued use of recommended mRNA
health systems in the Vaccine Safety Datalink (JO). Previous COVID-19 vaccines among all eligible persons aged ~s years.
CDC estimates found the highest risk for post-vaccination
myocarditis among males aged 16-17 years {10.6 per 100,000) cardiac outcomes.!! Fourth, case definitions for myocarditis,
during a 7-day risk window after receipt of a second mRNA pericarditis, or MIS were ICD-10-CM cod~based; diagno-
COVID-19 vaccine dose (.5). Estimates from the current study ses were not confirmed with chart review and are subject to
(22.0 per 100,000 males aged 12-17 years) are higher, likely misclassification. Fifth, cases of MIS among persons without
because outcomes were captured using ICD- 10-CM codes documented SARS-CoV-2 infection were not included (9).
alone rather than through passive reporting with subsequent Finally, some overlap might have occurred in risk windows
verification through medical record review. Even among for persons who had a SARS-CoV-2 infection soon after
males aged 12-17 years, the group with the highest incidence vaccination or a vaccination soon after infection. Exclusions
of cardiac complications after receipt of a second mRNA were made for persons who received COVID-19 vaccine doses
COVID-19 vaccine dose, the risk was 1.8-5.6 times as high s30 days before infection or who had infections s30 days
after SARS-CoV-2 infection than after vaccination. · before vaccination.
The findings in this report are subject to at least six limita- Cardiac complications were rare after SARS-CoV-2 infec-
tions. First, data were obtained using a query that returned tion or mRNA COVID-19 vaccination. However, the risks
aggregate data from sites, precluding adjustment for potential for these complications were higher after infection than after
confuunders. Stratification by age and sex was performed vaccination among males and females in all age groups. These
because oftheir clear prior association with cardiac outcomes. findings provide important context for balancing risks and
Second, outcomes were rare in some cohorts, leading to benefits of mRNA COVID-19 vaccination among eligible
wide Cls around RR estimates. Third, only SARS-CoV-2 test persons <!5 years.
results and mRNA COVID-19 vaccinations documented in
,-,- If patients who rcccivcd a SARS-CoV-2-positivc test result at a health care
EHRs were available for assessment. SARS-CoV-2 infections system were more likdy ro return to the same health care system for
were not captured if testing occurred in homes, schools, com- myocarditis, paicarditis, or MIS treatment than were patients who had their
munity sites, or pharmacies. Similarly, EHR data in this study mRNA COVID-19 vaccination documented at the health care system, then
the undcrasa:rt2iruncnt of outcomes might be higher in the vaccination
captured <! 1 dose of mRNA COVID-19 vaccine for 28% of cohorts, introducing bi.as away from the null. This scenario might occur ifa
persons aged <!5 years. Nationally, 82% ofpersons aged <!5 years person was more likdy to visit a tcniaJy care rcfcm.l ccntcr participating in
this srudy if they were more scvady ill with a cardiac complication after
were reported to have received any COVID-19 vaccination;
SARS-CoV-2 infection than a perhaps mild cardiac complication after
97% ofall vaccinations administered were mRNA COVID-19 COVID-19 vaccination. However, if the cardiac complications wcrc more
vaccines.§§ Underascertainment of SARS-CoV-2 infections commonly I.inked ID vaa:ination than in.fu:t:ion in the EHR. bias would be
roward the null. This scenario might occur if clinicians were more likely ID
and mRNA COVID-19 vaccinations reduced sample size and document an mRNA COVID-19 -nccination in the EHR if a cardiac
might have introduced bias ifcapture of infection or vaccina- complication was noted after vaa:ination than if the cardiac complication
tion within the EHR occurred differentially for those with occurred after S.ARS-CoV-2 infection.
§§ https://<XJYid.ak.gov/rovid-<lata-mckcr/#vaa:inations(Aa:i=;dMan:h29,2022).
6 MMWR / April 1, 2022 / Vol. 71

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Acknowledgments References
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5. Oster ME, Shay DK. Su JR, et al Myocarditis cases reponed after
Health, Bchavior and Dcvdopmcnt, Scanl.c Children's Rcscarch Institute, Scanl.c
Children's Hospital, Seattle, Washington; 7Dcpanment ofPopulation and Data
mRNA-based COVID-19 vaccination in the US from Deccmher 2020
Sciences and Department of Immunology, University ofTaas Southwestern to August 2021. JAMA 2022;327:331-40. PMID:35076665 hnps://
Medical Center, Dallas, Texas; 8Ccntcr fur Gastrointestinal Biologyand D ~ doi.org/10.1001/jama.2021.24110
University ofNorth Carolina School ofMedicine, Chapel Hill, North Carolina; 6. CDC. Multisystem Inflammatory Syndrome (MIS). Atlanta, GA: US
91bc Fcnway Institute, Fcnway Health, Harvard Medical School, Boston, Department of Health and Human Services, CDC; 2021. Accessed
MassachuscttS; 10Childrcn's Healthcare of Atlanta, Emory University School March 10, 2022. hnps://www.cdc.gov/mis/inda.html
ofMedicine, Atlanta, Georgia; 11Department of Medicine, Lewis Karz School 7. Forrest CB, McTigue KM, HernandezAF, et al. PCORnet" 2020: current
ofMedicine atTanplc University. Philadelphia, Pennsylvania; 120CHIN, Inc., state, accomplishments, and future directions. J Clin Epidemiol
Portland, Oregon; 13Nemours Cardiac Center, Nemours Children's Health 2021; 129:60-7. PMID:3300263 5 https://doi. org/10.1016/j.
System, Wilmington, Ddawarc. jclinepi.2020.09.036
8. Yousaf AR. Concse MM, Taylor AW, et al.; MIS-C Investigation
All authors have completed and submitted the International Authorship Group. Reponcd cases of multi.system inflammatory
Committee of Medical Journal Editors form for disclosure of syndrome in children aged 12-20 years in the USA who received a
potential conflicts ofinterest. Jason P. Block, Christopher B. Forrest, COVID-19 vaccine, December, 2020, through August, 2021: a
Grace M. Lee, and Thomas W. Carton report support from the survcillance investigation. Lancet Child Adolesc Health 2022;S2352-
4642(22)00028-l. PMID:35216660 https://doi.org/10.1016/
National Institutes of Health (NIH) as part of the Researching
S2352-4642(22)00028-l
COVID to Enhance Recovery (RECOVER) program. Nidhi 9. Feldstein LR, Rose EB, Horwitz SM, et al.; Overcoming COVID-19
Ghildayal reports NIH funding for a postdoctoral position. Investigators; CDC COVID-19 Response Team. Multisystem
Michad D. Kappelman reports grants from NIH, PCORI, Helmslcy inflammatory syndrome in U.S. children and adolescents. N Engl J Med
Trust, Abbvie, Arenapharm, Boehringer Ingelheim, Bristol Myers 2020;383:334-46. PMID:32598831 https://doi.org/10.1056/
Squibb, Celtrion, Eli Lilly, Genentech, Janssen (a subsidiary of NEJMoa2021680
10. Klein NP, Lewis N, Goddard K, et al. Surveillance for adverse events
Johnson & Johnson, Pfizer, and Takeda) and consulting fees from after COVID-19 mRNA vaccination. JAMA 2021;326:1390-9.
Abbvie, Janssen, Takeda, and Pfizer; payment for service on a data PMID:34477808 https://doi.org/10.1001/jama.2021.15072
safety monitoring board for Eli Lllly, and payment for service on the
editorial board of the American Journal of Gastroenterology.
Kenneth H. Mayer reports grant support from NIH's COVID-19
Vaccine Trials Network for a Phase III AstraZeneca SARS-CoV-2
vaccine trial. Matthew E. Oster reports institutional support from
. NIH's National Hean. Lung, and Blood Institute. No other potential
conflicts of interest were disclosed.
Readers who have difficulty accessing this PDF file may aca:ss the HTML file at https://www.cdc.gov/mmwr/volumes/71/wr/mm7ll4el.
htm?s_cid=mm7114el_w. Address all inquiries about the MMWR Series, including material to be considered for publication, to Editor,
MMWR Series, Mailstop V25-5, CDC, 1600 Clifton Rd., N .E ., Atlanta, GA 30329-4027 or to mmwrq@cdc.gov.
MMWR / April 1, 2022 / Vol. 71 7

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WITHDRAWN: A Report on Myocarditis Adverse Events in the U.S.

Vaccine Adverse Events Reporting System (VAERS) in Association
with COVID-19 Injectable Biological Products
Jessica Rose PhD, MSc, BSc, Peter A. McCullough MD, MPH
PII: S0146-2806(21 )00226-7

DOI: https://doi.org/10.1016/j.cpcardiol.2021.101011
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To appear in: Current Problems in Cardiology
Please cite this article as: Jessica Rose PhD, MSc, BSc, Peter A. McCullough MD, MPH, WITH-
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Reporting System (VAERS} in Association with COVID-19 Injectable Biological Products>
Jessica Rose, PhD, MSc, 8Sca••jessicarose1974@protonmail.com and Peter A. McCullough, MD,
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TAB 56
AR07948

FEDERAL COURT
BETWEEN:
NABIL BEN NAOUM
Demandeur
et
Défendeur

AND BETWEEN:
Demandeur
et
Défendeur

AND BETWEEN:
AND AEDAN MACDONALD
Applicants
and
Respondent
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AND BETWEEN:
Applicants
and
Respondent
_________________________________________________________________
CROSS-EXAMINATION OF DR. VALENTINA CVETIC

May 13, 2022
_________________________________________________________________
Sharlene Telles-Langdon For the Respondent

Keith Wilson For Dr. Cvetic
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INDEX
PAGE
Exhibits ................................................... 4
DR. VALENTINA CVETIC

Cross-Examination by Ms. Telles-Langdon ............... 5
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EXHIBITS
PAGE
1. SOGC Statement on Covid-19 Vaccination ................ 24
2. Product Monograph for FluLaval Tetra for 2021-2022 .... 36
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1 MAY 13, 2022
4 VALENTINA CVETIC, affirmed, testified:
5 COURT REPORTER: Can you just state your full name for
6 the record and then spell it?
7 MS. CVETIC: Valentina Cvetic, V-a-l-e-n-t-i-n-a, C-
8 v-e-t-i-c.
9 COURT REPORTER: Perfect. Thank you. Counsel, we’re on
10 the record whenever you’re ready.
11
12 CROSS-EXAMINATON BY MS. TELLES-LANGDON
13
14 MS. TELLES-LANGDON:
15 1 MS. TELLES-LANGDON: Thank you, good morning, Dr. Cvetic.
16 For the record would you please confirm that you are
17 the Valentina Cvetic who swore an affidavit dated
18 March 11, 2022 in the Brian Peckford et al. v. Canada

19 proceedings in the Federal Court?
20 A. Yes.
21 2 Q. This morning I have some questions for you based on
22 the affidavit you swore on March 11th, okay?
23 A. Okay.
24 3 Q. I’m going to begin with a few housekeeping matters.
25 A. Hm..mm.
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1 4 Q. We will be referring to your affidavit during the
2 cross-examination. Do you have it there available
3 with you for your reference?
4 A. Yeah. Yeah.
5 5 Q. And, Dr. Cvetic, where are you physically located
6 right now?
7 A. I am in Kitchener, Ontario.
8 6 Q. In your room?
9 A. At my office. My clinic.
10 7 Q. Yes, okay. And would you please confirm that you are
11 the only person in the room?
12 A. I have a - my brother’s here. He’s in the - at the
13 desk next door to me.
14 8 Q. There’s a desk next door to you?
15 A. It’s the - he’s in the secretary’s desk.
16 9 Q. Is your office a closed office or are you...
17 A. It’s a closed office. There’s no patients.
18 10 Q. Okay, Dr. Cvetic, it’s important that you not speak or
19 - to your brother during the cross-examination.
20 A. No.
21 11 Q. Will you please confirm that during the breaks in
22 cross-examination you will not communicate with any
23 party outside of this virtual meeting, including your
24 brother or your lawyers? Or take instructions from
25 anyone during this examination?
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1 A. Absolutely.
2 12 Q. Other than properly framed objections on this virtual
3 hearing?
4 A. Yeah. Yes.
5 13 Q. Will you please confirm for me that during your cross-
6 examination you’ll not be viewing or referring to any
7 notes or documents either paper or electronically
8 other than your affidavit or as I request documents

9 that are presented to you during the cross-
10 examination?
11 A. Okay.
12 14 Q. Would you confirm that you have no other documents on
13 the desk right in front of you or on your computer
14 screen?
15 A. I have them next – don’t next to me. Do you want me
16 to get rid of them?
17 15 Q. What in - what documents are you - are they documents
18 that are relevant to this cross-examination?
19 A. They’re all the studies that have been quoted in -
20 referenced in your - your expert witnesses.
21 16 Q. Okay. For the sake of clarity, Dr. Cvetic, when I
22 refer to a page number in your affidavit it will be
23 the page number in the upper right hand corner of your
24 affidavit, okay? And that will include the exhibits
25 and your report. As a housekeeping matter, Dr.
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1 Cvetic, would you please tell me which documents you
2 reviewed in preparing for this cross-examination?
3 Well, I’ll be more specific. Did you review the
4 affidavit of Dr. Vanessa Poliquin?
5 A. Yes.
6 17 Q. Do you have Dr. Poliquin’s affidavit available to you?
7 A. Yes.
8 18 Q. Did you review the affidavit of Dr. Dawn Bowdish?

9 A. Yes.
10 19 Q. Moving on to your qualifications, Dr. Cvetic, in
11 paragraph 2 of your affidavit you’ve indicated that
12 you are a practicing obstetrician and gynecologist.
13 Which percentage of your work would you say is spent
14 on your obstetrics practice?
15 A. So, prior to July of last year I was doing obstetrics
16 and gynecology about 50/50, probably more obstetrics
17 than gynecology. As of July 1st I am doing 100%
18 gynecology.
19 20 Q. Okay. And just - would it be a fair description to
20 say that obstetrics deals with pregnancy, childbirth,
21 and maternal health during the postpartum period?
22 A. Yes.
23 21 Q. And just because - to make sure the Court understands,
24 is it fair to say that the postpartum period typically
25 lasts for a few months after childbirth?
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1 A. Yes.
2 22 Q. And you’ve already answered the percentage of your
3 work...
4 A. Well, can I clarify that?
5 23 Q. Yes.
6 A. So, it’s not a few months, it’s technically 42 days
7 after delivery.
8 24 Q. Okay. And you did answer - so the percentage of your

9 professional work is spent on gynecology and you said
10 since July 1st it’s been 100% gynecology?
11 A. Yes.
12 25 Q. And I understand that there’s in part because you
13 resigned your privileges at Cambridge Memorial
14 Hospital on July 1st of 2021, correct?
15 A. Yes.
16 26 Q. In your CV at page 7 of your affidavit you do not list
17 any other hospital privileges, is that correct?
19 27 Q. In your CV you do not list any publications or
20 research projects regarding Covid or Covid vaccines,
21 correct?
22 A. Correct. I’m a clinical physician, I just see
23 patients.
24 28 Q. Okay, and I’m just going to ask a few clarifying
25 questions. I’m sorry, you may find that they are
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1 repetitive but I’d like to get it on the record,
2 please. In your CV you did not list any education,
3 publications or research projects in immunology,
4 correct?
5 A. That’s correct, I’m a community physician.
6 29 Q. You are not an immunologist correct?
7 A. I’m not an immunologist.
8 30 Q. In your CV you do not list any education, publication

9 or research projects in vaccinology, correct?
10 A. Correct.
11 31 Q. And you are not a vaccinologist, correct?
12 A. Correct.
13 32 Q. In your CV you do not list any education, publication,
14 or research projects in epidemiology, correct?
15 A. Correct.
16 33 Q. You are not an epidemiologist, correct?
17 A. Correct.
18 34 Q. In your CV you do not list any education,
19 publications, or research in emerging diseases,
20 correct?
21 A. Correct.
22 35 Q. You are not an emerging diseases expert, correct?
23 A. Correct.
24 36 Q. In your CV you do not list any education,
25 publications, or research projects in public health,
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1 correct?
2 A. Correct.
3 37 Q. You are not a public health expert?
4 A. Correct.
6 research projects in human medicine, correct?
7 A. Correct.

9 research projects in obstetrics or gynecology,
10 correct?
11 A. Correct.
12 40 Q. You are not a clinical scientist, correct?
13 A. Correct.
14 41 Q. In your CV you do not identify any academic
15 appointments or affiliations with a university medical
16 school, correct?
17 A. Correct.
18 42 Q. In your CV you do not list any courses that you teach
19 in any subject, correct?
20 A. Correct.
21 43 Q. And I think you’ve already confirmed this, so it’s
22 fair to say that professionally you’ve been
23 exclusively an obstetrics and gynecology practitioner
24 or clinician, whichever word you prefer, correct?
25 A. Correct.
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1 44 Q. Do you prefer practitioner?
2 A. Doesn’t matter to me. I’m a doctor that looks after
3 patients 100% of the time.
4 45 Q. I’d like to go to the substance of your report now,
5 Dr. Cvetic. Would you please turn up paragraph 6 of
6 your affidavit on page 3.
7 A. The only problem is I don’t have a copy of the
8 physic... I have mine. I didn’t get a - I didn’t

9 print off the actual physical affidavit. Can I do
10 that, or can I use my copy that I gave to the lawyers?
11 46 Q. You can - you can...
12 A. You just have to tell me what - what question it is
13 you want me to answer and what paragraph.
14 47 Q. Well, in your affidavit can you look at paragraph 6,
15 please.
16 A. Okay.
17 48 Q. Okay? And, Dr. Cvetic, I would - what I want you to
18 do is I would like you to confirm...
19 A. Yes.
20 49 Q. ...that the conclusions that you list in this
21 paragraph of your affidavit are a reproduction of the
22 summary that you provided in your report, and I have
23 page 11 of the affidavit the e-report which was
24 Exhibit B to your affidavit. There is a summary of
25 points at the beginning of your report?
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1 A. Right.
2 50 Q. It’s page 11 in the affidavit.
3 A. I have to print the affidavit. I haven’t done that.
4 51 Q. But this...
5 MR. WILSON: Perhaps I could assist, Sharlene. I
6 could - I can cross-reference because I have it with
7 the PDF page numbers printed out, so but I think
8 what’s confusing, at least confusing for me is you’re

9 referring to page 11 of her affidavit, and I don’t
10 believe the affidavit has 11 pages. I think...
11 MS. TELLES-LANGDON: Okay, so but you paginated the entire
12 document, and her affidavit includes the exhibits that
13 are attached to it.
14 MR. WILSON: Right, so I just - if we could - it - I
15 think it might helpful if you refer the exhibit is
16 what I’m getting at.
17 MS. TELLES-LANGDON: I - okay, it might also...
18 MR. WILSON: When you say page 11...
19 MS. TELLES-LANGDON: Mr. Wilson and Dr. Cvetic, it might
20 also be helpful if we do take a moment and let you
21 print it out so that you have it with the paginated -
22 the full paginated numbers.
23 MR. WILSON: So, for example...
24 MS. TELLES-LANGDON: Keith, do we want to just go off of the
25 record for a minute?
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1 MR. WILSON: Sure.
2 MS. TELLES-LANGDON: Okay.
4 OFF RECORD
6 52 MS. TELLES-LANGDON: Good morning, Dr. Cvetic, I just...
7 A. I’m sorry about that.
8 53 Q. ...just for the purposes of the record, during the

9 break you were provided with and have printed out a
10 copy of your complete affidavit as sworn, along with
11 the exhibits attached to your affidavit.
12 A. Yes.
13 54 Q. And in the copy that you printed out do you have
14 numbers in the upper right hand corner of the
15 affidavit?
16 A. Yes.
17 55 Q. All the way through including the exhibits?
18 A. Yes.
19 56 Q. When I refer to the page numbers in your affidavit...
20 A. Hm..mm.
21 57 Q. ...those are the page numbers that I will be referring
22 to. So, it may be a page number in your report that
23 is attached to your affidavit and therefore forms part
24 of your affidavit.
25 A. Okay.
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1 58 Q. What I have - would like you to do, Dr. Cvetic...
2 A. Yeah.
3 59 Q. ...I’d like you to turn to paragraph 6, which is in
4 your affidavit itself at page 3, and I would - and
5 also page 11, which is the summary in your report at
6 Exhibit B. And I just want you to confirm, Dr.
7 Cvetic, that the conclusions that you list in
8 paragraph 6 of your affidavit are a reproduction of

9 the summary that you produced in your report at page
10 11 of your affidavit.
11 A. Yes.
12 60 Q. And, well, mostly state in your report, Dr. Cvetic, at
13 paragraphs 10 and 11 of your report, you acknowledge
14 that pregnant patients will become ill from Covid-19
15 have a higher risk of ICU admissions and mechanical
16 ventilation when compared to non-pregnant patients in
17 the same age group, correct?
18 A. Now, where - okay, which paragraph is that?
19 61 Q. Eleven and 12 of your report.
20 A. Of my report.
21 62 Q. On page 14 and 15 of the... Do you have paragraphs 10
22 and 11 in front of you now, Dr. Cvetic?
23 A. What about - yeah, yeah. I have them right.
24 63 Q. I’m just asking you to confirm, Dr. Cvetic, that you
25 in your report have acknowledged that pregnant
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1 patients who become ill from Covid-19 have a higher
2 risk of ICU admissions and mechanical ventilation when
3 compared to non-pregnant patients in the same age
4 group, correct?
5 A. That can be - that can be elaborated a little bit more
6 is that - are we talking about hospitalizations or ICU
7 admissions? Pregnant women who become ill with Covid-
8 19, and if they’re severely ill with comorbidities,

9 comorbidities will likely be admitted to the ICU more
10 often that their non-pregnant counterparts because
11 just so their pregnant state physicians are quite
12 worried about them and want them admitted for
13 monitoring, yes.
14 64 Q. Dr. Cvetic, would you accept that pregnant women have
15 a higher risk of severe morbidity if infected compared
16 to non-pregnant counterparts?
17 A. Depends on their comorbidities. So, if I have a
18 pregnant patient who’s 350 pounds with diabetes and
19 high blood pressure, on insulin, and she develops
20 Covid, versus a 20-year-old thin healthy woman, you
21 can’t compare the two. So, I believe that it’s an
22 individual risks that certain women aren’t at certain
23 risk, high risk factors that have comorbidities, and
24 others, although they can become sick with - with
25 Covid or ill with Covid they do not necessarily wind
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1 up in the ICU.
2 65 Q. All right. Thank you, Dr. Cvetic. At paragraph 10 of
3 your affidavit, you acknowledge that there’s an
4 increased risk of preterm delivery associated with
5 Covid-19. Would you agree, Dr. Cvetic, that preterm
6 delivery can result in consequent morbidity to the
7 infant related to prematurity?
8 A. Depends on how premature the baby is delivered. So

9 between 32 to 34 weeks there’s some increased
10 morbidity but after 34 to 36 weeks babies tend to do
11 quite well.
12 66 Q. Before...
13 A. With first world medicine, by the way. We’re talking
14 in Canada.
15 67 Q. At the fourth bullet of your summary, Dr. Cvetic,
16 which is page 11 of your affidavit, you state your
17 conclusion that there are no studies that prove these
18 vaccinations are not associated with miscarriage if
19 given in the first and early trimester. As I
20 understand it, Dr. Cvetic, at paragraphs 53 to 61 you
21 discuss two specific studies and you set out your
22 reasons why these studies cannot confirm that
23 vaccinations are not associated with miscarriage,
24 correct?
25 A. Which set - which page again?
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1 68 Q. Well, the bullet of your summary - the fourth bullet
2 of your summary on page 11...
3 A. Yeah.
4 69 Q. ...and then in paragraphs 53 through 61 you discuss
5 two specific studies, and you set out your reasons why
6 these studies cannot confirm that vaccinations are not
7 associated with miscarriage, correct?
8 A. Yes.
9 70 Q. However, in your report you have not identified any
10 studies that had demonstrated that mRNA vaccines are
11 associated with miscarriage, correct?
12 A. Because the studies only include one vaccine dose.
13 The majority of the studies only included one vaccine
14 dose, and the majority of the studies don’t actually
15 give it in the first trimester.
16 71 Q. My question was in your report you have not identified
17 any studies that have demonstrated that mRNA vaccines
18 are associated with miscarriage, correct?
19 A. Lack of evidence doesn’t imply safety.
20 72 Q. But there is no evidence that there is - that they’re
21 not safe, correct?
22 A. The studies haven’t - I will say that you cannot say
23 that there is - that these vaccines are safety - safe
24 based on the lack of evidence. You understand?
25 Studies include small numbers of women who have only
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1 been vaccinated once in their pregnancy and they don’t
2 actually look at women less than six weeks when most
3 miscarriages occur, and we know that a lot of the
4 complications with vaccines happen after the second -
5 or dose or the booster, and this has - and it doesn’t
6 show anything about future - future risks. So, just a
7 lack of evidence does not imply safety.
8 73 Q. I understand your position, Dr. Cvetic, but there - I

9 would ask again you have not identified any studies
10 that have demonstrated that mRNA vaccines or any Covid
11 vaccines are associated with miscarriage, correct?
12 MR. WILSON: I’m objecting to that question. You’ve
13 asked the question three times, she’s answered it
14 three times with - each time with a greater level of
15 detail. Her answer is that the absence of evidence is
16 not evidence of something, and I - I don’t think -
17 she’s answered your question three times.
18 MS. TELLES-LANGDON: All right. I will move on.
19 74 Q. Dr. Cvetic, as a practicing obstetrician and
20 gynecologist, and a professional, would you agree that
21 it’s your responsibility to continue to evaluate
22 emerging evidence?
23 A. Absolutely.
24 75 Q. At paragraph 10, footnote 6, you cite the Society of
25 Obstetricians and Gynecology Canada statement on
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1 Covid-19 vaccation (sic)...vaccinations in pregnancy.
2 I am going to share my screen, Dr. Cvetic. Dr.
3 Cvetic, what I’m showing you is the Society of
4 Gynecology, the SOGC statement on Covid-19 vaccination
5 in pregnancy. Are you able to see that clearly on
6 your screen, Dr. Cvetic?
7 A. Yes, I’m well aware of it.
8 76 Q. And you would see, Dr. Cvetic, that this is issued on

9 behalf of the Infectious Diseases Committee of the
10 Society of Obstetricians and Gynecologists of Canada?
11 A. Yeah.
12 77 Q. And this is - this version is revised and updated as -
13 as of March 14, 2022?
14 A. Yeah.
15 78 Q. You see, Dr. Cvetic, that the Society of Obstetricians
16 and Gynecology provides - Canada - provides five
17 consensus statements?
18 A. Yes.
19 79 Q. You see this - the SOGC’s first state...first
20 statement - consensus statement is that Covid-19
21 vaccination is recommended during pregnancy in any
22 trimester and while breastfeeding? Do you see that,
23 Dr. Cvetic?
24 A. Yeah.
25 80 Q. Do you see this - the SOGC’s sec...second consensus
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1 statement is that all available Covid-19 vaccines
2 approved for Canada can be used during pregnancy and
3 breastfeeding, and presently preference is given to
4 the use of mRNA vaccinations during pregnancy as more
5 data on safety and efficacy during pregnancy is
6 available for these vaccines? See that, Dr. Cvetic?
7 A. Yeah. Yes.
8 81 Q. Do you see, Dr. Cvetic, the consensus statement number

9 5 that giving - given that pregnant people are at
10 increased risk of morbidity from Covid-19 infection,
11 all pregnant persons should be prioritized to receive
12 a Covid-19 vaccination? Do you see that, Dr. Cvetic?
13 Do you see that, Dr. Cvetic?
14 A. Yes, I do.
15 82 Q. I’m going to scroll down - oops. Sorry, I need to re-
16 share my screen. Can you see again the - re-seeing
17 your screen, Dr. Cvetic? It says the Society...sorry,
18 I’m having a bit of a technical issue here. Yeah, are
19 you, again, now seeing the statement...
20 A. Yes.
21 83 Q. ...the SOGC statement on your screen, Dr. Cvetic?
22 A. Yes.
23 84 Q. I’m going to scroll down slowly to the last paragraph
24 on page 3 of this document. You see the first two
25 sentences here say, “While pregnant and breastfeeding
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1 individuals were excluded from the available Phase 2
2 and Phase 3 studies for the Pfizer and BioNTech and
3 Moderna Covid-19 vaccines, a growing body of data
4 demonstrates no differences in rates of spontaneous
5 abortion, stillbirth, pre-term birth, or other
6 pregnancy complications. The V-safe Registry in the
7 United States has reported over 7,000 pregnant women,
8 including a robust representation of women vaccinated

9 in early pregnancy who received either the Pfizer
10 BioNTech vaccine or the Moderna vaccine and identified
11 no differences in the rate of adverse pregnancy and
12 neonatal outcomes in vaccinated women compared to pre-
13 pandemic rates.” Do you see that, Dr. Cvetic?
14 A. Yes.
15 85 Q. The last sentence of this paragraph states, “Most
16 recently analysis of U.S. and Norwegian population
17 level data reporting on 105,446 and 18,477 pregnancies
18 respectively have demonstrated no evidence of
19 increased risk for early pregnancy loss following
20 Covid-19.” Do you see that, Dr. Cvetic?
21 A. I see that.
22 86 Q. Do you accept, Dr. Cvetic, that these studies are
23 report - as reported by the SOGC are directly relevant
24 to the opinion you provided to this report? That’s
25 fair?
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1 A. I’m from...sorry.
2 87 Q. Sorry, do you...
3 A. Which part?
4 88 Q. Yeah. Do you agree, Dr. Cvetic, that these studies as
5 reported by the SOGC are directly relevant to the
6 opinion you provided to the Court that there are no
7 studies that prove these vaccinations are not
8 associated with miscarriage?

9 A. Every single one of the studies that they quote has
10 problems with it. Every single one. They all either
11 use one vaccine, one dose of the vaccine, they use at
12 few weeks, they give it in the third trimester a few
13 weeks before delivery. There’s a very small
14 percentage of women who receive the vaccine in the
15 first trimester which is when miscarriages happen.
16 So, every single one - I can do through everyone of
17 those studies and tell you exactly how the data was
18 manipulated, the numbers were manipulated to make
19 things look worse than they are, and then better than
20 they are. So, you can’t tell me that just because
21 there’s a whole bunch of poor quality studies that
22 implies safety. And none of them - absolutely none of
23 them - imply that its safe in the long term, like in
24 the long run, that there won’t be problems after two
25 doses, after a booster, and a second booster. There
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1 is no data available that shows that any of these are
2 safe in pregnancy with the way we’re giving the
3 boosters now.
4 89 Q. Thank you, Dr. Cvetic. I would like to enter the SOGC
5 Statement on Covid-19 Vaccination as Exhibit 1.
8 EXHIBIT 1: SOGC Statement on Covid-19 Vaccination.

9
10 90 MS. TELLES-LANGDON: Just waiting to make sure the court
11 reporter is ready to go again. Okay. I take it,
12 then, Dr. Cvetic, that none of the studies reported in
13 the SOGC document change your - have changed your
14 opinion?
15 A. No, actually they strengthened it by the last two
16 weeks going through every single dat - every single
17 study and actually looking at the raw data, not the
18 statistical analysis, no, it doesn’t change my mind.
19 And, you know what? My clinical experience. I know
20 you’ve made a very significant point that I’m not - I
21 don’t work at a university, I don’t do research, I
22 haven’t done any published works, I’m not an
23 epidemiologist, and I’m not a public health doctor,
24 but I look after pregnant women, and during the
25 pandemic, in my clinical experience, the majority of
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1 pregnant women with Covid either had no symptoms, mild
2 or moderate symptoms, and none of my patients ended up
3 in the hospital. So, what they’re confounding is
4 that, yes, I agree that pregnant women with any kind
5 of respiratory virus can become sick, but you have to
6 look at the individual woman. Okay, what are her risk
7 factors? Medicine isn’t, like I said in my report,
8 it's not cookie cutter. It’s - you don't apply the

9 same thing to everybody. You have to have a
10 conversation with your patient. You have to sit there
11 and say what are your risk factors, do I recommend
12 this, what are the unknowns of this vaccine, and then
13 make a decision together. Not have it mandated by
14 your employer or the government. It’s between patient
15 and doctor the decision. And when we have a vaccine
16 that is very, very new, we’ve never used this
17 technology on such a mass scale, we have never, that
18 you can’t imply safety just because we don’t have the
19 data yet. You can’t do that. You can’t just assume.
20 Real life doesn’t work that way. It may work on
21 paper, the vaccine may look safe and good on paper,
22 but it reacts differently in every person, and it’s
23 individual care.
24 The other point I wanted to make is that I’ve
25 gone through all the studies, and I can go through
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1 each one of them if you’d like.
2 91 Q. Dr. Cvetic, in reaching your opinion if there are no
3 studies, did you in your report review the study by
4 Dr. DeRose et al?
5 A. Which one?
6 MR. WILSON: Which was...
7 92 MS. TELLES-LANGDON: The study by DeRose et al entitled Sars
8 CoV 2 Vaccines During Pregnancy and Breastfeeding: A

9 Systematic Review of Maternal Neonatal Outcomes. Did
10 you review that report - that publication in your
11 report, Dr. Cvetic?
12 A. I can’t - I don’t know - let me just...
13 MR. WILSON: Counsel, was that a report - can you
14 give us some context? Is that a report that just
15 exists in the world, or is that a report that was
16 attached to one your experts?
17 93 MS. TELLES-LANGDON: It was referenced by Dr. Poliquin - Dr.
18 Vanessa Poliquin.
19 A. Poliquin, which - which reference is it?
20 94 Q. Paragraph 22 of her report at page 10 of...
21 A. Ten?
22 95 Q. ...of her report. The question is straightforward
23 though, Dr. Cvetic, did you review this article in
24 your report?
25 A. Well, I would like the chance to see which one it is.
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1 I’m not very...
2 MR. WILSON: If...
3 A. ...names of researchers so I’ve got to take a look at
4 it. Page 10, yeah. Which one?
5 95 MS. TELLES-LANGDON: The report referenced at paragraph 22
6 of Dr. Vanessa Poliquin’s report.
7 MR. WILSON: Take your time, Dr. Cvetic.
8 A. What was the name of the...I don’t see it in her - I

9 have her entire thing here, where is it?
10 96 MS. TELLES-LANGDON: Paragraph 22 of Dr. Poliquin’s report.
11 The article is by Dominico Umberto DeRose et al,
12 titled Sars CoV 2 Vaccines During Pregnancy and
13 Breastfeeding: A Systematic Review of Maternal and
14 Neonatal Outcomes, published in the journal Viruses in
15 2022.
16 A. 2022, paragraph - like number 22 on page...
17 97 Q. Paragraph 22 on page 10 of - sorry, of - again I’m
18 referring to the - yeah, page 10 of Dr. Poliquin’s
19 report. But the question, Dr. Cvetic, is did you
20 review this paper in your report?
21 A. In my report.
22 MR. WILSON: Just before - before the witness
23 answers, as is clear there’s lots of page numbers,
24 there’s lots of references, there’s lots of reports.
25 I think the witness should be allowed to get her
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1 bearings, locate paragraph 22 of the respondent’s
2 expert’s report at page 10 to see the reference and be
3 clear about what is being referred to before the
4 witness is required to answer.
5 MS. TELLES-LANGDON: Certainly, Mr. Wilson and Dr. Cvetic,
6 please take your time. Yeah, you will obviously also
7 need to have your own report because the question is
8 did you refer to this paper and discuss it in your

9 report?
10 A. Not in my report but I have - I have looked at it
11 after the fact.
12 98 Q. Okay, did you consider the study by Zauche, Z-a-u-c-h-
13 e, et al, titled Receipt of mRNA Covid-19 Vaccines and
14 Risk of Spontaneous Abortion, published in the New
15 England Journal of Medicine in 2021. It is referred
16 to at paragraph 28 of Dr. Poliquin’s report. The same
17 question is did you consider this study in your
18 report, Dr. Cvetic?
19 MR. WILSON: Just wait a minute. In fairness to the
20 witness let’s not, you know, rush her through the door
21 here. I think we first need to identify the
22 reference, make sure the witness is aware of the
23 reference you’re referring to, then ask the question
24 about whether it was considered. I - I am concerned
25 this is getting a little - with all due respect - a
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1 little pushy.
2 MS. TELLES-LANGDON: I’m sorry, Mr. Wilson, I was just
3 attempting to be very specific and - and to ensure
4 that she understood what the question was going to be
5 as she was locating the reference.
7 99 MS. TELLES-LANGDON: Dr. Cvetic, are you - have you now
8 found the reference to...

9 A. Of this study, yes.
10 100 Q. Did you reference this study in your report?
11 A. No, but I’m going to couch it and answer it. That
12 just because I didn’t reference it doesn’t mean that I
13 haven’t now read it, and I - it hasn’t changed my
14 mind. The study for Zauche et al chose - looks at
15 miscarriages between six weeks and 20...less than 20
16 weeks after one dose of vaccine, and no control group,
17 and the fact that they didn't include less than six
18 weeks miscarriages which is the majority of
19 miscarriages happen before six and seven weeks. So,
20 this doesn’t change my opinion at all that there isn’t
21 an increased risk. It’s an incomplete study. You
22 can’t say that there’s increased risk when it’s an
23 incomplete study.
24 101 Q. Dr. Cvetic, did you consider the study by Wainstock et
25 al, W-a-i-n-s-t-o-c-k? It is referenced at paragraph
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1 29 of Dr. Poliquin’s report. It’s titled Prenatal
2 Maternal Covid-19 Vaccine - sorry - Vaccination and
3 Pregnancy Outcomes, published in the journal Vaccine
4 in 2021. Same question again, Dr. Cvetic, did you
5 consider this publication in your report?
6 A. I did not see this before my report, but going through
7 it after your expert witness showed it in her report,
8 there again it does not change my opinion. Only 900

9 patients were in that study and they were given a
10 vaccine only five to seven weeks before their
11 delivery. That's not enough time to effect anything
12 significantly what they were looking for.
13 102 Q. Did you consider the study by Kharbanda, K-h-a-r-b-a-
14 n-d-a, et al, titled Spontaneous Abortion Following
15 Covid-19 Vaccination During Pregnancy, published in
16 JAMA in 2021, referred to at paragraph 30 of Dr.
17 Poliquin’s report?
18 A. Yeah. I did not reference that in my report, but
19 again going through it, it does not change my mind.
20 There is no mention of how many doses they were given.
21 It assumes that only 7% were given one dose is six of
22 - of Pfizer, six or seven were given one dose of
23 Moderna. This does not imply safety if you’re dealing
24 two doses or you’re getting boosters. You cannot
25 equate the two.
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1 103 Q. Have you subsequently considered the study by Fell et
2 al, F-e-l-l, entitled Association of Covid-19
3 Vaccination in Pregnancy with Adverse Peripartum
4 Outcomes, published in JAMA On Line on March 24, 2022,
5 which is referenced at paragraph 33, page 19 of Dr.
6 Poliquin’s report?
7 A. Yes. Yeah, the majority of the patients there
8 received one dose of the vaccine in a third trimester

9 closer to delivery without much time to see if it
10 really has anything to affect the baby, but it’s nice
11 to know that it doesn’t cause postpartum hemorrhage.
12 104 Q. Have you subsequently considered the study by Magnus
13 et al, M-a-g-n-u-s, titled Association of Sars CoV 2
14 Vaccination During Pregnancy with Pregnancy Outcomes,
15 publish in JAMA - J-a-m-a - On Line on March 24, 2022,
16 referred to in Dr. Poliquin’s report at paragraph 34,
17 page 19?
18 A. Yes, less than 1% of patients were vaccinated in the
19 first trimester, only 8% were vaccinated in their
20 second, and only 9% were vaccinated in the third.
21 That’s not a very big percentage. There is no way
22 that you can state that that low a vaccination
23 occurring later in pregnancy will prevent - well it
24 has no association with small for gestational age.
25 So, little infants, so growth restricted babies
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1 usually come from a problem with the placenta.
2 There’s problem with the placenta and blood flow, and
3 if - that usually starts when the placenta’s
4 developing in the first and second trimester. So, if
5 you’re giving a vaccine, the first dose in the third
6 trimester, it’s not going to affect birth. So, just
7 because they’re saying there’s no association with a
8 small for gestational age babies it’s because the

9 vaccine was given later in pregnancy. Now, it is nice
10 to know that there weren’t any increased ICU
11 admissions, but again these are small numbers with,
12 like, one vaccine.
13 So, again we cannot apply that to now where we’re
14 recommending two vaccines plus a booster to pregnant
15 women. How do you - how do you say that... Okay, one
16 - one’s safe, how do you know that two or three are
17 safe? And the other thing is for the preterm
18 delivery. It says that there was no association
19 between the vaccine and preterm birth. You have to
20 actually - none of these studies actually define
21 preterm birth as far as how it happens. So, preterm
22 birth can happen naturally, or it can happen where we
23 interfere into the pregnancy and deem that the baby
24 should be delivered. So, those - like that’s
25 something that needs to be clarified in all of these
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1 studies that are showing that Covid causes preterm
2 delivery but not the vaccine.
3 105 Q. Despite the cumulative effect of all of these studies,
4 Dr. Cvetic, which demonstrate that there is no
5 association between vaccination and either miscarriage
6 or other negative outcomes, would you accept that the
7 absence of an identified association cumulatively
8 given all of these studies is equivalent to a

9 demonstration of safety for pregnancy outcomes?
10 A. No. Just because you have a whole bunch of stuff
11 showing the same thing, and it’s all poor studies that
12 are only showing one dose later in pregnancy, that
13 doesn’t mean that two or three doses are safe.
14 106 Q. Going back to your report, Dr. Cvetic, in paragraph 18
15 of your report you note that pregnant individuals are
16 at an increased risk from influenza. So, the medical
17 community routine - routinely recommends the flu
18 vaccination before or in pregnancy, correct?
19 A. Correct.
20 107 Q. In that same paragraph you also note that the flu
21 vaccine has been proven to be safe during pregnancy
22 and childbearing years, correct?
23 A. It has been used for decades, yes. And it is a very
24 different vaccine, you have to point that out. The
25 flu vaccine is a traditional vaccine with a piece of
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1 the actual virus in it that stimulates the immune
2 system. mRNA, the vaccine that’s for Covid, is a
3 completely new technology that has not been used on
4 this mass scale that we’re using it now. So, you
5 cannot equate the flu vaccine with the Covid vaccines.
6 They’re apples and oranges.
7 108 Q. Have you reviewed the product monograph for the common
8 flu vaccine?
9 A. Yes.
10 109 Q. Are you aware, Dr. Cvetic, that the product monograph
11 for the flu vaccine FluLaval Tetra, which I understand
12 is a common - the common flu vaccination used, states
13 that, “The safety of FluLaval Tetra when administered
14 to pregnancy women has not been evaluated. Animal
15 studies with FluLaval Tetra do not indicate direct or
16 indirect harmful effects with respect to reproductive
17 and developmental toxicity. FluLaval Tetra should be
18 used during pregnancy only when clearly needed and the
19 possible advantages outweigh the potential risks for
20 the fetus.” Have you reviewed - have you seen that in
21 the product monograph, are you aware that that is in
22 the product monograph?
23 A. I just briefly saw it this morning when I was given a
24 copy of it, yes.
25 110 Q. All right. I’m am going to share my screen again, Dr.
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1 Cvetic, hopefully with more success than last time.
2 Dr. Cvetic, what I’m showing you is the product
3 monograph for the flu vaccine FluLaval Tetra for 2021-
4 2022. Do you see that clearly on your screen, Dr.
5 Cvetic?
6 A. Yes.
7 111 Q. Please... I’m going to make it a little smaller so
8 you can see the full page. Do you still see it

9 clearly when it’s at that size, Dr. Cvetic?
10 A. Yes.
11 112 Q. Please review the cover page on - that you see on the
12 screen and tell me when you have finished doing so.
13 A. So, I’d like to just clarify something, that this is
14 the flu vaccine for the season of 2021-2022.
15 113 Q. That’s fine. Yes, thank you, Dr. Cvetic.
16 A. Because flu vaccines change every season, right,
17 depending on the strain that’s around. But if this is
18 more like the classical flu vaccine that we’ve always
19 used, then I am familiar with it.
20 114 Q. Have you finished reviewing the cover page, Dr.
21 Cvetic?
22 A. Yes.
23 115 Q. I’m going to scroll past the table of contents to the
24 third page which describes the vaccine. Can you
25 please take a moment to review that page, Dr. Cvetic,
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1 and let me know when you have finished doing so.
2 A. Okay.
3 116 Q. Again, I’m going to move to the fourth page of this
4 document. Please review it and tell me when you have
5 finished doing so.
6 A. Okay.
7 117 Q. Having reviewed these pages, Dr. Cvetic, do you
8 acknowledge that this document is the product

9 monograph for the flu vaccine FluLaval Tetra, F-l-u-l-
10 a-v-a-l...space...T-e-t-r-a for 2021-2022?
11 A. Yes.
12 118 Q. Under the warning and precaution sections here, I’m
13 going to scroll down to the subheading Special
14 Populations. Do you see pregnant - the warning for
15 pregnant women under Special Populations?
16 A. Yes.
17 119 Q. And this warning states exactly as I presented to you
18 earlier, correct?
19 A. Yes.
20 MS. TELLES-LANGDON: I’d like to mark this as Exhibit 2,
21 please.
23
24 EXHIBIT 2: Product Monograph for FluLaval Tetra for 2021-
25 2022.
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2 COURT REPORTER: It’s been marked.
3 120 MS. TELLES-LANGDON: Dr. Cvetic, at paragraph 25 to 29 of
4 your report you discuss the findings - sorry, you
5 discuss the findings of what you have described as
6 Pfizer’s Japanese Biodistribution Study. In your
7 summary of this section, which is back at the summary,
8 you state that “The finding that the nano lipid

9 capsule and spike protein in the body post Covid-19
10 vaccinations are found in the ovaries is of concern as
11 they are toxic.” I’d like to ask you a few questions
12 about that conclusion. Turning first to paragraph 28
13 of your affidavit...
14 A. I just need a few minutes to find it.
15 121 Q. Yes.
16 A. What page was it?
17 122 Q. Well, it’s paragraph 28 of your affidavit, page 19.
18 A. Okay.
19 123 Q. First you set out at paragraph 28 of your affidavit -
20 I’m sorry. As you set out at paragraph 28 of your
21 affidavit, your statement - would it be fair to say
22 that your statement in your summary that the spike
23 protein is toxic is based on the fact that the spike
24 protein from the Covid virus that causes infections,
25 inflammation and tissue, and what you state is then a
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1 logical suggestion that the vaccine spike protein
2 would also be toxic.
3 A. So, there are two things that could be toxic with the
4 Covid vaccine is that - yes, with the Covid virus it
5 would be spike protein can be toxic, and inflammatory
6 to tissues. But with the vaccine it could be the
7 spike protein or it could the nano lipid particle
8 capsule that the - encapsulates the mRNA. Both of

9 them can be.
10 124 Q. At paragraph 44 of your affidavit you also state that
11 a possible theoretical cause of menstrual variation
12 following vaccination is due to the spike protein from
13 the vaccines binding to the Ace2 - A-c-e-2 - receptors
14 in the ovaries, correct?
15 A. In the ovaries and - yes, yes. Essentially it could
16 be also effect inflammation in the uterus as well.
17 125 Q. So, Dr. Cvetic, if an immunologist explained to you
18 that in order for the vi...for the virus to bind to
19 the Ace2 receptor and enter a cell, the spike protein
20 must change shape? The spike protein is normally in a
21 closed formation, also called the prefusion
22 confirmation. When it encounters the Ace2 receptor it
23 becomes open, also known as the fusion confirmation.
24 However, the mRNA instructions used in the mRNA
25 vaccine encodes - encodes the closed formation of the
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1 spike protein, and consequently the spike protein that
2 is produced by the vaccine cannot bind to the Ace2
3 receptor as the spike protein... Sorry, cannot bind
4 to the Act 2 receptor and cannot cause any of the
5 health issues that occur when the virus binds to the
6 Ace2 receptor as the spike protein opens. That was a
7 lot to digest. Perhaps I will put to you Dr.
8 Bowdish’s report. Do you have Dr. Bowdish’s report

9 with you?
10 A. I do.
11 126 Q. Just give me a moment.
12 A. And I - if I can add something to what you just said,
13 that - what everything that you just described is in a
14 perfect world. So, that is what hap...that is what is
15 in the research papers, that is the theoretical of how
16 this vaccine works, but if anybody who’s been in
17 clinical medicine, okay, and I’m talking about seeing
18 patients, you know, we are taught to look at symptoms,
19 diagnose diseases, and treat them, according to
20 textbooks and - and teachings when we’re in medical
21 school. When you get out in real life you realize
22 very quickly that life is not like a textbook, that
23 things happen that are unexplained, okay, and that are
24 things that we couldn’t have even known would happen.
25 Vaccines and drugs act differently in every
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1 individual.
2 127 Q. Right.
3 A. I can have a patient in my practice - patients in my
4 practice that I gave the same drug to. I can have 20
5 women I gave the same drug to. They all have a
6 different reaction to it. And just because on paper
7 it says that that’s what happens does not mean that
8 that happens in real life when you mass vaccinate

9 everyone, which is why some people are absolutely fine
10 after the vaccine, and some people have adverse
11 reactions.
12 128 Q. Dr. Cvetic, can you please turn to Exhibit C in Dr.
13 Bowdish’s report. It’s page 5 of her report in
14 Exhibit C, which - I know you have it in paper, so...
15 A. Is it the part where she mentions my name about the
16 Ace2 receptor?
17 129 Q. It is the last paragraph...
18 A. Hm..mm..
19 130 Q. ...on page 5.
20 A. May I read it?
21 131 Q. Yes, you may. I was actually going to ask you to do
22 so.
23 A. “Dr. Cvetic asserts that because the ovaries have Ace
24 2 receptor, the spike protein produced by the vaccine
25 might accumulate there and cause menstrual changes.
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1 However, there is no experimental evidence for this.
2 Moreover, as previously stated, the spike protein is
3 anchored to the cells that produce it and enclose
4 formation so that is not biologically feasible.”
5 I have two studies recently that show circulating
6 spike protein and parts of the spike protein in
7 people’s blood. So, the first one is Ogata et al, and
8 it was published by the New England Journal, and it

9 says, “Circulating Sars CoV 2 vaccine antigen in
10 plasma the vaccine recipients.” This was done at
11 Brigham Women’s College.
12 You have another - this - the next one was
13 actually published by Stanford University this
14 January, and it says, “Pfizer vaccinated individuals
15 showed level of spike protein in their blood similar
16 to the amount of spike protein in the blood of acute
17 Covid patients. These levels stayed elevated for two
18 days in 96% of the individuals.” So, you can say that
19 that spike protein stays on that vaccine - on the
20 cells that the vaccine simulates, but there’s evidence
21 coming out now that there’s actually spike protein
22 circulating in the body. If it can circulate in the
23 body it can go to the ovaries and it can go to the
24 uterus. This is stuff we’re going to find out later
25 because we’re now doing all this research and we have
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1 enough time of using this vaccine that we’re going to
2 see...
3 132 Q. Dr. Cvetic, would you accept that circulating in the
4 blood is not the same thing as binding to the Ace2
5 receptor?
6 A. If it circulates in the blood it will circulate to the
7 ovary and it can bind to the receptors there. If she
8 can theorize it can’t, then you can theorize that it

9 can. This is where you’re getting experts differing,
10 because we still have yet to prove what’s happening.
11 133 Q. Right. And, Dr. Cvetic, I recall you acknowledging
12 that you were not an immunologist, correct?
13 A. But I am a clinician with over 25 years of experience.
14 I know how to read data and I know how to look at
15 things because unlike some of my colleagues, I am
16 worried about my patients. I want to know what’s
17 happening. And patients are asking me about this,
18 they’re asking me about these studies, so I have to
19 know. I have to know what’s going on. So, just
20 because I’m not an immunologist doesn’t mean that I
21 don’t have the background, the basic knowledge of
22 medicine and science to understand these things.
23 134 Q. Dr. Cvetic, I would take you back to paragraph 28 of
24 your report where you state that the Bi...the Japanese
25 Biodistribution Study shows that the spike protein
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1 accumulates in organs and tissues, including the
2 ovaries. However, I put it to you, Dr. Cvetic, this
3 study did not measure the mRNA or spike protein at
4 all. It was only the lipid nano particles.
5 A. Lipid nano particles, okay, and I think I worded it
6 wrong. I should have put nano particles, but this is
7 what spurred me to start looking at this, because in
8 2017 and 2018 studies came out showing that because we

9 were starting to use these nano particles in
10 medications and treatments they wanted to know what
11 the concerns were, because nano particles can go to
12 the brain, they can go to the ovaries, they can go to
13 the testes. So, when I saw that the mRNA vaccine was
14 was going to use a nano lipid particle, yes, I’m
15 worried. I’m worried that it’s gone to the ovary,
16 because it’s - it’s so tiny it will go to the ovary,
17 the lipid nano particle. And it can cause
18 inflammation, apoptosis, which is cell death, and who
19 knows what else it can cause because we don’t know,
20 and that’s the thing.
21 135 Q. And, Dr. Cvetic, will you accept that that - do you
22 agree that the - I think you acknowledged this in your
23 report in fact that the Japanese Biodistribution Study
24 used doses at 300 times the level that is included in
25 the Pfizer vaccine?
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1 A. They’re supposed to use it because what you want to do
2 is you want to use the highest dose you can to see if
3 it’s going to kill them and where its going to go.
4 Like that’s what you do with animal studies, you use
5 doses that are way above what we would use for humans,
6 right? And so, yes, I agree that they used higher
7 doses, but that’s on purpose, right? And I do mention
8 that Dr. Bowdish does say, well, just this very, very
9 tiny portion ends up in the ovary after several days,
10 and you can’t compare the rat ovary to the human
11 ovary. I understand that, too. But then if it’s
12 still going to end up in the ovary what’s your safe
13 level? Do you know what the safe level is? We don’t
14 know what the safe level is.
15 136 Q. Regarding menstrual variation, Dr. Cvetic, would you
16 agree that menstrual variation is common in many
17 women?
18 A. Depends what you mean by many women, depends on how
19 long, and ages.
20 137 Q. Would it be common for women in their twenties to have
21 some menstrual cycles that are heavier than other
22 menstrual cycles?
23 A. Agree.
24 138 Q. Okay.
25 A. But what you’re seeing - what I’m seeing,
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1 unfortunately, is that I see a very skewed population,
2 so I see everyone who has menstrual irregularities, so
3 to ask me what the average is, I’m not a family
4 doctor, right? So, I am a specialist, so what I see
5 is a majority of my patients are coming in with
6 menstrual irregularities. But, yes, are you saying
7 that women can have one or two periods that are
8 heavier, one or two periods that are a little bit

9 longer, or a little bit more painful? Yes, I agree.
10 139 Q. Do you agree, Dr. Cvetic, that menstrual variation is
11 reported following Covid infection?
12 A. In my clinical practice I have seen many women with
13 menstrual irregularities, menstrual pain, pelvic pain,
14 and heavy periods after Covid vaccination. I haven’t
15 seen any after the virus. Now, does that mean that it
16 doesn’t happen? I’m sure it does, but they don’t get
17 referred to me.
18 140 Q. Would you agree, Dr. Cvetic, that stress can cause
19 menstrual variation?
20 A. Yes, it can, but usually one or two cycles. And
21 sometimes longer but not to the point where patients
22 are seeing me in consult for.
23 141 Q. In your report, Dr. Cvetic, did you consider the study
24 by Wesselink et al, W-e-s-s-e-l-i-n-k, entitled A
25 Perspective Cohort Study of Covid-19 Vaccination,
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1 Sars CoV 2 Infection, and Fertility, published in the
2 American Journal of Epidemiology which was reviewed in
3 Dr. Poliquin’s report at paragraph 22 - sorry 52?
4 A. The Edelman (ph)? Yeah.
5 142 Q. Did you consider this study in your report?
6 A. Not in my - no, not in my report but I’ve gone over
7 it, and doesn’t change anything. It says, that
8 “Importantly in all groups, cycle length returned to

9 normal by two menstrual cycles following vaccination,
10 applying a transient effect on menstruation which is
11 likely of limited clinical significance.”
12 I have two comments for that. One, the vaccine
13 wears off by two to three months. We know that, we’ve
14 seen it. So, yes, we do see menstrual - menstruation
15 and problems sometimes go away after three months and
16 then come back after the booster or the second shot.
17 And just because there’s no proof of clinical
18 significance doesn’t mean there isn’t any. The
19 la...again, the lack of evidence doesn’t mean in -
20 doesn’t mean that its safe and not affecting women
21 negatively. All right? So, just because that it gets
22 better doesn’t mean that what was the basis of it.
23 143 Q. Would you agree, Dr. Cvetic, that observational data,
24 as opposed to retrospective data, demonstrates
25 reassuringly that menstrual changes subsequent to
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1 Covid-19 mRNA vaccination are minimal, transient, and
2 clinical insignificant?
3 A. No, I don’t agree.
4 144 Q. That’s it...
5 A. I would like you to meet some of my patients that have
6 been bleeding continuously since the summer when they
7 first received their first and second doses, and I
8 would like you to talk to some of my patients that

9 have such severe pain that they can’t be intimate with
10 their partners. How about my post - post menopausal
11 women, so women who haven’t have menses for -
12 menstrual periods for five to ten years and suddenly
13 they start bleeding. So, no, I don’t agree that it’s
14 just transient and of unlikely significance and not
15 bothersome because I’m getting a lot of referrals for
16 these women, and they are bothered by it, and I know
17 it may not be clinically significant to the
18 researchers, but it’s very significant to these women.
19 145 Q. At paragraph 44 of her report - actually - oh, I’m -
20 with respect to paragraph 31 of your report where you
21 express concern about the lack of evidence
22 demonstrated that Covid-19 vaccines do not affect
23 fertility, did you consider the Wesselink study, and
24 I...that - sorry... I need to find that. I need to
25 find the paragraph for you in Dr. Poliquin ...
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1 A. Oh, and by the way, I just wanted to add something to
2 that menstrual regul...menstrual problems of the -
3 with the Covid vaccine. As I mentioned I’ve been in
4 practice for 25 - 25 years or so. I have never seen
5 menstrual irregularities after the flu vaccine or any
6 other vaccine. I just wanted to point that out that
7 this is a new phenomena that we just are seeing since
8 the summer when you started mass vaccinating young

9 women.
10 146 Q. Paragraph 48 is the paragraph in Dr. Poliquin’s
11 affidavit. Did you consider the Wesselink et al, W-e-
12 s-s-e-l-i-n-k, et al, study entitled A Perspective
13 Cohort Study of Covid-19 Vaccination, Sars CoV 2
14 Infection, and Fertility, published in the American
15 Journal of Epidemiology, 2022, in your discussion
16 regarding fertility in your affidavit and report?
17 A. I did not use it in my affidavit. I’d gone through
18 each one of the fertility studies that Dr. Poliquin
19 mentioned, and each one had either a very small number
20 of couples who were doing IVF who already have
21 fertility issues, and invitro fertilization you are
22 given hormones to prepare the uterus for implanting
23 the fetus, so you’re actually helping them along, so I
24 don’t see how one vaccine dose - again one dose, not
25 two, not three, not four - one - doesn’t cause a
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1 miscarriage or problems in getting pregnant, but you
2 can’t equate these studies with problems in the future
3 for getting multiple doses of this vaccine.
4 147 Q. In the Wesselink study at paragraph 44 of her report,
5 Dr. Poliquin explains that this study considered 2,126
6 couples achieving natural conception as opposed to
7 conception in the context of fertility treatments, and
8 found no changes in the probability of achieving

9 pregnancy within one menstrual - menstrual cycle
10 following either infections of Covid-19 vaccination -
11 or, sorry - following either infection of Covid-19 or
12 vaccination with Covid-19. Do you accept, Dr. Cvetic,
13 that this study added considerable value to the
14 literature given that it was considering couples
15 acceding (sic) - achieving natural conception as
16 opposed to conception in the context of fertility
17 treatment?
18 A. Is it reassuring? If you’re giving a vaccine and then
19 trying to get pregnant right away, sure. But if
20 you’re giving a vaccine to a 16-year-old that is not
21 trying to get pregnant yet and we don’t know the
22 outcome of what that’ll be when she’s 24 and wants to
23 conceive, does it really add anything when I’m
24 counselling a 16-year-old on whether to get it or not?
25 148 Q. Dr. Cvetic, do you accept that to date neither animal
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1 nor human fertility studies demonstrate an association
2 between Covid-19 mRNA vaccination and negative
3 fertility outcomes?
4 A. Which animal study are you talking about?
5 149 Q. I’m saying that to date no animals nor human fertility
6 studies demonstrate an association between Covid-19
7 mRNA vaccination and negative fertility outcomes to
8 date.
9 A. There was one. Yeah, there was one. One that Pfizer
10 wrote - that the - I think it was Dr. Bowdish or Dr.
11 Poliquin. If you give me two seconds I can find it.
12 Here we go. No, wait a minute. I’ll have to find it
13 in my stuff here. Oh, here we go. Okay, it’s Bowman
14 et al, and it was - I think it was - I think both
15 doctors quoted it, so Bowman et al. It’s A Lack of
16 Effects on Female Fertility and Prenatal and Postnatal
17 Offspring Development in Rats with the Covid-19
18 vaccine from Pfizer. And they had looked at, I
19 believe, 44 rats, and all that they found no
20 association between - between the doses and anything -
21 any birth defects or problems with the - the rat
22 babies, the pups and all that. So that’s the only
23 study, by the way, okay?
24 I’d like to make a few points about it. One is
25 that the study researchers for this paper are all
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1 employed by Pfizer. They all have - and it actually
2 says on the paper very interesting - they all have
3 shares in Pfizer, and the funding for this research
4 was done by Pfizer. So, right there I have a problem.
5 I would like to finish what I’m going to say.
6 One animal study to say that this is safe and doesn’t
7 cause birth defects and doesn’t cause fertility issues
8 is inappropriate. We have examples of animal studies

9 in rats showing teratogenic birth defects from
10 medications. A good is thalidomide in the 1950s. Rat
11 studies showed it was fine. It was given to thousands
12 of pregnant women for nausea in pregnancy, and it was
13 taken off the shelves in the 1960s after they found
14 that it was causing horrible birth defects in babies.
15 When they looked back at the studies they found that
16 rats metabolize the drug differently than humans which
17 is why it never showed up in the rats, the birth
18 defects. So, that’s one example.
19 Another is whenever a vaccine is going to be used
20 in pregnant women or in young reproductive women, you
21 should have more than one animal study, and you
22 actually should have it in non-human primates which
23 are closer to us in their physiology and biology than
24 rats are. So to say that that one study is proof that
25 this is safe for fertility and for birth defects, I’m
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1 sorry, I can’t agree to that.
2 150 Q. Okay well so, Dr. Cvetic, the question was that - so
3 I’ll focus on animal studies - that to date...
4 A. All right.
5 151 Q. ...the animal study that you just referenced did not
6 demonstrate an association between the mRNA
7 vaccination and negative fertility outcomes.
8 A. One animal study that doesn’t show an association does

9 not mean that this vaccine is safe. I don’t know how
10 many times I can tell you that. One study does not
11 mean safety.
12 MS. TELLES-LANGDON: Thank you, Dr. Cvetic, those are all my
13 questions, Mr. Wilson.
14 MR. WILSON: Thank you. I’m wondering if we might
15 have a pause so that I can mute my mike and consult
16 with my counsel as to see if we have anything on
17 redirect.
18 MS. TELLES-LANGDON: Yes, certainly, Mr. Wilson, but of
19 course you can’t speak with Dr. Cvetic during the
20 break.
21 MR. WILSON: No, I’ll - you two can leave your mikes
22 live and I’ll just mute mine.
24
25 OFF RECORD
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2 MR. WILSON: I can advise that we have nothing for
3 this witness by way of redirect.
5 MR. WILSON: Does this conclude this cross-
6 examination, counsel?
7 MS. TELLES-LANGDON: This concludes this cross-examination.
10 CROSS-EXAMINATION ENDS
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Court Transcriber
ACT ID: 2887221650
May 17, 2022
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SOGC Statement on COVID-19 vaccination in Pregnancy

POLIQUIN, V; CASTILLO, E; BOUCOIRAN, I; WONG, J; WATSON, H; YUDIN, M; MONEY, D; VAN
2
SCHALKWYK, J; ELWOOD, Con behalf of the Infectious Disease Committee of the Society of 0
Obstetricians and Gynaecologists of Canada .::
Q.
~
(.)
Original date: December 18th, 2020 en
Revised and reaffirmed date: March 14th, 2022 2
<(
a::
1-
CONSENSUS STATE MENTS: .J
..,~
1. COVID-19 vaccination is recommended during pregnancy in any trimester and while
breastfeeding
2. All available COVID-19 vaccines approved in canada can be used during pregnancy and
breastfeeding. Presently, preference is given for the use of mRNA vaccinations during
pregnancy as more data on safety and efficacy during pregnancy is available for these
vaccines.
3. The SOGC recommends following provincial and territorial guidelines on type of vaccine to
prioritize for pregnant and breastfeeding individuals.
4. Individuals should not be precluded from vaccination based on pregnancy status or
breastfeeding.
5. Given that pregnant people are at increased risk of morbidity from COVID-19 infection, all
pregnant persons should be prioritized to receive a COVID-19 vaccination.
Vaccinations are an important part of primary and preventative healthcare for pregnant women. The
benefit of vaccination during pregnancy for the infant (e.g. pertussis and influenza) is recognized and
recommendation of these vaccinations is part of routine prenatal care.
SARS-CoV-2 and the impact on pregnancy
Compared to non-pregnant women with COVID-19, pregnant women are at increased risk of admission
to hospital, critical care and invasive ventilation compared to age-matched peers.1• 2 Canadian and
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international data from large studies spanning multiple jurisdictions demonstrate that approximately 7-
11% of pregnant women will require hospitalization for COVID-related morbidity and between 1-4% of
pregnant women require admission to an intensive care unit (ICU). 1• 2• 3 Recently, a prospective cohort
study of 5183 pregnant women compared to 175 905 non-pregnant women demonstrated that
pregnancy conferred an increased risk of death from COVID-19 (OR 1.84, Cl 1.60-2.16). The risk of severe
morbidity from COVID-19 in pregnant women appears to be associated with risk factors including age~
1 2
35 years old, asthma, obesity, preexisting diabetes, preexisting hypertension and heart disease. • In
addition, both Canadian and US data1• 2 • 3 show an increased risk of preterm delivery associated with
COVID-19 infection in pregnancy which can result in consequent morbidity to the infant related to
prematurity.
COVID-19 vaccines approved for use in Canada
mRNA Vaccine Platforms
In Canada, the dominant vaccines in use to prevent infection with SARS-CoV-2 are the mRNA vaccine
platforms. This model consists of messenger RNA (mRNA) encapsulated by a lipid nanoparticle (LNP),
which allows the mRNA entrance into host (human) cells. The mRNA in the vaccine codes for the SARS-
CoV-2 spike protein utilized by the virus to bind to human receptors and promote viral replication. The
vaccine provides the host cell instructions to manufacture only this spike protein and express it on its
surface. Recognizing the spike protein as a foreign antigen, the host immune system is then activated to
produce an immune response. 4 The mRNA does _n ot enter the nucleus or alter human DNA and human
cells do not have the machinery to allow it to do so.
The Pfizer-BioNTech and Moderna COVID-19 vaccines were originally evaluated in licensure trials as a
series of two intramuscular injections given 21-28 days apart.5 However, since then, considerable data
has been generated on different dosing intervals. 6 The efficacy of the Pfizer-BioNTech COVID-19 vaccine
has been demonstrated for adults 16 years and older in Phase II and Phase Ill trials involving the
randomization of approximately 44,000 individuals. 7 These trials demonstrated a vaccine efficacy of
94.6% for preventing symptomatic COVID-19 cases at least 7 days following the second dose.7 In Phase
Ill trials for the Moderna COVID-19 vaccine involving the randomization of 30,000 individuals, the
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vaccine was reported to have 94.1% efficacy against symptomatic COVID-19 with no serious safety
concerns identified during the initial 2 month follow-up period.8 Since the initial clinical trials, numerous
population-based studies have·reported on real-world vaccine efficacy. Among these, Canadian _d ata
from Quebec and British Columbia have demonstrated vaccine efficacy greater than 80-90% for
6 9
infection for at least 4 months after the 2nd dose and including against infections with Delta variant. •
Vaccine efficacy data specific to pregnant women are emerging and suggest that COVID-19 mRNA
10 11
vaccine efficacy is comparable to the vaccine efficacy observed in non-pregnant persons. •
In Phase Ill trials for both Pfizer-BioNTech and Moderna COVID-19 vaccines, there were no clinically
meaningful differences in adverse events or severe adverse events in the vaccine group compared to
control except for lymphadenopathy which occurred in approximately 0.3% of the vaccine group
compared to <0.1% of the placebo group for the Pfizer-BioNTech COVID-19 vaccine. The most reported
side effects from the mRNA COVID-19 vaccines were pain at the injection site, fatigue and headache.
7
Fever was reported in 11-16% of patients, particularly following the second dose. Data from the US v-
safe pregnancy registry demonstrates that pregnant women are more likely than non-pregnant women
to report injection site pain following administration of COVID-19 mRNA vaccines, but are less likely to
report headache, myalgia, chills and fever. 12
While pregnant and breastfeeding individuals were excluded from the available Phase II and Phase Ill
studies for the Pfizer-BioNTech and Moderna COVID-19 vaccines a growing body of data demonstrates
no difference in rates of spontaneous abortion, stillbirth, preterm birth or other pregnancy
complications. The V-Safe registry in the US has reported on over 7,000 pregnant women (including a
robust representation of women vaccinated in early pregnancy) who received either the Pfizer-BioNTech
vaccine or the Moderna vaccine and identified no differences in the rates of adverse pregnancy and
neonatal outcomes in vaccinated women compared to pre-pandemic rates. 11• 12 Additional US data from
the University of Washington, demonstrated that COVID-19 vaccination in pregnant and lactating
individuals can induce an immunogenic response, does not raise significant vaccine-related adverse
events or obstetrical and neonatal outcomes, and is effective in preventing COVID-19 disease.13· 14 Most
recently, analyses of US and Norwegian population-level data reporting on 105,446 and 18,477
pregnancies, respectively, have demonstrated no evidence of increased risk for early pregnancy loss
following Covid-19 vaccination. 15• 16
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Canadian data on vaccines in pregnancy are now available from Ontario and have been published as 2
online reports. (Better Outcomes Registry & Network (BORN) Ontario. COVID-19 Vaccination During
Pregnancy in Ontario: Surveillance Report #2, Reporting Interval December 14, 2020 to June 30, 2021.
Ottawa, ON: BORN Ontario; July 30, 2021.) During this entire reporting period, there were 39,985
women who received at least one dose of COVID-19 vaccine during pregnancy. Of note 26,381 had
received 1 dose and 13,604 had received 2 doses. Monthly uptake of vaccines increased over this time
period from 0.02% to 45.4% by June 2021. There was no evidence of any pregnancy specific increase in
any risks associated with vaccine uptake. The second source of Canadian data will be the Canadian
COVID-19 Vaccine Registry for Pregnant & Lactating Individuals (COVERED) whose objective is to assess
the safety and effectiveness of vaccination against COVID-19 in pregnancy (registration is open and
available on the website: https://covered.med.ubc.ca/).
Data on the safety of COVID-19 vaccines in lactating women or the effects of mRNA vaccines on the
breastfed infant or on milk production is limited, however because mRNA vaccines are not live virus
17
vaccines, they are not hypothesized to be a risk to the breastfeeding infant.
Recently approved vaccine platforms
In early 2022, two new vaccines platforms were approved for use in Canada. Novavax Nuvaxovid
contains a recombinant SARS-CoV-2 spike protein vaccine and Medicago Covifenz contains a plant-based
virus-like particle of the SARS-CoV-2 spike protein. The adjuvants contained in both vaccine platforms
are oil-in-water emulsion adjuvants that have been used widely and in diverse populations including
18
pregnant women and children, most notably during the 2009-2010 HlNl influenza pandemic. Both
vaccine platforms use technology that is well established and used for other vaccines that are
administered safely to pregnant women (e.g. hepatitis, pertussis and tetanus vaccines). There is no
theoretical reason why the Novavax Nuvaxois or the Medicago Covifenz vaccines should not be
administered to pregnant or lactating women, although safety and efficacy data specific to pregnancy is
°
not yet available. 19• 2 Following informed discussion, these vaccines could be considered as an
alternative for pregnant and lactating women who cannot use the mRNA vaccine platform due to side
effects or those who are opposed to using an mRNA vaccine platform.
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Considerations for COVID-19 vaccination during pregnancy
Decades of experience with other vaccines administered during pregnancy would suggest that we could
expect a similar efficacy for the COVID-19 vaccines in pregnant women compared to non-pregnant
women. Vaccines in general are immunogenic, safe, and efficacious when delivered to pregnant
persons. Recently COVID-19 vaccination has been shown to be efficacious in preventing infection in
pregnant women. 21 While further primary prospective clinical data on safety and efficacy of COVID-19
vaccines in pregnant populations is forthcoming, growing post-marketing surveillance has identified no
signals for adverse pregnancy or neonatal outcomes associated with administration of COVID-19
vaccinations.
What is known is that an unvaccinated pregnant woman remains at risk of COVID-19 infection and
remains at heightened risk of severe morbidity if infected compared to non-pregnant counterparts.
Severe infection with COVID-19 carries risks to maternal, fetal and neonatal health. While pregnancy
itself does not appear to increase the risk of becoming infected with SARS-CoV-2, pregnant individuals
may be in work-related (e.g. health-care worker, front line workers etc.) or community situations (e.g.
caregiver, Indigenous communities, outbreak setting, etc.) where the risk of infection is considerable.
Owing to maternal age, underlying comorbidities, or social marginalization, some pregnant individuals
are at higher risk of severe COVID-related morbidity.
We recommend pregnant individuals should be offered vaccination against COVID-19 at any time
during pregnancy or while breastfeeding, if no contraindications exist. This recommendation extends
to those who have previously been infected with SARS-CoV-2.22
In Canada, NACI has preferentially advised that "a complete vaccine series with an mRNA COVID-19
vaccine should be offered to individuals in the authorized age group who are pregnant or
breastfeeding. Informed consent should include discussion about emerging evidence on the safety of
mRNA COVID-19 vaccines in these populations. (Strong NACI Recommendation). Contraindications to
vaccination are few and a complete description is available within the National Advisory Committee
on Immunization guidance document. 23
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Anticipatory guidance for vaccination during pregnancy
Individuals should be informed of the expected side effects following vaccination. While pain at the
injection site, fatigue and headache are the most commonly reported symptoms following vaccination,
fever was reported 16% of the time for younger, non-pregnant individuals.8 Pregnant individuals can be
counselled to treat mild post-vaccination fevers with antipyretics (e.g. acetaminophen).
Timing of vaccin ati on during pregnancy and neonatal protection
The primary indication for administration of COVID-19 vaccination is for maternal protection. Therefore
the decision around timing of vaccination should be optimized for maternal benefit.
In theory, immunization of a pregnant woman may confer benefit to a newborn infant through a
mechanism of maternal vaccination similar to what is seen for pertussis and influenza vaccination during
pregnancy. While natural COVID-19 infection does appear to result in placental antibody transfer,
vaccination negates the fundamental risk of COVID-19 in pregnancy while conferring the same neonatal
benefit. 24 Evidence demonstrates that vaccine-generated antibodies are present in umbilical cord blood
following maternal vaccination with a rapid rise in titres occurring by 15d post-vaccination. 14• 25 There
appears to be efficient antibody transfer via the placenta, similar to pertussis vaccination which does
confer neonatal protection. 14• 25• 26• 27 Recent data from a case-control study conducted by the US-CDC
demonstrates that receipt of a two-dose series of a mRNA COVID-19 vaccination during pregnancy is
associated with a reduction in COVID-associated infant hospitalizations <6 months. 28 In general maternal
antibody transfer via the placenta is a more efficient way to confer neonatal protection than
breastfeeding. Antibodies are also transferred to breast milk post vaccination,29• 30• 31• 32• 33• 34 but there is
yet no data on associated neonatal protection.
Vaccine Spacing
There is no clear evidence to direct whether spacing of other vaccines is required, relative to the COVID-
19 vaccine. Recently NACI has changed its recommendation to support simultaneous vaccination of
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COVID-19 with any other vaccine. This is uniquely applicable to pregnant persons in that there is no
required delay of any vaccine (e.g. Tdap or influenza vaccination) or Rh-immunoglobulin for COVID-19
vaccination and vice versa. Of note, pregnant women and infants remain at increased risk of morbidity
and mortality from seasonal influenza compared to general population and vaccinating pregnant women
against influenza remains part of routine prenatal care during the pandemic.
Vaccination of the pregnant patient in the context of limited vaccine

supply
Given that pregnant women are at higher risk of severe COVID-related morbidity and mortality, they
represent a population that should be prioritized for vaccination in situations where vaccine supply is
limited. Specifically, the WHO has recommended that pregnant women be prioritized in stage II,
representing a situation where the supply is only sufficient to immunize 11-20% of a population.
Importantly, the WHO recommendation is upheld in all epidemiologic situations including community
transmission, sporadic cases as well as no cases.35
Inadvertent pregnancy following vaccination
Individuals who are discovered to be pregnant during their vaccine series or shortly afterward should
not be counselled to terminate pregnancy based on having received the vaccine. If conception is
presumed to predate the first dose, it is recommended to follow the same procedures for active
surveillance (as available) as would be activated if the pregnancy was known at the time of vaccination.
A registry to track pregnancy outcomes for individuals receiving any vaccine doses during pregnancy is
being planned for Canada. Pregnant individuals can get more information here: http://med-fom-
ridprogram.sites.olt.ubc.ca/vaccine-surveillance/.
Where pregnancy is detected during the vaccine series (i.e. following the first dose, but ahead of the
second dose), pregnant individuals should continue to be offered the opportunity to complete their
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vaccination series. Pregnant individuals should not be precluded or forced to delay the vaccine series in
any trimester.
Individuals contemplating pregnancy
Ideally, an individual would be immunized against COVID-19 ahead of pregnancy to benefit from
maximal vaccine efficacy throughout the entire pregnancy. There is no reason to delay pregnancy upon
receipt of vaccination.
Booster doses
Pregnant women mount immune responses comparable to t he non-pregnant population and vaccine
efficacy of the COVID vaccines among cohorts of pregnant women are comparable to non-pregnant
women. There is no data to suggest that pregnant women who meet criteria for a booster dose should
be treated differently than the non-pregnant population. While timing and criteria for booster doses
may vary by jurisdiction, pregnant women should receive a booster dose when recommended.
Future research
As the evidence evolves, it is becoming clear that pregnant and postpartum individuals represent a
population at increased risk of COVID-related morbidity. Severe COVID-19 infection during pregnancy
has important implications for both maternal and fetal health. NACI acknowledges that people of
reproductive age constitute a substantial proportion of the Canadian population, yet _
l imited data on the
use of COVID-19 vaccine in pregnancy are available. We support NACl's recommendation for the
inclusion of pregnant individuals in clinical trials of COVID-19 vaccines. This will help to ensure that this
population has equitable access to COVID-19 vaccine options, and that vaccination decisions can be
36
informed by robust safety, immunogenicity, and efficacy data.
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References
1. Allotey J, Stallings E, Bonet M, et al. Clinical manifestations, risk factors, and maternal and
perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-
analysis. BMJ. 2020;370:m3320.
2. Zambrano LD, Ellington S, Strid P, et al. Update: Characteristics of Symptomatic Women of

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treatment. htm1.
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Injection (Product Monograph). Available at https://covid-vaccine.canada.ca/info/pdf/pfizer-biontech-
covid-19-vaccine-pml-en.pdf.
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immunization-naci/extended-dose-intervals-covid-19-vaccines-early-rollout-population-protection.html .
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Vaccine. N Engl J Med. 2020;383:2603-15.
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9. Skowronski OM, Setayeshgar S, Zou· M, et al. Two-dose vaccine effectiveness against SARS-CoV-2
infection and hospitalization, including Delta variant: a test-negative design in British Columbia, Canada.
BC CDC. 2021.
2781 chemin Lancaster Road , Suite 200, Ottawa, ON K1B 1A7 Tel/Tel: (800) 561-2416 or (613) 730-4192 Fax/Telecopieur: (613) 730-4192 SOgC.org
AR08011
10. Dagan N, Barda N, Biron-Shental T, et al. Effectiveness of the BNT162b2 mRNA COVID-19 vaccine
in pregnancy. Nat Med. 2021.
11. Goldshtein I, Neva D, Steinberg DM, et al. Association Between BNT162b2 Vaccination and
Incidence of SARS-CoV-2 Infection in Pregnant Women. JAMA. 2021;326:72 8-35.
12. Shimabukur o TT, Kim SY, Myers TR, et al. Preliminary Findings of mRNA Covid-19 Vaccine Safety
in Pregnant Persons. N Engl J Med. 2021;384:2273-82.
13. Kachikis A, Englund JA, Singleton M, et al. Short-term Reactions Among Pregnant and Lactating
Individuals in the First Wave of the COVID-19 Vaccine Rollout. JAMA Netw Open. 2021;4:e2121310.
14. Gray KJ, Bordt EA, Atyeo C, et al. COVID-19 vaccine response in pregnant and lactating women: a
cohort study. Am J Obstet Gynecol. 2021;225:3 03.el-el 7.
15. Kharbanda EO, Haapala J, DeSilva M, et al. Spontaneous Abortion Following COVID-19
Vaccination During Pregnancy. JAMA. 2021;326:1629-31.
16. Magnus MC, Gjessing HK, Eide HN, et al. Covid-19 Vaccination during Pregnancy and First-
Trimester Miscarriage. N Engl J Med. 2021.
17. Cohn A, Mbaeyi S. What Clinicians Need to Know About the pfizer-BioNTech COVID-19 Vaccine.
Centers for Disease Control and Prevention (CDC) [Internet]. 2020.
18. O'Hagan DT, van der Most R, Lodaya RN, et al. "World in motion" - emulsion adjuvants rising to
meetthe pandemic challenges. NPJ Vaccines. 2021;6:158.
8
19. Medicago Inc. Product Mongraph including Patient Medication Information . COVIFENZ COVID-
19 Vaccine (plant-based virus-like particles [VLP], recombinan t, adjuvanted) . 2022. Available at
https://med icago.com/ app/upload s/2022/02/C ovifenz-PM-en.pdf. Accessed March 23, 2022.
20. Dunkle LM, Kotloff KL, Gay CL, et al. Efficacy and Safety of NVX-CoV2373 in Adults in the United
States and Mexico. N Engl J Med. 2022;386:531-43.
21. Pratama NR, Wafa IA, Budi DS, et al. Covid-19 Vaccination in Pregnancy: A Systematic Review.
medRxiv. 2021:2021.07.04.21259985.
ET GYN~COLOGUE S OU CANADA
THE SOCIETY OF OBSTETRICIANS AND GYNAECOLOGISTS OF CANADA · LA SOCl~T~ DES OBST~TRICIENS
or (613) 730-4192 Fax/Telecopieur: (613) 730-4192 SOgC,Org
2781 chemin Lancaster Road, Suite 200, Ottawa, ON K1B 1A7 Tel/Tel: (800) 561-2416
AR08012
22. National Advisory Committee on Immunization. NACI rapid response: Updated guidance on
COVID-19 vaccination timing for individuals previously infected with SARS-CoV-2. 2022. Available at
https://www. ea nada .ea/en /pu bi ic-hea lth/services/i mm u nization/national-advisory-com m ittee-on-
imm uni zatio n-naci/rapid-response-gu ida nce-covi d-19-vacci nati on-ti mi ng-ind ivid uals-previ ously-
infected-sars-cov-2. htm I. Accessed March 23, 2022.
23. Government of Canada. Recommendations on the use of COVID-19 vaccines. Contraindications

and precautions. 2021. Available at https://www.canada.ca/en/public-
health/services/immunization/national-advisory-committee-on-immunization-naci/recommendations-
use-covid-19-vaccines.html#a 7 .9.
24. Mithal LB, Otero S, Shanes ED, et al. Cord blood antibodies following maternal coronavirus
disease 2019 vaccination during pregnancy. Am J Obstet Gynecol. 2021;225:192-4.
25. Beharier 0, Plitman Mayo R, Raz T, et al. Efficient maternal to neonatal transfer of antibodies
against SARS-CoV-2 and BNT162b2 mRNA COVID-19 vaccine. J Clin Invest. 2021;131.
26. Collier AV, McMahan K, Yu J, et al. lmmunogenicity of COVID-19 mRNA Vaccines in Pregnant and
Lactating Women. JAMA. 2021;325:2370-80.
27. Friedman MR, Kigel A, Bahar Y, et al. BNT162b2 COVID-19 mRNA vaccine elicits a rapid and
synchronized antibody response in blood and milk of breastfeeding women. medRxiv.
2021:2021.03.06.21252603.
28. Halasa NB, Olson SM, Staat MA, et al. Effectiveness of Maternal Vaccination with mRNA COVID-
19 Vaccine During Pregnancy Against COVID-19-Associated Hospitalization in Infants Aged <6 Months -
17 States, July 2021-January 2022. MMWR Morb Mortal Wkly Rep. 2022;71:264-70.
29. Perl SH, Uzan-Yulzari A, Klainer H, et al. SARS-CoV-2-Specific Antibodies in Breast Milk After
COVID-19 Vaccination of Breastfeeding Women. JAMA. 2021;325:2013-4.
30. Golan Y, Prahl M, Cassidy A, et al. Immune response during lactation after anti-SARS-CoV2
mRNA vaccine. medRxiv. 2021:2021.03.09.21253241.
31. Selma-Rayo M, Bauerl C, Mena-Tudela D, et al. Anti-Sars-Cov-2 lgA And lgG In Human Milk After
Vaccination Is Dependent On Vaccine Type And Previous Sars-Cov-2 Exposure: A Longitudinal Study.
medRxiv. 2021:2021.05.20.21257512.
THE SOCIETY OF OBSTETRICIANS AND GYNAECOLOGISTS OF CANADA· LA SOCIETI~ DES OBSTETRICIENS ET GYNECOLOGUES DU CANADA
2781 che min Lancaster Road, Suite 200, O«awa, ON K1B 1A7 Tel/Tel: (800) 561-24 16 or (613) 730-4192 Fax/Telecopieur: (613) 730-4192 SOgc.org
AR08013
32. Fox A, Norris C, Amanat F, et al. The vaccine-elicited immunoglobulin profile in milk after COVID-
19 mRNA-based vaccination is lgG-dominant and lacks secretary antibodies. medRxiv.
2021:2021.03.22.21253831.
33. Low JM, Gu Y, Ng MSF, et al. BNT162b2 vaccination induces SARS-CoV-2 specific antibody
secretion into human milk with minimal transfer of vaccine mRNA. medRxiv.
2021:2021.04.27 .21256151.
34. Esteve-Palau E, Gonzalez-Cuevas A, Guerrero ME, et al. Quantification of Specific Antibodies

Against SARS-CoV-2 in Breast Milk of Lactating Women Vaccinated With an mRNA Vaccine. JAMA Netw
Open. 2021;4:e2120575.
35. World Health Organization. WHO SAGE values framework for the allocation and prioritization of
COVID-19 vaccination 2020. Available at
https://apps.who.int/iris/bitstream/handle/10665/334299/WHO-2019-nCoV-SAGE Framework-
Allocation and prioritization-2020.1-eng.pdf?ua=l. Accessed November 8, 2021.
36. National Advisory Committee on Immunization. Research priorities for COVID-19 vaccines to
support public health decisions. Health Canada [Internet]. 2020. Available at
https://www. ea n ada .ea/en /pu bi ic-heaIth/services/i mm uni zation/n atio na1-advisory-com m ittee-on-
imm u nization-naci/research-priorities-covid-19-vacci nes. htm I.
THE SOCIETY OF OBSTETRICIANS AND GYNAECOLOGISTS OF CANADA· LA SOCl(;T(; DES OBSTf;TRICIENS ET GYN(;COLOGUES DU CANADA
2781 chemin Lancaster Road. Suite 200, On awa, ON K1B 1A7 Tel/Tel: (800) 561-2416 or (613) 730-4192 Fax/Telecopieur: (613) 730-4192 SOgc.org
AR08014
FLULAVAL TETRA (2021 -2022) GlaxoSmithKline
PRODUCT MONOGRAPH
FLULAVAL TETRA
(2021-2022)
Quadrivalent Influenza Vaccine (Split Virion, Inactivated)
Suspension for Injection
ATC Code: J07BB02
Manufactured by:
ID Biomedical Corporation of Quebec
Quebec, Quebec, Canada
Distributed by: Date of Revision:

06 April 2021
GlaxoSmithKline Inc.
7333 Mississauga Road
Date of Approval:
Mississauga, Ontario
14 April 2021
LSN 6L4
Control No.: 251450
©2021 GSK group of companies or its licensor.

Trademarks are owned by or licensed to the GSK group ofcompanies.
JML TRANSCRIPTION
1-888-288-6817
DATE: f--l?j 1-:3, dQ,::} .).....
EX#: :;)- IN IT IALS: A ·P
Approved: 14 A pril 2021
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AR08015
FLULAVAL TETRA (2021-2022) GlaxoSmithKline
Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION .........---········-······-····-··-··--·· 3

SUMMARY PRODUCT INFORMATION .................................................................. 3
DESCRIPTION.............................................................................................................. 3
INDICATIONS AND CLINICAL USE ........................................................................ 4
CONTRAINDICATIONS ............................................................................................. 4
W ARNIN"GS AN]) PRECAUTIONS ............................................................................ 4
ADVER.SE REACTIONS .............................................................................................. 6
DRUG IN'IBRACTIONS ............................................................................................ 14
DOSAGE AND ADMINISTRATION ........................................................................ 14
OVERDOSAGE .......................................................................................................... 16
ACTION AND CLINICAL PHARMACOLOGY ........... :.......................................... 17
STORAGE AND STABILITY .................................................................................... 17
SPECIAL HANDLING INSTRUCTIONS ................................................................. 17
DOSAGE FORMS, COMPOSITION AND PACKAGING ....................................... 18
PART Il: SCIBNTWIC IN'FORMATION ......................................................................... 19

PHARMACEUTICAL INFORMATION .................................................................... 19
CLINICAL TRIALS .................................................................................................... 19
TOXICOLOGY ........................................................................................................... 24
REF'ERENCES ............................................................................................................ 24
PART m: CONSUMER IN'FORMATION........................................................................ 25
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AR08016
FLULAVAL TETRA
(2021-2022)
Quadrivalent influenza vaccine (split virion, inactivated)
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION

Route of Dosage Form / Strength Clini~y Relevant Nonmedicinal
Administration Ingredients
Intramuscular Suspension for Injection Egg proteins, sodium deoxycholate,
available in multidose vial ethanol, formaldehyde, sucrose, a.-
and single-dose prefilled tocopheryl hydrogen succinate,
syringe* polysorbate 80.
Each 0.5 mL dose contains 15 Thimerosal preservative in the
µg of influenza virus multidose presentation only.
haemagglutinin/strain for each For a complete listing see Dosage
strain listed below (see Forms, Composition and Packaging
Description) section.
*The prefilled syringe presentation is not available for the 2021-2022 season
DESCRIPTION
FLULAVAL TETRA is a quadrivalent split-virion, inactivated influenza vaccine prepared from

virus grown in the allantoic cavity of embryonated hens' eggs. The virus is inactivated with
ultraviolet light treatment followed by formaldehyde treatment, purified by centrifugation and
disrupted with sodium deoxycholate.
This vaccine complies with the World Health Organization (WHO) recommendation (Northern
Hemisphere) for the 2021-2022 season.
Each 0.5mL dose of vaccine contains 15 micrograms haemagglutinin of each of the following four
influenza virus strains:
lSµg HA-ANictoria/2570/2019 (H1Nl)pdm09-like virus

15µg HA - A/Cambodia/e0826360/2020 (H3N2)-like virus
15µg HA- B/Phuket/3073/2013-like virus from B/Yamagata lineage
15 µg HA - B/Washington/02/2019-like virus from B/Victoria lineage
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AR08017
INDICATIONS AND CLINICAL USE
FLULAVAL TETRA is a quadrivalent vaccine indicated for active immunization of adults and
children from 6 months of age for the prevention of influenza disease caused by influenza virus
types A and B contained in the vaccine.
The National Advisory Committee on Immunization (NACI) provides additional guidance on the
use of the influenza vaccine in Canada. Please refer to published Statement on Seasonal Influenza
Vaccine for the current season.
CONTRAINDICATIONS
FLULAVAL TETRA should not be administered to subjects with known hypersensitivity to egg
proteins or after previous administration of any influenza vaccine produced in eggs or to any
component of the vaccine.
WARNINGS AND PRECAUTIONS
Serious Warnings and Precautions
As with all injectable vaccines, appropriate medical treatment and supervision should always
be readily available in case of an anaphylactic event following the administration of the
vaccine.
FLULAVAL TETRA should under no circumstances be administered intravascularly.
General
It is good clinical practice to precede vaccination by a review of the medical history (especially
with regard to previous vaccination and the possible occurrence of undesirable events) and a
clinical examination.
Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic
response to the needle injection. It is important that procedures are in place to avoid injury from
faints.
As with any vaccine, a protective immune response may not be elicited in all vaccinees.
FLULAVAL TETRA is not effective against all possible strains of influenza virus. FLULAVAL
TETRA is intended to provide protection against those strains of virus from which the vaccine is
prepared and to closely related strains.
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AR08018
Febrile or acute disease

As with other vaccines, vaccination with FLULAVAL TETRA should be postponed in subjects
suffering from an acute severe febrile illness. The presence of a minor infection, such as a cold,
should not result in the deferral of vaccination.
Hematologic
As with other vaccines administered intramuscularly, FLULAVAL TETRA should be given with
caution to individuals with thrombocytopenia or any coagulation disorder since bleeding may
occur following an intramuscular administration to these subjects.
Immune
An adequate immune response may not be elicited in patients receiving immunosuppressive
treatment or patients with immunodeficiency.
Local Skin Reactions at Vaccination Sites

Soreness and redness at the injection site may occur and may last for up to two days. Prophylactic
acetaminophen may decrease the frequency of pain at the injection site.
Neurologic
If Guillain-Barre syndrome has occurred within 6 weeks of receipt of prior influenza vaccine, the
decision to give FLULAVAL TETRA should be based on the careful consideration of the
potential benefits and risks.
Immunization should be delayed in a patient with an active neurologic disorder, but should be
considered when the disease process has been stabilized.
Respiratory
Revaccination of individuals who have previously experienced oculo-respiratory symptoms is
safe. Previously affected individuals should be encouraged to be revaccinated. The risk of
recurrence of oculo-respiratory symptoms after revaccination is minimal compared to the serious
threat posed by influenza. Please refer to the most current NACI recommendations regarding
revaccination of subjects who experienced more severe oculo-respiratory syndrome.
Special Populations
Pregnant Women: The safety of FLULAVAL TETRA when administered to pregnant women
has not been evaluated. Animal studies with FLULAVAL TETRA do not indicate direct or
indirect hannful effects with respect to reproductive and developmental toxicity. FLULAVAL
TETRA should be used during pregnancy only when clearly needed, and the possible advantages
outweigh the potential risks for the foetus.
ApProved· 14 April 2021

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AR08019
Nursing Women: The safety of FLULAVAL TETRA when administered to breast-feeding

women has not been evaluated. It is unknown whether FLULAVAL TETRA is excreted in human
breast milk. FLULAVAL TETRA should only be used during breast-feeding when the possible
advantages outweigh the potential risks.
ADVERSE REACTIONS
Adverse Drug Reaction Overview

In clinical trials, FLULAVAL TETRA was administered to more than 1,960 children between 6 -
35 months of age, more than 3,500 children between 3 - 17 years of age and more than 1,200
adults.
In adults, the most common (~10%) solicited local reaction was pain (60%); the most common
solicited systemic adverse events were myalgia (26%), headache (22%), fatigue (22%), and
arthralgia (15%).
In children 3 to 17 years of age, the most common (~10%) solicited local reaction was pain (65%).
In children 3 to 4 years of age, the most common (~ 10%) solicited systemic adverse events were
irritability (26%), drowsiness (21%), and loss of appetite (17%). In children·s to 17 years of age,
the most common (~10%) systemic adverse events were muscle aches (290/4), fatigue (22%),
headache (22%), arthralgia (13%), and gastrointestinal symptoms (10%).
In children 6 to 35 months of age, injection site pain was the most common (~10%) solicited local
reaction (40%). The most common solicited systemic adverse events were irritability (49%),
drowsiness (37%), and loss of appetite (29%).
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction
rates observed in the clinical trials may not reflect the rates observed in practice and
should not be compared to the rates in the clinical trials ofanother drug. Adverse drug
reaction information from clinical trials is useful for identifying drug-related adverse
events andfor approximating rates.
In clinical trials, FLULAVAL TETRA was administered to more than 6,660 subjects.
Adverse reactions reportedfor FLULAVAL TETRA are listed per dose according to the following
frequency categories:
Approved: 14 April 2021

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AR08020
Very common~l/10
Common ~1/100 to <1/10
Uncommon ~1/1,000 to <1/100
Rare ~1/10,000 to <1/1,000
Very rare <1/10,000
The following adverse reactions have been reported in all age categories:
System Organ Oass Adverse Reactions Frequency

Injection site pain Very common
General disorder and
administration site condition Injection site redness and
Common
fever
Upper respiratory tract
Infections and infestations Uncommon
infection
The following adverse reactions have also been reported depending of the age category:
Children (5-17) and Adults:

System Organ Class Adverse Reactions Frequency
Nervous system disorders Headache Very common
Musculoskeletal and Very common
Arthralgia, myalgia
connective tissue disorders
General disorder and Fatigue Very common
administration site condition Shivering and injection
Common
site swelling
Gastrointestinal
Gastrointestinal disorders symptoms (including
Common
nausea, vomiting,
diarrhea, abdominal pain)
Adults:
General disorder and
Injection site swelling Common
administration site condition
Blood and lymphatic
Lymphadenopathy Uncommon
disorders
Nervous system disorders Dizziness Uncommon
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AR08021
Children:
6-35months
Metabolism and Nutrition Very common
Appetite Loss
disorders
Psychiatric disorders Irritability Very common
Nervous system disorders Drowsiness Very common
Gastrointestinal disorders Vomiting, diarrhoea Uncommon
Respiratory, thoracic and Uncommon
Cough
mediastinal disorders
Skin and subcutaneous tissue Uncommon
Rash
disorders
General disorders and Uncommon
Injection site swelling
administration site conditions
3-4 years
Metabolism and Nutrition
Appetite loss1 Very common
disorders
Psychiatric disorders Jrritability l Very common
Nervous system disorders Drowsiness1 Very common
3-17years
Influenza like illness, and Uncommon
General disorders and ini ection site oruritus
administration site conditions Common
Injection site swelling
1
Reported as very common, with the same or lower percent frequency compared to 6-35 months
Adults: Study Q-QW-007 (lmmunogenicity Non-Inferiority and Superiority):

A randomized, double-blind, active-controlled study evaluated I, 703 adults 18 years of age and
older who received FLULAVAL TETRA, with two A strains and two B strains, one of Victoria
lineage and one of Yamagata lineage (N = 1,272), or a trivalent influenza vaccine (TIV):
FLUVIRAL (Influenza Virus Vaccine), manufactured for the 2010-2011 season with a B strain of
Victoria lineage (N = 213), or a TIV with the same two A strains as FLUVIRAL but with a B
strain of Yamagata lineage (N = 218). The mean age of subjects was 50 years. Solicited local
adverse reactions and systemic adverse events were collected using diary cards for 7 days (day of
vaccination and the next 6 days).

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AR08022
Table 1: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events
Within 7 Da:vsa of Vaccination in AduJtsh (Total Vaccinated Cohort)
FLULAVAL FLUVIRAL TIV
TETRAC (B Victoria)d (B Yamagata)e
N= 1,260 N=208 N=216
%· % %
Local
Pain 60 45 41
Swellin~ 3 1 4
Redness 2 3 I
S:vstemic
Mvalma 26 25 19
Headache 22 20 23
Fatieue 22 22 17
Arthralma 15 17 15
Gastrointestinal svmotomsr 9 10 7
Shiverin~ 9 8 6
Fever> 100.4°F (38.0°C) 2 1 1
TIV = trivalent influenza vaccine.
Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were
available.
a 7 days included day of vaccination and the subsequent 6 days.
b Study Q-QIV-007: NCT0I 196975.

c Contained two A strains and two B strains, one of Victoria lineage and one of Yamagata lineage.
d Contained two A strains and a B strain of Victoria lineage.

e Contained the same two A strains as FLUVIRAL and a B strain of Yamagata lineage.
r Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain.
Unsolicited Adverse Events: Unsolicited events that occurred within 21 days of vaccination (day
0-20) were recorded based on spontaneous reports or in response to queries about changes in
health status. The incidence of unsolicited adverse events reported during the 21-day post-
vaccination period for subjects who received FLULAVAL TETRA (N = 1,272), FLUVIRAL
(N = 213), or TIV (B Yamagata) (N = 218) was 19%, 23%, and 23%, respectively. Unsolicited
events reported for FLULAVAL TETRA considered as possibly related to vaccination and
occurring in ~-1 % of subjects included dizziness, injection site hematoma, injection site
hemorrhage, injection site warmth, lymphadenopathy, pruritus, rash, and upper respiratory tract
infection.

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AR08023
Children: Study Q-QIV-003 (lmmunogenicity Non-Inferiority and Superiority):

A randomized, double-blind, active-controlled study evaluated subjects 3 through 17 years of age
who received FLULAVAL TETRA, with two A strains and two B strains, one of Victoria lineage
and one of Yamagata lineage (N = 932) or a trivalent influenza vaccine (TIV): FLUARIX
(Influenza Virus Vaccine), manufactured for the 2010-2011 season with a B strain of Victoria
lineage (N = 929), or a TIV with the same two A strains as FLUARIX but with a B strain of
Yamagata lineage (N = 932). Among recipients ofFLULAVAL TETRA, 53% were male. The
mean age of subjects was 9 years. Children 3 through 8 years of age with no history of influenza
vaccination received 2 doses approximately 28 days apart. Children 3 through 8 years of age with
a history of influenza vaccination and children 9 years of age and older received one dose.
Solicited local adverse reactions and systemic adverse events were collected using diary cards for
7 days (Table 2).
Table 2: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events
Within 7 Daysa of First Vaccination in Children 3 to 17 Years of Ageh (Total Vaccinated
Cohort)
FLULAVAL FLUARIX TIV
TETRAC (B Victoria)d (B Yamagata)e
% % %
Ai e Group: 3 to 17 Years
Local N=913 N=911 N=915
Pain 65 55 56
Swellin~ 6 3 4
Redness 5 3 4
A !!e Group: 3 to 4 Years
Systemic N=l85 N=187 N=l89
Irritability 26 17 22
Drowsiness 21 20 23
Loss of aooetite 17 16 13
Fever ~100.4°F (38.0°C) 5 6 4
A: e Group: 5 to 17 Years
Systemic N=727 N=724 N=725
Muscle aches 29 25 25
Fathrue 22 24 23
Headache 22 22 20
Arthralgia 13 12 11
Gastrointestinal symptom/ 10 10 9
Shivering 7 7 7
Fever ~100.4°F (38.0°C) 2 4 3
TIV = trivalent influenza vaccine.
available.
b Study Q-QIV-003: NCT0I 198756

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AR08024
d Contained two A strains and a B strain of Victoria lineage.

e Contained the same two A strains as FLUARIX and a B strain of Yamagata lineage.
r Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain.
In children who received a second dose of FLULAVAL TETRA, FLUARIX, or TIV (B

Yamagata), the incidences of adverse events following the second dose were generally lower than
those observed after the first dose.
Unsolicited Adverse Events: Unsolicited adverse events that occurred within 28 days (day 0-27) of
any vaccination were recorded based on spontaneous reports or in response to queries about
changes in health status. The incidence of unsolicited adverse events reported in subjects who
received FLULAVAL TETRA (N = 932), FLUARIX (N = 929), or TIV (B Yamagata) (N = 932)
was 30%, 31 %, and 30%, respectively. Unsolicited events reported for FLULAVAL TETRA
considered as possibly related to vaccination and occurring in ~0.1 % of subjects included
influenza-like illness, injection site hematoma, injection site pruritus, rash, and upper respiratory
tract infection.
Children 6-35 months: Study Q-QW-022 (lmmunogenicity and safety):

A randomized, double-blind, active controlled study in which subjects received one or two 0.5 mL
doses of FLULAVAL TETRA (N = 1207) or a comparator quadrivalent influenza vaccine
(FLUZONE QUADRIVALENT N = 1217). Children with no history of prior influenza
vaccination received 2 doses approximately 28 days apart (43.0% and 43.5 % for FLULAVAL
TETRA and FLUZONE QUADRIVALENT, respectively). Children with a history of prior
influenza vaccination received one dose of vaccine (57.0% and 56.5%, respectively). Solicited
local adverse reactions and systemic adverse events were collected using diary cards for 7 days
(Table 3).

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AR08025
Table 3: Incidence of Solicited Local and Systemic Adverse Events Within 7 Daysa of First
Vaccination in Children 6 to 35 Months of A2eb (Total Vaccinated Cohort)
FLULAVAL FLUZONE
Children TETRAC QUADRIVALEN'r:
6-35 months % %
Local N= 1151 N= 1146
Pain 40.3 37.4
Redness 1.3 1.3
Swelling 1.0 0.4
Systemic N= 1155 N= 1148
Irritability 49.4 45.9
Drowsiness 36.7 36.9
Loss of appetite 28.9 28.6
Fever ~100.4°F (38.0°C) 5.6 5.8
b Study Q-QIV-022: NCT02242643
In children who received a second dose of FLULAVAL TETRA or FLUZONE

QUADRIVALENT the incidences of adverse events following the second dose were generally
lower than those observed after the first dose.
Unsolicited Adverse Events: Unsolicited adverse events that occurred within 28 days (day 0-27) of
any vaccination were recorded based on spontaneous reports or in response to queries about
changes in health status. The incidence of unsolicited adverse events reported in subjects who
received FLULAVAL TETRA (N = 1207), FLUZONE QUADRIVALENT (N = 1217) was
45.5% and 44. l %, respectively. Unsolicited events reported for FLULAVAL TETRA considered
as possibly related to vaccination and occuning in ~. l % of subjects included upper respiratory
tract infection, cough, diarrhea, nasopharyngitis and otitis media.
Children 3-8 years: Study Q-QIV-006 (Efficacy):

Safety information was collected in an observer-blind, non-influenza vaccine-controlled study
evaluating the efficacy of FLULAVAL TETRA. The study included subjects 3 through 8 years of
age who received FLULAVAL TETRA (N = 2,584) or HAVRIX (Hepatitis A Vaccine)
(N = 2,584). Children with no history of influenza vaccination received 2 doses of FLULAVAL
TETRA or HAVRIX approximately 28 days-apart. Children with a history of influenza
vaccination received one dose of FLULAVAL TETRA or HAVRIX. In the overall population,
52% were male. The mean age of subjects was 5 years. Solicited local adverse reactions and
systemic adverse events were collected using diary cards for 7 days (day of vaccination and the
next 6 days) (Table 4).
Approved· 14April 2021

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AR08026
Table 4: Incidence of Solicited Local and Systemic Adverse Events Within 7 Daysa of First
Vaccination in Children 3 to 8 Years of Aaeb (Total Vaccinated Cohort)
FLULAVAL TETRA BAVRIX
% %
Age Group: 3 to 8 Years
Local N=l,546 N=2,551
Pain 39 28
SwellinJ?: l 0.3
Redness 0.4 0.2
A2e Group: 3 to 4 Years
Svstemic N=898 N=895
Loss of appetite 9 8
Irritabilitv 8 8
Drowsiness 8 7
Fever> 100.4°F (38.0°C) 4 4
A2e Group: 5 to 8 Years
Svstemic N= 1,648 N = 1,654
Muscle aches 12 10
Headache 11 11
Fatim.ie 8 7
Arthraleia 6 5
Gastrointestinal svmotomsc 6 6
ShiverinJ?; 3 3
Fever> 100.4°F (38.0°C) 3 3
available.
b Study Q-QN-006: NCT01218308.
c Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain.
In children who received a second dose of FLULAVAL TETRA or HAVRIX, the incidences of
adverse events following the second dose were generally lower than those observed after the first
dose.
Unsolicited Adverse Events: Unsolicited events that occurred within 28 days of any vaccination
(day 0-27) were recorded based on spontaneous reports or in response to queries about changes in
health status. The incidence of unsolicited adverse events reported was similar among the groups
(33% for both FLULAVAL TETRA and HAVRIX). Unsolicited events reported for FLULAVAL
TETRA considered as possibly related to vaccination and occurring in ~. l % of subjects included
injection site pruritus.
Approved: 14Apri/ 2021

Pagel3of27
AR08027
Post-Market Adverse Drug Reactions
Immune system disorders

Rare: allergic reactions
As all three of the influenza strains contained in FLUVIRAL are included in FLULAVAL
TETRA, the following additional adverse events that have been obsetved for FLUVIRAL during
post-marketing surveillance may occur in patients receiving FLULAVAL TETRA.
System Organ Oass Adverse Reactions Frequency

Anaphylactic reactions
Immune system disorders and anaphylactoid Rare
reactions
Netvous system disorders Guillain-Barre syndrome Rare
Skin and subcutaneous tissue Urticaria, angioedema Rare
disorders
DRUG INTERACTIONS
Drug-Drug Interactions
If FLULAVAL TETRA is to be given at the same time as another injectable vaccine, the vaccines
should always be administered ~t different injection sites.
Drug-Laboratory Interactions
False positive ELISA serologic tests for lilV-1, Hepatitis C, and especially HTLV-1 may occur
following influenza vaccination. These transient false-positive results may be due to cross-
reactive IgM elicited by the vaccine. For this reason, a definitive diagnosis of IDV-1, Hepatitis C,
or HTLV-1 infection requires a positive result from a virus-specific confinnatory test (e.g.,
Western Blot or immunoblot).
Drug~Lifestyle Interactions
The vaccine is unlikely to produce an effect on the ability to drive and use machines.
DOSAGE AND ADMINIS TRATION
Recommended Dose and Dosage Adiustmen t
FLULAVAL TETRA should be administered as a single 0.5 mL injection.
Children 6 months to less than 9 years of age who have not previously been vaccinated against
influenza should receive a second dose of 0.5 mL after an interval of at least 4 weeks.

Page 14of27
AR08028
Administration
FLULAVAL TETRA must not be administered intravenously.
Vaccination should be carried out by intramuscular injection preferably into the deltoid muscle or
anterolateral thigh (depending on the muscle mass).
In the absence of compatibility studies, this medicinal product must not be mixed with other
medicinal products.
Any unused product or waste material should be disposed of in accordance with local
requirements. Since FLULAVAL TETRA is a split-virion, inactivated vaccine, it presents no risk
of contaminating the work area during manipulation.
For the multidose vial presentation:
The vaccine presents as an opalescent translucent to off-white suspension, that may sediment
slightly.
The vial should be shaken prior to each administration and inspected visually for any foreign
particulate matter and/or variation of physical aspect prior to administration. In the event of either
being observed, discard the vaccine.
Each vaccine dose of0.5 mL is withdrawn into a lmL syringe for injection and administered
intramuscularly. It is recommended to equip the syringe with a needle gauge not larger than 23-G.
Between uses, the multidose vial should be stored in a refrigerator (2°C - 8°C).

Pagel5of2 7
AR08029
For the single-dose prefmed syringe presentation:
The vaccine presents as an opalescent translucent to off-white suspension, that may sediment
slightly.
The syringe should be shaken and inspected visually for any foreign particulate matter and/or
variation of physical aspect prior to administration. In the event of either being observed, discard
the vaccine.
Instructions for administration of the vaccine presented in a PRTC (plastic rigid tip cap) prefilled
syrin_ge
Needle
1. Holding the syringe barrel in one hand (avoid holding the syringe plunger), unscrew the
syringe cap by twisting it anticlockwise.
2. To attach the needle to the syringe, twist the needle clockwise into the syringe until you
feel it lock (see picture).
3. Remove the needle protector, which on occasion can be a little stiff.
4. Administer the vaccine.
OVERDOSAGE
Insufficient data are available.
For management of a suspected drug overdose, contact your regional Poison Control Centre.

Page 16of27
AR08030
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
FLULAVAL TETRA provides active immunization against the four influenza virus strains (two A
subtypes and two B types) contained in the vaccine.
FLULAVAL TETRA induces humoral antibodies against the haemagglutinins. These antibodies
neutralize influenza viruses.
Specific levels of haemagglutination-inhibition (HI) antibody titer post-vaccination with

inactivated influenza virus vaccines have not been correlated with protection from influenza
illness but the IIl antibody titers have been used as a measure of vaccine activity. In some human
challenge studies, IIl antibody titres of~l:40 have been associated with protection from influenza
illness in up to 50% of subjects.
Annual revaccination with the current vaccine is recommended because immunity declines during
the year after vaccination, and because circulating strains of influenza virus might change from
year to year.
Pharmacodynamics/Pharmacokinetics
No pharmacokinetic studies have been conducted with FLULAVAL TETRA in accordance with
its status as a vaccine. Forpharmaco dynamic information see Clinical Trials.
Duration of Effect
Annual revaccination is recommended because immunity declines during the year after
vaccination, and because circulating strains of influenza virus change from year to year.
STORAGE AND ST~ILITY
Store in a refrigerator (2°C - 8°C).

Do not freeze.
Store in the original package in order to protect from light.
The vaccine is stable for 12 months.
Once entered, the multidose vial should be discarded within 28 days.
SPECIAL HANDLING INSTRUCTIONS
Any unused product or waste· material should be disposed of in accordance with local
requirements.

Page 17of27
AR08031
DOSAGE FORMS, COMPOS ITION AND PACKAG ING
This vaccine complies with the World Health Organization (WHO) recommendation (Northern
Hemisphere) for the 2021-2022 season. The quadrivalent vaccine contains 2 A strains and 2 B
strains.
Each dose of 0.5 mL ofFLULA VAL TETRA contains:
15µgHA- A/Victoria/2570/2019 (H1Nl)pdm 09-Iike virus (A/Victoria/2570/2019 IVR-215)

15µgHA- A/Cambodia/e0826360/2020 (H3N2)-like virus (A/Tasmania/503/2020 IVR-221)
15µgHA- B/Phuket/3073/2013-like virus (B/Phuket/3073/2013) from the BNamagata/16/88
lineage
15µgHA- B/Washington/02/2019-like virus (B/W ashington/02/2019) from the
BNictoria/ 2/87 lineage
The vaccine is formulated with phosphate buffered saline composed of: sodium chloride,
potassium chloride, disodium hydrogen phosphate heptahydrate, potassium dihydrogen phosphate
and water for injection. Each 0.5-mL dose contains, a.-tocopheryl hydrogen succinate (267 µg),
and polysorbate 80 (683 µg). Each 0.5-mL dose may also contain residual amounts of egg proteins
(ovalbumin ~0.3 µg), sodium deoxycholate, ethanol, formaldehyde and sucrose from the
manufacturing process.
The multidose vial presentation contains thimerosal, a mercury derivative, added as a preservative.
Each 0.5-mL dose contains 50 µg thimerosal (<25 µg mercury).
The single-dose prefilled syringe presentation does not contain thimerosal or any other
preservative.
Antibiotics are not used in the manufacture of this vaccine.
Multi-dose vial presentation:
5 mL vial (type I glass) containing 10 doses of 0.5 mL

Pack size of I vial.
The vial stopper does not contain lateJ.
Single-dose pref"dled syringe presentation:
0.5 mL single-dose PRTC prefilled type 1 glass syringe with TIP LOK.
Pack size of 1 or 10 syringes (packaged without needles).
The tip cap and plunger stopper of the prefilled syringe do not contain latex.
This presentation is not currendy available.
Af!.Proved· 14April 2021

Page 18of27
AR08032
PART II: SCIENTIFIC INFORMATION
PHARMACE UTICAL INFORMAT ION
Drug Substance
FLULAVAL TETRA contains four split-virion, inactivated influenza virus strains prepared from
virus propagated in the allantoic cavity of embryonated hens' eggs. Each of the influenza virus
strains is produced and purified separately. The virus is inactivated by treatment with ultraviolet
light followed by formaldehyde treatment, purified by centrifugation, and disrupted with sodium
deoxycholate.
Product Characteristics
FLULAVAL TETRA is a sterile, opalescent translucent to off-white suspension in a phosphate-
buffered saline solution that may sediment slightly. The vaccine has been formulated to contain
60 micrograms (µg) haemagglutinin (HA) per 0.5-mL dose in the recommended ratio of 15 µg HA
of each of the 4 influenza virus strains. Antibiotics are not used in the manufacture of this vaccine.
CLINICAL TRIALS
Study demographic s and trial design

The efficacy of the FLULAVAL TETRA has been demonstrated in children aged 3 to 8 years of
age. The immunogenicity and safety of FLULAVAL TETRA quadrivalent influenza vaccine has
been demonstrated in clinical trials involving adults 18 years and older and children aged 6
months to 17 years.
The h~oral immune response was assessed in terms of a serum haemagglutinin-inhibiting (HI)
antibody titer against each virus strain included in the Q-QIV vaccine. In adult studies the immune
response was assessed 21 days following vaccination. In pediatric studies, the immune response
was assessed 28 days following the last vaccination.

Page 19of27
AR08033
.
Ta bie 5 Summarv of patient demom-ao: 1cs or c 1mca tr1 S ID S1 )eel IC ID 1cation
Dosage, route of Study subjects1 Meanage2 Gender
Study# Trial design (n=number) (Range)
administration
rando~ double- 0.5mL,IM

blind, immunogenicity 8.9years F=406
Q-QIV-003 (unprimed: 2x0.5mL n=878 M=472
non inferiority and (3-17 years)
IM, 28 days apart)
safety
randomized, observer 0.SmL, IM 5.4years F= 1158
Q-QIV-006 blind, efficacy and (unprimed: 2x0.5mL, n=2376 M= 1218
(3-8 years)
safety IM, 28 days apart)
randomized, double-
blind, immunogenicity n= 1246 50.0years F=766
Q-QIV-007 0.5mL,IM (18-97 years) M=480
non inferiority and ~18yems
safety
rando~ double- 0.5mL,IM 18.2 months F= 149
Q-QIV-013 blind, immunogenicity (unprimed, 2x0.5mL n=284
(6-35 months) M=l35
and safety IM, 28 days apart)
randomized, observer- 0.5mL,IM 19.6 months F=67

Q-QIV-021 blind, immunogenicity (unprimed, 2x0.5mL n=l43
(6-35 montm) M=76
and safety IM, 28 days apart)
rando~ double- 0.5mL, IM 19.4 months F=462

blind, immunogenicity n= 1013
Q-QIV-022 (unprimed, 2x0.5mL
non inferiority and IM, 28 days apart) (6-35 months) M=551
safety
1
According to Protocol Cohort receiving FLULAVAL TEfRA
2 Total Vaccinated Cohort receiving FLULAVAL TErRA
Study results
Efficacy of FLULAVAL TETRA
Clinical study Q-QIV-006, performed in approximately 2,500 children 3 to 8 years of age,

evaluated the efficacy of FLULAVAL TETRA to prevent laboratory confirmed influenza A
and/or B disease presenting as influenza-like illness, compared to a non-influenza vaccine control.
Influenza-like illness (Il..I) was defined by the presence of an oral or axillary temperature 2:37.8°C
in the presence of at least one of the following symptoms on the same day: cough, sore throat,
runny nose or nasal congestion. See table below for results.
Approved: 14 April 202 J

Page20of27
AR08034
FLULAVAL TETRA (2021-2022) GlaxoSmithK line
Table 6: Attack rates and Vaccine Efficacy against mness associated with evidence of
influenza A and/or B Infection in children 3 to 8 years of age (According to Protocol cohort
for efficacy)
Attack Rates Vaccine Efficacy
(nJN)1
N N o/o o/o (CI2)
3
An:v RT-PCR confirmed influenza cases
FLULAVAL 58 2.4 55.4 (95% Cl: 39.1;67.3)
2,379
TETRA
Control 2,398 128 5.3 -
Moderate to severe influenza cases4
FLULAVAL 14 0.6 73.1 (97.5% CI: 47.1; 86.3)
2,379
TETRA
Control 2,398 52 2.2 -
1 n/N: number of case/total number of subjects
2
CI: Confidence Interval
3
Reverse Transcriptase Polymerase Chain Reaction
4 Moderate to severe influenza is defined by RT-PCR-conf irmed ILi with fever >39 degree
Celsius (39°C), and/or physician-verified shortness of breath, pulmonary congestion, pneumonia,

bronchiolitis, bronchitis, wheezing, croup, or acute otitis media, and/or physician-diagnosed
serious extra-pulmonary complication of influenza, including myositis, encephalitis, seizure,
and/or myocarditis
Immunogenicity of FLULAVAL TETRA versus FLUVIRAL, FLUARIX, FLUZONE and

FLUZONE QUADRIVALENT.
Clinical study Q-QIV-007 assessed the non-inferiority ofFLULAVAL TETRA versus

FLUVIRAL for ID Geometric mean antibody titer (GMT) at Day 21 and IIl seroconversio n rate
(4-fold rise in reciprocal titer or change from undetectable [< 10] to a reciprocal titer of2:'.: 40) in
adults 18 years of age and older.
Clinical study Q-QIV-003 assessed the non-inferiority of FLULAVAL TETRA versus FLUARIX
for lil GMT at Day 28 and lil seroconversion rate (4-fold rise in reciprocal titer or change from
undetectable [< 10] to a reciprocal titer of 2:'.: 40) in children 3 to 17 years of age. In an open-label,
independent arm of this study, the immunogenic ity and safety of the vaccine was evaluated in
children 6 to 35 months of age.
In both studies, the immune response elicited by FLULAVAL TETRA against the three strains in
common was non-inferior to FLUVIRAL or FLUARIX, providing evidence that the addition of
the second B strain did not result in immune interference to other strains included in the vaccine.
FLULAVAL TETRA elicited a superior immune response against the additional B strain included
in FLULAVAL TETRA compared to FLUVIRAL or FLUARIX.

Page21 o/27
AR08035
Clinical study Q-QIV-022 assessed the non-inferiority ofFLULA VAL TETRA versus
FLUZONE QUADRIVALENT for Ill GMT and Ill seroconversion rate (4-fold rise in reciprocal
titer or change from undetectab le[< 10] to a reciprocal titer of~ 40) 28 days after the last dose in
children 6 to 35 months of age. The immune response elicited by FLULAVAL TETRA against
the four strains was non-inferior to FLUZONE QUADRIVALENT based on GMT and
seroconversion rates. In addition, in two other studies (Q-QN-01 3 and Q-QN-021 ) in children 6-
35 months of age, FLULAVAL TETRA elicited a superior immune response against the
additional B strain included in FLULAVAL TETRA compared to FLUARIX or FLUZONE.
Adults 18 years of age and older

In clinical study Q-QIV-007, approximately 1,200 adults 18 years of age and older received a
single dose of FLULAVAL TETRA and approximately 200 subjects received a single dose of
FLUVIRAL.
Table 7: Post-vaccination GMTs and seroconversion rates from study Q-QIV-007 in adults
18 years of a2e and older (ATP1 cohort for analysis of immuno2enicity)
Adults FLULAVAL TETRA FLUVIRAL2
18 years of a2e and older N=1246 N=204
GMT5 (95% confidence interval)
A/HlNl 204.6 (190.4;219.9) 176.0 (149.1;207.7)
A/B3N2 125.4 (1 l 7.4;133.9) 147.5 (124.1; 175.2)
B (Victoria)2 177.7 (167.8; 188. 1) 135.9 (118.1;156.5)
B (Yamagata)3 39_9.7 (378.1;422.6) 176.9 (153.8;203.5)
~roconver sion rate (95% confidence interval)
A/HlNl 74.5% (71.9;76.9) 66.7% (59.7;73.l)
A/H3N2 66.5% (63.8;69.2) 73.0% (66.4;79.0)
B(Vktoria )3 55.2% (52.4;58.0) 48.8% (41.7;55.9)
B (Yamagata)4 54.8% (52.0;57.6) 33.3% (26.9;40.3)
1A TP: According-to-protocol
2Containing A/HlNl, A/H3N2 and B (Victoria lineage)
3
Recommended strain by WHO during the season 2010-2011
4
Additional B strain contained in FLULAVAL TETRA recommended in season 2008-2009
5
GMT is reported as the absolute value
Post-vaccination seroprotection rates (Day 21 reciprocal titer of~ 40) for FLULAVAL TETRA in
adults 18 years of age and older were 93.7% against A/HlNl, 90.8% against A/H3N2, 96.4%
against B (Victoria) and 99.8% against B (Yamagata).

Page22of2 7
AR08036
Children 3-17 years of age

In clinical study Q-QN-003 , approximately 1,700 children 3-17 years of age were randomized to
receive one or two doses based on prior vaccination status of FLULAVAL TETRA or FLUARIX.
Table 8: Post-vaccination GMTs and seroconver sion rates from study Q-QIV-00 3 in
children 3 to 17 years of a,ze (ATP1 cohort for analysis ofimmuno 1enicity)
Children FLULAVAL TETRA FLUARIX2
3-17 years of a2e N=878 N=871
GMT5 (95% confidence interval)
A/HlNl 362. 7 (335.3;392.3) 429.1 (396.5;464.3)
A/H3N2 143.7 (134.2;153.9) 139.6 (130.5; 149.3)
B (Victoria)2 250.5 (230.8;272.0) 245.4 (226.9;265.4)
B (Yamagata)3 512.5 (477.6;549.9) 197.0 (180.7;214.8)
Seroconve rsion rate (95% confidence interval)
A/HlNl 84.4% (81.8;86.7) 86.8% (84.3;89.0)
A/B3N2 70.1% (66.9;73.1) 67.8% (64.6;70.9)
B (Victoria)3 74.5% (71.5;77.4) 71.5% (68.4;74.5)
B (Yamagata)4 75.2% (72.2;78.1) 41.3% (38.0;44.6)
1
ATP: According-to-protocol
2
Containing A/HlNl, A/H3N2 and B (Victoria lineage)
3Recommen ded strain by WHO during the season 2010-2011
·
4
Additional B strain contained in FLULAVAL TETRA recommended in season 2008-2009
5
Post-vaccination seroprotection rates for FLULAVAL TETRA in children 3 to 17 years were

96.8% against A/HlNl, 92.9% against A/H3N2, 95.4% against B (Victoria) and 99.0% against B
(Yamagata).
Immunoge nicity of FLULAVAL TETRA versus FLUZONE QUADRIVALENT
Children 6-35 months of age
In clinical s~dy Q-QN-022 , children 6 to 35 months of age who received either one (57.0% of
subjects) or two doses (43.0% of subjects) ofFLULAV AL TETRA or FLUZONE
QUADRIVALENT were evaluated.

Page23 o/27
AR08037
Table 9: Post-vaccination GMTs and seroconversion rates from study Q-QIV-022 in

children 6 to 35 months of a te (A TP1 cohort for analysis of immunoeenicitv)
FLUZONE
Children FLULAVAL TETRA
QUADRIVALENT
6-35 months of age N=1013 N= 1028
2
GMT (95% confidence interval)
A/HlNl 98.8 (90.3;108.2) 84.4 (76.9;92.6)
A/H3N2 97.7 (90.3;105.7) 84.3 (77.6;91.6)
B (Victoria) 55.1 (50.8;59.8) 33.4 (30.6;36.4)
B (Yamagata) 257.5 (240.9;275.3) 164.2 (151.8;177.6)
Seroconversion rate (95% confidence interval)
A/HINl 73.7% (70.8;76.4) 67.3% (64.3;70.3)
A/H3N2 76. 1% (73.3;78.8) 69.4% (66.4;72.3)
B (Victoria) 64.9% (61.8;67.9) 48.5% (45.3;51.6)
B (Yamagata) 85 .5% (83 .2-87. 7) 73.8% (70.9;76.5)
1According-to protocol
2
Post-vaccination seroprotection rates for FLULAVAL TETRA in children 6 to 35 months were

80.4% against A/HlNl, 82.2% against A/H3N2, 66.0% against B (Victoria) and 97.0% against B
(Yamagata).
TOXICOLOGY
Non-clinical data reveal no special hazards for humans based on conventional studies of acute
toxicity, local tolerance, repeated dose toxicity and reproductive/developmental toxicity.
FLULAVAL TETRA has not been evaluated for carcinogenic or mutagenic potential.
REFERENCES
1. Langley JM, Carmona Martinez A, Chatterjee A, Halperin SA, McNeil S, Reisinger KS,
Aggarwal N, Huang LM, Peng CT, Garcia-Sicilia J, Salamanca de la Cueva I, Cabanas F,
Trevino-Garza C, Rodriguez-Weber MA, de la OM, Chandrasekaran V, Dewe W, Liu A,
Innis BL, Jain VK. (2013). lmmunogenicity and Safety ofan Inactivated Quadrivalent
Influenza Vaccine Can~date: A Phase m Randomized Controlled Trial in Children. The
Journal of Infectious Diseases; 208(4):544-53.

Page24o/27
AR08038
PART ID: CONSUMER INFORMATION What the important nonmedicinal ingredients are:
Phosphate buffered saline, polysorbate 80, a.-tocopheryl
hydrogen succinate. Trace amounts of: egg proteins, ethanol,
FLULAVAL TETRA (2021-2022) formaldehyde, sodium deoxycholate, and sucrose.
Quadrivalent Influenza Vaccine
Split Virion, Inactivated
The mutidose vial presentation contains thimerosaJ as a
preservative.
This leaflet is part ill of a three-part "Product Monograph"
published when FLULAVAL TEfRA was approved for sale The single-dose prefilled syringe presentation does not
in Canada and is designed specifically for Consumers. This contain thimerosal or any other preservative.
leaflet is a summruy and will not tell you everything about
FLULAVAL TETRA. Contact your doctor or pharmacist if What dosage forms it comes in:
you have any questions about the drug - multidose vial of 5 mL for 10 doses
- single-dose prefi.lled syringe of0.5 ml
...\80(.jT THIS \'...\C'CI\E W...\R\INGS ..\.\D PREC.-\l'TIO\S
What the vaccine is used for:

Serious Warnings and Precautions
FLULAVAL TETRA is a quadrivalent vaccine for use in
As with all injectable vaccines, appropriate medical
adults and children greater than 6 months of age to prevent
treatment and supervision should always be readily
influenza caused by influenza virus types A and B contained
available in case of an anapbylactic event following the
in the vaccine.
administrcttion of the vaccine.
Influenza is a disease of the upper ainvays and lungs caused
BEFORE you receive FLULAVAL TETRA talk to your
by infection with a flu virus. The most commons symptoms
are: high temperature (fever), sore throat, coughing, general doctor or nurse if:
aches and pains, headaches, weakness and tiredness. • You have a severe infection with a high
temperature. In these cases, the vaccination will be
What it does: postponed until you recover. A minor infection
FLULAVAL TETRA causes the body's immune system to should not be a problem.
make antibodies to protect the person from being infected by • You have a bleeding problem or bruise easily.
certain types of influenza virus. This vaccine is only • You have a weakened immune system due to lilV
effective against infection by A and B virus types it is infection or due to medicines that suppress the
designed to prevent and closely related types of virus. None immune system.
of the ingredients in the vaccine can cause influenza. As • You have fainted before or after a previous
with all vaccines, FLULAVAL TETRA may not fully injection.
protect all people who are vaccinated. • If you are taking any other medicines or you have
recently received any other vaccine.
When it should not be used: • If Guillain-Barre (GBS) has occurred within 6
If you had a severe allergic reaction (e.g., anaphylaxis) to weeks of receiving a previous influenza
egg proteins, a previous dose of any influenza vaccine vaccination.
produced in eggs or any ingredient in the vaccine. • If you are pregnant or breast-feeding seek advice
from your doctor.
What the medicinal ingredient is:
This vaccine complies with the World Health Organization
(WHO) recommendation (Northern Hemisphere) for the
2021-2022 season.
Each O.SmL dose of the vaccine contains 15 micrograms of
haemagglutinin, a type of protein that has been purified from
killed and split influenza viruses. The four virus strains in
this vaccine are:
15µg HA -A/Victoria/2570/2019 (H1Nl)pdm09-like virus
15µg HA - A/Cambodia/e0826360/2020 (H3N2)-like virus
15µg HA- B/Phuket/3073/2013-like virus
15µg HA - B/Washington/02/2019-like virus.

Page 25 of27
AR08039
IYfER.-\CTIONS WITH TH IS VACCINE

• difficulty in breathing or swallowing
• sudden drop in blood pressure and loss of
consciousness.
FLULAVAL 1ETRA must not be mixed with any other • Temporary inflammation of the neives causing pain,
vaccine in the same syringe. If FLULAVAL TETRA is to be weakness and paralysis called Guillain-Barre syndrome
given at the same time as another injectable vaccine. The
vaccines should always be administered at different This is not a complete list ofside effects. For any unexpected
injection sites. effects while taking FLULAVAL TEIRA, co~tact your
doctor, nurse or pharmacist.
PROPER USE OF THIS VACCINE

HO\\ TO STORE IT
Usual dose·
One injection of 0.5mL into the shoulder muscle or the mid- Store in a refrigerator between 2 and 8°C.
thigh muscle. Do not freeze.
Children 6 months to less than 9 years of age who have not
been vaccinated against influenm in the past will receive a
second injection at least one month after the fust injection.
Overdose:
In case of overdose, contact a health care practitioner,

hospital emergency department or regional Poison Control
Centre immediately, even if there are no symptoms.
SIDE EFFECTS .-\ND \YIIAT TO DO .-\BOLT HIBi
As with all medicines, FLULAVAL TETRA may cause side

effects in some persons. If any side effect worries you, or
you have any unusual symptoms, please contact your doctor,
nurse or pharmacist.
Very common (may occur with more than I in 10 doses):

• Pain at the injection site
• Fatigue
• Headache
• Aching muscles
• Joint pain.
Common (may occur with upto I in 10 doses)

• Redness and swelling at the injection site
• Shivering
• Fever
• Feeling sick, diarrhea, vomiting, stomach pain
In children, veiy common side effects are irritability and

drowsiness. A common side effect was loss of appetite.
Contact your doctor, nurse or pharmacist urgently if you

experience:
• Allergic reaction (including anaphylactic and .
anaphylactoid reactions). These can be recogmzed by:
• itchy rash of the hands and feet
• swelling of the eyes and face
ApProved· 14 April 2021

Page26of27
AR08040
RF.l"O R.T lNG SUS PEC TED

SID E EFF EC TS
©2021 GSK group ofcompanies or
its licensor.
To mon itor vac cine safety, the Pub Trademarks are owned by or licensed
lic Hea lth Agency of to the GSK group of
Can ada collects case reports on adv companies.
erse eve nts foll owi ng
immunization.
For hea lth car e professionals:

If a pati ent exp erie nce s an adverse
eve nt following
immunization, plea se complete the
appropriate Adverse
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(AE FI) Form and sen d it to
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ince/territory.
For the General Public:
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tor, nurse, or pha rma cist
to com plet e the Adverse Eve nts
foll owi ng Imm uniz atio n
(AE FI) Fonn.
If you hav e any que stio ns or hav

e difficulties con tact ing
you r local health unit, please con
tact Vaccine Safety Sec tion
at Pub lic Hea lth Agency of Canada
:
By toll-free telephone: l-866-84
4-0018
By toll-free fax: l-866-844-5931
By email: pha c.aefi-essi.aspc@ can ada ca
At th.e following website:
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heaJth/se1Yices/immunization/ca
nadian-ad,·crse -c,·cnts-
following- imm uniz atio n-su n·eillanc
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By regu lar mail:
The Pub lic Hea lth Age ncy of Can
ada
Vaccine Safety Sec tion
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NOTE: Sho uld you require informa

tion rela ted to the
man age men t ofthe side effect, plea
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i\lORE I\ FORi\J..\ TIO \
Thi s doc ume nt plus the full pro duc

t mon ogr aph , prep ared
for health professionals can be foun
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or by contacting the spo nso r, Gla
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Thi s leaflet was prepared by Gla

xoSmithKline Inc.
Las t revised: 06 April 2021
Approved: 14 Apr il 2021

Page 27 of2 7
AR08041
TAB 57
AR08042

FEDERAL COURT
BETWEEN:
NABIL BEN NAOUM
Demandeur
et
Défendeur

AND BETWEEN:
Demandeur
et
Défendeur

AND BETWEEN:
AND AEDAN MACDONALD
Applicants
and
Respondent
JML TRANSCRIPTION
AR08043
2

AND BETWEEN:
Applicants
and
Respondent
_________________________________________________________________
CROSS-EXAMINATION OF DR. Steven Pelech

May 16, 2022
_________________________________________________________________
Gregory Tzemenakis For the Respondent

Keith Wilson For Dr. Pelech
JML TRANSCRIPTION
AR08044
3
INDEX
PAGE
Exhibits ................................................... 4
Undertakings .............................................. 7
DR. STEVEN PELECH

Cross-Examination by Mr. Tzemenakis .................... 8
JML TRANSCRIPTION
AR08045
4
EXHIBITS
PAGE
1. Canadian Covid Care Alliance landing page on the CCCA
website, with the disclaimer in the red text box....... 45
2. Text of the actual disclaimer on the Canadian Covid
Care Alliance website.................................. 46
3. Landing page for Ichor Blood Services website.......... 47
4. Landing page for Ichor Health website.................. 47
5. Document entitled “European Commission Ebola:
Commission grants new market authorisations............ 58
6. Study entitled “Lipid nanoparticles for mRNA delivery.. 70
7. Pfizer document entitled “About Our Landmark Trial..... 74
8. Document entitled “Assessment of Deaths from Covid-19
and from Seasonal Influenza”, also referred at tab 11
of the expert report................................... 80
9. Excerpt from Dr. Kindrachuk’s report, page 8,
Exhibit D.............................................. 108

10. Ontario Science Table, Covid-19 Advisory Dashboard..... 122
11. Article entitled “Increases in Covid-19 are unrelated
to levels of vaccination across 68 countries and 2,947
counties in the United States”, referred to at
footnote 20............................................ 126
12. PDF of the first landing page of VAERS, which is the
Vaccine Adverse Event Reporting System, captured by
Mr. Tzemenakis on May 15, 2022......................... 142
JML TRANSCRIPTION
AR08046
5
EXHIBITS
PAGE
13. Live version of the VAERS landing page to compare
with the PDF captured May 15, 2022..................... 167
14. Screenshot of disclaimer page of the VAERS website..... 149
15. Screenshot of the data for 2021-43 from the Pan
American Health Organization for the United States
of America............................................. 155
16. Study entitled ”mRNA-1273 or mRNA-Omicron boost in
vaccinated macaques elicits comparable B cell expansion,
neutralizing antibodies and protection against Omicron,”
which is referred to at footnote 57 of paragraph 63... 176
17. Article entitled “Ivermectin for Prevention and
Treatment of Covid-19 Infection: A Systemic Review
Meta-analysis and Trial Sequential Analysis to Inform
Clinical Guidelines” at footnote 72, and is accessed
by the link PubMed.ntvi.nlm.nih.gov/35142702/.......... 189
18. “Public advisory. Ivermectin not authorized to
prevent or treat Covid-19; may cause serious health
problems,” dated 2021-10-19............................ 196
19. Article entitled “Why You Should Not Use Ivermectin
to Treat or Prevent Covid-19” was printed on the
12th of May 2022 at 6:27 p.m........................... 198

20. Study entitled, “A majority of uninfected adults show
pre-existing antibody reactivity against SARS-CoV-2”
by Majdoubi et al.................................... 201
JML TRANSCRIPTION
AR08047
6
EXHIBITS
PAGE
21. The VAERS disclaimer screenshot which was sent by
email to all counsel................................... 206
JML TRANSCRIPTION
AR08048
7
UNDERTAKINGS
PAGE
1. Produce the personal communication, if it exists in
writing, from the president of Ichor Blood Services.... 158
2. Produce a copy of the data provided by the president
of Ichor Blood Services................................ 159
3. Identify where in the study from paragraph 63,
footnote 57 of the study, the authors conclude that
the antibodies made against the original Wuhan strain
of the virus should and do work almost equally as
well against any of the variants, and vice-versa....... 169
4. To the extent that a correction needs to be made to
paragraph 71 to refer to Mr. Horowitz as Mister or
Doctor, can that be confirmed in writing............... 182
5. Provide documentation relating to the government
official, whether it was a Minister, an Associate
Minister referred to by the witness regarding how
doctors can prescribe ivermectin....................... 194
6. To provide the reference of the subsequent study
where the conclusion “It is unclear whether this
antibody reactivity may confer clinical benefits”
is rebutted............................................ 205
JML TRANSCRIPTION
AR08049
8
1 MAY 16, 2022 - 10:55:15 A.M.
2 CROSS-EXAMINATION
4 DR. STEVEB PELECH, affirmed, testified:
5 COURT REPORTER: Can you please just state and then
6 spell your name for the record?
7 DR. PELECH: My name is Dr. Steven Pelech, and it’s
8 spelled P-e-l-e-c-h.
10 CROSS-EXAMINATON BY MR. TZEMENAKIS
11
12 MR. TZEMENAKIS: Thank you, good morning, Dr. Pelech.
13 My name is Gregory Tzemenakis, and I am counsel for
14 the Attorney General of Canada, and I will be asking
15 you a series of questions today. I understand that
16 your counsel for the purposes of this cross-
17 examination, or your lead counsel for the purposes of
18 this cross-examination is Mr. Wilson. Good morning,

19 Mr. Wilson.
20 MR. WILSON: Good morning, sir.
21 1 MR. TZEMENAKIS: So, Dr. Pelech, I’m going to start with
22 introductory questions. You affirmed an affidavit on
23 March 11, 2022 in the Brian Peckford et al v. The
24 Minister of Transport and Attorney General of Canada
25 file, is that correct?
JML TRANSCRIPTION
AR08050
9
2 2 Q. And that affidavit attaches as Exhibit B to your
3 expert report, correct?
5 3 Q. Do you have that affidavit and your report available
6 to you during this cross-examination?
7 A. Yes, I do.
8 4 Q. And can you confirm, sir, that there are no changes

9 that you wish to make to your affidavit or to your
10 report before we begin?
11 A. There is a few minor changes I’d like to bring to your
12 attention. This relates to a section where I’m
13 talking about absolute risk reduction, and I define
14 that - this is in paragraph 14 which is on page 48,
15 and I have a couple of typos with respect to this
16 particular abbreviation. I do define it as, in
17 paragraph 14, as ARR, but I referred to it later in
18 that paragraph and the subsequent paragraph 15, as
19 AAR. That should be ARR in those three instances.
20 Otherwise its fine.
21 5 Q. Thank you for that clarification. Do you have any
22 other materials with you at this time?
23 A. I have my computer and I do have access to affidavits
24 from the Crown expert witnesses.
25 6 Q. All related to these matters?
JML TRANSCRIPTION
AR08051
10
2 7 Q. Okay. And is there anyone else in the room with you
3 at this time?
4 A. No, there isn’t.
5 8 Q. Okay. Sir, can you confirm that during any breaks in
6 this cross-examination you will not communicate with
7 any party outside of this virtual meeting or take
8 instruction from anyone during this examination other

9 than objections that might be by your legal counsel?
10 A. Yes, I understand that and will not.
11 9 Q. Okay. Thank you. And can you also confirm for me
12 that during this cross-examination you will not be
13 viewing or referring to any notes or other documents
14 either on paper or electronically, other than the
15 affidavit, your expert report, and/or other affidavits
16 that I will take you to in the context of these
17 proceedings.
18 A. Yes, I understand that.
19 10 Q. Perfect. And now as a final housekeeping matter, Dr.
20 Pelech, did you have the opportunity to review the
21 affidavits of Dr. Kindrachuk and Dr. Bowdish in your
22 preparations for today?
23 A. Yes, I did.
24 11 Q. So, let me turn to your affidavit, please, and I’m
25 going to ask you to turn to Exhibit A of your
JML TRANSCRIPTION
AR08052
11
1 affidavit...
2 A. Okay.
3 12 Q. ...on page...
4 A. Oh, that one.
5 13 Q. ...12.
6 A. Just give me a moment. This is my curriculum vitae is
7 it?
8 14 Q. Yes, sir.
9 A. Right. Okay. So, this is Exhibit B you referred to?
10 15 Q. No, sir. I’d like you to go to Exhibit A...
11 A. A...right.
12 16 Q. ...page - page 12.
13 A. Page 12, yeah. Okay, I’m there.
14 17 Q. Okay, so at paragraph 6, Dr. Pelech, you state “My
15 area of research expertise is signal transduction...”
16 A. Hm..mm.
17 18 Q. “...and there is growing appreciation of defective
18 cells signalling is at the root of cancer,” is that
19 correct?
20 A. That’s - that’s the paragraph, yes. And that same is
21 - is - is correct in part, yeah.
22 19 Q. Okay. And if you were to go forward with me to page
23 14 at paragraph 1, you state, “My research focuses on
24 the characterization of protein-serine kinases
25 involved in mitogen and stress signalling and cell
JML TRANSCRIPTION
AR08053
12
1 cycle control. Protein kinases are major
2 intracellular transducers of information from extra
3 cellular stimuli. Their defective signaling as a
4 consequence of mutations and the genes that encode
5 these enzymes underlies many degenerative diseases of
6 aging such as cancer, diabetes, heart disease and
7 neurological disorders.” That’s accurate?
8 A. That is accurate, and also would encompass, although

9 it’s not written there because I was focused on - on
10 the area of cell signaling, but it would also
11 encompass the action of viruses and bacteria.
12 20 Q. Okay. And at paragraph 2 on the same page 14...
13 A. Hm..mm.
14 21 Q. ...you - you go on to state that the main modal
15 systems that are under investigation in my laboratory
16 are oocytes from sea stars and frogs, human solid
17 tumours, insulin targeted tissues such as skeletal
18 muscle and hard from normal and diabetic rats, and
19 human brain and spinal cord tissues from patients with
20 neurological disorders. Is that an accurate statement
21 as well?
22 A. That is correct. Those are the main modal systems. I
23 have actually investigated a wide range of other
24 systems which also includes virus infected cells.
25 22 Q. Okay. So, Dr. Pelech, you are not a medical doctor,
JML TRANSCRIPTION
AR08054
13
1 correct?
2 A. I’m not a practicing physician, I’m not a medical
3 doctor. I’ve taken courses that are offered to
4 medical students but, no, that’s not my specialty.
5 23 Q. You were not a cardiologist?
6 A. I am not a cardiologist although I do study
7 cardiomyocytes in my research and I’ve done a number
8 of publications along that line.

9 24 Q. You’re not a virologist, sir?
10 A. Well, it depends on how define a virologist. I - I do
11 research in virology. I presently am conducting a
12 clinical trial that involves well over 3,500 people
13 measuring antibodies against viral proteins, and I do
14 study the action of the SARS-CoV-2 virus on infecting
15 cells and culture...
16 25 Q. And...
17 A. ...and I’m looking at the mechanisms of actions of the
18 reproduction of that - that virus and how its blocked
19 by protein kinase inhibitors, which is my specialty.
20 26 Q. And we’re going to come back to that in a moment, sir,
21 but let me - let me just drill down for a second. Do
22 you have formal training as a virologist, sir? Did
23 you go to school for that?
24 A. Yes, actually I did.
25 26 Q. Okay, no, that’s fine. And your - your - you - so
JML TRANSCRIPTION
AR08055
14
1 you’re educated as a virologist, am I correct?
2 A. I’ve taken all the courses that a undergraduate
3 student would take.
4 27 Q. Okay.
5 A. The Department of Microbiology at what is now called
6 Microbiology and Immunology I took all the viral -
7 virology courses that were offered.
8 28 Q. Okay.
9 A. And then since then viruses are actually very
10 important in the action of cancer and the study of
11 oncogenes, so I do a lot of research related to how
12 viruses actually cause cancer.
13 29 Q. Do you hold yourself out professionally as a
14 virologist, sir?
15 A. I’m a basic researcher that - that my research
16 encompasses cell signaling systems, and they’re at the
17 root of all these different diseases and the ability
18 of viruses and bacteria to actually be pathogens and -
19 and hosts - human host cells.
20 30 Q. So, the answer to my question is yes or no, do you
21 hold yourself out as a virologist?
22 A. Well, I’m - I’m very competent in the area of virology
23 and I do virology so I suppose I would say yes. I’m
24 trained in virology.
25 31 Q. And can you - and we can do this now or your counsel
JML TRANSCRIPTION
AR08056
15
1 can undertake to do it later...
2 A. Hm..mm.
3 32 Q. ...can you tell me where in your CV in Exhibit A you
4 hold yourself out to be a virologist, and b) where I
5 can see the formal training that you’ve taken in
6 virology?
7 A. Well, in my rec...my CV I don’t have a listing of all
8 of my courses that I took as an undergraduate student.

9 I mean I could provide that, I’m sure I could find it
10 in my university transcripts from that time.
11 33 Q. Okay. No, but just so that we’re on the same page,
12 sir, I’m just trying to figure out what’s in the box
13 and what isn’t. so, I understand you to say...
14 A. Hm..mm.
15 34 Q. ...that you do hold yourself out professionally...
16 A. Hm..mm.
17 35 Q. ...as a virologist with education and training,
18 correct?
19 A. Correct.
20 36 Q. And you took that education and training in your
21 undergraduate courses only, correct?
22 A. That’s correct in terms of formal course training.
23 37 Q. Correct. You did not do that as part of your Masters
24 or PhD, correct?
25 A. No, I did it as part of my post-docking work.
JML TRANSCRIPTION
AR08057
16
1 38 Q. Right.
2 A. We had a professor in the Department of Microbiology
3 and Immunology, Dr. Tony Possen. He’s probably was -
4 was probably one of the leading researchers in the
5 action of retroviruses, and I worked with him to
6 actually look at the ability of the sarc...the rous
7 sarcoma virus to infect cells and look at the
8 activation of protein kinexus systems. So actually

9 did research in that right after my post-docking, and
10 then since then more recently I’ve been looking at the
11 action of the SARS CoV 2 virus itself.
12 39 Q. I...
13 A. But I teach courses at UBC that...
14 40 Q. Sir, I don’t I want to interrupt you but - I don’t
15 want to interrupt you but I’m going to for a second.
16 A. Sure.
17 41 Q. I - I understand that you have a lot to tell me and
18 your report is 50 pages...
19 A. Right.
20 42 Q. ...and I’m going to ask you about pretty much every
21 paragraph in your report.
22 A. Okay.
23 43 Q. So, to the extent that we’re going to get to the
24 studies...
25 A. Hm..mm.
JML TRANSCRIPTION
AR08058
17
1 44 Q. ...that you’ve undertaken, we’re going to get to some
2 of your findings, we’re going to get to paragraphs and
3 reports. Please feel free to - to - just from an
4 efficiency perspective...
5 A. Hm..mm.
6 45 Q. ...please feel free to elaborate on your answer as you
7 see fit, but I - I do also want to get a direct answer
8 to the question that I’m asking.

9 A. Hm..mm.
10 46 Q. I appreciate that you’ve done research in a number of
11 different things, but at the end of the segment I’m
12 going to ask your counsel a very direct question, and
13 it’s going to be based on the answers that you give
14 us, okay?
15 A. Sure. Right. So - so to continue the work that I’ve
16 published that’s appeared in - in journals or at least
17 on line, is the preprint that’s in Biarfics (ph) which
18 basically outlines the studies that we’ve done to look
19 inhibitors of a protein kinase that blocks the ability
20 of the - the SARS CoV 2 virus to replicate in cells.
21 And a patent was filed on that as well with the
22 University of British Columbia Industrial Liaison
23 Office and we’re - we’re continuing those studies.
24 47 Q. Okay. Thank you. so, you talked to me about
25 virology. Do you consider yourself - sorry, do you
JML TRANSCRIPTION
AR08059
18
1 hold yourself professionally to be an epidemiologist?
2 A. I’m not an epidemiologist in that my research does not
3 involve going out there and canvassing people in terms
4 of - of the incidence of a disease or how they’re
5 responding to a treatment, which is what we consider a
6 classical epidemiologist, so be in the school of
7 public health for example, and policy. But I use the
8 same techniques that an epidemiologist uses to analyze

9 metadata. I do that routinely. And over the last few
10 years I’ve actually worked looking at epidemiology
11 data that’s provided by health authorities, including
12 the BC Centre for Disease Control and Public Health
13 Ontario, Public Health Alberta. And so I’ve been
14 analyzing that data with trained epidemiologists, and
15 from that I think I can make a pretty good sense of
16 epidemiological data and its limitations.
17 48 Q. Okay. So the answer to my question - well, let me ask
18 a different question.
19 A. Hm..mm.
20 49 Q. You do not hold yourself out professionally as an
21 epidemiologist, but you have worked with
22 epidemiologists and have conducted certain studies
23 relying on epidemiological data, is that correct?
24 A. Yes, and I have to use these now...
25 50 Q. Okay, so...
JML TRANSCRIPTION
AR08060
19
1 A. ...because I’m conducting a clinical trial, so - and
2 the clinical trial it is a - essentially
3 epidemiological data and I’m the lead on that trial.
4 51 Q. And do you have formal training and education in
5 epidemiology?
6 A. I do in statistics...
7 52 Q. Right.
8 A. ...which is what’s applied in epidemiology.

9 52 Q. So, let me try...
10 A. So, I can analyze...
11 53 Q. Let me try to bring this - sorry, we’re going to have
12 to do a better job of letting each other speak, so go
13 ahead.
14 A. I’m sorry. No, I was just saying that the - the basic
15 statistical analyses that are - are performed when
16 you’re doing a typical clinical trial or you’re
17 assessing the efficacy of a vaccine, for example, we
18 use the same - same statistical rules in terms of - of
19 t-tests and - and making sure that we have the data so
20 that it’s - it’s clinically significant. We - we
21 apply the same techniques in my standard research
22 which involves meta analysis using larger datasets.
23 54 Q. I - I have - I’m quite familiar with metadata and I’m
24 going to suggest to you...
25 A. Sure.
JML TRANSCRIPTION
AR08061
20
1 55 Q. ... Dr. Pelech, that I’m really just trying to
2 understand and have the Court understand what you’re
3 an expert in and what you’re not an expert in.
4 A. Sure.
5 56 Q. So, it - you know, feel free to bring up the studies
6 that you think are relevant...
7 A. Hm..mm.
8 57 Q. ...but my direct questions are just that...

9 A. Okay.
10 58 Q. ...they’re direct, meaning - and I just want to be
11 clear on the record...
12 A. Hm..mm.
13 59 Q. ...do you have formal training and education as an
14 epidemiologist?
15 A. I have partial training as an epidemiologist.
16 60 Q. Do you hold yourself out professionally to be an
17 epidemiologist?
18 A. That’s not my specialty, but I can analyze data very
19 easily that would be done by an epidemiologist.
20 61 Q. Okay. Do you consider yourself an expert in virology?
21 A. Yes, actually I - I do.
22 62 Q. Do you consider yourself an expert in immunology?
23 A. Yes, I do.
24 63 Q. Do you consider yourself an expert in epidemiology?
25 A. I think I’m - I have enough expertise so that I can -
JML TRANSCRIPTION
AR08062
21
1 I can read epidemiology journals, analyze the data and
2 critique it.
3 64 Q. Do you consider yourself an expert in cardiology?
4 A. In terms of - of cellular cardiology, yes. In terms
5 of the organ itself, no.
6 65 Q. You have a - you have a PhD in biochemistry, correct?
7 A. Right.
8 66 Q. And your area of expertise as identified in your CV is

9 signal transduction, correct?
10 A. Yes, cell signaling.
11 67 Q. Right.
12 A. Cell - it’s the same as signal transduction.
13 68 Q. And you - do you agree that your CV is silent in
14 respect of your expertise in virology, immunology,
15 epidemiology, and cardiology?
16 A. No, I completely disagree.
17 69 Q. All right.
18 A. I published several papers... Yeah, no, I disagree
19 that very much in fact.
20 70 Q. It’s fair for you to disagree...
21 A. Yeah.
22 71 Q. ...but what you’re telling me is that the papers that
23 are attached and summarized in your CV contain
24 information which hold you out to be an expert in
25 virology, immunology, epidemiology, and/or cardiology,
JML TRANSCRIPTION
AR08063
22
1 is that correct?
2 A. Well, for example in immunology there’s about a dozen
3 different journals - they’re immunology journals that
4 I’ve published in over the last 35 years.
5 72 Q. It’s one thing to publish, sir, it’s a whole other
6 thing to say I’m an expert in it, and I’m just trying
7 to understand if you consider yourself...
8 A. Well, I teach it to students, to graduate students, so

9 I mean I must know something about it, obviously.
10 73 Q. Right. I know - okay. So, is it fair to say...
11 A. The part that I said virology, I teach immunology, I
12 teach basically the - the underlying basis of even
13 cardiomyocyte function and contractility of cells that
14 underly how heart cells work.
15 74 Q. Yeah, and we’ll get to that in a moment if we can. Do
16 you consider yourself an expert in vaccine
17 development?
18 A. Yes, I do.
19 75 Q. Do you consider yourself an expert in vaccine
20 efficacy?
21 A. Yes, I do.
22 MR. TZEMENAKIS: Mr. Wilson, the question comes to you.
23 A. Hm..mm.
24 MR. TZEMENAKIS: Which is, can you please confirm on the
25 record what you are proposing to qualify Dr. Pelech as
JML TRANSCRIPTION
AR08064
23
1 an expert in, because that information is silent in
2 his affidavit and in his expert report.
3 A. If there is...
4 78 Q. The question is not directed to you, Mr. Pelech, it’s
5 directed to Mr. Wilson, so we have to kind of let this
6 play out, please.
7 A. Okay.
8 MR. WILSON: Counsel, thank you for the question and

9 the novel approach. I’m not a witness. We’ve
10 tendered an expert report. You have the testimony of
11 the witness. If you would like an undertaking from us
12 to provide you in writing the scope of the expertise
13 to remove any confusion for which we’re presenting
14 this witness, I’m happy to do that, but I’m not happy
15 to sit here and be questioned by counsel.
16 MR. TZEMENAKIS: My intent is not to question you, Mr.
17 Wilson. The Federal Court rules require that we
18 identify the area of expertise for a witness so as to
19 determine whether or not there’s an issue with that
20 witness’s qualifications. I’m simply asking you,
21 because his report is silent, on whether or not we are
22 tendering Mr. Pelech here today as an expert in the
23 fields that he has identified.
24 MR. WILSON: Well, I’m...
25 MR. TZEMENAKIS: And I’m happy to take a break for you
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1 to confer with your colleagues but I think I’m
2 entitled to know what he’s being tendered as an expert
3 in before I continue my cross.
4 MR. WILSON: All right, well, let’s set up a break
5 out room and we’ll take a break and go off record.
6 MR. TZEMENAKIS: Okay. Madam Reporter, do you mind
7 taking us off the record for...
9 OFF RECORD
10
11 MR. WILSON: Good morning. In answer to counsel’s
12 question, I can confirm that we are presenting Dr.
13 Pelech in accordance with the legal standard for what
14 the Court expects to see as an expert before they meet
15 that threshold. He’s being presented in this action
16 as a qual...qualified as an expert in immunology and
17 virology, as well as all of the subdisciplines that
18 are relevant to his testimony.
19 MR. TZEMENAKIS: Sorry, he’s... Can you just repeat
20 that for me, please? He’s being qualified as an
21 expert in immunology and virology?
22 MR. WILSON: And all of the subdisciplines that are
23 relevant to his testimony. You’ve heard him explain
24 the multidisciplinary aspects of medical research and
25 I think we’ll be hearing a lot about the complexities
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1 of the human body. These are not little simple silos
2 that one can confine themselves to.
3 MR. TZEMENAKIS: No, I under...I - first of all, thank
4 you, Mr. Wilson for that, and I’m happy to ask Mr...
5 Dr. Pelech this question, but for the purposes of the
6 Court, what can you identify the “subdisciplines”
7 relevant to his testimony?
8 MR. WILSON: Well, one of them would be matters

9 relating to the heart. I think it would be more
10 appropriate for him to do that. He has been doing
11 that throughout your questioning where you have tried
12 to, for example, when you asked him about
13 epidemiology, and he then explained, well, you can’t
14 be an epidemiologist and engaged in epidemiology
15 without an emphasis on statistics because that’s
16 largely what its about. So, it just appears, with due
17 respect, sir, that there’s some effort to confine and
18 compartmentalize this in a way that’s not consistent
19 with - with how the real world works. And so, we - we
20 have presented this witness as an expert that we
21 believe will meet the legal threshold test. And
22 remember, the legal threshold test is not that you’re
23 - you’re a member of the Epidemiologists Society or
24 something like that, it’s - the legal test from the
25 Supreme Court of Canada is very different, and we are
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1 confident that - that Dr. Pelech will be accepted by
2 the Court as a medical researcher with qualified
3 expert in virology, immunology, as well as the other
4 subdisciplines that will be relevant to his testimony
5 both in his report and in this cross-examination.
6 MR. TZEMENAKIS: So, again, thank you, Mr. Wilson, and I
7 just want to be clear, what I’m trying to do is
8 understand what Dr. Pelech is or is not an expert in.

9 I have your position on the record. I assume that
10 position applies to all of the consolidated
11 proceedings, correct?
12 MR. WILSON: Yes. Yes.
13 MR. TZEMENAKIS: And, you know, we will agree to
14 disagree on the import of White and Burgess, [2015] 2
15 SCR 182, from the Supreme Court of Canada, but that’s
16 not for the purposes of today. So, I’d like to go
17 back to the substance of my questions with Dr. Pelech.
18 So, the floor is now as between you and I, Dr. Pelech.
19 79 Q. I want to ask you some general statements about Covid-
20 19.
21 A. Hm..mm.
22 80 Q. Do you agree that severe acute respiratory coronavirus
23 2, SARS-CoV-2, is the etiological agent of the
24 coronavirus disease 2019?
25 A. Absolutely.
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1 81 Q. Do you - are you aware that Covid-19 was first
2 designated as a public health...excuse me - a public
3 health emergency of international concern by the World
4 Health Organization in January of 2020?
5 A. Yes.
6 82 Q. Do you agree that Covid-19 remains a public health
7 emergency of international concern as designated by
8 the World Health Organization?

9 A. That’s a very good question. I - certainly the World
10 Health Organization believes it - it does.
11 83 Q. That was my question...
12 A. Yeah.
13 84 Q. ...if - if you’re aware that the World Health
14 Organization continues...
15 A. Yes.
16 85 Q. ...to designate Covid-19.
17 A. That - that I agree, yes.
18 86 Q. Okay. Do you agree that Covid-19 infections severity
19 ranges from asymptomatic to more serious and possibly
20 critical disease?
21 A. And death, yes.
22 87 Q. Do you agree that the magnitude of the immune response
23 is usually proportionate to the severity of the
24 infection although there is considerable variability?
25 Is that a fair statement?
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1 A. Yes, it’s great variability and in fact one of the
2 reasons why it can be lethal is because the immune
3 system is over reactive.
4 88 Q. Do you agree that the highest risks of severe disease
5 are associated with age and underlying health
6 conditions, with age being the most prominent factor?
7 A. Yes, and also obesity in addition to the comorbidities
8 I think you were alluding to.

9 89 Q. Is it fair to say that the risk increases for people
10 over age 50 with perhaps the highest risk for those
11 over age 85?
12 A. Yes.
13 90 Q. Do you agree that Covid-19 can also result in long
14 term complications, and by that I mean fatigue,
15 shortness of breath, joint and chest pain?
16 A. You’re referring to long covid and, yes, about five to
17 ten percent of people do have that.
18 91 Q. Thank you. And it - do you agree that Covid-19 can
19 lead to long covid independent of disease severity in
20 age, meaning that there’s - it’s not limited to those
21 two demographics?
22 A. There are reports of people that are younger that do
23 have long covid, so yes, you’re correct.
24 92 Q. I want to ask you some general questions about
25 vaccines, if I can.
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1 A. Hm..mm.
2 93 Q. Do you agree that no vaccine is considered to be 100%
3 safe?
4 A. That’s true.
5 94 Q. Do you agree that vaccine safety is influenced by a
6 number of factors? For example, the components of the
7 vaccine.
8 A. Yes.
9 95 Q. The injection procedures?
10 A. yes.
11 96 Q. Individual variations in the immune response?
12 A. Ab...yes, absolutely.
13 97 Q. Health status?
14 A. Yes.
15 98 Q. Environmental influences?
16 A. Yes.
17 99 Q. Genetic background?
18 A. Yes.
19 100 Q. Do you agree that vaccination provides an additional
20 layer of protection against infection from Covid-19?
21 A. Well, specifically depends on the vaccine that you’re
22 talking about, but - but in general they are
23 efficacious, at least to a certain extent.
24 101 Q. So, for the - thank you for making that clarification.
25 For the purposes of my questioning today I’m going to
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1 limit it - limit my questioning to mRNA vaccines.
2 A. Okay.
3 102 Q. Okay? So, if I’m talking about vaccination it’s going
4 to be vaccination from mRNA vaccines, and I will be as
5 precise as I can.
6 A. Sure.
7 103 Q. Do you agree that vaccination from mRNA vaccines
8 provides an additional layer of protection against

9 serious disease and death from Covid-19?
10 A. Yes. I think initially it does. It is efficacious
11 for a period of time.
12 104 Q. Do you agree that for the elderly the risk of Covid-19
13 may exist - may exceed, excuse me... Scratch that.
14 Do you agree that for the elderly the risk of Covid-19
15 may exceed the risk of vaccine adverse events from
16 mRNA vaccines?
17 A. I would say yes, but I would qualify that. That
18 depends on how old and feeble the individual is. In
19 that event the vaccine injury could actually be more
20 lethal than the virus. But I think in general you’re
21 correct for people that are over 75 there may well be
22 an advantage, at least initially, provided that they
23 don’t have severe comorbidities.
24 105 Q. All right. do you agree that for those with risk
25 related comorbidities, so obesity, diabetes, smoking,
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1 cardiovascular disease, the risk of Covid-19 may exist
2 - may exceed the risk of vaccine adverse events from
3 mRNA vaccines?
4 A. Yes, it may.
5 106 Q. Do you agree that for pregnant women and the
6 developing fetus there are insufficient data to
7 determine that Covid-19 vaccinations are safe for use?
8 A. Yes, I think there is insufficient data to support

9 that at this time. We don’t have any long term safety
10 data in this respect.
11 107 Q. And - and to be fair to you, sir, that is the position
12 that you state at paragraph 52 of your report..
13 A. Hm..mm.
14 108 Q. ...that you - you take the view that more data is
15 required in order to ascertain the efficacy of these
16 vaccines for pregnant women and the developing fetus?
18 109 Q. Do you agree that Covid-19 vaccination helps prevent
19 acute infection?
20 A. Again, it depends. Initially you’ll have a protective
21 effect but in some people, and with repeated injection
22 that efficacy is shorter and in fact it may actually
23 increase the prospects of getting Covid-19. In
24 pregnant women...
25 110 Q. And is...
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1 A. ...is the...
2 111 Q. I’m sorry, I didn’t - you paused so I thought you were
3 finished, but please continue.
4 A. Well, what we do know is that in pregnant women
5 they’re actually less likely to get covid in the first
6 place by about 50%.
7 112 Q. So, my general statement was whether or not covid
8 vaccination helps prevent acute infection, and I had

9 understood you earlier to tell me, and please tell me
10 if I’m wrong...
11 A. Hm..mm.
12 113 Q. ...that vaccine safety and efficacy is influenced by a
13 number of factors, is that correct?
14 A. Correct.
15 114 Q. And so your comment about the vaccine being initially
16 effective or having efficacy in the initial period and
17 it varies over time...
18 A. Right.
19 115 Q. ...is - is - that is not, if I can use a colloquial
20 term, that’s not a one-size-fits-all answer...
21 A. That...
22 116 Q. ...because...
24 117 Q. ...it depends on the particular circumstances of the
25 individual.
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1 A. Exactly.
2 118 Q. Okay.
3 A. There’s a lot of factors that come into play.
4 119 Q. Do you agree that Covid-19 vaccination helps prevent
5 long covid?
6 A. It can. Depends on the individual.
7 120 Q. Do you agree that Covid-19 vaccination at a population
8 level...
9 A. Hm..mm.
10 121 Q. ...helps reduce infections in more vulnerable
11 individuals? So, older individuals or individuals
12 with comorbidities as examples.
13 A. I would say at a population level, the effect is - is
14 a fraction of a percent.
15 122 Q. So, the answer is yes but minimal?
16 A. Yes. It’s a - this is a - comes to the question of -
17 of absolute risk reduction, and you can apply that in
18 a population setting. And so in terms of the overall
19 reductions in society it’d be around a percent
20 reduction, and that’s including everyone not just the
21 people that are - have a high - high risk factor.
22 That’s an overall statistic.
23 123 Q. Okay. And we’re going to come to that...
24 A. Hm..mm.
25 124 Q. ...shortly. I just have a few more questions in this
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1 area. Do you agree that Covid-19 vaccination at a
2 population level helps reduce the emergence of new
3 variants?
4 A. No, actually I don’t.
5 125 Q. Okay. Do you agree that Covid-19 vaccination at a
6 population level helps reduce community burden of
7 infection?
8 A. And again we’re all talking about the RNA vaccines

9 here, right?
10 126 Q. Correct.
11 A. Yeah. No, I would say no. Well, in terms of
12 infection are we talk...we’re talking about the - just
13 infection itself, or are we talking about severe
14 infection that leads to hospitalization and
15 potentially death?
16 127 Q. So, we’re talking about covid infection and where I
17 particularize it to severe infection and where ICU
18 admission or hospitalization or death, I will - I
19 will...
20 A. Sure.
21 128 Q. ...qualify my question in that regard.
22 A. Okay, so...
23 129 Q. Okay.
24 A. ...in that respect I think initially it - it can be
25 protective but what’s happening now with the newer
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1 strains of variants of SARS-CoV-2, it seems as though
2 actually we put people at higher risk as they get more
3 vaccinated of actually getting infected and having
4 severe outcomes, including increased death, based on
5 the data that I’m seeing out the BC Centre for Disease
6 Control, for example, the latest data.
7 130 Q. Sorry, when you say the latest data is that data
8 that’s included in your report?

9 A. No, that’s not included in my report.
10 131 Q. Okay.
11 A. Because my report is about a month-and-a-half old.
12 132 Q. And just generally you - generally speaking, are you
13 aware that some 11-billion doses of both adenovirus
14 and mRNA vaccines have been administered globally to
15 date?
16 A. Yes, I am.
17 133 Q. So, I’m going to ask you, please, to go to your
18 affidavit...
19 A. Hm..mm.
20 134 Q. ...and I’m going to direct your attention to paragraph
21 2 of your affidavit. So, this is not your report,
22 it’s your actual affidavit. Do you have that in front
23 of you, sir?
24 A. Exhibit B?
25 135 Q. No, sir, it’s your affidavit, it’s - the actual - it’s
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1 the first part.
2 A. Okay, so this is the af...
3 136 Q. It’s the one that says - it has on the top on the page
4 Affidavit of Dr. Steven Pelech, and it start at page
5 2.
6 A. Yes, I have it.
7 137 Q. So, with reference to paragraph 2, I understand that
8 you are the president, founder, and chief science

9 officer of Kinexus Bioinformatics Corporation?
11 138 Q. And that is a for profit private corporation?
13 139 Q. And that corporation is engaged in the development of
14 drugs that inhibit protein kinases primarily for
15 oncology and diabetes?
16 A. No. No, we - we’re - we’re engaged in the development
17 of drugs for our clients. So, we don’t actually
18 develop drugs ourselves. We test drugs that our - our
19 clients have, so they will have their own model
20 systems where they treat animals or people with these
21 drugs, and then they provide us with the tissues, and
22 then we do the analysis of whether or not these drugs
23 seem to be having the effects that are desired, and
24 whether there’s any evidence of side effects that
25 would be deleterious that would preclude actually
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1 continuing with those drugs in clinical trials. So -
2 so we do that as - as part of the service that we’ve
3 been doing to about 2,000 labs over the last 22 years,
4 which encompasses at least 29 of the top 30
5 pharmaceutical companies.
6 MR. TZEMENAKIS: Thank you. I’m going to direct a
7 question to Mr. Wilson, so bear with me. Mr. Wilson,
8 I’m going to ask you to revisit, if you can, paragraph

9 2 of the affidavit because I understood Mr. Pelech -
10 Dr. Pelech to say specifically that the statement -
11 sorry, I’m going to scratch that. I’m going to come
12 back to it.
13 140 Q. Dr. Pelech...
14 A. Hm..mm.
15 141 Q. ...can you go to your affidavit, about halfway down
16 there’s a statement in there that says, “Kinetek was
17 engaged in the development of drugs that inhibit
18 protein kinases primarily for oncology application and
19 diabetes.” Is that a true statement?
20 A. Sorry, you’re - this is in which paragraph?
21 142 Q. Paragraph 2...
22 A. Yes.
23 143 Q. ...of your affidavit.
24 A. Yes. When I say primarily I’m trying to encompass the
25 main areas where we’ve done work. The protein
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1 kinases, the main application of inhibitors is for
2 treatment of oncology, and potentially diabetes, but
3 may have greater applications in neurology, and
4 actually for inhibiting the action of bacteria and
5 viruses. This is what we were looking at more
6 recently in the last two years with SARS CoV 2.
7 144 Q. So, I just want to be clear.
8 A. Hm..mm.
9 145 Q. Kinetek was engaged in the development of drugs...
10 A. Oh, Kinetek...my first company, yes.
11 146 Q. But...
12 A. There’s a little confusion here.
13 147 Q. No, just let me get my question out so we can clarify
14 it if we can. So, Kinetek was engaged in the
15 development of drugs...
16 A. But...yeah...
17 158 Q. ...but Kinexus is not engaged in the development of
18 drugs, correct?
20 159 Q. Thank you. Is Kinexus engaged in the development of
21 vaccines generally?
22 A. Yes. So, let me - let me clarify this. The nature of
23 the business is that we use antibodies that we develop
24 ourselves in animal models, primarily in rabbits, to
25 make antibodies against target proteins of interest
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1 and they happen to be generally cell singling
2 proteins, but we have made antibodies against many of
3 the SARS CoV 2 virus proteins as well recently. And
4 so the nature of our business is that we have to
5 create the antigens, the - the - the bits and pieces
6 of the target protein that we’re interested in,
7 manufacture them within our company, and then we have
8 them injected into the animals. And then we take the

9 blood from these animals and we purify those
10 antibodies, and then we use immunological techniques
11 to characterize those antibodies that they are
12 actually potent, and that they’re specific, and we
13 actually developed techniques within our company,
14 which I lead, to improve the production of these
15 antibodies to get better efficacy and to map the
16 epitopes in which in defining the sequences of the
17 amino acids in the probes that we put into these
18 animals so they’ll be even more efficacious. And in
19 the case of the SARS CoV 2, we - we try to actually
20 identify which parts of the viral proteins are the
21 most immunogenic - that means antibody eliciting - so
22 that these could be used in principle to make vaccines
23 in people that doesn’t - that would be cheaper and
24 doesn’t require putting in an intact functional
25 protein that would have less risk of having biological
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1 effects apart from actual antibody production. So,
2 we’ve been engaged in this for the last 22 years. We
3 - we’ve made over 1,600 antibodies in - in rabbits,
4 and basically they are the products that we sell to -
5 to basically help research in all areas of biomedical
6 research, everything from virology applications
7 through to various diseases, understanding the
8 molecular mechanisms that lead to the pathology in

9 these systems. Because it turns out that defects in
10 protein kinase singling systems underlie over 400
11 different diseases, excluding infectious diseases is
12 an additional application for those kind of compounds.
13 And so I’ve been doing collaborations with many
14 people over the years with - with different bacterial
15 systems, and also viral systems.
16 160 Q. Do you - do you remember what my initial question was?
17 A. I think your initial question was - was do - are we...
18 It goes back... You asked me the question in terms of
19 the applications of the products that we - that - that
20 - we’re...
21 161 Q. No, I was... let me help you. So, you said to me a
22 moment ago that your company provides analytical
23 services to other companies, top 29, 30 related to
24 protein kinases and bioinformatics, and...
25 A. Yeah, and (inaudible) yeah.
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1 162 Q. My question was does your company develop vaccines?
2 In other words are you in the business of developing
3 vaccines? I thought the answer to that was no, but
4 you’re telling me the answer to that is yes.
5 A. Yes. In a sense that’s not our - our - it’s not our -
6 our real business focus but as of late we undertook
7 this activity because we had the capabilities that
8 would be useful for vaccine development against SARS-

9 CoV-2.
10 163 Q. Right. And we’re going to come to your studies in
11 some detail. Is It fair to say that your company,
12 Kinexus Bioinformatics Corporation is not currently
13 developing a vaccine related to Covid-19?
14 A. No, we’re not because...
15 164 Q. And has not since January of 2020?
16 A. No, I wouldn’t say that. The intent at the time that
17 we started our work was that we thought that we might
18 be able to come up with something that’d be useful for
19 vaccine development. We decided not to continue down
20 that stream because there was such a great deal of
21 effort around the world to develop a vaccine, and it
22 seems that those were pretty advanced efforts, so it
23 didn’t make any business sense for us to pursue that
24 direction. Our intent was then simply to put our
25 results out there in the scientific literature so that
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1 other parties could benefit from it, which would lead
2 to products, hopefully, that - that would be useful
3 for treating people. I mean with the SARS...
4 165 Q. Right, and the approach that you just described, sir
5 for Covid-19 is actually the approach you use for
6 other stat...other analysis you do involving protein
7 kinases. So, for example, in oncology and in cancer
8 research.
9 A. No. No, that’s not exactly right because we don’t
10 normally go and initiate clinical trials where we’re
11 soliciting blood from people in order to determine
12 whether they have antibodies against a particular
13 pathogen. That’s not what we normally did before.
14 All of our technologies were amenable to that and so
15 we made the - the strategic decision that we would do
16 what we could as a business to help in the effort to
17 control the SARS CoV 2 virus. And we thought that
18 this was an important way to do it.
19 166 Q. Okay. Thank you for that clarification. Let me ask
20 you to go to paragraph 4 of your affidavit, which is
21 on page 3.
22 A. Hm..mm.
23 167 Q. I understand, and can you please confirm that you were
24 one of the founders of the Canadian Covid Care
25 Alliance?
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1 A. That’s - that’s true. I wasn’t the very original
2 founders before it was incorporated, but I was
3 certainly one of the founders of the incorporated
4 alliance. Is that - is that clear?
5 168 Q. Yes, sorry I just got momentarily - yes, that’s fine.
6 MR. TZEMENAKIS: Now just a question directed to your
7 counsel, Mr. Wilson. We sent over some documents via
8 Titan file. Do you know, sorry, can you confirm that

9 the documents were provided to Dr. Pelech?
10 MR. WILSON: I don’t - I can’t confirm that yet.
11 MS.PEJOVIC: This is Allison Pejovic for the record.
12 I sent Dr. Pelech an email about two minutes before
13 his cross-examination began. I don’t know if he’s
14 received it or not, but I did send him those
15 documents.
16 MR. TZEMENAKIS: So...
17 DR. PELECH: I can see if I have them, if you like.
18 MR. TZEMENAKIS: I didn’t put them on this, so we’re
19 going to go off the record for a moment.
20 MR. WILSON: Okay.
21
22 OFF RECORD: 12:03:24 P.M.
23
24 169 MR. TZEMENAKIS: Okay, so before the break we talked
25 about the fact that you were one of the founders of
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1 the Canadian Covid Care Alliance after it was
2 incorporated correct?
3 A. Hm..mm. correct.
4 170 Q. And this is an alliance that reviews scientific
5 literature and produced reports and videos that
6 analyze and critique information related to SARS CoV 2
7 and the Covid-19 disease?
8 A. Yes, that’s part of our activity, the part that I’m

9 involved in.
10 171 Q. Okay. So, sir, I’m going to share my screen with you,
11 and on the screen you’re going to see a web capture...
12 A. Hm..mm.
13 172 Q. ...of the Canadian Covid Care Alliance website. It
14 says pages 1 of 5 in the top right hand corner. Do
15 you see that?
16 A. Yes, I do.
17 173 Q. That is the landing page for the Canadian Covid Care
18 Alliance. Does that look - does that sound right to
19 you?
20 A. Yes, that looks - looks very familiar.
21 174 Q. All right, and in the middle of the first page there
22 is a red box with the words, “Please Read Our Website
23 Disclaimer By Clicking Here”. Do you see that?
24 A. Yes.
25 175 Q. And if we click on that website disclaimer...
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1 A. Hm..mm.
2 176 Q. ...it takes us to a document which I’m now showing you
3 on the screen entitled “Disclaimer: given the speed at
4 which new laws, regulations and policies have been
5 implemented to control the COVID-19 pandemic, it is
6 possible that the responses below will be impacted.”
7 Do you see that?
8 A. Yes.
9 177 Q. And do you acknowledge that the Canadian Covid Care
10 Alliance has a disclaimer on its website and that...
11 Well, let me ask that question first. Has a
12 disclaimer on its website, yes?
13 A. Yes.
14 178 Q. And that what I’m showing you here is the actual
15 disclaimer from the website?
17 179 Q. All right. I want to draw your attention to the
18 second paragraph of that disclaimer, and in particular
19 the first three sentences, which reads:
20 “While we have made every effort - every attempt to
21 ensure that information...” Scratch that. Drawing
22 your attention to the second paragraph, “While we have
23 made every effort - every attempt...”
24 I’m going to try that again because I can’t read
25 this morning, sorry.
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1 A. Okay.
2 180 Q.
3 “While we have made every attempt to ensure the
4 information contained in this site has been
5 obtained from reliable sources, Canadian Covid
6 Care Alliance is not responsible for any errors
7 or omissions, or for the results obtained from
8 the use of this information. All information in
9 this site is provided “as is”, with no guarantee
10 of completeness, accuracy, timeliness or of the
11 results obtained from the use of this
12 information.”
13 Is that an accurate summary of the disclaimer?
14 A. That’s what the disclaimer says, yes.
15 MR. TZEMENAKIS: Mr. Wilson, can we mark the Canadian
16 Covid Care landing page with the disclaimer in the red
17 text box as Exhibit 1?
18 MR. WILSON: Yes, no objection.
19
20 EXHIBIT 1: Canadian Covid Care Alliance landing page
21 on the CCCA website, with the disclaimer in the red
22 text box.
23
24 MR. TZEMENAKIS: And can we mark as Exhibit 2, the text
25 of the actual disclaimer from the Canadian Covid Care
26 Alliance website?
27 MR. WILSON: Yes, no objection.
28 MR. TZEMENAKIS: Thank you.
29 EXHIBIT 2: Text of the actual disclaimer on the
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1 Canadian Covid Care Alliance website.
3 181 Q. I’m just going to leave this on for a moment because
4 I’m going to come back to the next exhibit. Mr... Dr.
5 Pelech, you refer in your report to Ichor Blood
6 Services, spelled I-c-h-o-r...
7 A. Yes.
8 182 Q. ...is that correct?

10 183 Q. And I’m showing you the landing page for Ichor Blood
11 Services...
12 A. Hm..mm.
13 184 Q. ...which is a pri...which provides private lab
14 services in Covid-19 testing. Is that accurate?
15 A. Yes, they do.
16 185 Q. And Ichor Blood Services used to be known as Ichor
17 Heath, which I’m also showing you on the screen.
18 A. Hm..mm.
19 186 Q. Are you aware of that?
20 A. Yes.
21 187 Q. And are you aware that Ichor Health is a private
22 company?
23 A. Yes.
24 188 Q. You’re aware that it is a for profit company?
25 A. Yes.
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1 189 Q. Are you aware that it is not engaged in the
2 development of vaccines generally?
3 A. I’m not aware of them being involved in vaccines, no.
4 190 Q. And are - you refer to and rely upon a private
5 communication from that company in your report,
6 correct?
7 A. Well, multiple communications actually.
8 191 Q. Right, but you actually cite to one specifically at

9 paragraph 57, footnote 54?
10 A. Yes.
11 192 Q. And for the purposes of your cross-examination today
12 you have not produced that private communication,
13 correct?
14 A. That - that’s correct.
15 193 Q. Right. We’re going to come to that...
16 A. Hm..mm.
17 194 Q. ...when we’re talking about paragraph 54, but Mr.
18 Wilson, I do want you to know that there is a private
19 communication referred to. Absolutely no information
20 about the substance of that private communication has
21 been provided, so I will likely ask you for an
22 undertaking to produce it. It - when we get to
23 paragraph.
24 A. I should explain it, that it’s a - most of it’s from a
25 phone conversations that are not actually recorded.
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1 195 Q. It’s a fair point, sir, and when we get to paragraph
2 57 I’m going to ask you specifically about the
3 statement that you attribute to Ichor Blood Services.
4 A. Sure.
5 MR. TZEMENAKIS: Mr. Wilson, can we please mark as
6 Exhibit 3 the landing page for Ichor Blood Services?
9 EXHIBIT 3: Landing page for Ichor Blood Services
10 website.
11
12 MR. TZEMENAKIS: Can we please mark as Exhibit 4 the
13 landing page for Ichor Health, which is the
14 predecessor to Ichor Blood Services.
16
17 EXHIBIT 4: Landing page for Ichor Health website.
18
19 MR. TZEMENAKIS: Thank you, sir. Just bear with me
20 while I stop sharing my screen, and for reasons that
21 are not clear to me it is not letting me do that, so
22 we’re just going to go off record for a minute.
23
24 OFF RECORD
25 186 MR. TZEMENAKIS: Thank you. so, Dr. Pelech, I’m going
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1 to ask you some questions in relation to paragraphs 7
2 to 13 of your expert report at Exhibit B, as in Bravo,
3 to your affidavit.
4 A. Right, so which paragraphs again?
5 187 Q. This is paragraphs 7 to 13 under the heading
6 “Experimental Nature of Covid-19 Vaccines”.
7 A. Okay.
8 188 Q. I’m going to ask you some general questions first and
9 then I’m going to get to some more specific questions.
10 A. Sure.
11 189 Q. So, Dr. Pelech, are you aware that nucleic acid based
12 vaccines have been in development for multiple
13 decades?
14 A. Yes. I mean...
15 190 Q. Are...
16 A. ...Dr. Robert Malone would like to take credit for
17 that back, you know, almost 25 years ago, yes.
18 191 Q. Are you aware, sir, that Covid-19 vaccine design and
19 development was quickly undertaken to identify
20 putative candidates for the human population?
21 A. Are you talking about parts of the virus that would be
22 targeted? I’m not quite sure I understood...
23 192 Q. Okay, that’s fair. Are you aware, for example, that
24 the SARS CoV 2 design was aided by the prior work done
25 with both SARS in 2003 and with the Middle Eastern
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1 Respiratory Syndrome coronavirus in 2012?
2 A. In - in the context of the RNA viruses, I don’t think
3 so, but in context of trying to develop vaccines
4 against both SARS-CoV-1 and MERS yes. There were
5 efforts in animal studies to develop vaccines, but to
6 my knowledge nothing materialized that went into human
7 trials. They had bad results with the animals,
8 unfortunately.
9 193 Q. So, just to be clear, you’re - you’re saying that you
10 are not aware of that with respect to mRNA vaccines?
12 194 Q. Okay. Are you aware that prior work on both SARS in
13 2003 and the Middle Eastern Respiratory Syndrome
14 coronavirus in 2012...
15 A. Hm..mm.
16 195 Q. ...demonstrated the importance of the viral spike
17 protein for facilitation - for facilitating viral
18 binding to host cells?
19 A. Yes. That was well known.
20 196 Q. Okay, do agree that the prior work on the
21 coronaviruses - SARS and MERS, Covid-2 - demonstrated
22 that importance, the importance of the spike protein?
23 A. Well, it was the obvious target because it was the
24 largest protein of the viruses, and it’s on the
25 surface of the virus particle and it engages the ACE2
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1 receptor which in principle you should be able to
2 develop an antibody that targets that portion of the
3 protein to block the binding, and therefore entry of
4 the virus into cells. So, it’s a - it’s a - it’s an
5 obvious target.
6 197 Q. Okay. So my - to be fair to you, my question - my
7 first question was whether or not you were aware of
8 something and then a second question was whether or

9 not you agreed to it, and I did that on purpose
10 because I don’t want you to agree to something that
11 you’re not aware of. Fair?
12 A. Right. But I’m not aware of any work with mRNA
13 vaccines to develop against those specific target
14 proteins in those viruses.
15 198 Q. Are you aware that the public availability of the full
16 genome sequences of the SARS-CoV-2 in early January
17 2020 provided scientists around the world with a
18 direct mechanism for assessing the amino acid sequence
19 of a spike protein?
20 A. Yes, that’s correct.
21 199 Q. Do you agree that the public availability of that full
22 genome sequence allowed scientists around the world
23 were provided scientists around the world with a
24 direct mechanism for assessing the amino acid sequence
25 of the spike protein?
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1 A. Yes.
2 200 Q. Do you agree, sir, that the understanding of pre and
3 post fusion spike conformation was critical to the
4 development of SARS Covid-2 mRNA vaccines?
5 A. No, I don't agree, for two reasons. One, I don’t
6 think it’s actually necessary to be a - in the
7 prefusion form because the AstraZeneca vaccine doesn’t
8 do that.
9 201 Q. Yes, the AstraZeneca vaccine is an adenovirus,
10 correct?
11 A. Correct. But clearly it doesn’t have to be in a
12 conformation that is in the locked form with the 2
13 proline residues to put it in the prefusion form.
14 That’s not necessary to develop an antibody. But the
15 other thing, too, was it was a - the other reason why
16 I had a problem with your question... Can you repeat
17 the question just to make sure I’m answering it
18 properly?
19 202 Q. Of course. And just so that we’re clear, if there’s
20 anything that you don’t understand, ask me...
21 A. Right.
22 203 Q. ...and I will clarify as we’re going along.
23 A. Okay.
24 204 Q. So, my original question was do you agree that the
25 understanding of pre and post fusion spike
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1 conformation...
2 A. I never...
3 205 Q. Let me get that on the record.
4 A. Yeah.
5 206 Q. Just put...
6 A. You can’t - you can’t tell from the amino acid
7 sequence what the structure of the protein is going to
8 be beyond the primary amino acid sequence. You can

9 use modelling to maybe predict but ultimately it
10 required crystallization of the protein and x-ray
11 crystallography data to determine what the
12 conformation actually was. So, you need the sequence
13 in order to - then make the protein so that you can
14 then do the crystallography work, and then from that
15 you can get a sense of what the effects of mutations
16 would be, like putting in those proline residues and
17 how that would give you the overall structure of the
18 protein.
19 207 Q. Right. And my... So, I want to make two points.
20 Number one, we’re both going to try to do a better job
21 of not interrupting each other otherwise the
22 transcript is not going to be readable to the Court,
23 okay?.
24 A. Sure.
25 208 Q. And in the second thing was while I appreciate what
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1 you’ve just said, my question was that this - this pre
2 and post fusion spike conformation...
3 A. Hm..mm.
4 209 Q. ...was part of the development of the SARS CoV 2
5 vaccine. I didn’t say it was the only thing, I said
6 it was a critical part of the development, and I’m
7 understanding you to say no, with two caveats. Is
8 that correct?
9 A. Right. It’s not critical. You could do it without
10 it. You can actually do it without even the sequence
11 of the virus as long as you can purify it.
12 210 Q. Okay. And, sir, Dr. Kindrachuk noted in his report...
13 A. Hm..mm.
14 211 Q. ...that mRNA vaccines can be manufactured without the
15 requirement for cell culture. I’m wondering if you
16 agree with that statement.
17 A. Well, yes. You’re using the - the enzymes that are in
18 those cells to catalyze the reactions that you need to
19 produce the RNA from a template.
20 212 Q. And for the benefit of my friends, that reference is
21 on page 22 of Exhibit B...
22 A. Hm..mm.
23 213 Q. ...to Dr. Kindrachuk’s report.
24 A. Hm..mm.
25 214 Q. So, I’m going to take you to paragraph 7 of your
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1 expert report.
2 A. Okay.
3 215 Q. Now, at paragraph 7 of your expert report, you say at
4 the end of that paragraph...
5 A. Hm..mm.
6 216 Q.
7 “Prior to the approvals of these vaccine
8 formulations by the U.S.F.D.A. and Health Canada
9 in the Fall of 2021, no such lipid nanoparticles
10 or adenovirus had been approved for any RNA-DNA
11 based vaccine to produce immunity against a
12 pathogen’s protein in humans by specifying their
13 production within the body’s own cells.”
14 Do you see that?
15 A. Yes, I do.
16 217 Q. Do you stand by that statement today?
17 A. No. It’s come to my knowledge that - that Ebola virus
18 was actually used with an RNA to produce proteins and
19 antibodies - elicit antibody production in - ideally
20 in people. But the problem is it’s not approved in
21 the U.S. or in Canada, but the European Medicine
22 Agency has approved it. It’s been under emergency use
23 authorization and they said the equivalent to that in
24 - in Europe. It’s not - it’s been given to people -
25 certainly I think well over 100,000 people to date -
26 but it’s never been tested in people for Ebola itself.
27 Only in animal models. But that’s to my knowledge the
28 only case, and that was in, I think, 2020 that that
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1 was approved. So that’s (inaudible).
2 218 Q. Dr. Pelech...
3 A. Okay.
4 219 Q. So, Dr. Pelech, I’m going to ask you a very direct
5 question.
6 A. Hm..mm.
7 220 Q. I don’t want you to take this in a way other than its
8 intended. Did you know that before I provided your

9 counsel with a copy of an exhibit that says exactly
10 what you just said?
11 A. No, I did not know that before that.
12 221 Q. Okay. So...
13 A. I wouldn’t have made that statement had I was...if I
14 was aware of it.
15 222 Q. Okay. So, I’m going to share my screen again...
16 A. Hm..mm.
17 223 Q. ...and what I’m showing you here is an excerpt from
18 the European Commission entitled “Vaccine Against
19 Ebola:”...
20 A. Hm..mm.
21 224 Q. “...Commission grants new market authorizations”.
22 A. Hm..mm.
23 225 Q. Do you see that in front of you, sir?
24 A. No, actually I don’t.
25 MR. WILSON: Nor do I. And now I do.
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1 226 MR. TZEMENAKIS: Do you see that in front of you, sir?
2 A. Yeah.
3 227 Q. And you are aware that the European Union approved an
4 Ebola vaccine in 2020, correct?
5 A. They approved its use, yes, that’s correct.
6 228 Q. Right.
7 A. You’re - again an emergency use type authorization.
8 229 Q. Right. Are you aware that the Zabdeno - Zabdeno virus
9 based Ebola virus vaccine that utilizes a replication
10 deficient adenovirus to carry RNA encoding the Ebola
11 virus glycoprotein. Is that something that you’re
12 aware of?
13 A. Actually I - I need to look at that because I would’ve
14 thought they would’ve used DNA not RNA.
15 230 Q. Okay. Are you aware that the Ebola virus vaccine is
16 currently in use?
17 A. Yes it’s been given to people.
18 231 Q. Right.
19 MR. TZEMENAKIS: Mr. Wilson, can we mark the document
20 entitled “European Commission Vaccine against Ebola:
21 Commission grants new market authorisations” as
22 Exhibit Number 5, please?
24
25 EXHIBIT 5: Document entitled “European Commission
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1 Ebola: Commission grants new market authorisations.
3 MR. TZEMENAKIS: Thank you. Madam Reporter, could you
4 stop sharing my screen, please? Thank you.
5 A. Yeah, I feel it would definitely be DNA. I - I think
6 there’d be a lot of problems if they were using RNA in
7 an adenovirus construct. Because - because they’re...
8 232 Q. So, I made note of what you said and I’m going to take
9 a look at the break.
10 A. Yeah.
11 233 Q. What I’d like to do is...
12 A. Although - although is that an RNA virus? If it’s an
13 RNA virus it’s okay. And now I’m trying to think. It
14 should...here’s my confusion. The adenoviruses that I
15 know are DNA tumour viruses. So, they should be -
16 they should have DNA in them. But I seem to recall
17 some - reading somewhere else about RNA, and so I’m a
18 little bit confused about this.
19 234 Q. So, why don’t it give you the break to - to check to
20 see...
21 A. What they use.
22 235 Q. ...if you can resolve the confusion, but the point
23 that I simply wanted to make, and I think we’ve
24 established is that the Ebola vaccine has been
25 approved by the European Union. Yes? You said yes to
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1 that?
2 A. Yes.
3 236 Q. And that you were aware that its currently in use?
4 A. Right.
5 237 Q. And, so when I go back to paragraph 7...
6 A. Hm..mm.
7 238 Q. ...what I - what I understand you to be saying is that
8 neither the U.S.F.D.A. or Health Canada has approved

9 any such RNA or DNA based vaccine. You’re not saying
10 it hasn’t been approved by other jurisdictions?
11 A. Right. Right. But when I wrote that I - I agree, I
12 was not aware of - of how that particular vaccine that
13 - how it was actually... I’m pretty sure it’s DNA
14 because the way you make these vaccines is you have to
15 actually use culture - cell culture to produce the
16 vaccine particles. You can’t create this the same way
17 you do with the mRNA vaccines. And that means that
18 the genetic material inside has to be completely
19 reproduceable, and I - I can’t imagine how you could
20 have a mixture of DNA and RNA in that - that
21 adenovirus vaccine. Or in the (inaudible).
22 239 Q. Two questions before we take a break. Is this
23 something that you - is this an area that would fall
24 within your scope of expertise as defined by Mr.
25 Wilson in this matter?
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1 A. Well, yes. I mean one of the projects from my
2 students in - in a course that I teach, a graduate
3 course, was to look at all of the pathogenic human
4 viruses, and we had about 200 we identified, and my
5 students prepared detailed reports that I had to then
6 go through and proof and mark. So, but in the courses
7 that I teach, adenovirus is a tumour virus. It - it’s
8 a DNA tumour virus.

9 240 Q. No, I understand.
10 A. Yes.
11 241 Q. But are you saying that Ebola specifically was one of
12 those 200 pathogens that were identified by your
13 students and that you looked at?
14 A. Yes, it was.
15 242 Q. Okay. And are you saying that your expertise is based
16 in part on the fact that you reviewed papers prepared
17 by students on the number of pathogens?
18 A. No, not at all. No, I’m just saying...
19 243 Q. No, I know, I’m just clarifying here.
20 A. I’m just saying that - that - that it was one of the
21 subject matter in the course that I was teaching
22 because I knew a fair amount about it beforehand, and
23 then the students were very interested so they decided
24 that they wanted to make it as part of a class project
25 that we divided out all of the known viruses that are
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1 pathogenic in people. I had to do the groundwork
2 first to identify all of the viruses, and then I
3 assigned the students the particular virus that they
4 were going to cover, so we could divide it out, you
5 know fairly. And so I had to do a lot of groundwork
6 on that before I even gave them the assignment.
7 244 Q. Okay. Is - is this - is - is this an area that falls
8 within the scope of your research, i.e. have you

9 published anything on this?
10 A. On - on - like a review? Well, the intent actually
11 was to eventually put - publish it on a website. I
12 just haven’t had a chance yet to do that.
13 245 Q. So, this is a recent project with your students.
14 A. We did it in 2020 because, you know, SARS was around
15 and they’re very interested and I thought, well, this
16 would be a good... Because our focus was actually
17 looking at cell signaling systems that those viruses
18 were utilizing in order to get into cells and then to
19 hijack them to replicate more virus particles.
20 246 Q. Okay, so prior to Covid-19 had you published any
21 research on mRNA vaccines?
22 A. No. No, I’m - I was not working with mRNA vaccines.
23 My - my research focuses less on the genomics side and
24 much more on the proteomic side.
25 247 Q. All right. So, Dr. Pelech, in keeping with our
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1 agreement and subject to Mr. Wilson’s concurrence,
2 we’re going to take a fifteen minute break at this
3 time, and we’re going to resume at 12:47 Eastern, or
4 11:47 Central time.
5 MR. WILSON: Can we go off the record for a minute?
7 OFF RECORD: 12:32:16 P.M. TO 12:51:50 P.M.
9 248 MR. TZEMENAKIS: So, Dr. Pelech, you had an opportunity
10 to review Exhibit 5 during the break, yes?
11 MR. WILSON: Counsel, before - before you go further
12 I’d like to on the record confirm that the applicants
13 in this matter, at least the Peckford applicants, have
14 had difficulties receiving the access - access to the
15 aids to cross the practice of the respondent Attorney
16 General has been to send them very shortly before the
17 cross-examination of one of our witnesses commences.
18 That email from the Attorney General is not sent
19 directly to the witness. It is only sent to counsel.
20 We then forward it on our side to a paralegal who
21 converts it into a format that is more user friendly
22 and accessible - can be made accessible to the witness
23 by email. We then email that link within minutes of
24 the cross-examination beginning, and that was the
25 process that occurred this morning, and I can confirm
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1 that while we were off the record I asked counsel to
2 stay on the video link to observe for himself the
3 challenges that Mr...Dr. Pelech was having accessing
4 the documents and observing him open the first
5 document relating to the European Commission. I just
6 wanted to have that on the record, thank you.
7 MR. TZEMENAKIS: So, just briefly in response for the
8 purposes of the record, at number one, it is a

9 courtesy on the part of the Attorney General of Canada
10 to share cross-examination exhibits in advance, as we
11 expect the same courtesy to be afforded to us.
12 Number two, the link was sent to all counsel in
13 all files at 10:03 Eastern, 9:03 Central time, which
14 is one hour before the examination was scheduled to
15 commence, and that was when the final version of the
16 documents were pulled together.
17 And then finally, number three, I can’t speak to
18 the inner workings as between counsel for the
19 applicants and their witness about how the witness is
20 going to access documents, but we do not generally
21 send documents directly to witnesses who are
22 represented by counsel.
23 And finally, I want to revisit what we said off
24 the record is we want to work collaboratively with you
25 to ensure that the process is smoother, but the Titan
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1 file is the main document transfer system used by the
2 Department of Justice and has been used by the
3 Department of Justice since 2019. So, let’s move that
4 to the side.
5 249 Q. Mr. Pelech - Dr. Pelech, did you have a chance to
6 review Exhibit 5 which was in relation to the Ebola
7 virus?
8 A. Yes.
9 250 Q. And do you - you want to clarify the evidence you gave
10 regarding a DNA versus RNA?
11 A. Right. So, yes, I do. And so I confirm, not from
12 that document, but I confirm that in fact the
13 adenovirus vector that’s utilizing a DNA version of
14 genes that are from the Ebola virus, along with other
15 genes that give you a replication incompetent version
16 of the adenovirus that’s being used.
17 251 Q. And do you know, sir, if at an intermediary step RNA
18 was used in the development of the Ebola vaccine?
19 A. No, it - it wasn’t, but - but the cells that are -
20 that get infected with this - this vector they will
21 make an intermediate copy that’s an RNA copy as part
22 of the process to then duplicate to make more of
23 the... Well, they would normally make an RNA copy
24 that can then be used to make the protein that’s
25 specified from that Ebola virus.
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1 252 Q. Okay. Thank you. I’m going to move to a different
2 area, and I’m still generally in the - that part of
3 your affidavit dealing with the alleged experiment...
4 experimental nature of the Covid-19 vaccines, so
5 paragraphs 7 through 13.
6 A. Okay.
7 253 Q. And I - I’d like to know, sir, did you agree with the
8 position of Dr. Kindrachuk that lipid nanoparticles

9 are the most clinically advanced of the mRNA delivery
10 vehicles available?
11 A. Well, I would - I would agree that they’re the ones
12 that are being advanced into the clinic and having
13 success, so, yes.
14 254 Q. Okay. Are you aware that mRNA vaccines have been in
15 development for some three decades?
16 A. Of - in one way or another the delivery system has
17 been very different, but the concept of using RNA to
18 get inside cells, not to make vaccines actually for
19 three decades, but more to actually produce proteins
20 that would be involving maybe gene therapy where
21 you’re producing a protein that’s not normally present
22 in the cells. Usually host proteins like - like that
23 would normally be missing in those cells that you want
24 to correct a disease, or they were used to produce
25 toxic - toxic-like chemicals for cancer cells. So,
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1 but - but as a vaccine that’s been probably more of
2 the last decade that that’s been conceived.
3 255 Q. Okay. Are you aware that mRNA vaccines were used in
4 Phase 1 and 2 clinical trials for vaccine candidates
5 against HIV, rabies, Zika, and influenza?
6 A. Yes. Yeah. There was animal studies to do this,
7 that’s correct.
8 256 Q. But there was actually - yes, there was also Phase 1
9 and Phase 2 clinical trials.
10 A. I’m not aware of the Phase 1 or 2 clinical trials with
11 these...the - we’re talking about like with lipid
12 nanoparticles for delivery?
13 257 Q. Yes.
14 A. No, I’m not aware of that.
15 258 Q. Okay.
16 A. Certainly none of them have been approved, so they
17 were obviously failures.
18 259 Q. Do you agree generally with the statement that lipid
19 nanoparticle technology had been approved for multiple
20 different uses prior to Covid-19 vaccine development?
21 A. Yes. Yah.
22 260 Q. Are you aware of a study entitled “Lipid nanoparticles
23 for mRNA delivery”?
24 A. You’ll have to be more specific.
25 261 Q. So, what I’m going to do...
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1 A. Hm..mm.
2 262 Q. ...is I’m going to share my screen with you, and you
3 can either look at my screen, sir, or you could look
4 at the document that has been provided to you prefaced
5 with the number 6, and I’m going to situate that.
6 A. I’m not sure I’ve seen this particular...
7 263 Q. So...
8 A. ...one but - but the material that’s in it reminds me

9 of other reviews that I’ve seen.
10 264 Q. Okay, so sir, what you have in front of you is a study
11 entitled “Lipid nanoparticles for mRNA delivery”...
12 A. Hm..mm.
13 265 Q. ...by the authors Hou, H-o-u, Zaks, Z-a-k-s, Langer,
14 L-a-n-g-e-r, and Dong, D-o-n-g.
15 A. Right.
16 266 Q. And I’m going to direct your attention to page 2 of
17 that study.
18 A. Okay, I have...
19 267 Q. Figure 1...
20 A. ...I have...
21 268 Q. ...which has a visual depiction of the development of
22 mRNA or the uses of mRNA and lipid nanoparticles in
23 various clinical trials. And I’m wondering if you’ve
24 had occasion to review this study before.
25 A. Not this particular document.
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1 269 Q. Okay.
2 A. But I have seen other documents that do a profile the
3 development over the last 30 years. I - I notice in
4 this one they’re commenting the first human test of
5 personalized mRNA again for cancer applications that I
6 was mentioning earlier.
7 270 Q. Right. Did you - just so that we’re clear, did you
8 consider this study when writing your report?

9 A. It wasn’t - it wasn’t - it wasn’t a question that I
10 was specifically trying to answer in terms of the
11 experimental... I gather - I gather I understand what
12 you’re trying to say is, well, how experimental is
13 this if fact there’s been all this research that’s
14 been going on. You have to remember that all this
15 research is experimental in the first place.
16 271 Q. I understand that that is the - that is the
17 perspective you are advancing.
18 A. Hm..mm.
19 272 Q. But I - my question was that prior to - well, my
20 question is prior to the development and the use of
21 mRNA vaccines in... You may scratch that. My
22 question is prior to the development of Covid...
23 A. Hm..mm.
24 273 Q. ...mRNA vaccines, that there were in fact other
25 instances where both mRNA and nanoparticle technology
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1 was considered and used. Is that a fair statement?
2 A. Yes, experimentally. I mean even - even the Ebola
3 virus, which I think is - is again an adenovirus -
4 that’s never actually been demonstrated to actually
5 work in humans, and so that even remains experimental
6 even though it’s approved.
7 274 Q. So that’s - that’s - to the best of your knowledge,
8 correct?
9 A. They...all that I could see on that was that it was
10 approved because it was considered ethically wrong to
11 use this on healthy people to infect them with Ebola
12 to see how well that - the vaccine worked. And so
13 they actually do not have any data with that vaccine
14 with humans, only with animals and there’s about a 50%
15 efficacy in the animal models.
16 275 Q. Right. And coming back to the question I asked you
17 which is are you aware that mRNA vaccines and the use
18 of nanoparticle technology was in use prior to the
19 development of Covid mRNA vaccines. I believe you
20 said the answer was yes...
21 A. Yes.
22 276 Q. ...and then you qualified that as experimental.
23 A. Experimental, that’s right.
24 277 Q. And that’s - and that’s your position, correct?
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1 MR. TZEMENAKIS: Okay. Madam Reporter, can I stop
2 sharing my screen, please. Mr. Wilson, can we please
3 mark as Exhibit Number 6 the study entitled “Lipid
4 nanoparticles for mRNA delivery”.
6 MR. TZEMENAKIS: On what grounds, sir?
7 MR. WILSON: Sorry, I said no objection.
8 MR. TZEMENAKIS: Oh, I didn’t hear the no part. Thank

9 you.
10 MR. WILSON: Be on the grounds that I consent.
12
13 EXHIBIT 6: Study entitled “Lipid nanoparticles for
14 mRNA delivery.
15
16 278 MR. TZEMENAKIS: Dr. Pelech, I’m going to take you to
17 paragraph 8 of your affidavit.
18 A. Hm..mm.
19 279 Q. So, at paragraph 8 of your affidavit you state, among
20 other things, that the Pfizer vaccine is still in
21 Phase 3 trials that are not scheduled to be concluded
22 until July of 2023. Do you see that?
23 A. Yeah, that’s the one reference. Other references I’ve
24 seen have suggested the end of March in 2023, but yes,
25 they’re still in Phase 3 trials.
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1 280 Q. And you stand by that statement today?
2 A. Yes.
3 281 Q. And are you aware, sir that clinical trials have both
4 primary and secondary efficacy endpoints?
5 A. Yes.
6 282 Q. Are you aware that the Pfizer faced re clinical trial
7 primary efficacy endpoint was testing to see whether
8 or not the vaccine produced - protected against

9 infection?
10 A. That’s correct, yes.
11 283 Q. Are you aware that the Pfizer Phase 3 clinical trial
12 secondary efficacy endpoints include testing to see
13 how the vaccine works against emerging variants, as
14 well as safety duration?
15 A. I think when they designed the trial, I’m not sure
16 that they actually had in mind that they would be
17 testing against future variants.
18 284 Q. Okay, but is it - is it - do you agree though that one
19 of the Phase 3 clinical trials secondary efficacy
20 endpoints was testing to see how the vaccine worked
21 from a safety perspective - safety duration
22 perspective?
23 A. Well, this is a main reason why if it - the trial
24 would’ve been extended because you’re looking for a
25 long term safety data and efficacy. I don’t think
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1 that they expected that they’d be doing three booster
2 shots within a year at the time that they started the
3 trial.
4 285 Q. Did you expect that there would be three booster shots
5 within a year of the time you started the trial or
6 they emerg...
7 A. I don’t think they expected it.
8 286 Q. I’m not asking you - did you expect it?

9 A. No, I thought they would do a better job.
10 287 Q. Okay. Are you aware that in the pharma industry...
11 A. Hm..mm.
12 288 Q. ...and that it is common practice to complete analysis
13 of one - well, say of the primary endpoint in a
14 trial..
15 A. Hm..mm.
16 289 Q. ...publish, provide the study results, and then move
17 on to regulatory approval? Is that something that you
18 would be aware of?
19 A. Yes, that’s pretty common in the industry for drugs.
20 290 Q. Okay. Do you - do you either through your individual
21 self or through your involvement with Kinexus
22 Bioinformatic Corporation...
23 A. Hm..mm.
24 291 Q. ...have direct experience with either the U.S.F.D.A.
25 or Health Canada’s regulatory approval process for
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1 vaccines?
2 A. Yeah - well, not for vaccines, for drugs, yes. I did
3 it not through Kinexus but through Kinetek. I
4 actually took a compound through Phase 1 human trials.
5 292 Q. Okay, so not for vaccines but for drugs is what I
6 think I heard you say.
7 A. That’s correct. It was quite some time ago but we
8 were involved with both Health Canada and with the FDA
9 on that.
10 293 Q. Okay. So, so I’m going to share my screen...
11 A. Hm..mm.
12 294 Q. ...and so that the Court has a complete record, what
13 I’m showing you, sir, is an excerpt form Pfizer
14 entitled “About Our Landmark Trial”. And in the first
15 paragraph of that document, it states that

16
17 “The Phase 3 clinical trial was designed to
18 determine if the Pfizer-BioNTech Covid-19 vaccine
19 is safe and effective in preventing Covid-19
20 disease. The trial began July 27, 2020,
21 completed enrolment of 46,331 participants in
22 January 2021. On November 18, Pfizer and
23 BioNTech announced that, after conducting the
24 primary efficacy analysis, their mRNA-based
25 Covid-19 vaccine met all of the study’s
26 primacy...primary efficacy endpoints.”
27 Do you see that?
28 A. Yeah.
29 295 Q. And does that accord with your understanding that
30 Pfizer completed the primary efficacy endpoints and
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1 then went on to seek regulatory approval for its Covid
2 mRNA vaccine?
3 A. Well, I have a lot of concerns about the trial itself
4 and how that...
5 296 Q. Correct, but that’s not...
6 A. ...but again the FDA...
7 297 Q. I appreciate we’re going to get...
8 A. ...gave them an approval to go ahead with a - with an

9 emergency use authorization to release it to 12 to - I
10 guess is was 12 years in - sorry, 18 year...19 years
11 and older.
12 MR. TZEMENAKIS: Mr. Wilson, can we please mark as the
13 next exhibit the document from Pfizer entitled “About
14 Our Landmark Trial”, and that would be Exhibit Number
15 7, please.
18
19 EXHIBIT 7: Pfizer document entitled “About Our
20 Landmark Trial.
21
22 MR. TZEMENAKIS: Madam Reporter, if you could stop
23 sharing my screen. Thank you.
24 298 Q. I’m going to move to a different area and we’ll move
25 to that portion of your report that deals with vaccine
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1 efficacy, and I’m going to ask you to go to paragraph
2 17, and let me know when you have that, please.
3 A. Let’s see, oh it’s a PDF, sorry.
4 299 Q. This is on page 49 of your expert...
5 A. Yeah, okay, so is - did you say it was 17, paragraph?
6 300 Q. Yes.
7 A. Okay, this is the one that begins, “The overall
8 chances of surviving Covid”?

9 301 Q. Correct.
10 A. Okay.
11 302 Q. So, in the last two sentences of - of this
12 paragraph... Sorry, in the last sentence of this
13 paragraph you state,

14
15 “By comparison influenza, even with an existing
16 strong vaccination program for those of greatest
17 risk has a case fatality rate in the Spring of
18 2020 in the U.S. that was not that much different
19 from Covid-19 before its vaccines were
20 available.”
21 Do you see that?
22 A. That’s right, yes.
23 303 Q. And you stand by that statement, sir?
24 A. Yes.
25 304 Q. And in support of that statement you rely on a study
26 at footnote 11...
27 A. Hm..mm.
28 305 Q. ...entitled “Assessment of Deaths from Covid-19 and
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1 From Seasonal Influenza, published by the J-A-M-A
2 internal medicine journal”. Do you see that?
3 A. Yes.
4 306 Q. All right, so I’m going to share my screen again.
5 A. Hm..mm.
6 307 Q. So, before you you have the study entitled “Assessment
7 of Deaths from Covid-19 and From Seasonal Influenza,”
8 correct?
9 A. Hm..mm.
10 308 Q. So, sir, I’m going to take you to the body of the
11 article...
12 A. Hm..mm.
13 309 Q. ...on page 2...
14 A. Hm..mm.
15 310 Q. ...and I’m going to read these passages into the
16 record for you, and then I’m going to ask you
17 questions about them.
18 A. Sure.
19 311 Q. So, the second last paragraph states,
20
21 “Directly comparing data for two different
22 diseases when mortality statistics are obtained
23 by different methods, provides inaccurate
24 information.”
25 A. Hm..mm.
26 312 Q.
27 “Moreover the repeated failure of government
28 officials and others in society to consider these
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1 statistical distinctions threatens public health.

2 Government officials may rely on such comparisons
3 thus misinterpreting the CDC’s data when they
4 seek to reopen the economy and de-escalate
5 mitigation strategies. Although officials may
6 say that SARS-CoV-2 is ‘just another flu’, that
7 is not true.
8
9 “In summary our analysis suggests that
10 comparisons between SARS-CoV-2 mortality and
11 seasonal influenza mortality must be made using
12 an apples-to-apples comparison, not an apples-to-
13 oranges comparison. Doing so better demonstrates
14 that the true...better demonstrates the true
15 threat to public health from Covid-19.”
16 A. Hm..mm.
18 A. Yes, I do.
19 314 Q. You did not qualify your opinion in your report that
20 directly comparing the data for two different diseases
21 when mortality statistics are obtained by different
22 methods provides inaccurate information, correct?
23 A. I did not comment on the - these last two paragraphs.
24 315 Q. Okay, but...
25 A. But...
26 316 Q. ...but you still stand by your conclusion and you site
27 this study in support of your conclusion, correct?
28 A. Because there was data there with respect to the
29 incidence of influenza, which I could then try to make
30 the comparison myself. I recognize from the start and
31 I - I think it’s clear in the paragraph we have a
32 different situation where in 2012 there was no
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1 vaccine, but we could calculate what the case fatality
2 rate was for SARS-CoV-2. In this case here there -
3 they are calculating the rate of death and that’s in
4 view of the fact that about a third of the people do
5 get influenza shots in their population, and
6 especially those that are most vulnerable. And
7 despite that these statistics are actually quite
8 comparable.
9 317 Q. And my question to you is that the very thing you are
10 doing in paragraph 17 which is comparing mortality
11 statistics from Covid-19 and Covid is precisely what
12 the authors are saying, you should not do because it
13 provides inaccurate information. Do you agree with
14 that?
15 A. No, I don’t agree with it...
16 318 Q. Okay.
17 A. ...because a lot of parallels between these - the
18 influenza vac...virus and SARS-CoV-2. They’re both
19 respiratory virus. The viruses are about the same
20 size. They’re transmitted very similarly, and they
21 both have lethality but it - and they both have issues
22 of mutations that can occur.
23 319 Q. I understand that there’s similarities...
24 MR. WILSON: But counsel, could - could the client -
25 could the witness answer the question, please? You’re
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1 interrupting him.
2 A. So base...if you’re going to try to make such a
3 comparison, this would be the best example that you
4 could provide.
5 320 MR. TZEMENAKIS: Right. And sir, just so that we’re
6 clear, you’re relying on this study in support of the
7 last statement at paragraph 17, correct?
8 A. I’m using it because it has the data that I think is

9 pretty reliable with respect to influenza.
10 321 Q. Right, and you do not dis...sorry. You agree with me
11 that the study authors conclude that the analysis
12 suggest the comparisons between SARS-CoV-2 mortality
13 and seasonal influenza mortality must be made using an
14 apples-to-apples comparison and not an apples-to-
15 oranges comparison? You agree that that’s what the
16 study concludes, correct?
17 A. Well, they’re saying this but I - I don’t know how
18 else are you going to do such a comparison?
19 322 Q. Okay.
20 MR. TZEMENAKIS: Counsel, would you agree to mark this
21 document as Exhibit Number 8, and the document is
22 entitled “Assessment of Deaths from Covid-19 and from
23 Seasonal Influenza,” and is also referred to at tab
24 number 11 of the expert report?
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1 A. And that is...that is a...
2 MR. TZEMENAKIS: Hold on, Mr. Pelech. Sorry, counsel,
3 what did you say?
5 MR. TZEMENAKIS: Thank you, Mr. Wilson.
7 EXHIBIT 8: Document entitled “Assessment of Deaths
8 from Covid-19 and from Seasonal Influenza”, also

9 referred at tab 11 of the expert report.
10
11 MR. TZEMENAKIS: Can you stop sharing my screen, please?
12 Thank you.
13 323 Q. So, I’m going to take you to paragraph number 18 of
14 your report, Mr. Pelech, and I want to take you to the
15 conclusion of paragraph number 18 and ask a couple of
16 questions. So, at paragraph 18 in bold face font you
17 say,
18 “All of this...”
19 ...which is a reference to the data that precedes,

20
21 “...seriously calls into question the wisdom of
22 vaccination of children and young adults at such
23 low risk of hospitalization and death. In my
24 opinion, especially in view of potential vaccine
25 injury in the short or long term.” Do you see
26 that, sir?
27 A. Yes, I do.
28 324 Q. And that - you stand by that statement today?
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1 A. Yes, I do.
2 325 Q. So, I just want to parse this out. When you say the
3 data calls into question the wisdom of vaccination of
4 children and young adults, is the opposite of that
5 equally true? Meaning that the data does not call
6 into question the wisdom of vaccination for those aged
7 70 and above?
8 A. No, I wouldn’t say that. I mean there’s a lot more

9 issues at stake with respect to the elderly people.
10 They are going to be at more risk, we’ve established
11 that, but we also know that some of those people that
12 are very elderly, depending upon what their condition
13 is, the vaccine could actually be quite harmful. And
14 the concern is that we are seeing increased rates of
15 infection amongst triple vaccinated people, and if the
16 whole point is for avoiding them getting infected with
17 SARS-CoV-2 in the first place, then we may actually be
18 making it easier for them to get infected. So, it’s a
19 - it’s a very grey zone is what I’m saying. I - I
20 can’t say the opposite statement would be true for
21 elderly people.
22 326 Q. Okay. So, I want to be fair to you...
23 A. Yeah.
24 327 Q. ...okay? You provided statistics...
25 A. Hm..mm.
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1 328 Q. ...for young Canadians.
2 A. Right.
3 329 Q. You provided statistics for those aged 30 to 49, for
4 those aged 50 to 69, and for those aged over 70.
5 A. Right.
6 330 Q. However, your conclusion, sir, is I only call into
7 question the wisdom of vaccination of children and
8 young adults. So, if you wanted to call into question

9 the wisdom of vaccination for these other age groups,
10 I assume you would’ve said so. Am I wrong in my
11 reading of this?
12 A. You’re wrong in your reading of this. I’m using the
13 most obvious case.
14 331 Q. But that - you’ll agree with me that’s not what you
15 said in paragraph 18. You don’t say anything in
16 paragraph 18 about these other demographics in your
17 conclusion.
18 A. Not in the conclusion, no.
19 332 Q. Okay.
20 A. Not in this - not in this portion of my report.
21 333 Q. Well, we’re going to come back to your general
22 conclusions in a moment, but let me move on to another
23 area, and that’s at paragraph 19. So, for the
24 purposes of the record, some of the statements in
25 paragraph 19 should be read together with the
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1 statements made in paragraph 64.
2 A. Hm..mm.
3 334 Q. So at paragraph 19, sir, you state that the next
4 important question in understanding Covid-19 vaccines
5 is how effective the vaccine program has been,
6 correct?
7 A. Hm..mm.
8 335 Q. You have to say yes or no for the purposes of the

9 record.
10 A. Yes.
11 336 Q. And you admit that it is very tricky to estimate that
12 due to a number of confounding factors, correct?
13 A. Correct.
14 337 Q. And some of those confounding factors include the
15 emergence of new variants, correct?
16 A. That’s one of them, yes.
17 338 Q. Age, correct?
18 A. Yes.
19 339 Q. Underlying health conditions, correct?
20 A. Yes.
21 340 Q. Comorbidity factors, correct?
22 A. Yes.
23 341 Q. Is it equally true that a confounding factor - these
24 confounding factors, so new variants, age, underlying
25 health conditions also impact how effective natural
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1 immunity to Covid-19 is?
2 A. Well, yes, they do have an influence, yes. The immune
3 systems are different in young children compared to
4 especially elderly people.
5 342 Q. Right. My - to be fair to you my point is that you’re
6 not saying that these factors were only relevant to
7 Covid-19 vaccination but they’re just relevant to
8 natural immunity and Covid-19 vaccination.

9 A. Yes. I think those are very general, but there are
10 certain characteristics about, for example, influenza
11 compared to Covid-19 where they’re different - very
12 different with respect to how they affect children,
13 right? Children are at higher risk with influenza,
14 especially in 1918, whereas the Covid-19 from what
15 we’ve seen, children are quite spared.
16 343 Q. I’m going to ask you to go to page 51...
17 A. Hm..mm.
18 344 Q. ...and the last two sentences at paragraph 19.
19 A. Hm..mm.
20 345 Q. I’m going to read these into the record, so then I’m
21 going to ask you a few questions. So, paragraph 19
22 states in part:
23
24 “Serological testing of blood samples in
25 unvaccinated people for SARS-CoV-2 protein
26 directed antibodies at my company Kinexus, and
27 independently at Ichor Blood Services puts this
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1 number above 50% with natural immunity.”

2 A. Right.
3 346 Q.
4 “In fact, 90% of the 3,500 participants in the
5 Kinexus SARS-CoV-2 antibody testing clinical
6 study, which includes 138 children between ages 2
7 and 11, showed clear evidence of antibodies that
8 targeted multiple SARS-CoV-2 viral proteins in
9 their blood samples.”
10 Have I read that accurately?
11 A. Yes, you have.
12 347 Q. Is there any other study that has replicated these
13 findings 50% above with nature immunity and 90%.
14 A. Yes. It wasn’t available at the time that I wrote
15 this affidavit, but Ichor Blood Services released
16 their data of testing people in La Crete, Alberta, in
17 the northwestern part of Alberta, and they tested well
18 over 900 unvaccinated people, and they found that 89%
19 of them tested positive for the SAR...the spike
20 protein and SARS-CoV-2. And so they found that it was
21 equivalent in intensity as what they saw with
22 vaccinated individuals in that study. So, based on
23 that, since then as well there’s been a publications
24 from Canadian Blood Services, and they approximate
25 somewhere close to - in their study they were looking
26 at the nucleic capsid protein, and they approximate
27 about 24% to the people that they had tested that had
28 donated blood had antibodies. But the problem for
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1 them is, and I know this now from our own work, the
2 nucleic capsid protein is an unreliable marker in
3 general for people who’ve had SARS-CoV-2 infections,
4 and we find that actually less than 70% of the people
5 who’ve PCR positive tested with SARS-CoV-2 and were
6 sick with the symptoms actually have any antibodies
7 against the nucleic capsid protein. And this is the
8 standard protein that’s been used by the ABC study

9 which has informed government on the extent of natural
10 immunity. It dramatically underestimates the extent
11 of natural immunity. Our test is better because we
12 test for ten different proteins in the SARS-CoV-2
13 virus in the same test. So, Ichor Blood Services, at
14 the time that I wrote this with the communications,
15 they actually had it posted on their website but they
16 took it down when I tried to use it as a reference.
17 But I do have correspondence that basically says it
18 was fine for me to mention their results, and so I can
19 provide that to you if you like, for the president of
20 the company.
21 348 Q. I’ll leave that, yes, but I have a number of
22 questions.
23 A. Hm..mm.
24 349 Q. So, number one, the study was actually available and
25 done and published - or apparently published...
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1 A. Hm..mm.
2 350 Q. ...in December and January of 2022. December of 2021,
3 January of 2022, and correct me if I’m wrong, your
4 report was finalized in March of 2022, correct?
5 A. That’s, so you...
6 351 Q. That’s number one...
8 352 Q. Number two, there was a CBC article...

9 A. Hm..mm.
10 353 Q. ...and in fact Alberta Health and Health Canada both
11 came out...
12 A. Hm..mm.
13 354 Q. ...challenging the - or urging caution, if I can put
14 it that way...
15 A. Hm..mm.
16 355 Q. ...about relying on the study prepared by Ichor Blood
17 Services. Were you aware of that?
18 A. I have not seen that - that correspondence.
19 356 Q. Correct
20 A. That was published in a - a - a journal, or was it on
21 their website or...
22 357 Q. It’s captured in a number of different places. It’s -
23 it was - it is available for sure...
24 A. Hm..mm.
25 358 Q. ...in widespread media reporting, and also there was a
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1 direct response to the La Crete hamlet suggestion that
2 Covid-19 is over the - the pandemic is over because of
3 this item, but what you’ve...
4 A. Yes, I know how...
5 359 Q. ...what you’ve just...
6 A. I wouldn’t say the pandemic’s over because of that,
7 but what it demonstrates is that these people have
8 been infected already with the virus, and that doesn’t

9 mean they can’t get it again. I don’t think I would
10 ever argue that. I know certainly from our own trial
11 people that had antibodies from being infected two
12 years before did get Omnicron again just as many
13 vaccinated people now.
14 360 Q. So, I’m just want to - I want to - I want to focus if
15 I can for a minute on your study.
16 A. Hm..mm.
17 361 Q. Do you acknowledge that the estimate of 90% antibody
18 production is significantly higher than most other
19 published studies in this area?
20 A. Not anymore. For example, just a week ago the results
21 of a salivary test that was done in the United Kingdom
22 where they tested high school students, they found
23 that 97% of those students that were tested had
24 antibodies against the SARS-CoV-2 virus proteins. And
25 I think it was somewhere around - I may not have this
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1 exactly right but it was in the order of around 60% of
2 elementary school kids had antibodies, again against
3 the SARS-CoV-2 virus proteins by the serological
4 testing. So - so, there’s a lot of reports that are
5 starting to emerge now indicating very high rates of
6 natural immunity. I think South Africa - I was just
7 reviewing a document that was sent to me where they’re
8 seeing over 70% natural immunity. It was estimated in

9 India, for example, that at the end of June of 2021
10 after that terrible big spike, which by the way per
11 capita was about the same as - as the incidence in
12 Ontario, but they have so many more people, so they
13 have...
14 362 Q. So...
15 A. ...100,000. So they estimated that they had about 70%
16 natural immunity at that point.
17 363 Q. So, so...
18 A. Or at least this kind of numbers.
19 364 Q. So, I want to - I want to do a couple things here.
20 So, first of all, the UK study that you just referred
21 to...
22 A. Hm..mm.
23 365 Q ....and the Ichor Blood Services study that you just
24 referred to... Well, the UK study is not referenced
25 in your report because you’re saying its recent,
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1 correct?
2 A. Yeah they were just - they just published I think
3 within about last week or two weeks.
4 366 Q. Right. So, I’m going to digress for a minute.
5 A. Hm..mm.
6 367 Q. And my underlying degree is in organizational
7 behaviour, and so, sir, every time you speak to me and
8 you speak about studies, you’re looking to off to your

9 left hand side. Can you tell me what you’re reading,
10 please?
11 A. Oh, nothing. I’m looking - I’m looking at the sky,
12 and it just...
13 368 Q. Actually...
14 A. ...helps my concentration. By not looking at you I’m
15 concentrating on what it is to reply to you with the
16 correct answer the best to my ability. There’s - I
17 can - I can show you around the room, there’s nothing
18 that - that’s, you know, on the table.
19 369 Q. That’s fine. I just - I just want to...
20 A. Sorry, it’s just a bad habit.
21 370 Q. You - no, no, I’m not suggesting anything.
22 A. Yeah.
23 371 Q. I’m simply asking because at the beginning of this
24 examination we agreed that you wouldn’t be reading any
25 notes or any electronic notes, in paper or
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1 electronically. So I know what you’re showing me
2 around the room.
3 A. Oh...
4 372 Q. I’m just going to ask you to reconfirm...
5 A. ...on my computer screen it’s only the documents...
6 373 Q. ...you’re not reading anything...
7 A. ...you’ve asked me to look at.
8 374 Q. Okay. So, just so that I get my question out.

9 A. Hm..mm.
10 375 Q. You’re not looking at notes other than your report and
11 your affidavit electronically on your screen, correct?
12 A. And the documents that you’ve asked me to look at.
13 376 Q. Thank you. Coming back to your study...
14 A. Hm..mm.
15 377 Q. ...do you have a threshold by which you determined
16 that the presence of antibodies amounted to natural
17 immunity? So, it’s - my question is...
18 A. Yeah.
19 378 Q. ...90% of what?
20 A. Yes, I understand what you’re saying. So, the
21 quantitation that we’re trying to make is compared to
22 a reference of someone who we believe has not been
23 infected with Covid-19. As it stands the best
24 references we have are serum samples from people from
25 2019 which we investigated and included probably about
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1 40 such samples in our analysis. And then we looked
2 to see the range from people who have not reported
3 having any symptoms, and it’s difficult because of
4 what we find is most people, even when they don’t have
5 symptoms get positive results on our screen.
6 However, we’ve also tested babies, and that was
7 reported in our original study that was published in
8 JCI Insights. So, we had around 20 six-month old

9 children - babies - and they had absolutely clean
10 blots.
11 So, we have people that we encounter that have,
12 like the babies, absolutely clean blots, but the vast
13 majority of people we see, because we’re monitoring so
14 many different parts of the virus proteins, we want to
15 see a threshold because we do recognize that there may
16 be cross reactivities with - with antibodies that
17 these people have from exposure to other coronaviruses
18 where there could be cross reactivity. So, all I can
19 say is that these individuals have antibodies that
20 will recognize the actual sequences from the SARS-CoV-
21 2 virus, nobody - there is no test that actually can
22 determine whether or not a person actually has
23 immunity that - that if they get infected that they
24 are not going to present symptoms. I don’t think
25 there’s any test that exists for this.
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1 379 Q. Okay, so - so do you agree that the - if I’m
2 understanding correctly...
3 A. Hm..mm.
4 380 Q. ...do you agree that the mere presence of antibodies
5 in the blood is not necessarily equivalent to natural
6 immunity? They’re just present.
7 A. Well, the natural immunity means that you have an
8 antibody or an immune response that will be

9 protective. Maybe not completely protective, but will
10 offer some degree of protection. How much depends
11 upon the levels of antibodies, but not just that. You
12 - you have three components to your immune system, an
13 aid immunity, P-cell immunity, B-cell antibody
14 directed immunity, and so you may be higher in one
15 than the other, and so you - unless you do a complete
16 analysis you won’t really know, but we have been doing
17 studies at Kinexus, looking at T-cell immunity with
18 diagnostics DX, with the same samples with the people
19 that we’ve tested with our antibodies and with the T-
20 cell testing, and we find a very good correlation.
21 So, generally if we have detectable antibodies, they
22 have detectable T-cells as well, they’re directed
23 against those specific antigens for the SARS-CoV-2
24 virus.
25 381 Q. So, so thank you for that. I’m not trying to be
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1 difficult by what I’m about to say...
2 A. Yeah, sure.
3 382 Q. ...but I’m trying to focus my efforts on what you’ve
4 said in paragraph 17 and not other studies.
5 A. Okay.
6 383 Q. And - and otherwise we will - no chance we will finish
7 today...
8 A. Sure.
9 384 Q. ...and we will have to come back for another day.
10 But, so I just - I heard you say a moment ago that
11 your study found that there was some protective - some
12 degree of protection in 90% of the 3,500 participants,
13 is that fair?
14 A. Yes...
15 385 Q. In that...
16 A. ...and there’s other studies that support that, too.
17 386 Q. Right.
18 A. But I can mention a few if you are interested.
19 387 Q. Well, let me just get to - to this particular one and
20 then if your counsel wants to ask questions in re-exam
21 he can. Can you tell me that all 90% of the 3,500
22 participants have the same threshold?
23 A. No, no, it varies. It varies dramatically. As you
24 would - as you would - the responses actually of which
25 parts of the virus that they make antibodies against
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1 is completely different. And the intensities of those
2 antibodies against those various parts is generally
3 completely different.
4 388 Q. So...
5 A. As is with the vaccine people that have had - that
6 have been vaccinated that we’ve tested we see the same
7 thing.
8 389 Q. So, and I’m going to - I’m going to try to - to

9 conceptualize this in - in my head, if I can. In
10 hopefully simple terms I’m going to analogize. Let’s
11 assume the threshold is 5.
12 A. Hm..mm.
13 390 Q. Doesn’t matter what 5 - 5. Is it the case that all
14 90% of these people were above 5 - at 5 or above, or
15 is it that they had that the - that both the quantity
16 and the quality of the protein - of the antibodies
17 develop raised from a low number to a high number?
18 A. Yeah. I know this is...
19 391 Q. It’s really hard but I want to - I want to...
20 A. I don’t think - actually I understand the difficulty
21 because many of the tests that are on the market,
22 they’ll give you a hard number because they’re only
23 measuring one marker. When we do our tests we’re
24 measuring a minimum of 41 markers to as many as 300
25 markers. So, I can give you numbers for individual
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1 markers and - and give - and give you that answer, but
2 we don’t know what the combination of markers is,
3 never mind the intensities of those markers, to get a
4 sense of - of, you know, is this a really strong
5 immune response. What we do see is we have some
6 people that have a lot of spots representing positive
7 detection of antibodies for those particular parts of
8 the virus proteins, and some where its weaker, and we

9 know that over time the signals will get weaker
10 because the antibodies have a very short half life.
11 And until - unless they’re continually exposed, the B-
12 cells that produce these antibodies to the pathogen,
13 then they will wane. It doesn’t mean, though, that
14 that person no longer has immune protection because
15 everybody that - that understands immunology
16 recognizes the existence of B-cells that are memory
17 cells and plasma cells, and they stay alive for even
18 decades, and they will be reactivated and produce
19 antibodies again. So, it depends on how long since
20 you’ve been infected, whether you’ve been exposed to
21 the virus in between and you get booster shots.
22 So, all I can say is that this individual has
23 been exposed to a virus before, most likely depending
24 upon how good the response is, and whether it’s going
25 to be sufficiently protective, that I can’t tell
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1 unless I do more experiments.
2 392 Q. Okay.
3 A. Which I’ve done actually for variants. In our
4 research.
5 393 Q. All right. So, I’m going to... Thank you - thank you
6 for that explanation. Let me move briefly to
7 paragraph 20, if I can. Paragraph 20 you state, “As
8 the pandemic progresses those that are more

9 susceptible to succumbing to Covid-19 die leaving the
10 survivors with natural immunity.”
11 A. Hm..mm.
12 394 Q. And I just want to be clear, is it your view that -
13 that it’s - it’s just natural immunity that’s at play
14 versus for example the impact of vaccinations,
15 lockdowns...
16 A. Well, are you...
17 395 Q. No, I’m asking you what you mean by this statement
18 because this statement suggests that it’s ...
19 A. I see...
20 396 Q. ...it’s only natural immunity, and so I want to
21 understand.
22 A. No, I’m just saying that that’s one of the factors
23 that determines the - whether or not in the future
24 when you’re looking at the numbers as a population in
25 general, I mean the - the nursing homes got hit pretty
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1 hard with Covid early on. They’re very susceptible
2 and they were - government policy was or health policy
3 was to leave these people in the nursing homes and
4 just fill the atmosphere with the virus and just made
5 it easier to infect everybody else that was in those
6 nursing homes. So, as a result many people died.
7 They count for more than 80% of the deaths in our - in
8 our country, and those people that survived, about

9 four out of five at least, they have natural immunity.
10 They had - something allowed them to overcome the
11 virus, and that was natural immunity. Until the -
12 until the vaccines were available, then with the
13 vaccines then there was immunity provided by the
14 vaccines at least for - for a few months.
15 397 Q. Do you acknowledge that during this time there were -
16 leaving aside the debate as to whether or not they
17 were appropriate or appropriate in your view, that
18 there were significant health restrictions in place
19 such as lockdowns?
20 A. Sorry, are you saying did the lock...did the lockdowns
21 make a difference in my opinion?
22 398 Q. I’m saying that paragraph 20...
23 A. Hm..mm.
24 399 Q. ...doesn’t make reference to, for example, lockdowns
25 doesn’t make reference to mask mandates...
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1 A. No.
2 400 Q. ...doesn’t make deference to economic shutdown, et
3 cetera?
4 A. I can’t comment on how effective those were, frankly,
5 because of the data doesn’t support them being
6 effective. I have no direct link that the lockdowns,
7 especially in the case of where we had these people in
8 nursing homes, protected them. In - in fact by

9 keeping the people there it made it probably worse,
10 and...
11 401 Q. And you’ll...sorry, go ahead.
12 A. And so - so the - what we do know is ever since the
13 vaccines were first introduced that - that when we had
14 this big third - third wave of - of basically case
15 numbers, that that’s when we started to see a decline
16 in people that were very elderly, and - and since then
17 the death rate for elderly people is much lower in
18 2020...2021 than we saw in 2020. And so the vaccines
19 were just being introduced at that point in time. And
20 I think that there was a protective effect during that
21 period of time as well, but it was already on the
22 decline before they even got vaccinated.
23 402 Q. And Dr. Pelech, you’ll agree with me from just a pure
24 content perspective, there’s no reference to the
25 majority of what you just said about long term care
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1 health facilities, leaving people in long term health
2 care facilities, et cetera, anywhere in your report,
3 correct?
4 A. Not in this report, no.
5 403 Q. Okay.
6 A. You just asked me what I thought and I’m just...
7 404 Q. No, that’s fair.
8 A. Yeah.
9 405 Q. But it’s not in this report. Okay. I want to take a
10 look at paragraph 21 of your report, and paragraph 21
11 does a number of things.
12 A. Hm..mm.
13 406 Q. So, I’m - you rely on a snapshot of data from BC,
14 Ontario, and Alberta...
15 A. Right.
16 407 Q. ...in paragraph 21, is that correct?
17 A. yes, at least Ontario and BC.
18 408 Q. Okay. So, let’s - let’s go to...
19 A. It’s quite different in - in the Prairie Provinces,
20 especially in the Maritimes and Quebec.
21 409 Q. Yeah, let me start with BC, if I can. So, my
22 understanding is you rely on data for the period from
23 January 8th to February 7th for the BC data.
24 A. January 10th was the second wave, and it goes through
25 to around - I think it was around January 7th of 2022.
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1 410 Q. Right. Let me just direct your attention to the
2 middle paragraph of...
3 A. Well, I see - I see down below that in terms of the
4 vaccination status that’s correct.
5 411 Q. Okay. And...
6 A. I’m - I’m talking about the waves of Covid-19 is...
7 And I try to coincide them as best as I can.
8 412 Q. Okay. And, sir, you - you mentioned at the beginning

9 of this cross-examination that you had occasion to
10 look at the report from Dr. Kindrachuk, that’s
11 correct?
12 A. Yes. Yes.
13 413 Q. All right. And so what I’m going to do is I’m going
14 to share on my screen an excerpt of that report...
15 A. Hm..mm.
16 414 Q. ...which is at Exhibit D, as in Delta, to his
17 affidavit, page 8 of that report for the purposes of
18 the record. And...
19 A. Document 9?
20 415 Q. Yes, it is extract - it is number 9 on the list of
21 documents sent to you.
22 A. Okay.
23 416 Q. Do you see that, sir?
24 A. I have it now, yeah.
25 417 Q. Okay. So, in - in the data provided by Dr.
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1 Kindrachuk, he notes, and I simply want to know
2 whether or not you agree or disagree with this
3 statement...
4 A. Hm..mm.
5 418 Q. ...that the following statements... So, the
6 unvaccinated individuals accounted for 40%...47% of
7 the cases in BC at this time. That’s the second graph
8 next to the words “Number of Cases”, do you see that?

9 A. Hm..mm.
10 419 Q. Do you agree with that?
11 A. Well, it’s not that simple. I agree that the data
12 that he’s show here he’s extracted from the BC Centre
13 for Disease Control website for a specific time
14 period, which is...
15 420 Q. Similar - similar to the specific time period of data
16 that you extracted from your report, correct?
18 421 Q. Okay.
19 A. But the data that I extracted was actually from also
20 the BC Centre for Disease Control. So - so...
21 422 Q. Okay.
22 A. ...so, the presentation of the data that you see here
23 is in the top part is total number of cases, and then
24 as this has been getting worse they then start to do
25 it as per capita, like per 100,000 people assuming
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1 that they’re all the same within that group of 100,000
2 people in terms of their - their vaccine status, for
3 example. So, when you look at - at the trends that
4 are shown here, you - there is a - a breakdown that
5 you to have to also look at summing the results for
6 each of the vaccination states. They’re separated
7 here to see in fact the - the improvement that occurs
8 when you’ve - when you’ve got the triple vaccination

9 for at least this period of time where you’re - it’s
10 very clear that if you’re double vaccinated you lose
11 your protection after about certainly six months. But
12 if you get boosted again you can actually improve your
13 resistance of getting infected, and so this is what
14 they’re trying to illustrate here, that the case
15 numbers of hospitalizations is reduced and the case
16 number of cases.
17 You’ll notice that when you compare in the case
18 numbers that there are way more in the double
19 vaccinated group than you see in the unvaccinated
20 group. But the triple vacated group is now reduced
21 similar to what we see in the unvaccinated.
22 Now, the reason why that’s not fair is they’re
23 trying to use this data to make a case as an
24 individual are you better protected if you’re triple
25 vaccinated than if you were double vaccinated, for one
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1 thing. This is to encourage people to get another
2 shot, and make that comparison with unvaccinated
3 people. So, the issue that we have here is that it’s
4 - it’s serious Covid that we’re really worried about,
5 something that’s going to be life threatening and may
6 in fact cause deaths. So, when you look at the data
7 as shown here, it looks like the number of
8 hospitalizations is higher and the critical - the

9 critical care numbers are higher, and this is looking
10 at a - at an age breakdown within a certain period of
11 time, right?
12 So, when you continue to look at this data, as
13 time goes on it actually changes dramatically. So,
14 even the - what you’re seeing down below here, these
15 rates of increased hospitalization and increased
16 critical care and deaths, those are actually adjusted
17 numbers. They don’t explain how they adjusted the
18 numbers to come up with these actual values. When you
19 take a look at the same data from, for example the
20 Ontario Science Table, these numbers are actually even
21 more dramatic, and - but when you actually look at the
22 data in Ontario that’s on the Public Health website,
23 it does not match at all what the Science Table has.
24 So, if you look at the most recent data from
25 BC...
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1 423 Q. We’re not talking about the most recent data from BC,
2 are we?
3 A. Okay.
4 424 Q. Do you remember what my question was?
5 A. Yes.
6 425 Q. What was my question?
7 A. During the period of time from January 8th to February
8 7th, and your question is do I agree that the data

9 that’s here is - is correct.
10 426 Q. That wasn’t my question, sir.
11 A. And this is what Dr. Kindrachuk has - has offered to
12 say that this is not matching my data.
13 427 Q. So, my - my simple question was, according to the data
14 provided by Dr. Kindrachuk, which is referred to at
15 page 8 in Exhibit D of his affidavit, that this
16 information suggest that the unvaccinated accounted
17 for 47% of the number of cases recorded in BC for the
18 same time period as that referred to in paragraph 21
19 of your affidavit.
20 A. Right. And - and my answer to that question
21 specifically is that these numbers I think are
22 incorrect.
23 428 Q. Okay.
24 A. And they’re incorrect because of the way you determine
25 what is vaccinated and what is single vaccinated and
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1 double vaccinated and triple vaccinated because in BC
2 if a person gets Covid-19 within three weeks of being
3 their first vaccine shot, they’re considered
4 unvaccinated and their Covid case is lumped in with
5 the unvaccinated.
6 429 Q. And so that we’re clear...
7 A. Hm..mm.
8 430 Q. ...in paragraph 21 you’re relying on the same data

9 from BC.
10 A. Yeah.
11 431 Q. You said that to me a moment ago, correct?
12 A. That’s right. That’s where I got the data from.
13 432 Q. Okay.
14 MR. TZEMENAKIS: Counsel, can we mark this excerpt from
15 Dr. Kindrachuk’s report, page 8, Exhibit D, as Exhibit
16 Number 9, please.
17 MR. WILSON: Only if you agree to stop interrupting
18 the witness.
19 MR. TZEMENAKIS: Only if he agrees to maybe answer the
20 question that I’ve asked?
21 MR. WILSON: He’s entitled to give his answer.
22 Counsel, these are incredibly complex matters, and
23 your attempt to simplify things is to the point of
24 leading to inaccuracies. This is a matter of great
25 importance to millions of Canadians.
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1 MR. TZEMENAKIS: I’m not...
2 MR. WILSON: This is a very important credible
3 witness and you have been continually interrupting
4 him. You’ve been replacing - interjecting his answers
5 to questions with a new question. These are complex
6 matters, and he’s entitled to give a full answer, so
7 I’m not going to object to this as an exhibit, but I’m
8 going to ask that you stop interrupting this witness

9 and let him finish his answers.
10 MR. TZEMENAKIS: Mr. Wilson, you and I are going to
11 agree to disagree. A witness who’s trying to put into
12 play his particular views, studies that are not
13 referred to his report when we’re talking about
14 specific words and items and paragraphs that were used
15 in his report is not answering the question. We can
16 agree to disagree, we can deal with this in front of a
17 judge if we need to, but...
18 MR. WILSON: For sure.
19 MR. TZEMENAKIS: ...please don’t suggest to me that I’m
20 being disrespectful or that I’m interrupting him.
21 Where I have interrupted him I have asked him if he
22 has had anything else to add.
23 MR. WILSON: Well, you haven’t.
24 MR. TZEMENAKIS: The fact that I’ve - the fact that I am
25 trying...
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1 MR. WILSON: You have not.
2 MR. TZEMENAKIS: ...the fact that I am trying to ensure
3 that the Judge has a clear answer to a question, even
4 if it’s - I don’t care what the answer is - if he says
5 this is not the correct answer, that’s fine. But it
6 cannot be the case that in the course of does the
7 report say X, I’m faced with 26 other studies that are
8 not even referenced in the report. So we’re going to

9 agree to disagree.
10
11 Exhibit 9: Excerpt from Dr. Kindrachuk’s report, page
12 8, Exhibit D.
13
14 433 MR. TZEMENAKIS: Dr. Pelech, we’re going to - I’m going
15 to ask you one other series of questions and then
16 we’re going to take a break for lunch.
17 A. Sure, I - I...
18 434 Q. I would encourage you to give me a fulsome answer to
19 your questions as I have from the beginning of this
20 examination.
21 A. Yeah. No, I - I’m - I’m not offended. What I wanted
22 to add was - is the reason why I have concerns about
23 the data as presented is, first I’ve mentioned the
24 definition of what constitutes someone being
25 vaccinated or unvaccinated and at what stage because
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1 of this issue, that we know from data from Alberta
2 that when you are vaccinated and you get Covid, you’re
3 most likely to get it in the first - first two weeks,
4 in fact, and it goes - the - the risk increases in the
5 first seven days, stabilizes at high level, and then
6 drops down as the person develops immunity. That’s
7 one concern.
8 The second concern is that during this period of

9 time there was actually a much higher rate of testing
10 of actually younger people than ever before. And so
11 this has skewed the data with respect to age, in part.
12 There’s also the issue that if you are very
13 elderly and - and, as I said, feeble as I’ve mentioned
14 before, there is a reluctance to actually vaccinate
15 those people, and they are, of course, the ones that
16 are most likely to actually die soon, or require
17 critical care. So, again, that kind of skews the data
18 to the unvaccinated as well because those cases will
19 end up there.
20 There’s also a concern that many of the cases
21 that are hospitalized, and this is the data out of
22 Ontario, that they figure that about 46% of cases that
23 were hospital cases weren't these individuals going to
24 the hospital because they had Covid, and - and for
25 that reason they were seeking medical attention, but
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1 that they had other reasons why they went to hospital,
2 and either they had Covid at the time of admissions,
3 or they acquired it while they were in the hospital,
4 and those cases will also be lumped in with this data.
5 So, this makes it actually very hard to analyze this
6 data when you don’t have it separated as well. Once
7 they start separating the data as they do in the
8 United Kingdom, then you start to see the data looks

9 quite a bit different.
10 435 Q. So, now...
11 A. It’s evolved to be essentially what we see in the UK.
12 436 Q. Are you done, sir?
13 A. Yes. Thank you.
14 437 Q. Okay. So, I just want to be clear, the four factors
15 that you just identified apply equally to the data
16 that you rely upon in paragraph 21, correct?
17 A. Yes, these...
18 438 Q. You’re not just - you’re not just taking issue with -
19 it applies equally to the data that you rely upon.
20 A. That’s correct. That’s the best we can do because I -
21 I don’t know the extent of how important those
22 parameters are in the overall results.
23 439 Q. Then do you agree, sir, that the data published by BC
24 in the Ontario Science Table...
25 A. Hm..mm.
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1 440 Q. ...which is - is the - the best data that’s available
2 at - or was available at the time that these - you
3 wrote you report?
4 A. I actually don’t trust the Science Table data. I
5 trust the data out of Public Health Ontario.
6 441 Q. Okay. And you’re aware that the whole purpose behind
7 the Ontario Science Table is to help inform Ontario’s
8 response to Covid-19?
9 A. Yes, and I think that actually - they’ve actually made
10 mistakes.
11 442 Q. Okay. So, just before we end I’m just going to put up
12 this next exhibit.
13 A. Hm..mm.
14 443 Q. And then we’re going to take a break. I’ll share my
15 screen with you, sir.
16 A. Okay.
17 444 Q. So, this is - hold on. It’s number 10 on your list.
18 A. Okay.
19 445 Q. So, what you see here is an excerpt from the Science
20 Table, Covid-19 Advisory for Ontario. Can you just
21 confirm this is what you see, please?
22 A. I see Science Table, yeah.
23 446 Q. Okay.
24 A. I see on from - on your shared screen.
25 447 Q. Okay.
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1 A. Pull up the document.
2 448 Q. Well, I just want to take you to - and I appreciate
3 everything you’ve said about the concerns you have
4 with the data.
5 A. Hm..mm.
6 449 Q. I’m taking you to page 4 of this - sorry, page 4, at
7 the top of the page 4 you see a table entitled
8 “Protection Against Infection...”

9 A. Yes, I see that.
10 450 Q. “...Hospital and ICU Admission Associated with at
11 Least 2 Vaccine Doses,” do you see that?
12 A. Hm..mm.
13 451 Q. And do you, at least from a Science Table
14 perspective...
15 A. Hm..mm.
16 452 Q. ...it shows that protection against hospital and ICU
17 admissions associated with at least 2 vaccine doses is
18 above infection rates, so I’m colour blind but I
19 assume the red line...
20 A. Hm..mm.
21 453 Q. ...and the green line are above the SARS-CoV-2
22 infection line. Do you - do you see that?
23 A. Yes, I do.
24 454 Q. And then...
25 A. On my they’re saying...
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1 455 Q. No, I appreciate you have some concerns with the data.
2 A. Yes, I do.
3 456 Q. Table 2 shows case count hospitalizations and ICU
4 admissions as compared between vaccinated people with
5 at least two doses, and the unvaccinated, and do you
6 agree that this data shows that in all cases...so in
7 all situations that the unvaccinated have a higher
8 number of Covid cases, Covid-19 patients in hospital,

9 and... Well, let me stop there because the third
10 graph got cut off. Do you - do you see that that’s
11 what the data shows?
12 A. Well, I see they’ve got a graph here that says
13 Protection Against Infection, and I have no idea how
14 they came up with these numbers.
15 457 Q. Okay.
16 A. It’s just - it’s - it’s just unclear to me.
17 458 Q. And I think you said earlier...
18 A. And I mean in the concept that - and the concept that
19 you have 100% almost infection in the beginning of
20 August of 2021, I mean how can - like we know that
21 there was people that were in hospital that had Covid
22 that were vaccinated. I mean I just - I don’t know
23 where they get these numbers. And then certainly when
24 you look today it’s nothing like this.
25 The crossover that we saw when we tried to
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1 analyze this data from Ontario Public Health occurred
2 around December 24th where the number of people that
3 had Covid that was equal to the number of people that
4 were vaccinated - that were unvaccinated - there -
5 there - there is, and I do agree, that for a time
6 period there was - because there was vaccination
7 happening during that time period, again with booster
8 shots, that these did provide some level of protection

9 during that period.
10 I also know, and this data is not shown in these
11 kind of graphs, that if a person got their third shot,
12 they also had increased cases of Covid associated with
13 that, especially in elderly people which are going to
14 be the ones that are more likely go to hospital, and -
15 and potentially ICU units and may die, is what the
16 data from the United Kingdom clearly shows. So, I
17 think you’d have to look at the combination of not
18 just the protection that’s afforded people if they get
19 Covid and go to the hospital, but you need to also
20 factor in what happens in terms of their risks from
21 the vaccine injury during that period. And it’s
22 clearly increased cases of Covid that coincide
23 precisely with the vaccination of the elderly in the
24 UK.
25 459 Q. Right. And you agree with me we’re not talking about
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1 the UK here, correct?
2 A. Not talking about the UK, but we expect that...
3 460 Q. Do you agree with...
4 A. ...the physiology is very similar.
5 461 Q. But we’re not talking...
6 A. And we might put it - that to happen here, too. And
7 - and we do see that. It just takes a little bit
8 longer for it to show up here.

9 462 Q. Sir, I’m not disagreeing with what might be going on,
10 but that’s not what we’re talking about...
11 A. No.
12 463 Q. ...and I’m going to ask you, sure...
13 A. I don’t know what the data is actually showing. I
14 don’t know how its calculated.
15 464 Q. So, can we do two things?
16 A. Hm..mm.
17 465 Q. If I agree not to interrupt you, you should agree not
18 to interrupt me and then I can get my question on the
19 record...
20 A. And...
21 466 Q. ...and my comment on the record and we can have -
22 continue to have a pleasant afternoon, is that fair?
23 A. Yes.
24 467 Q. So, I appreciate what you said about the Ontario
25 Science Table. All I want you to confirm for me as I
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1 wasn’t talking about the UK data, or the recent UK
2 data. I was talking about the fact that you make
3 reference to Ontario - to - to Ontario data in
4 paragraph 21, correct?
5 A. Hm..mm. Right.
6 468 Q. And I’m showing you other data from Ontario for the
7 same time period that might lend itself to a different
8 interpretation of the results. That’s all.

9 A. Hm..mm.
10 MR. WILSON: And counsel, the witness explained to
11 you why he doesn’t think that’s accurate because of
12 the problems with the data, and in order to
13 demonstrate that, among other things, made reference
14 to UK data. So, don’t - please don't try and confine
15 my witness to the scope of his answers. He clearly
16 established why introducing UK data is relevant to
17 answering your question. Just because you don’t like
18 the answer doesn’t mean he’s not allowed to give it.
19 MR. TZEMENAKIS: Well, hold on a second, Mr. Wilson. I
20 didn’t say anything about - it’s my job to like or not
21 like the answer, but the reality is he could’ve
22 amended his report to talk about this UK data which he
23 hasn’t identified, no name of a report, no
24 identification where its been published, and is not
25 going to be of much utility to the Court in
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1 understanding what they’re supposed to do with this UK
2 data when his report in paragraph 21 talks
3 specifically about BC, Alberta, and Ontario. Again,
4 you and I can agree to disagree on the import of that,
5 and I’m...
6 MR. WILSON: We can also agree - also agree that
7 argument is best left for the courtroom and not a
8 transcript in a cross-examination, so, I just want to

9 make it clear...
10 MR. TZEMENAKIS: I can...
11 MR. WILSON: ...that when you’re trying to narrow
12 the scope of my client’s answer, I - that’s improper,
13 and I’m going to continue to object each time you try
14 to do it.
15 MR. TZEMENAKIS: And I...
16 MR. WILSON: He’s entitled to give a fulsome answer
17 to your question. These are complex matters. This is
18 a global events, and humans are the same across the
19 planet, and so we can move forward but please stop
20 trying to basically frankly intimidate my client into
21 narrowing the scope of his response.
22 MR. TZEMENAKIS: Hold on a second. Hold on a second. I
23 personally am offended by that comment. I’m going to
24 ask that the witness be excused and we’re going to
25 deal with this on the record. Mr. Pelech, we will see
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1 you in 30 minutes from now. We will resume your
2 cross-examination, please.
3 DR. PELECH: Okay, thank you very much.
4 MR. TZEMENAKIS: Thank you, Mr. Pelech.
6 (DR. PELECH LEFT THE CROSS-EXAMINATION)
8 MR. TZEMENAKIS: We’re still on the record.

9 MR. WILSON: Yes, we’re still on the record.
10 MR. TZEMENAKIS: Please, Madam Reporter. Mr. Wilson,
11 the suggestion that I’m trying to intimidate your
12 questioning - your witness by asking him difficult
13 questions on difficult subject matter is quite simply
14 offensive. My job is to understand what he’s an
15 expert in, what he’s not an expert in, and what he
16 says about statements that are contained in his
17 report.
18 I appreciate that there are two schools of
19 thought. I appreciate that that the debate is
20 rigorous. I’d appreciate that people on one side of
21 the debate have very strong views as similar to people
22 on the other side of the debate. My job is not to
23 take sides on a debate. My job is to present the
24 Court with a fulsome unbiased appreciation of the
25 events, and that’s what I’m trying to do.
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1 I am not, and I would seriously ask you consider
2 it over lunch, taking that statement back. I am not
3 intimidating your witness.
4 MR. WILSON: Okay. Sir, as the transcript will show
5 you effectively told the witness that he cannot refer
6 to UK data. You were implying to him, and it’s what I
7 took your implication to be, that there's a limitation
8 of scope on his answer, and I did not want him moving

9 forward thinking that was true or proper. If he
10 believes as the expert that in order for the Court to
11 have a full understanding of the medical science and
12 the data, that he needs to refer to UK, or India, or
13 Australia, or the United States, he should be free to
14 do so, and I took the aggressive manner in which you
15 presented that, which won’t be revealed from the
16 transcript but I saw it on my screen and I heard your
17 tone, to be whether it was intended or not, and I’m
18 going to absolutely assume it was unintended, to be
19 intimidating in nature. So, I’m not going to retract
20 my statement. It’s going to stay on the record.
21 We’ve conducted all of our...
22 MR. TZEMENAKIS: I just want to...
23 MR. WILSON: ...other examinations in this matter
24 with great civility and I’m confident that we can do
25 that going forward, but we need to slow this down, you
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1 need to let the answer that the - the witness answer
2 the question. I realize he is at times spoken over
3 you, but the transcript will clearly show who was
4 doing the interrupting, and let’s - let’s get the
5 fullness of information in front of the Court, so
6 that’s my request.
7 MR. TZEMENAKIS: Okay, so in response I’m simply going
8 to say for the sake of the record, and my tone was not
9 aggressive, I did not raise my voice, I’m quite calm.
10 The video will show that and we can play that if we
11 like to the Court.
12 MR. WILSON: Sure.
13 MR. TZEMENAKIS: But I have tried and I will continue to
14 try to ensure that civility amongst counsel and
15 civility as between counsel and the witness is - is
16 upheld. My personal views on this matter and your
17 personal views on this matter are irrelevant. We’re
18 just simply trying to make sure the Court has the
19 benefit of a fulsome record when its determining these
20 extremely important matters in - in the Fall. So,
21 with that we’re going to take a break. It’s 2:11.
22 I’m going to suggest that we come back at 2:41, and I
23 would ask if you could just let Mr. Pelech know that
24 we’ll resume at 2:41 as opposed to the time that he
25 went off the record, please.
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1 MR. WILSON: I’ll have Allison do that, and just for
2 the record because we’re - are we still on the record?
3 Okay. For the record, at no time, counsel, have I
4 suggested that my personal views are relevant. You
5 put those words into my mouth. I haven’t suggested
6 that your personal views are relevant, so I just
7 wanted to note that and let’s break for lunch.
8 MR. TZEMENAKIS: Very good. We’ll see you at 2:41.

9
10 OFF RECORD FROM 2:12 P.M. TO 2:43 P.M.
11
12 (DR. PELECH RETURNS TO THE CROSS-EXAMINATION
13
14 MR. WILSON: Counsel, I just want to make it clear
15 before we resume because the witness was not in the
16 room virtually when this discussion occurred, that its
17 our position that when answering your questions,
18 particularly brand new questions that obviously the
19 witness doesn’t know about, that its permissible in
20 our view for him to be recite...referring to data from
21 other countries, other sources of information, other
22 journals, other research from around the world if it -
23 if need be, that he’s not geographically confirmed to
24 Canada with respect to data and research.
25 MR. TZEMENAKIS: Thank you, Mr. Wilson. And just so
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1 that we’re clear, our position is that Mr. Pelech
2 prepared his report and filed it in March of 2022,
3 made statements in that report, and he has footnoted
4 to the appropriate references that he found material
5 in support of those statements. And while there might
6 be additional information that is relevant, my
7 questions are somewhat focused on the actual words
8 used in his report, and so I would ask him to answer

9 my question, and then if he wants to supplement it, he
10 can.
11 So, the one thing that I don't believe we did,
12 and before we end it, was mark the Ontario Science
13 data as the next exhibit, and I’m wondering, Mr.
14 Wilson, if we could mark the Ontario Science Table,
15 Covid-19 Advisory Dashboard as Exhibit Number 10,
16 please.
18
19 EXHIBIT 10: Ontario Science Table, Covid-19 Advisory
20 Dashboard.
21
23 469 Q. Mr. Pelech, I’m going to ask you to go to paragraph 27
24 of your affidavit. Do you have that in front of you,
25 sir?
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1 A. Yes, I do now. The Harvard study.
2 470 Q. Yes. So, at paragraph 27...
3 A. Hm..mm.
4 471 Q. ...you state in reliance - well, you state,

5
6 “Significantly, a Harvard study published in the
7 International Journal of Epidemiology analyzing
8 68 countries, found no discernable relationship
9 between the percentage of the population fully
10 vaccinated and the total number of cases of
11 Covid-19.”
12 A. Hm..mm.
14 A. Yes.
15 473 Q. Do you stand by that statement, sir?
16 A. Yeah, I do. The study was actually also looked at - I
17 think it was around 2,000 counties in the United
18 States and saw the same thing.
19 474 Q. In reliance on this statement in your affidavit you
20 cite to footnote number 20...
21 A. Hm..mm.
22 475 Q. ...which is an article entitled “Increases in Covid-19
23 are unrelated to levels of vaccination across 68
24 countries, and 2,947 counties in the United States.”
25 This...
26 A. Right - that’s right.
27 476 Q. And I’m showing the article...
28 A. Yeah.
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1 477 Q. ...or I’m going to in a moment.
2 A. I - I remember the article. The authors noted a trend
3 but they didn’t think it was statistically significant
4 of an increased rate of Covid cases with increased
5 vaccination. Actually, since this article’s come out
6 there’s been a lot more showing even stronger
7 correlations now.
8 478 Q. So, Mr....Dr. Pelech, I’m taking you to the article

9 that you rely on in footnote number 20.
10 A. Okay.
11 479 Q. I’m directing your attention to the section entitled
12 “Findings”, and I’m reading for you the very first
13 sentence, which says,

14
15 “At the country level there appears to be no
16 discernable relationship between percentage of
17 population fully vaccinated...”
18 A. Hm..mm.
19 480 Q.
20 “...and new Covid-19 cases in the last seven days.”
21 Do you see that?
22 A. Actually I see it on your screen. I don’t see it as
23 an exhibit in the downloads. Is there - is there a
24 number for this one?
25 481 Q. It’s number 12, sir.
26 A. Twelve. National Library of Medicine Art, okay.
27 Good. Okay.
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1 482 Q. So, I just want to confirm, sir, that the statement in
2 the report reads,

3
4 “At the country level there appears to be no
5 discernable relationship between percentage of
6 population fully vaccinated and new Covid-19
7 cases in the last seven days.”
8 A. Yes.
9 483 Q. And do you agree that your report - so, your paragraph
10 27...
11 A. Hm..mm.
12 484 Q. ...omits the words “in the last seven days”?
13 A. Yes, it does omit it, “in the last seven days,” that’s
14 correct. It has to be during a time period. I - I
15 thought that’d be implicit. I didn’t - I didn’t go
16 into the time period.
17 MR. TZEMENAKIS: And, counsel...
18 A. And also it’ll vary. It’ll - it’s obviously
19 important, too, because they didn’t have the Omicron
20 strain at that time, so I imagine the data’s quite a
21 bit different.
22 485 Q. It might be, sir. I - I don’t know, I’m just relying
23 on the study that you have footnoted...
24 A. Hm..mm.
25 486 Q. ...in support of the statement.
26 MR. TZEMENAKIS: So, counsel, can we please mark this
27 document as Exhibit Number 11. It’s an article
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1 entitled “Increases in Covid-19 are unrelated to
2 levels of vaccination across 68 countries and 2,947
3 counties in the United States”, and it is referred to
4 at footnote 20.
8 EXHIBIT 11: Article entitled “Increases in Covid-19

9 are unrelated to levels of vaccination across 68
10 countries and 2,947 counties in the United States”,
11 referred to at footnote 20.
12
13 487 MR. TZEMENAKIS: Dr. Pelech, I’m going to ask you to
14 move forward to paragraph 34. Give me one second,
15 please.
16 A. Hm..mm.
17 488 Q. Dr. Pelech, I - I just - before I move to the next
18 section I just wanted to acknowledge that in some
19 cases I refer to you as Mister, and in other cases I
20 refer you as Doctor.
21 A. It’s okay.
22 489 Q. It’s not my intention to - to somehow suggest
23 disrespect by calling you Mister instead of Doctor.
24 A. No - no offence taken.
25 490 Q. Great. Thank you. I’m going to take you forward to
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1 paragraph 34.
2 A. Hm..mm.
3 491 Q. And at paragraph 34, I’m going to give you an
4 opportunity to look at it.
5 A. I’ve got it.
6 492 Q. You - you state that Covid-19 vaccines are “leaky”...
7 A. Hm..mm.
8 493 Q. ...so do you see that?

9 A. yes.
10 494 Q. And would you use the term “leaky”, you’re using that
11 as the opposite of sterilizing, correct?
12 A. Yeah, that’s - that’s the terminology that’s been
13 actually widely adopted.
14 495 Q. Okay.
15 A. But I think you under...I think it’s clear what I mean
16 here.
17 496 Q. Okay. And when you say they’re “leaky” it’s because
18 they do not completely prevent infection nor stop
19 transmission, correct?
20 A. That - that’s correct.
21 497 Q. And do you agree that sterilizing immunity is not a
22 requirement for a successful vaccination program?
23 A. I would agree with that, yes.
24 498 Q. Are you aware... Actually, that’s fine. I’m going to
25 go to paragraph 37, please. It’s all right.
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1 A. Oh, I see a typo.
2 499 Q. Apologies, but every pen I’m picking up is not
3 working. I got to go to paragraph 37, please, and
4 we’ll talk a little bit about vaccine injury.
5 A. Hm..mm.
6 500 Q. So, I’m going to do my best as a non-scientist to try
7 to put some questions to you.
8 A. Hm..mm.
9 501 Q. So, my first question is do you agree that the spike
10 protein is on the surface of the virus and binds to
11 the ACE2 receptor on human cells to allow it to enter
12 cells and start an infection?
13 A. Yes, that’s the primary protein that will - the spike
14 protein - can bind, but there are many others as well.
15 There are pillid (ph) and a few others, but this is
16 the one that - that seems to be the most likely entry
17 point for the virus into cells.
18 502 Q. And do you agree that the current mRNA vaccines, and
19 viral vector vaccines, target this spike protein?
20 A. Yes.
21 503 Q. Do you agree that the current mRNA vaccines generate
22 antibodies to the spike protein that stick to it and
23 prevent it from binding to the ACE2 receptors?
24 A. We’re talking about, like, the most recent strain,
25 Omicron?
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1 504 Q. We’re - I think if there’s a distinction to be made
2 between Omicron and prior strains...
3 A. There is a bit...
4 505 Q. ...then feel free to do so.
5 A. Sure. So, I mean in general, yes, these antibodies
6 that are generated from the vaccine do recognize the
7 receptor binding domain often, but not always. From
8 our own work that we’ve been tracking in people, we -

9 we find that many people that have natural immunity do
10 not target that region with antibodies that we can
11 detect. And interestingly likewise in vaccinated
12 people, too. But because of the mutations that are
13 occurring in the variants of concern, and the Omicron
14 is the most evolved in this respect, a lot of the
15 antibodies that would be made against the Wuhan strain
16 sequence, don't necessarily work, depending on the
17 person, against the receptor to bind them in. So,
18 they won’t be what we call neutralizing.
19 There is, actually a little bit of misconception
20 in most people’s mind about what neutralizing means.
21 It’s really specifically referring to the ability of
22 the antibody to bind at or near the receptor binding
23 domain to inhibit the ability of the virus to bind to
24 ACE2 or whatever receptor otherwise that it targets
25 and get inside cells.
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1 That doesn’t mean that the antibodies that are
2 available are any less useful, because any antibody
3 that will bind to the surface of the spike protein or
4 the membrane or envelope proteins will tag that - that
5 virus and allow the innate immune system to recognize
6 it and take it out.
7 506 Q. Okay. so, is it fair to say that generally speaking
8 the mRNA vaccines stop or try to slow down virus entry

9 into the cells?
10 A. Well, that’s the - that’s the hope, and it does
11 happen, but not always.
12 506a Q. Okay. Is it fair to say that the mRNA vaccines also
13 help generate T-cells that recognize the spike protein
14 and in essence kill the infected cell?
15 A. Yes. I think that’s - there’s - there’s good evidence
16 for that, although I have to admit I’m a little
17 shocked by some recent data that I’ve observed looking
18 at T-cell responses to the vaccines, and this is with
19 immunity DX with Dr. Ismael Samuday (ph), and he’s
20 showing me data now showing no increase at all with
21 the second shot in t-cell recognition. It is actually
22 going down compared to the first shot in - in the
23 people that he’s tested that have been double
24 vaccinated. So, I don’t know what to make of that
25 data yet. It is a little bit surprising, but that’s
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1 the actual data that I’ve seen but not yet published.
2 We’re going to actually publish the data because we
3 think its very important.
4 507 Q. So, just on that point, the data is not publicly
5 available yet?
6 A. Not published yet, no. And this is, you know, even a
7 lot of my antibody studies has not yet been formally
8 published because we want to make sure that we’re

9 doing everything properly and it’s very comprehensive
10 studies. So, I’m only talking about the results of
11 our study because I’ve been asked.
12 507a Q. Sorry, you’ve been asked by who?
13 A. By - by, first of all people that are involved in the
14 Canadian Covid Care Alliance, so I’ve presented the
15 data there, and occasionally if I’m asked to give a
16 talk or - or if I’ve been interviewed about my study,
17 a clinical trial that I’ve expressed some of the
18 results, but I’ve certainly been made - made it
19 available to anyone who wants to see it. So, I have a
20 lot of data. And in fact I’ve been putting them in
21 the affidavits.
22 Unfortunately the affidavit that I provided for
23 this particular case doesn’t actually present the
24 data. I just discuss it. Subsequent affidavits that
25 I’ve been doing I actually put the data in the
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1 affidavits. And I can certainly happy to provide you
2 with that if you so desire.
3 508 Q. No, I think your explanation is fulsome, thank you. I
4 just want to get back, if I can, to - to - to spike
5 proteins and - and - and vaccines. So, my - my next
6 question is as follows. Do you agree that the spike
7 protein has to change shape I order for the virus to
8 find to the ACE2 receptor? What I’m...

9 A. No, I disagree. No,, and - and I - I’ve tried to
10 really investigate this in the literature, and as far
11 as I can tell, we know for sure that there is two
12 states - two basic states of the receptor - a - a
13 prefusion state and a post fusion state. And the
14 difference between the two is that I believe that the
15 receptor binding domain... First of all the - the
16 spike protein is actually a trimer, it’s three copies
17 that are bundled together and on the top part, the
18 part that’s kind of sticking on the spike, that’s
19 where your receptor binding domains are. And so for
20 the three of them there’s - there’s - I’ve seen expert
21 crystographic (sic) data of where there’s two of the
22 domains down and one up, but most of the trend I’m
23 seeing is crystal structures where it’s either all
24 three domains are sticking up, or they’re all three
25 sticking down, and in the virus it seems to oscillate
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1 between those two states. On the surface of cells
2 I’ve not seen any data in this regard, but at least
3 the data that I have seen it would appear as though at
4 least one, and probably three of them at some point in
5 time, in the prefusion state are actually exposed and
6 accessible. And so I see no reason why it shouldn’t
7 be able to bind to the receptor.
8 The distinction is that once you get that binding

9 it triggers a conformational change that can occur
10 which puts it into the - the fusion state so it’s now
11 able to attract a protease that’s there that together
12 they will allow that protein to now pull the virus
13 into the cell. So, I see no reason at this stage for
14 the data that I’ve seen that the actual engagement of
15 the receptor still occurs even in the prefusion state.
16 And the vaccine is engineered with a double proline
17 mutation to lock it in that prefusion state. So that
18 much we know for sure that you’re not going to have
19 the entry of the virus into the cell, but I see no
20 data that says from the literature that I’ve read
21 through, and I really wanted to know the answer to
22 this question, that the engagement of the receptor
23 itself with ACE2 is blocked.
24 509 Q. So, I just heard you say, and I’m asking you to
25 confirm...
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1 A. Right.
2 510 Q. ...that the mRNA vaccine - you used the word locked...
3 A. Yeah.
4 511 Q. ...but is it fair to say it - it locks it in - in the
5 - in the - in the closed formation?
6 A. Three piece... No. No, it can be open. It can be
7 open, but it can’t - it can’t fuse. It can’t undergo
8 a second conformation that allows the fusion of the

9 virus with that spike protein detached to get inside
10 the cells. There’s many more steps that are required
11 after that. And so that locking of that
12 conformational change means it can’t get inside the
13 cell. But as far as I can tell it can still attach to
14 the cell via the ACE2 receptor.
15 512 Q. So, because this is somewhat important...
16 A. Yes.
17 513 Q. ...and I want to make sure that I’m not putting words
18 into your mouth...
19 A. Right.
20 514 Q. ...and that I’m understanding what you’re telling me
21 is...
22 A. Hm..mm.
23 515 Q. ...that, number one, that - that it could be in the -
24 what I’ll call open or closed conformation state, but
25 that regardless of that...
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1 A. Right.
2 516 Q. ...the vaccine, it - it’s - it cannot get into the
3 cell itself, is that fair?
4 A. Right. Yes, so there’s a distinction between open and
5 closed. When we say open and closed we’re talking
6 about the exposure, the receptor bindaments. That’s
7 independent, as far as I can tell from the literature,
8 from the effect of the proline residues to prevent the

9 fusion stage, which requires a protease to - to
10 interact and allow to facilitate that kind of binding
11 of the membrane of the virus with the membrane of the
12 target cell that - that presents the ACE2 receptor.
13 517 Q. Is it fair - scratch that. So, do you agree that the
14 spike protein produced by the mRNA vaccine cannot bind
15 to the ACE2 receptor?
16 A. No, I don’t see why it couldn’t.
17 518 Q. Are you aware that the spike protein encoded by the
18 mRNA vaccines...
19 A. Hm..mm.
20 519 Q. ...are permanently in the closed position so that the
21 spike protein that is produced cannot bind to the
22 ACE...to a receptor?
23 A. I’ve seen no data to support that conclusion. I only
24 know that you cannot have the conversion to the post
25 fusion state so that it can actually get - the virus
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1 can get inside. I see no reason from the crystal data
2 that’s been presented that I could - I’ve seen in
3 journals that the receptor bind domain is accessible.
4 520 Q. And when I use the term “closed”, just so that we can
5 finish the terminology here...
6 A. Hm..mm.
7 521 Q. ...when I say closed you mean - are we agreed that
8 that’s a reference to prefusion?

9 A. I - I’m not sure what is - is being referred to here
10 because closed confirmation - this - this term has
11 been used but I don’t know where they’re getting this
12 kind of statement that the spike protein in that form
13 can’t interact with the receptor. I - I don’t see why
14 it wouldn’t from the 3-D structure of that form that
15 would be a pre...and - and there is structure
16 available of the mutative form that’s with the virus
17 protein, like the spike protein and the mRNA. And -
18 and those structures you can clearly see, at least in
19 some of them, I’ve read it could all three receptor
20 bind domains are exposed, but the worst I’ve seen is
21 that it’s - it’s one that’s exposed and two that are
22 down.
23 522 Q. Okay, and just to round this out, your comments just
24 now are based on the data that you have seen, correct?
25 A. That’s correct. In the crystographic data, yeah.
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1 523 Q. Does that data include the data published by Pfizer
2 and Moderna and the analysis of that data from Health
3 Canada and the USFDA?
4 A. I’m not sure of the answer to that question because
5 when I looked at it, I have to admit I looked at it
6 from the standpoint I was more interested in the
7 structure and less of who the authors were and which
8 companies that they were representing. But I wouldn’t

9 - I wouldn’t be surprised if some of the authors
10 weren’t from Pfizer or Moderna.
11 524 Q. Right. But in addition to that I also asked you if
12 you were - if your - if the data that you’re relying
13 upon also includes data from the USFDA and Health
14 Canada.
15 A. I haven’t seen that in - in the responses of the - of
16 the reports, the review of that data for - with
17 respect to that question.
18 525 Q. Okay.
19 A. There’s a few things that I’ve tried to look for but
20 frankly I just haven’t found in those documents. Now,
21 even - even how this - this vaccine works is very
22 unclear from all the data that’s been published and
23 even I think some of the expert reports that I’ve read
24 from your witnesses, I don’t think they really know
25 the answer themselves.
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1 526 Q. Well, we’ll - we’ll let your counsel ask the witnesses
2 those question, but I think that your evidence on this
3 point is clear...
4 A. Hm..mm.
5 527 Q. ...and to the extent that there’s a divergence, well
6 we’ll deal with that in a different form.
7 A. Hm..mm.
8 528 Q. I’m going to ask you to go to paragraph 43 of your

9 report, and in paragraph 43 you discuss adverse events
10 recorded in VAERS.
11 A. VAERS.
12 529 Q. V-a-e-r-s, for the record.
13 A. Right.
15 A. Yeah.
16 531 Q. Okay. So, so I’m going to share my screen with you.
17 A. Hm..mm.
18 532 Q. So, what you have in front of you, Dr. Pelech, is the
19 landing page...
20 A. Hm..mm.
21 533 Q. ...when you go to the VAERS which is...
22 A. Right.
23 534 Q. I’m just going to try to get my question out - my
24 description out. What you have in front of you is a
25 landing page for VAERS which is the vaccine adverse
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1 event reporting system. Do you have that in front of
2 you, sir?
3 A. Yes, I do.
4 535 Q. All right, when you go to the landing page there’s an
5 ability here to access the VAERS data tab.
6 A. Right.
7 536 Q. And I’m going to show you the next document, which is
8 also from the VAERS site, and it’s called to what -

9 it’s entitled “A Guide to Interpreting VAERS Data”.
10 Have you seen this before, sir?
11 A. Yes, I have. I’ve actually used the system, and I’ve
12 actually recovered data from it in the regard to
13 Covid-19 myself. I think the - I did a more recent
14 update since I did this last affidavit, but yes, I’ve
15 gone through it and I’m also familiar with how the
16 VAERS data should be used.
17 537 Q. Okay. And so I just want to draw your attention to a
18 couple of paragraphs in - on the VAERS website when it
19 speaks to guide - when it... Scratch that. I want to
20 draw your attention to a couple of references in this
21 document that first appears in the first full
22 paragraph which reads, and I quote:

23
24 “When evaluating data from VAERS, it is important
25 to note that for any reported event no cause-and-
26 effect relationship has been established.
27 Reports of all possible associations between
28 vaccines and adverse events (possible side
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1 effects) are filed in VAERS. Therefore, VAERS

2 collects data on any adverse event following
3 vaccination, be it coincidental or truly caused
4 by a vaccine. The report of an adverse event to
5 VAERS is not documentation that a vaccine caused
6 the event.”
7 Do you see that?
8 A. Yes, and I - I’ve seen it before and I understand it.
9 538 Q. And towards the bottom of that page, in the last
10 paragraph on page 2 it states:

11
12 “A report to VAERS generally does not prove that
13 the identified vaccines caused the adverse event
14 described. It only confirms that the reported
15 event occurred sometime after vaccine was given.
16 No proof that the event was caused by the vaccine
17 is required in order for VAERS to accept the
18 report. VAERS accepts all reports without
19 judging whether the event was caused by the
20 vaccine.”
21 Do you see that as well?
22 A. Yes, and I recognize that.
23 539 Q. Okay.
24 A. And it’s all those same - same thing could be said for
25 any Phase 3 clinical trial data.
26 MR. TZEMENAKIS: Mr. Wilson, I’m wondering if you would
27 consent to marking the first landing page of VAERS,
28 which is the Vaccine Adverse Event Reporting System,
29 as Exhibit Number 12?
30 MR. WILSON: Is this a live retrieval or is this -
31 was this retrieved on a different date?
32 MR. TZEMENAKIS: This was...
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1 MR. WILSON: Are we watching the website live right
2 now?
3 MR. TZEMENAKIS: We are not watching the website live,
4 but I can pull it up live. I validated this last
5 night at 11:00 p.m.
6 MR. WILSON: Okay, this is...
7 MR. TZEMENAKIS: The same information.
8 MR. WILSON: As long as the description makes it

9 clear that it’s the landing page as it was retrieved
10 on May 15th, I consent to that.
11 MR. TZEMENAKIS: Okay.
12
13 EXHIBIT 12: PDF of the first landing page of VAERS,
14 which is the Vaccine Adverse Event Reporting System,
15 captured by Mr. Tzemenakis on May 15, 2022.
16
17 MR. WILSON: My concern being that it can change
18 tomorrow or right now and I don’t want - this is
19 something obviously none of us control, or at least
20 the applicants and the witnesses certainly don’t, so I
21 think the best he can do is - we can agree that – that
22 and I’m taking your word for it, counsel. I have no
23 hesitation in doing that, that it was retrieved
24 yesterday.
25 DR. PELECH: I mean I could add some - some points
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1 about this because this - this is the website that was
2 created I guess about 30 years ago - 31 years ago, and
3 the point of it was to identify whether or not that
4 any vaccine that was going to be introduced had
5 associated post marketing information, a risk
6 associated, even down to the batch number of that
7 vaccine. So, it’s a safety system. There’s been over
8 70 vaccines that have been in this system over the

9 last 30 years, and the reports that we’re getting on
10 the Covid-19 vaccines, the three of them that are
11 available in the U.S., exceed the sum of all the other
12 reports put together with respect to safety and
13 deaths. And most of those reports are actually filed
14 by medical doctors. Anyone can file them, but - and
15 they’re also vetted internally to make sure that there
16 isn’t redundancies and they seem to be legitimate.
17 So there is a fair amount of vetting that
18 actually goes on in this website despite the fact that
19 anyone can report it. The bulk of those reports are
20 actually from doctors, and they are thought to be
21 dramatic underestimates of the actual incidents. And
22 so studies have been done as you may be aware of the
23 Harvard Pilgrim study I think looked at this, and they
24 were trying to evaluate you know what they represent.
25 And it’s very clear the numbers do vary, but people
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1 would at least multiply those numbers by at least
2 tenfold to get an accurate sense.
3 So, it’s - it’s a very valuable website. The FDA
4 has invested a lot of money into maintaining it and
5 utilizing it, so I wouldn’t discount it. And what is
6 important to do is to - you - you can’t make a
7 correlation necessarily that what you’re seeing is due
8 to the vaccine, but the closer that the events occur

9 to the point at which the person’s been vaccinated,
10 that strong temporal correlation gives you much
11 stronger sense and the number of reports that this is
12 actually a legitimate concern that’s tied to the
13 vaccine.
14 But the caveat is that there is a background that
15 where these injuries occur, and this is the reason why
16 the best data should be in a Phase 3 clinical study of
17 sufficient size, but unfortunately we don’t have that
18 kind of data, and so now we’re relying on passive
19 reporting and this is just one of the best systems
20 that’s available at this time.
21 MR. TZEMENAKIS: So, Dr. Pelech, I’m going to ask for a
22 moment that you be placed in a break out room just for
23 a minute.
24 DR. PELECH: Okay.
25 MR. TZEMENAKIS: Madam Reporter, if you wouldn’t mind?
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1 COURT REPORTER: Yeah, I’m going to try to create one
2 now.
3 MR. TZEMENAKIS: Just take a moment, Mr...Dr. Pelech for
4 the reporter to create a break out room.
5 DR. PELECH: Sure.
6 MR. TZEMENAKIS: And then she’ll bring you right back a
7 minute later.
8 DR. PELECH: Yeah, no problem.

9 MR. TZEMENAKIS: Do we have a room?
10 COURT REPORTER: I think you should have a notification
11 to join it. Do you see - okay.
12
13 (DR. PELECH PLACED IN A BREAK OUT ROOM)
14
15 MR. TZEMENAKIS: Great. So, I simply wanted to note it
16 for the record, Mr. Wilson, that that is - I did not
17 interrupt your witness, but I asked him a simple
18 question about VAERS and he went on to recount the
19 contents of paragraph 43, which in my view,
20 unfortunately, are not relevant to the answer - to -
21 to the question that I asked him. I don’t mind him
22 providing context, but at least provide context in
23 relation to the specific questions that are being
24 asked, so I didn’t ask him about the numbers of
25 adverse events. I’m going to get to it right now but
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1 this is an example of where you and I might disagree
2 as to the scope of latitude that should be afforded to
3 the witness. However, consistent with our agreement
4 I’m going to give him that latitude, but I may take a
5 firmer position in our written materials before the
6 Court.
7 MR. WILSON: That’s fine.
8 MR. TZEMENAKIS: Madam Reporter, can you please bring

9 the witness back?
10 COURT REPORTER: It just says it’ll take 60 seconds for
11 him to get back.
12 MR. TZEMENAKIS: No problem. Thank you, Madam Reporter.
13
14 (DR. PELECH RETURNS TO THE CROSS-EXAMINATION MEETING)
15
16 540 MR. TZEMENAKIS: Thank you, Dr. Pelech. So, I’m going
17 to share my screen right now...
18 A. Hm..mm.
19 541 Q. ...and I’ve going to show you the live website version
20 of the VAERS Guide to Interpreting Data.
21 A. Hm..mm.
22 MR. TZEMENAKIS: I want you to take a moment. You’ll
23 see at the first paragraph I read to you is identical
24 to the PDF version...
25 DR. PELECH: Hm..mm.
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1 MR. TZEMENAKIS: ...that I showed you earlier, and
2 you’ll also see that the last paragraph of that is
3 also identical to the version that I read to you, so,
4 Mr. Wilson, can we agree to mark the PDF version as
5 Exhibit Number 13, please?
6 MR. WILSON: And this was retrieved from the VAERS
7 website?
8 MR. TZEMENAKIS: This was retrieved from the VAERS

9 website last evening at 11:00 p.m. and I’m showing you
10 that the version on the website currently is identical
11 to the one that was retrieved last night
12 MR. WILSON: Thank you. No objection.
14
15 EXHIBIT 13: Live version of the VAERS landing page
16 to compare with the PDF captured May 15, 2022.
17
18 542 MR. TZEMENAKIS: Actually, I’ll share my screen again
19 because there’s one more exhibit that I’d like to put
20 to you. So, Dr. Pelech, you see in front of you at
21 the moment the VAERS Guide to Interpreting VAERS Data
22 webpage, correct?
23 A. Hm..mm.
24 543 Q. Sorry, you have to say yes or no, sir.
25 A. Yes.
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1 544 Q. All right. And if we click on VAERS datasets...
2 A. Hm..mm.
3 545 Q. ...it takes you to a webpage entitled “VAERS Data”.
4 Do you see that?
5 A. Yeah.
6 546 Q. And the way you search the data is by clicking on the
7 toggle identified as “Search CDC Wonder”.
8 A. Right.
9 547 Q. And you’ve...
10 A. You have to do a - also an agreement...
11 548 Q. Yeah.
12 A. ...with it.
13 549 Q. But you - you’ve used this before, correct?
14 A. Yes.
15 550 Q. All right, so...
16 A. It’s been a while, but - but I did...yeah?
17 551 Q. So, when I click on that button a disclaimer comes up.
18 A. That’s right.
19 552 Q. Right. And I just want to draw your attention to the
20 second full paragraph of that disclaimer that reads as
21 follows:
22
23 “VAERS reports may contain information that is
24 incomplete, inaccurate, coincidental, or
25 unverifiable. Reports to VAERS can also be
26 biased. As a result there are limitations on how
27 the data can be used scientifically. Data from
28 VAERS reports should always be interpreted with
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1 these limitations in mind.”

2 Have you seen the disclaimer before?
3 A. Yes, I have.
4 MR. TZEMENAKIS: And... Okay. The - counsel, we’re to
5 going to - offline, take a screenshot of this
6 disclaimer. We’ll send that to you, and would like to
7 have it marked as the next exhibit, which is going to
8 be number 14.
10
11 EXHIBIT 14: Screenshot of disclaimer page of the
12 VAERS website.
13
14 553 MR. TZEMENAKIS: I’ll stop sharing my screen. Just bear
15 with me. So, in paragraph 43 you comment on the fact
16 that there were 122,833 serious adverse events
17 recorded in relation to the Covid-19 vaccines,
18 correct?
19 A. Right at the end of October 2021.
20 554 Q. Right. Do you know how many doses had been
21 administered by that point?
22 A. No, not off hand.
23 555 Q. So, you’re going to be with me, sir...
24 A. I would expect certain several hundreds of thousands.
25 Well, hundreds of - probably millions of doses. At
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1 this point in time there’s been over a billion doses
2 given.
3 556 Q. So, I’m going to share my screen with you again.
4 A. Hm..mm. And data’s for U.S. specifically. VAERS
5 actually covers more than that, but those are the U.S.
6 numbers.
7 557 Q. Correct. So, I’m going to share my screen with you...
8 A. Hm..mm.
9 558 Q. ...and what you see on the screen - I’ll try to make
10 it a little bit bigger...
11 A. Hm..mm.
12 559 Q. ...is an excerpt - an excerpt from PAHO, which is the
13 Pan-American Health Organization. Have you seen this
14 website before, sir?
15 A. No, I haven’t seen this particular website.
16 560 Q. Okay. So, we might need to mark this exhibit for
17 identification purposes, but this website gathers data
18 from around the world, and if you pick the tab
19 identified as Country/Territory Details...
20 A. Hm..mm.
21 561 Q. ...it takes you to the United States of America.
22 A. Hm..mm.
24 A. Yeah.
25 563 Q. And there’s a graph on the bottom of the page that
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1 talks about the number of first doses, second doses,
2 single dose, first additional dose, second additional
3 dose, et cetera.
4 A. Hm..mm.
6 A. Yes
7 565 Q. And week 43, so 2021, week 43 corresponds to the last
8 week of October...
9 A. Hm..mm.
10 566 Q. ...in 2021, and if you click on - anywhere in that
11 graph you’ll see that a textbox opens up...
12 A. Right.
13 567 Q. ...and it states that the total number of doses
14 administered is 424,089,661.
15 A. Hm..mm.
16 568 Q. So, from a contextual perspective is it fair to say
17 that the 122,833 reports of serious adverse events
18 needs to be contextualized to the total number of
19 doses administered which, according to this website,
20 is 424,089,661. Is that a fair statement?
21 A. Well, it needs to be contextualized, and I agree with
22 that, and so I - when I do this I look at the number
23 of deaths that have happened in the U.S. that have
24 been linked, granted that these are associations. It
25 doesn’t mean it’s causal, but recognizing that the
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1 number of actual events that are probably being
2 underrepresented here could be as much as 40 times,
3 which is a number that - a number of people have done
4 studies on this, and you take the number of deaths and
5 you multiply that by 40, and we’re talking about
6 hundreds of thousands of deaths that have had some
7 potential linkage with the Covid-19 vaccines.
8 If we’re looking about a million deaths in the

9 U.S. due to Covid itself, having a number that’s in -
10 almost within the same magnitude - is very
11 disconcerting.
12 569 Q. Okay. But that number, again, would have to be -
13 there - that evidence would have to be put before the
14 Court in order for the Court to have a context...of a
15 contextual picture. I’m not - I don’t know the answer
16 to your question...
17 A. right.
18 570 Q. ...all I’m saying to you is that - that number is
19 based on - what I hear you to be saying is that the
20 number is based on multiplying the VAERS numbers by
21 40.
22 A. Right. Now, I agree that when it comes to death,
23 probably there is going to be a higher rate of
24 reporting than it would be a - an injury that’s less
25 severe, but also to put it into context, if you - if
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1 you look at actual reporting of vaccine injury in the
2 Pfizer Phase 3 clinical trial, 5% of those people had
3 serious adverse events as - as described on the Pfizer
4 clinical trial itself.
5 However, if you look at the VAERS reporting data,
6 it’s a fraction of a percent as you have acknowledged
7 here that for the number of vaccines administered, and
8 the number of reports that have been made, it seems

9 like - like it’s just a tiny fraction of a percent.
10 Yet in a clinical trial, which should be the best
11 evidence that we can have, it’s 5%.
12 571 Q. But it’s - is it...do you know...
13 A. We should see 5% on the VAERS system of serious
14 in...we should see 5% of serious injury on the VAERS
15 system if it reflects what the Phase 3 clinical trial
16 data has shown us. And 70% of actual adverse effects,
17 most of them mild, but when you take a look at your
18 placebo control, you have a 75% increase in the Pfizer
19 trial where you actually have a control group to
20 compare it to with vaccine injury that’s serious.
21 572 Q. Dr. Pelech, if you’ll permit me...
22 A. Hm..mm.
23 573 Q. ...you’re not talking about the Phase 3 clinical
24 Pfizer trials in paragraph 43. You’re talking
25 about...
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1 A. No, I’m not doing...
2 574 Q. ...you’re not...
3 A. ...I’m trying - I’m trying to - sorry.
4 575 Q. Sorry, I - I appreciate you’re trying to provide some
5 context...
6 A. Right.
7 576 Q. ...from something else, and all I was trying to
8 accomplish was simply to contextualize the data for

9 the Court. And - and by comparing it to the
10 information that’s available in terms of adverse
11 events and total number of doses administered, and I
12 heard you to say, and please correct me if I’m wrong,
13 that yes, total number of doses is a factor to
14 contextualize, but there are others..
15 A. Hm..mm.
16 577 Q. ...is that fair?
17 A. Yes, that’s fair. And I...
18 578 Q. Okay.
19 A. ...I only brought up the Phase 3 clinical trial
20 because that gives you a sense of what kind of vaccine
21 injury you might expect to see in reality in a
22 controlled situation. So, when you look at the VAERS
23 data you have to figure out what should you have seen
24 based on the clinical trial data which is much more
25 reliable. And I think we both agree.
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1 579 Q. I - I’m not in a position to express an expert opinion
2 on that. That’s why beyond my competency level.
3 A. Hm..mm.
4 MR. TZEMENAKIS: But what I will say is - to your
5 counsel is - counsel, we’re going to take a snapshot
6 of the... So, first of all this document is entitled
7 - is from the Pan American Health Organization for the
8 United States of America - we’re going to take a

9 snapshot of the data that appears for 2021-43 which
10 corresponds to the last week of October, a web capture
11 as it appears on your screen, and I’d like to mark
12 that as the next exhibit.
13 MR. WILSON: I have no objection.
15
16 EXHIBIT 15: Screenshot of the data for 2021-43 from
17 the Pan American Health Organization for the United
18 States of America.
19
20 580 MR. TZEMENAKIS: So, I want to jump, if I can, to a
21 discussion about natural immunity add vaccine-induced
22 immunity.
23 A. Hm..mm.
24 581 Q. And start with some general questions, Dr. Pelech. Is
25 it fair to say that there is considerable debate in
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1 the literature as to the role of a previous Covid-19
2 infection in providing protective immunity?
3 A. If you’re talking about the scientific literature,
4 yes, those papers, I would say it’s - it’s - there’s
5 probably more of a consensus that natural immunity
6 works really well. In terms of messaging coming from
7 Public Health and mainstream media, I - you get the
8 opposite message.
9 582 Q. And do you agree that this - what I call debate and
10 you call consensus...
11 A. Hm..mm.
12 583 Q. ...is impacted by a number of factors such as what we
13 discussed earlier, for example age, do you agree with
14 that?
15 A. It turns out that younger people don’t make antibodies
16 as - as effectively, and this is quite evident even
17 with the vaccine trials that have been done from 5 to
18 11 years olds, so there’s clearly some evidence there
19 that a very young age don’t make antibodies as
20 efficiently.
21 However, there are good antibody production in
22 elderly people. They do make antibodies. This is one
23 of the reasons why the vaccine itself has some
24 efficacy in elderly people as well.
25 584 Q. So, the proposition I put to you that age is a factor
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1 that affects the degree of natural immunity, is...
2 A. It’s a parameter, yeah.
3 585 Q. Is a parameter. And similarly so is comorbidities,
4 correct?
5 A. Yes...
6 586 Q So is a...
7 A. ...if you’re compromised especially.
8 587 Q. And so is the severity of infection?

9 A. Interestingly, it’s not a - apparently from the
10 literature there’s not a good correlation between the
11 symptomatic nature of a Covid infection whether
12 someone’s asymptomatic or symptomatic or very sick. I
13 would’ve expected to see higher antibody levels, but
14 that doesn’t seem to be what the data is showing.
15 588 Q. But is it - is it fair to say that, just to round this
16 out, that underlying health conditions, whatever they
17 might be, autoimmune issues, et cetera, can also lead
18 to different immune responses which generated a
19 different level of natural immunity?
20 A. Oh, yes, because - because when you have - appear
21 immune compromised, you know, unless it’s something
22 like AIDS where you’re taking out the T-helper cell
23 that the virus actually attacks the T-helper cell, it
24 compromised most of your immune system. But in many
25 other types of immunity it may be one - one portion of
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1 your immune system which is compromised.
2 589 Q. All right. I’m going to take you to paragraph 57, and
3 we - we talked about this a moment ago at the
4 beginning of your examination, and it’s - it’s a...
5 A. Hm..mm.
6 590 Q. ...it’s a - in this paragraph you reference a study
7 performed by Ichor Blood Services...
8 A. Right.
9 591 Q. ...in Alberta that showed that about 51% of serum
10 samples from unvaccinated people that they have tested
11 have detectable spike and nucleal capsid antibodies
12 that are comparable to those that are found in PCR
13 confirmed Covid cases.
14 A. Right.
16 A. Yes.
17 593 Q. And the reference to that is footnote 54, which is a
18 personal communication.
20 MR. TZEMENAKIS: Right. And question to your counsel,
21 would you undertake to - if it exists in writing - to
22 produce that personal communication?
23 DR. PELECH: I can certainly provide my email
24 correspondence to you with - with the president of
25 that company, and unfortunately in that correspondence
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1 he doesn’t have the data in it, and I’ve been trying
2 to search my computer when I originally prepared this
3 document, to actually provide that because he gave me
4 permission to - to present it. But if in fact this
5 work has been available somewhere else, I’d love to
6 get that reference myself. But I can certainly
7 provide you with my correspondence.
8 MR. TZEMENAKIS: So, let me ask two questions of your

9 counsel and then I’m going to let him tell me what
10 he’d like to do, so first is can I get a copy of the
11 email correspondence that’s just referred to by the
12 deponent with the president of Ichor Blood Services?
13 And second, to the extent that Ichor Blood Services
14 has provided the deponent with the data...
16 MR. TZEMENAKIS: ...that to support this statement, can
17 we please get a copy of that data?
18 MR. WILSON: I have no concerns with those
19 undertakings. We’ll - we’ll do that.
20 DR. PELECH: Yeah, I’ll endeavour to look - work a
21 little harder and find it.
22
23 UNDERTAKING 1: Produce the personal communication, if
24 it exists in writing, from the president of Ichor
25 Blood Services.
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1 UNDERTAKING 2: Produce a copy of the data provided by
2 the president of Ichor Blood Services.
4 594 MR. TZEMENAKIS: Thank you. I’m going to direct your
5 attention to paragraphs 58 to 61, and here in these
6 paragraphs you talk about the Kinexus study that we
7 spoke about earlier today.
8 A. Hm..mm.
9 595 Q. And apologies, Dr. Pelech, you’re going to have to say
10 yes or no for the record, okay?
11 A. Yes.
12 596 Q. And I’m going to direct your attention to paragraph
13 61. And in paragraph 61 in bold you state:

14
15 “In fact we have now been able to show that the
16 presence of multiple antibodies against the SARS-
17 CoV-2 protein are clearly evident in people at
18 least 22 months after their initial infection
19 with SARS-CoV-2, which demonstrates the
20 establishment of lasting immune memory.”
21 Do you see that statement, sir?
22 A. Yes.
23 597 Q. Yes. Can you tell me how many people of the sample of
24 3,000 had the presence of multiple antibodies against
25 the SARS-CoV-2 protein 22 months after their initial
26 infection?
27 A. The original one where we went for about just short of
28 12 months was 100 people, and for the 22 months we’re
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1 going back now to probably around 60 people. We -
2 we’re going to the stages now of going back to many of
3 the people who had been in our trial with the second
4 phase to reinvite them to submit their blood sample.
5 So, I hope to have more data on that with more people.
6 But - but clearly with staff that had antibodies we -
7 we’ve been able to retest them and they clearly have
8 antibodies, including myself.

9 598 Q. Okay. And thank you for that. And is it the case
10 that the 60 people...
11 A. Hm..mm.
12 599 Q. ...who had antibodies present 22 months later...
13 A. Hm..mm.
14 600 Q. ...had it all at the same level, or was it like you
15 said earlier - sorry, this is not a very good
16 question. Let me try that again.
17 A. I get what you’re saying.
18 601 Q. Is it the case that the 60 people had the same level
19 of antibodies, or did it vary amongst that group?
20 A. Well, what’s happened is in some cases these are
21 individuals who tested PCR positive. We hadn’t
22 necessarily tested them in a - in a few cases, but
23 they were PCR positive and they had their symptoms and
24 we tested them two years later. And then there's
25 other cases where we had tested them early on and have
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1 the data afterwards.
2 The interesting thing with this study with the
3 100 people with the 12 months is that the pattern was
4 exactly the same when these people retested a year
5 later and the intensity of the spots was pretty much
6 the same, too. And I can certainly provide
7 documentation of this. And the interesting thing is
8 that I was surprised when I saw the data until I

9 thought about it and I recognized that, well, this is
10 what would happen if an individual had Covid,
11 developed antibody response, and then got re-exposed
12 to it on a regular basis, which is exactly what’s
13 happening with the pandemic. So, in retrospect I’m
14 actually not surprised by the data. I’m not surprised
15 by the data because studies have been done with SARS-
16 CoV 1 back, you know, seventeen years ago, and they
17 followed up on those people that had natural immunity,
18 and they could show even three years later they still
19 had antibodies. And the same phenomenon was observed
20 with MERS where people have made - had an immune
21 response and, again, up to three years later they can
22 still detect antibodies in the serum, and also
23 protection - T-cell immunity protection. So this is
24 not surprising data.
25 602 Q. So, apologies, so if I’ve - if I’ve misunderstood, but
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1 I’m not sure I heard you answer whether or not in the
2 group of 60...
3 A. Hm..mm.
4 603 Q. ...who showed antibodies after 22 month...
5 A. Right.
6 604 Q. ...the level of antibodies was the same, or did it
7 vary amongst that group?
8 A. So - so, the answer to that question is for some of

9 that 60 we don’t have a measurement right after they
10 had Covid, but only two years later. Others we do
11 have an initial measurement and two years later, and
12 the intensity for the ones that we have measures,
13 they’re exactly the same. And for the ones where we
14 don’t have initial measures they’re actually quite
15 similar to in terms of what we see with people with
16 Covid in general that have been more recent.
17 605 Q. And would you agree with me...
18 A. Hm..mm.
19 606 Q. ...that the explanation that you just provided, so,
20 i.e. that for some you had measures, for some you
21 didn’t, and for the 100 after 12 months it was
22 consistent amongst that group that that is not
23 reflected in your expert report.
24 A. Yeah, well, then I probably should’ve expanded on that
25 more, and so that’s - that’s my error. But I do
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1 certainly have the data and that’s what our
2 observations are. And - and it makes a lot of sense.
3 607 Q. And in your professional opinion was the presence of
4 antibodies in the 60 people...
5 A. Hm..mm.
6 608 Q. ...after 22 months sufficient to prevent infection?
7 A. No. I - we - I can’t answer that question. I
8 certainly know people that we have detected antibodies

9 in the past from two years ago did get Omicron
10 infections, so none of them got very sick to - no
11 severe illness, but they did get sick.
12 609 Q. Okay, and...
13 A. And quite - quite common.
14 610 Q. Okay. And just to - to round out the - the reference
15 to 60 and 100...
16 A. Hm..mm.
17 611 Q. ...I - I assume, so correct me if I’m wrong...
18 A. Hm..mm.
19 612 Q. ...that it varied between participants. So, you’re
20 not - you’re not retesting the same participant.
21 A. Oh, no, that - that 60 that - that had, like, for the
22 12 months, that was the same participant tested for
23 that - for the 60 where it was for, you know, just
24 un...just about a year. For - for the ones that we
25 tested that was, like, over a two year period, that’s
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1 a more variable group. Some of them we have initial
2 measurements and other ones we don’t. But when we
3 look at the ones where they had Covid, they - they
4 recovered, they were PCR confirmed, two years later we
5 can still see antibodies that they have in their
6 serum.
7 613 Q. So, the last question I have to - before I move on to
8 paragraph 63 is, am I correct that there were

9 differences in the levels of antibodies between
10 participants? So, Participant X could’ve had one
11 amount of antibodies, and Participant Y could’ve had a
12 different amount of antibodies, it wasn’t the case
13 that everybody had the same number?
15 614 Q. Okay.
16 A. And - and I guess I should explain that when we
17 originally developed this test we actually did all of
18 the proteins in the virus, and we made portions that
19 overlapped slightly by two amino acids. So the spike
20 protein’s about 1,273 amino acids, so we actually made
21 hundreds and hundreds of staggering pieces of that.
22 And after we’d initially tested a number of people
23 that were confirmed Covid cases, we - we found the
24 ones that were the most positive in terms of
25 reactivity that people had antibodies against those
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1 portions, and we tried to find the ones that was most
2 common. But what we observed is that when we narrow
3 it down to the smaller test that we have, we’re
4 actually excluding many other possibilities that in
5 certain individuals could’ve been super strong and we
6 just didn’t test for it. So, we’re trying to optimize
7 with our test with 41 markers, the one that we did
8 about 3,000 people, we’re - we’re trying to find

9 something that’s more likely to catch an antibody
10 event. So, the patterns are different. Some people
11 have a lot of weaker spots, but a lot of them. Other
12 people have some super strong spots but not as many of
13 them. So, it’s a very different response from person
14 to person, but it’s a stable response that - that is
15 consistent with that person even tested a year later.
16 615 Q. Thank you for that further explanation. I’m going to
17 move to paragraph 63.
18 A. Hm..mm.
19 616 Q. And what I’m - what I’m going to do is I’m going to
20 ask my questions on this paragraph and then I’m going
21 to stop and take a break. I know its getting darker
22 where I am because we’re in the middle of a massive
23 thunderstorm so hopefully won’t lose any power.
24 A. Well, like yesterday.
25 617 Q. But that’s not on me. I’m not purposely darkening
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1 things. So, let me set the foundation for this. So,
2 at paragraph 63 you state that,

3
4 “Therefore antibodies made against the original
5 Wuhan strain of the virus should and do work
6 almost equally as well against any of the
7 variants and vice-versa. Such observations have
8 been recently confirmed in studies with monkeys
9 boosted with RNA for the spike protein of the
10 Wuhan and Omicron variant of SARS-CoV-2.”
11 Do you see that?
12 A. Right. Yeah.
13 618 Q. And...
14 A. Yes.
15 619 Q. ...the study in question that you rely upon is at
16 footnote number 57.
17 A. Hm..mm. Yes.
18 620 Q. Yes. So, for your counsel’s benefit I will tell you
19 that when you click on the link to footnote 57,
20 sometimes you get the study, sometimes you don’t.
21 A. Oh, no.
22 MR. TZEMENAKIS: So, I am going to put the study up on

23 my screen, and you’re actually going to see that it is
24 the exact same reference that you have in your
25 footnote. I just want to share that with your counsel
26 so that he’s aware.
27 So, you’ll see, sir, that I’ve just put up a
28 document in front of you, and it starts of with
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1 “BioRxiv preprint,” and then it says “doi:” and then
2 it gives you an https website which is the same as
3 that that appears at paragraph - at footnote 57 of
4 paragraph 63.
5 MR. WILSON: Agreed.
6 621 MR. TZEMENAKIS: Okay. So, so my first question to you,
7 Dr. Pelech, is am I correct the study involved monkeys
8 vaccinated with a spike protein from the Wuhan strain

9 and then moneys vaccinated with a spike protein from
10 both the Wuhan and the Omicron strains?
11 A. Yeah, well, you’re kind of right. I mean it’s the RNA
12 which is the instructions to make those proteins,
13 either the original Wuhan protein version, or the
14 Omicron version. And so you have two separate
15 vaccines that were created. They’re identical except
16 the RNA that’s in them one specifies the Wuhan spike,
17 and the other one specifies the Omicron spike.
18 622 Q. Okay.
19 A. And then that’s what we’re using to see how well they
20 work in immunized monkeys against SARS-CoV-2.
21 623 Q. So, I’m glad to say that we have the same
22 understanding but you put it more eloquently than I
23 did. My - my second question is, am I correct that
24 the study found that the vaccine that was from both
25 the Wuhan and Omicron variant did not produce more
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1 antibodies than the original Wuhan strain?
2 A. That’s correct. It worked equally well. The - the
3 one against the Wuhan strain on the Omicron infection
4 of the - the monkeys. It was the Omicron virus they
5 used.
6 624 Q. Okay. Am I also correct then that the study found
7 that both strains, Wuhan and Wuhan and Omicron,
8 produced fewer antibodies against Omicron than against

9 the original Wuhan variant, but the original Wuhan
10 Covid-19 ...
11 A. I don’t recall that. I thought it was actually pretty
12 equivalent when it came down to it. I guess I’ll have
13 to go back to the paper, but my recollection is that
14 there was not much of a difference.
15 625 Q. Okay.
16 A. And it’s not surprising, frankly. And - and, by the
17 way, similar data has been recently reported by
18 others. It doesn’t really look like it makes much
19 difference to us the RNA, and that explains why the -
20 the vaccines against the original Wuhans work well on
21 Omicron. If you were to test the - the vaccine now
22 against the original Wuhan strain you’d get probably
23 the same results that you get with the Omicron. It
24 just doesn’t seem to establish immune memory.
25 MR. TZEMENAKIS: So, I’m - I’m in your hands here...
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2 MR. TZEMENAKIS: ...and I’m going to direct this
3 question to Mr. Wilson. So, Mr. Wilson, I am happy to
4 take a break and ask Dr. Pelech to review the study...
6 MR. TZEMENAKIS: ...and - and to identify where in the
7 study the authors conclude that the antibodies made
8 against the original Wuhan strain of the virus should

9 and do work almost equally as well against any of the
10 variants, and vice-versa. Or from an efficiency
11 perspective I’m also happy to have you take that as an
12 undertaking, for him to tell me if it appears in the
13 study and to point me in the right direction as to
14 where in the study I find that support for that
15 conclusion.
16 MR. WILSON: Given the compressed and extensive
17 cross-examination schedule with a large number of
18 witnesses, I’d prefer the undertaking just for
19 efficiency’s sake to allow you to cover as much ground
20 today as you can, counsel.
21 MR. TZEMENAKIS: Yeah, thank you, Mr. Wilson, and I’m
22 going to endeavour to finish today. That’s going to
23 be my goal.
24
25 UNDERTAKING 3: Identify where in the study from
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1 paragraph 63, footnote 57 of the study, the authors
2 conclude that the antibodies made against the original
3 Wuhan strain of the virus should and do work almost
4 equally as well against any of the variants, and vice-
5 versa.
7 626 MR. TZEMENAKIS: My last comment - excuse me, question
8 to you, Dr. Pelech, am I correct that this study is

9 preprint, which means it has not been certified by a
10 peer review yet?
11 A. It’s interesting your choice of words of certified.
12 627 Q. I’m just reading what it says. Apologies for
13 interrupting you, but it says, “The copyright
14 holder...”
15 A. Yeah.
16 628 Q. “...for this preprint, which was not certified by peer
17 review, is the author/funder.”
18 A. Right. Anything that appears in - in by bioRxiv, and
19 also metRxiv (ph) can be submitted by the author
20 without peer review. There is opportunity for
21 comments to be made to the publication, but the -
22 ultimately it’ll have to be submitted to a journal,
23 will be reviewed by typically two, maybe three, other
24 scientists that are considered experts in that field.
25 So, it hasn’t gone through that peer review yet. Most
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1 of these publications in SARS-CoV-2, they - they get
2 published this way first because it could take up to a
3 year to get a paper published. Just - sometimes its
4 very fast, but in the interests of advancing the
5 scientific field most people publish their results
6 prior to publication in this area this way. And so we
7 have to judge it based on the confidence that we have
8 in the authors and their - and their expertise if we

9 recognize them, and then what methods they used,
10 whether they sound - sound methods that would be
11 appropriate, the results that they get, making sure
12 that all the controls are there. And then that the
13 conclusions from those results are justified by those
14 results and properly discussed in terms of the
15 caveats. So, we would act as individual reviewers of
16 the paper just as would reviewers from a journal if
17 you have expertise in this area. So, it’s much more
18 incumbent upon the viewer to be very critical, and we
19 don’t have the advantage at this point of having it
20 vetted by an independent party yet, so that’s the
21 difference.
22 629 Q. Okay. And you reviewed this report for the purposes
23 of including it as a reference in paragraph 63,
24 correct?
25 A. No, actually, I was interested in this subject. It’s
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1 a - it’s of great interest to people because for quite
2 some time now, about two years, we’ve been hearing
3 that - that with these new variants that are emerging,
4 certainly when I think it was the - even when the
5 Alpha variant was becoming the predominant one and
6 displacing the Wuhan version, the plan was to
7 actually... Pfizer talked about this, as did Moderna,
8 that they were going to come up with a vaccine that

9 was based on the Alpha strain. And then we heard they
10 were going to do one on the Delta strain, but we never
11 had any data available to see how it worked. And so
12 finally with Omicron, you know, research was done and
13 they did the experiment and surprisingly it doesn’t
14 seem to make much difference. There were - 97% of the
15 structure of the spike protein in the Omicron is
16 identical to the Wuhan spike protein. So, there are
17 some regions where they’re a little bit different, and
18 that’s what we talked about the receptor binding to
19 may - that there’s a few mutations in there that might
20 affect the ability of the virus, as it turns out with
21 Omicron to bind a little tighter, but apart from that
22 from immunogenic standpoint of all the different
23 places where the body might recognize that to make
24 antibodies, they’re 90...97% identical. The - 97% of
25 response is actually going to be working just as well
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1 on both versions. And - and that’s basically what
2 this paper demonstrates.
3 630 Q. So, my - my - my questions were simply going to be did
4 you review it, and my second question was based on
5 your comments about peer review, do you have
6 confidence in it, and I think the answer to that is...
7 A. It is.
8 631 Q. ...yes you have confidence in it.

9 A I do.
10 632 Q. All right. I’m going to take you to the very first
11 full paragraph of this report, which is now up on your
12 screen.
13 A. Right.
14 633 Q. The very first...
15 A. Abstract. The summary.
16 634 Q. ...it says summary.
17 A. Hm..mm.
18 635 Q. And I’m going to read this into the record. “SARS-
19 CoV-2 Omicron is highly transmissible...” That’s not
20 where I want to go, excuse me. I want to make sure
21 I’m in the right place. Here I am. I’m actually
22 taking you to Introduction.
23 A. Hm..mm.
24 636 Q. Starting on page 3, and it reads as follows:
25 “The Covid-19 mRNA vaccines BNT162b2...”
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1 It’s a reference to Pfizer...
2 “...and mRNA-1273...”
3 ...which is a reference to Moderna...

4
5 “...provide highly effective protection against
6 symptomatic and severe infection with ancestral
7 SARS-CoV-2.”
8 A. That’s the Wuhan strain.
9 637 Q. More rec...excuse me?

10 A. That’d be the Wuhan strain.
11 638 Q. Right.
12
13 “More recently, more protective efficacy has
14 declined due to both waning vaccine-elicited
15 immunity and antigenic shifts in variants of
16 concern including Beta, Delta...”
17 Leaving out some of the citations to the other
18 authors...
19 A. Right.
20 639 Q.
21 “Importantly, the introduction of a boost after
22 the initial vaccine regime enhances immunity and
23 vaccine efficacy against symptomatic disease,
24 hospitalization and death across a broad range of
25 age groups. However, the timing and selection of
26 boost is a major scientific and clinical
27 challenge during this evolving pandemic in which
28 emerging variants of concern have distinctive
29 patters of transmission and virulence and against
30 which vaccine-elicited antibody neutralization is
31 reduced.”
32 A. Right. And I would point out that when they’re saying
33 neutralization they’re talking specifically about the
34 ability of the antibodies to block the binding of ACE2
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1 to its - the spike protein to the ACE2 receptor.
2 640 Q. Okay. With that caveat do you agree with these
3 statements that are in this report that I’ve just read
4 to you?
5 A. Well, this is certainly what most people suggest is
6 true in the field. It sounds reasonable to me, yes.
7 Is there a lot of - these are questions that we’re
8 trying to answer, and - and the authors are -

9 obviously put a lot of work into this to try to
10 address that question.
11 641 Q. All right, so, thank you, Dr. Pelech.
12 MR. TZEMENAKIS: Mr. Wilson, can we agree to mark this
13 study entitled ”mRNA-1273 or mRNA-Omicron boost in
14 vaccinated macaques elicits comparable B cell
15 expansion, neutralizing antibodies and protection
16 against Omicron,” which is referred to at footnote 57
17 of paragraph 63 as the next exhibit, being number 16,
18 please?
21
22 EXHIBIT 16: Study entitled ”mRNA-1273 or mRNA-Omicron
23 boost in vaccinated macaques elicits comparable B cell
24 expansion, neutralizing antibodies and protection
25 against Omicron,” which is referred to at footnote 57
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1 of paragraph 63.
3 MR. TZEMENAKIS: So, it’s four o’clock Eastern, three
4 o’clock Central. I’m going to take a 15 minute break.
6 MR. TZEMENAKIS: And I’m going to try to try to finish
7 off what we need to do in order to get you done today,
8 Dr. Pelech. Does that sound okay with you?

9 DR. PELECH: Yeah, I’m at your pleasure.
10 MR. TZEMENAKIS: And Mr. Wilson, is 15 minutes okay?
11 MR. WILSON: That’s fine. Thank you very much.
13
15
16 642 MR. TZEMENAKIS: Dr. Pelech, I’m going to direct your
17 attention to paragraph 64, and in particular to
18 footnote number 58, and to do this efficiently I’m
19 going to actually put your affidavit up on the screen.
20 So, can you take a look at paragraph (sic) 58, please?
21 A. Okay. Yeah.
22 643 Q. This - excuse me, paragraph 64 is what I meant to say.
23 A. Sure.
24 644 Q. So, in this paragraph towards the bottom of the page
25 you make the statement,
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1
2 “The Kinexus SARS-CoV-2 antibody test results
3 were cross-validated with another SARS-CoV-2
4 antibody test developed and marketed by the U.S.
5 company MesoScale Devices.”
6 Do you see that?
7 A. Yes.
8 645 Q. And you cite to 58.
9 A. Hm..mm.
10 646 Q. Okay, so when I click on 58 I come to this page, and
11 is this the document you intended to cite?
12 A. Yes, I believe that’s correct.
13 647 Q. This is...
14 A. They may have changed the page a little bit but that
15 seems to be the description of their test.
16 648 Q. Okay. And I’m just - I’m just scrolling through it...
17 A. Hm..mm.
18 649 Q. ...but if I go back to - I just want to be clear that
19 we’re on the same thing - we’re on the same page.
20 A. Hm..mm.
21 650 Q. It says that they were cross-validated with another
22 SARS-CoV-2 antibody test developed and marketed by
23 U.S. company MesoScale.
24 A. Yes.
25 651 Q. Is this in fact the - the data that you and - that you
26 rely upon?
27 A. Yes. So, this - this data was - the test itself was
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1 performed by the BC Women’s and Children’s Hospital.
2 They have the instrumentation. It’s a very special
3 type of equipment, and you can put different probes on
4 plates that this company manufactures, and they have
5 specific plates that were meant to detect SARS-CoV-2
6 proteins, the spike and the receptor bind remain of
7 the spike, and the nuclear caps of protein. And they
8 also had versions of some the cold corona viruses as

9 well. And so that test was done against all of those
10 different markers.
11 652 Q. Okay. So, I just wanted to - I don’t mean to
12 interrupt you but I just want to confirm this is a
13 document that you indeed intended to rely upon,
14 correct?
15 A. Yes.
16 653 Q. Right. And that’s fine.
17 A. The best description I could - I could offer for the
18 test.
19 654 Q. I’m going to come back to this question in a moment,
20 because I wanted to make sure that was the case. Can
21 I ask you to move forward with me to paragraph number
22 71. And now, at paragraph number 71, you - you
23 reference a Doctor - you reference to a study posted
24 on the Covid Care Alliance website...
25 A. Hm..mm.
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1 655 Q. ...and you reference this study at footnote 63.
2 A. Right. Actually looking at this I should point out
3 that Daniel Horowitz - I can’t confirm he’s a doc...a
4 doctor.
5 656 Q. Well, he’s... Okay. He is...we can take you to this
6 if you want. He’s actually a - an employee of
7 theblaze.com...
8 A. Hm..mm.
9 657 Q. ...and my understanding is theblaze.com is part of the
10 Blaze Group Media Company.
11 A. Hm..mm.
12 658 Q. And that Daniel Horowitz is not medical doctor.
13 A. Yes.
14 659 Q. Nor does he told a PhD. Does that accord with your
15 understanding?
16 A. Okay. Well, I’d - I’m not - I’m not sure what his
17 status actually was. It was an assumption on my part
18 because of what he wrote and how he wrote it, but -
19 but I can’t confirm he’s a - that he’s a medical
20 doctor, or a PhD.
21 660 Q. Okay, so if we - just give me one second here. So, so
22 I’m going to do a couple things here. First of all on
23 your screen, sir, you see a link to the footnote where
24 you reference the study, and this is a reference to a
25 post on the BlazeMedia site.
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1 A. Right.
2 661 Q. And the title of the article is “Horowitz: 15 studies
3 that indicate natural immunity from prior infection is
4 more robust than the COVID vaccines.” Do you see
5 that?
6 A. Yes, I do.
7 662 Q. And is that the study?
8 A. That’s the original study.

9 663 Q. That’s the original.
10 A. But we were more interested in the references that he
11 cited.
12 664 Q. Okay. And then at...
13 A. Hm..mm.
14 665 Q. ...if I follow a link at footnote 63...
15 A. Hm..mm.
16 666 Q. ...it takes you to the Covid Care Alliance...
17 A. Hm..mm.
18 667 Q. ...to a study entitled “Natural versus Vaccine
19 Immune...Induced Immunity”, do you see that?
20 A. Yes.
21 668 Q. And if we click... Right underneath the picture it
22 says, “A review of a collection of 15 studied compiled
23 by Daniel Horowitz at TheBlaze.com. All credit to
24 Horowitz with additional references and commentary
25 prepared for the Canadian Covid Care Alliance.”
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2 669 Q. Do you see that? And if we click on the “read more”
3 button, we note that on page 1 we identify the authors
4 of this particular study, and again it references the
5 fact that Daniel Horowitz is - that the studies have
6 been compiled by Daniel Horowitz at TheBlaze.com.
7 A. Right.

9 A. Yeah.
10 671 Q. So, does this give you any more certainty in helping
11 me with whether or not Dr. Horowitz is a medical
12 doctor?
13 A. You know, this is - you can have people that are
14 medical doctors or PhD scientists putting posts on
15 these kind of social media cites. I can’t judge from
16 that alone. My interest is in this was his
17 references. What were his citations, and that’s what
18 we tore apart and looked to see if they were valid and
19 built on that to try to put together a sense of what -
20 what is better, that was the question. So, we were
21 trying to take his - his references that he - he found
22 and see if they stand up to scrutiny.
23 MR. TZEMENAKIS: Okay. So, Mr. Wilson, to the extent
24 that a correction needs to be made to paragraph 71 to
25 refer to Mr. Horowitz as Mister or Doctor, can I get
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1 you to confirm that in writing to me, please?
2 MR. WILSON: Sure. Can we make that an undertaking
3 just so we’re clear that that’s what we’re doing?
4 MR. TZEMENAKIS: Points...
5 MR. WILSON: Yeah.
8 UNDERTAKING 4: To the extent that a correction needs to be

9 made to paragraph 71 to refer to Mr. Horowitz as
10 Mister or Doctor, can that be confirmed in writing.
11
12 672 MR. TZEMENAKIS: I’m going to stop share...actually,
13 these are all footnotes to your report.
14 A. That - that’s my error, and it’s partly reflection of
15 when you’re in doubt you - you call a person Doctor.
16 673 Q. To be fair when I’m in doubt I call a person sir or
17 mam, so we’ll go from there.
18 A. Okay.
19 674 Q. Let me turn to - to paragraph 77...
20 A. Hm..mm.
21 675 Q. ...and which is under the hearing of Alternative
22 Treatments in your report, and I just want to confirm
23 on the basis of the scope of the expertise described
24 by your counsel on the record...
25 A. Hm..mm.
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1 676 Q. You believe that it is within your scope of your
2 expertise to comment on the efficacy of ivermectin,
3 hydroxychloroquine, fluvoxamine, and quercetin,
4 correct?
5 A. Yes, because I’m a biochemist and I look at the
6 interactions of drugs. As it turns out most of the
7 drugs that are currently on the market for cancer and
8 many other diseases effects cell signaling proteins,

9 and so that’s my expertise, not just protein kinases
10 but G-protein coupled to receptors, for examine...
11 677 Q. Thank you.
12 A. ...and most of the drugs on the market target G-
13 protein target receptors and vitamin action. Again,
14 this is all biochemistry. So, I can - I can read the
15 clinical studies that are done with this, and
16 ascertain whether or not they make any sense.
17 678 Q. Okay. And apologies for interrupting. Have you
18 published any studies - scientific studies in relation
19 to ivermectin, hydroxychloroquine, fluvoxamine, and
20 quercetin?
21 A. With quercetin, yes. I have worked with this because
22 it’s actually a very good protein kinase inhibitor.
23 And in the case of these other drugs I’ve not
24 published on them myself. I think I was - I am
25 involved in some reviews on ivermectin because there's
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1 some clinical studies that were performed, but I think
2 Edward Mills, I think it is, of McMaster University,
3 led a study called the Together Study where they
4 looked at ivermectin, hydroxychloroquine, fluvoxamine,
5 amongst others. They actually found a positive result
6 that fluvoxamine seems to be able to reduce the - the
7 symptoms and accelerate the recovery from Covid-19.
8 There was some data with ivermectin from that study

9 that actually, although it wasn’t statistically
10 significant by the way the data was presented. We’re
11 now critically analyzing that - that clinical study
12 and we’re finding a lot of faults with it, so I’m
13 actually involved in the preparation of a scientific
14 paper that critiques the - the Together Study with
15 ivermectin.
16 679 Q. Okay. And just - just point me, sir, just so that I’m
17 clear...
18 A. Hm..mm.
19 680 Q. ...is that one of the studies that’s referenced or
20 cited in your report on page 71, which is footnote 71
21 to 75?
22 A. No, not in that study, because I - I felt at the time
23 that there was - we... Well, here’s the problem. The
24 results of the study were reported by the lead
25 investigator, Dr. Mills, but the data was never
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1 presented. It was just released a couple weeks ago.
2 Six months later after he made a public announcement
3 that it doesn’t work, and now there’s actually groups
4 that are in the United States and ourselves, the
5 Canadian Covid Care Alliance, that we’ve been finding
6 a lot of faults with that study, and so now we’re
7 actually writing scientific papers to actually go back
8 to the scientific journals and raise our concerns with

9 that trial.
10 681 Q. Okay. So, you’re - so you’re...
11 A. So I couldn’t cite it because there was no paper for
12 it at the time.
13 682 Q. I understand.
14 A. Yes.
15 683 Q. I - I’m - I was simply wanted to ask an easy question
16 about whether or not its here, and that’s fine. Let
17 me ask you - let me take you to paragraph 78...
18 A. Hm..mm.
19 684 Q. ...paragraph 78 you state,

20
21 “A systemic review of 15 clinical trials
22 indicated that Nobel Prize winning antiparasitic
23 drug ivermectin can be successfully applied to
24 the treatment of viral diseases including Covid-
25 19 and reduces infection by an average of 86%.”
26 A. Right.
27 685 Q. You see that? And in reliance on that you cite to a
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1 study by Bryant et al entitled, “Ivermectin for
2 Prevention and Treatment of Covid-19 Infection: A
3 Systemic Review Meta-analysis and Trial Sequential
4 Analysis to Inform Clinical Guidelines” at footnote
5 72. Is that right?
6 A That’s right.
7 686 Q. So, I’m going to share my screen with you again, sir.
8 A. Hm..mm.
9 687 Q. And I’m going to take you - you see paragraph 78 in
10 front of you, yes, sir?
11 A. yes.
12 688 Q. And you see footnote 72?
13 A. Hm..mm.
14 689 Q. We’re going to go to footnote 72. You’ll see that
15 there is no, what I’ll call link to this. So, what
16 I’m going to do is I’m going to copy it and I’m going
17 to place it into a web browser.
18 A. Yeah.
19 690 Q. Just give me one second.
20 A. Hm..mm.
21 691 Q. I want to do that. And of course my computer system
22 is not allowing me to open it because it’s deemed
23 unsafe, so just bear with me.
24 So, I’m showing you, sir, on my screen...
25 A. Hm..mm.
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1 692 Q. ...an article by the same name except you’ll see that
2 it is a different website, and the website appears on
3 the top of the page over here.
4 A. Right. This looks like the work was now published in
5 a scientific journal since then.
6 693 Q. Okay.
7 A. That’s what you’re looking at.
8 694 Q. Right. And can you tell me, sir, what an expression
9 of concern is?
10 A. Well, an expression of concern is when it’s been
11 flagged to the journal that people that are - are
12 reading these articles have a concern about the
13 article, that maybe they see some sort of a flaw. I
14 don’t know what the nature of that concern is. There
15 may be something there to refer to, but usually it’s
16 put there when they’re reconsidering the article based
17 on feedback from the general public. That’s the
18 scientists that are in the field.
19 695 Q. So, this is...
20 A. But this is - this is a very, very controversial area,
21 so I’m not surprised if someone has decided to
22 complain about the article.
23 696 Q. Right, and I’m not - I’m not - I’m not making any
24 qualitative - qualitative assessment on the expression
25 of concern. All I’m suggesting to you is that there
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1 is an expression of concern that has been identified
2 in relation to the contents of the article.
3 A Sure.
4 697 Q. Is that fair?
5 A. Hm..mm. Just like we’re going to do an expression of
6 concern for the Mills study.
7 MR. TZEMENAKIS: Right. And, Mr. Wilson, if you are
8 able to provide a workable link for footnote 72,

9 that’s great. If not can I get your consent to mark
10 this article which appears on the website
11 PubMed.ntvi.nlm.nih.gov/35142702?
12 MR. WILSON: Slash.
13 MR. TZEMENAKIS: Slash.
14 MR. WILSON: Yeah, no objection to that being marked
15 as an exhibit.
16 MR. TZEMENAKIS: Right, and that’ll be the next one in
17 the sequence, Madam Reporter.
18
19 EXHIBIT 17: Article entitled “Ivermectin for
20 Prevention and Treatment of Covid-19 Infection: A
21 Systemic Review Meta-analysis and Trial Sequential
22 Analysis to Inform Clinical Guidelines” at footnote
23 72, and is accessed by the link
24 PubMed.ntvi.nlm.nih.gov/35142702/.
25
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1 698 MR. TZEMENAKIS: Dr. Pelech, are you aware that
2 ivermectin has not been authorized by Health Canada as
3 a treatment for Covid-19?
4 A. It’s not recommended. They don’t have any statement
5 either way. When you look at what the Health Canada
6 website says, along with what a response to a petition
7 that was given to the House of Parliament, and they
8 have a response there, is that they actually note that

9 a doctor is able to prescribe ivermectin for off-
10 labelled use such as treatment of Covid-19, and they
11 actually prefer that a doctor prescribes it, so that
12 way patients are getting the proper dosage and
13 concerns of overdosing, which they raised earlier
14 because people were using horse paste ivermectin at
15 doses that would be more toxic. They think that they
16 actually recommend that the doctors prescribe it.
17 699 Q. So...
18 A. But they have - what you’re looking for is a clinical
19 trial that’s going to be conducted so that they can
20 then say, yes, there is evidence that this works for
21 Covid-19. But until someone is willing to sponsor
22 such a trial, and that there’s positive results,
23 they’re not going to make any recommendation on it.
24 700 Q. Dr. Pelech, I want to be entirely fair to you, but I
25 don’t believe that is an accurate statement, and so
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1 what I’m putting on my screen to show you...
2 A. Hm..mm.
3 701 Q. ...is a Government of Canada...
4 A. Hm..mm.
5 702 Q. ...recall and safety alert.
6 A. That’s the one about the veterinary supply of
7 ivermectin. That’s correct. That’s what I was
8 referring to.
9 703 Q. Mr...if possible, can I get my question out before you
10 comment on where I’m going?
11 A. Hm..mm.
12 704 Q. Right. So, this document, for the record, is
13 published by the Government of Canada on 19 October
14 2021. It’s entitled, Public advisory. “Ivermectin
15 not authorized to prevent or treat Covid-19; may cause
16 serious health issues,” and what I’m going to take you
17 to is under Issue. The first paragraph reads,

18 “Health Canada is reminding Canadians not to use
19 ivermectin to prevent or treat Covid-19.
20 Canadian Poison Centres have seen an increase in
21 reports concerning ivermectin over the summer.
22
23 “There’s no evidence that ivermectin works to
24 prevent or treat Covid-19, and it is not
25 authorized for this use. To date Health Canada
26 has not received any drug submission or
27 applications for clinical trials for ivermectin
28 for the prevention or treatment of Covid-19.
29
30 “Ivermectin has been authorized by Health Canada
31 for human use as a prescription antiparasitic
32 drug for the treatment of parasitic worm
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1 infections.”
2 Have I accurately read what you see on your screen,
3 sir?
4 A. Yes, you’ve read accurately what’s on the screen.
5 705 Q. Okay. I didn’t get my question...
6 A. But a more recent public...a more recent statement
7 from Health Canada says what I exactly stated to you
8 in Court.
9 706 Q. So...
10 A. And we can provide you with a copy of that link that
11 will demonstrate that Health Canada actually
12 recommend...does not say that doctors cannot prescribe
13 ivermectin for any off-labelled use including Covid-19
14 and they recommend that a doctor prescribes it.
15 707 Q. So, I’ll leave it to your counsel to provide that
16 information to me, but you will - and I think you have
17 acknowledged that this document seems - not seems -
18 states that ivermectin is not authorized for use to
19 prevent or treat Covid-19. So...
20 A. Yes, the wording’s a little bit different in the
21 statement in Parliament from the Health Minister.
22 708 Q. Okay, so I...
23 A. House of Commons.
24 709 Q. Sorry, is it now a statement in Parliament or is it an
25 official notice...
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1 A. If it...
2 710 Q. If I could finish my question.
3 A. Sure.
4 711 Q. Is it a statement from the Minister in Parliament, or
5 is it a official notice from Health Canada saying it
6 can be recommended? Because you’re saying two
7 different things and I want to understand...
8 A. Fair.
9 712 Q. ...what is the basis for your statement, please.
10 A. Right. So, there was a petition to Parliament that
11 was reviewed by the House of Commons, and a response
12 was made by the Minister of Health, by his - I think
13 it’s - it’s not himself but his - one of the other
14 Members of Parliament that’s I guess like a Deputy
15 Minister, that had a statement that was issued from
16 Health Canada that summarizes their taking on the
17 validity or the use of ivermectin. And basically what
18 they say there - they don’t actually say it’s not
19 authorized for this use. Basically they say that they
20 don’t have any evidence, as stated here, that it
21 works. So, they’re ignoring probably close to 100
22 scientific papers now and a lot of organizations that
23 have had very positive results with ivermectin and
24 saying that there is no evidence. So, that’s - that’s
25 really up to Health Canada to decide.
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1 713 Q. So, you’ll - do you acknowledge that there is a
2 probably equal number of scientific studies on the
3 other side that say the opposite of that conclusion?
4 A. No. Actually that’s not correct.
5 714 Q. Okay, so we’re going to...
6 A. There is - there is a few meta-analyses that have been
7 performed where some of them say that it works, and
8 other ones says that it doesn’t. The biggest issue

9 has been a sizeable clinical trial that’s double blind
10 that can answer this question once and for all. And
11 the hope was that the Together Trial that Dr. Edward
12 Mills was leading would address that question. And in
13 the end it’s become very ambiguous from the way the
14 paper itself has been performed, and the study that
15 generates that data.
16 MR. TZEMENAKIS: Okay. So, first thing, based on the
17 answer of the deponent, Mr. Wilson, will you undertake
18 to produce the petition and the answer to the Q&A that
19 Dr. Pelech has referred to?
20 MR. WILSON: Certainly. I - just as long as I think
21 none of us want - I don’t know if there’s 100,000
22 signatures on it.
23 DR. PELECH: Oh, no, no, not the petition...
24 MR. TZEMENAKIS: We’re talking about – no, no. Keith, I
25 don’t want to make more work for absolutely anybody
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1 because I think we have enough.
2 MR. WILSON: Yeah, we do. Thank you.
3 MR. TZEMENAKIS: I just think that to the extent that
4 it’s there it should be put before the Judge.
5 DR. PELECH: Very easy to get this...yes.
6 MR. TZEMENAKIS: Similarly...
7 MR. WILSON: We - we - I will - I will undertake to
8 provide you with documentation relating to the

9 government official, whether it was a Minister, an
10 Associate Minister referred to by the witness
11 regarding how doctors can prescribe ivermectin.
12
13 UNDERTAKING 5: Provide documentation relating to the
14 government official, whether it was a Minister, an
15 Associate Minister referred to by the witness
16 regarding how doctors can prescribe ivermectin.
17
18 MR. TZEMENAKIS: Okay. And just so that we have a
19 complete record for the Court, can we mark as the next
20 exhibit the document that currently appears on your
21 screen entitled, “Public advisory. Ivermectin not
22 authorized to prevent or treat Covid-19; may cause
23 serious health problems,” dated 2021-10-19.
24 MR. WILSON: Can you scroll down?
25 MR. TZEMENAKIS: Yes. It’s actually in the documents
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1 that I sent you as well.
2 MR. WILSON: Okay. As long as it includes
3 everything that’s on that page right down to the
4 Government of Canada logo, I have no objection to that
5 being marked as an exhibit.
6 MR. TZEMENAKIS: Okay. So let me just...
7 MR. WILSON: That would be...
8 MR. TZEMENAKIS: This is the public advisory. This is

9 what I sent you and you’re going to see that it goes
10 all the way down the five pages, and that it
11 includes...
12 MR. WILSON: Excellent. That’s fine.
13 MR. TZEMENAKIS: Okay, so we’ll mark this as the next
14 exhibit.
15 MR. WILSON: I believe we’re at Exhibit 18.
17
18 EXHIBIT 18: Document entitled “Public advisory.
19 Ivermectin not authorized to prevent or treat Covid-
20 19; may cause serious health problems,” dated 2021-10-
21 19, and to include the Canada logo at the bottom.
22
23 A. Fluvoxamine wasn’t recommended before either.
24 715 Q. So, I’m just going to bear with me and - just bear
25 with me for a second, Mr...sorry, Dr. Pelech, and I’m
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1 going to get to my next question in a minute. I just
2 want to touch base on something. All right. I’m
3 going to - staying in the same paragraph...
4 A. Hm..mm.
5 716 Q. ...are you aware that ivermectin has not been
6 authorized by the USFDA to prevent or treat Covid-19
7 in humans or animals?
8 A. That’s correct by the FDA. There are some States now

9 that have approved it but not the FDA.
10 717 Q. Mr...I’m going to share my screen once again. So, on
11 the screen before you is the article - the reference
12 in question, it was printed on May 12, 2022 at 6:27
13 p.m. It’s entitled “Why You Should Not Use Ivermectin
14 to Treat or Prevent Covid-19”.
15 A. Hm..mm.
16 718 Q. Scrolling down, and under the heading “Here’s What You
17 Need to Know about Ivermectin”, the FDA states,

18
19 “The FDA has not authorized or approved
20 ivermectin for use in preventing or treating
21 Covid-19 in humans or animals. Ivermectin is
22 approved for human use to treat infections caused
23 by some parasitic worms and head lice and skin
24 conditions like rosacea.”
25 Do you see that?
26 A. Yes, I do.
27 719 Q. Okay, and is this consistent with the answer you gave
28 me previously that the USFDA has not authorized or
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1 approved the use of ivermectin for the - to prevent or
2 treat Covid-19?
3 A. That’s correct. It - it is actually one of the safest
4 drugs on the - on the UN list of medications and Nobel
5 Prizes have been given for it as a very high
6 therapeutic window. It means you can go to very high
7 doses before you have any toxic effects. It’s one of
8 the least toxic drugs that’s on the market today.

9 720 Q. Well, I appreciate that but that really has limited
10 utility in for the question that I asked you. I
11 under...I - I’m not get - I’m not going to ask you any
12 questions about the efficacy of ivermectin and its
13 uses.
14 A. Hm..mm.
15 MR. TZEMENAKIS: I think your report speaks for itself,
16 but what I am going to ask Mr. Wilson is whether we
17 can agree to mark this document as the next exhibit,
18 and it would be number 19, and Madam Reporter, it
19 should be noted that this exhibit entitled “Why You
20 Should Not Use Ivermectin to Treat or Prevent Covid-
21 19” was printed on the 12th of May 2022 at 6:27 p.m.
23
24 EXHIBIT 19: Article entitled “Why You Should Not Use
25 Ivermectin to Treat or Prevent Covid-19” was printed
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1 on the 12th of May 2022 at 6:27 p.m.
3 MR. TZEMENAKIS: So, what I’d like to do is take a short
4 break. I want to revisit a couple of points and we
5 may - we may be very close to concluding, Dr. Pelech.
6 That okay with you, and with you, Mr. Wilson?
7 DR. PELECH: Yes.
8 MR. WILSON: That’s fine. We’ll just - I’ll just

9 turn my camera off and mute my microphone and we’ll
10 await your return.
11 MR. TZEMENAKIS: Very good. Thank you
12
14
15 721 MR. TZEMENAKIS: So, Dr. Pelech, I’m going to take you
16 back to paragraph 64, if you wouldn’t mind.
17 A. Hm..mm. Yes.
18 722 Q. And here’s - in paragraph 64 in the middle of the
19 paragraph you make a statement, “Some of this work has
20 already been published in the peer reviewed flagship
21 journal “The American Society for Clinical
22 Investigation.”
23 A. Hm..mm.
24 723 Q. And you cite the footnote...
25 A. Yes.
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1 724 Q. ...number 1. Do you see that, sir?
2 A. Yes.
3 725 Q. So, I’m going to share my screen with you, and
4 footnote number 1 takes you to an article published in
5 Nature, entitled “The tangled history of mRNA
6 vaccines.” Is this the reference you intended to
7 provide?
8 A. No.
9 726 Q. Okay.
10 A. The reference actually in the affidavit actually with
11 that number.
12 727 Q. I’m showing you on your screen, sir...
13 A. Hm..mm.
14 728 Q. ...an article from JCI Insight entitled “A majority of
15 uninfected adults show pre-existing antibody
16 reactivity against...”
17 A. That’s the correct citation.
18 729 Q. Sorry, is that the correct citation?
19 A. Yes.
20 MR. TZEMENAKIS: All right. So, Mr. Wilson, for the
21 purposes of the record can we agree that the reference
22 in paragraph 64 to footnote 1 is inaccurate and was
23 intended to be a reference to the study entitled, “A
24 majority of uninfected adults show pre-existing
25 antibody reactivity against SARS-CoV-2” by Majdoubi et
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1 al?
2 MR. WILSON: Yes.
3 MR. TZEMENAKIS: And so that we have a clean copy, could
4 we agree to mark this document as the next exhibit to
5 this cross-examination, please?
6 MR. WILSON: No objection, Exhibit 19 (sic).
9 EXHIBIT 20: Study entitled, “A majority of uninfected
10 adults show pre-existing antibody reactivity against
11 SARS-CoV-2” by Majdoubi et al.
12
13 730 MR. TZEMENAKIS: So, I have just two quick questions on
14 this. You’re - you’re familiar - first of all just to
15 set it up, you’re familiar with this study, yes, Dr.
16 Pelech?
17 A. Oh, absolutely, I helped write it.
18 731 Q. Okay. I’m going to take you to...right, no page
19 numbers, so just bear with me. So, I’ll take you to -
20 we’ve actually produced this - a copy of this in the
21 documents that were sent over you today - sent over to
22 you today.
23 A. Okay.
24 732 Q. All right. And I’m going to share my screen, and here
25 it is again. So, this is - this is the JCI, same
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1 title. I’ve just downloaded it from the web as a PDF
2 document, okay?
3 A. Okay.
4 733 Q. Okay, so proceeding on that - proceeding on that...
5 A. It’s number 18, I think, in your list.
6 734 Q. Yes. It’s going to be a different number. We just
7 marked it as 19, but it’s - it’s - I want to assure
8 your counsel that it’s the same as the one that I just
9 showed you on the web, and if there’s any concerns he
10 can let me know.
11 But I want to take you to paragraph - to page
12 number 6 on this study, and on page 6 under
13 Discussion...
14 A. Hm..mm.
15 735 Q. ...it says...now I’ve got to find it. One second and
16 I’ll stop sharing the screen and I’ll come right back
17 to you. Not sure I have the right page number so give
18 me one second. Here you go, okay. It’s actually page
19 7. So, just to situate you, sir, the discussion
20 starts on page 6. Do you see that in front of you?
21 A. Yes.
22 736 Q. And then it goes on to page 7. Right after Figure 3,
23 it makes the following statement:

24
25 “It is unclear whether this antibody reactivity
26 may confer clinical benefits - for instance,
27 modulating the severity of a SARS-CoV-2
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1 infection. Data indicate that a past circulating

2 coronavirus infection may decrease the severity
3 of a subsequent SARS-CoV-2 infection. Others
4 have linked pre-existing seroreactivity against
5 circulating coronaviruses to increased SARS-CoV-2
6 pseudovirus neutralization in vitro, although
7 this remains debated. Individuals with high RBD
8 reactivity showed the most structurally diverse
9 antibody reactivity against spike epitopes, which
10 may enhance viral clearance in addition to the
11 improved neutralizing activity specific to RBD-
12 specific antibodies.”
13 Do you agree with those statements, sir?
14 A. At the time that we did this study it was unclear. We
15 did subsequent experiments that clarified that.
16 But...
17 737 Q. And we’re...
18 A. But you have to remember that this state...this
19 article was written by many different authors, and
20 actually I was at odds with the rest of the authors on
21 some of the statements that were made in the paper,
22 but I agreed to let it stand as it was, and
23 subsequently it turned out that my instincts were
24 correct.
25 738 Q. And study...
26 A. Hm..mm. Yes.
27 739 Q. ...right to the beginning... So, this study was - I’m
28 trying to figure out the dates. It’s copyrighted -
29 submitted November 23, 2020, accepted March 12, 2021,
30 and published on March 15, 2021.
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3 A. Yeah.
4 741 Q. And the subsequent study that you referred to, was
5 that available to you before you finished your report
6 in March of 2022?
7 A. Sorry, March of 2022?
8 742 Q. Right, your report here is dated March of 2022.

9 A. Yes, yes.
10 743 Q. So, was that study available to you prior to
11 submission of your report?
12 A. You challenge what we said originally in this
13 publication? Yes.
14 744 Q. But you don’t refer to that in your report, do you?
15 A. I - I - I do actually refer to that in my report.
16 745 Q. Because we find that...
17 A. Keep in mind that the majority of even asymptomatic
18 people that we test have antibodies against the virus.
19 746 Q. So, can you just point me to the paragraph in the
20 reference where you refer that - to that please?
21 A. I’ll have to do some searching. I can try.
22 MR. TZEMENAKIS: Okay. Well, again, Mr. Wilson, to be
23 efficient do you mind taking that as an undertaking,
24 or we can let Dr. Pelech do that now.
25 A. But I can elaborate on that if you wish.
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1 MR. TZEMENAKIS: Just let me get an answer to the first
2 question.
3 MR. WILSON: So, the undertaking would be to provide
4 the reference in his expert report as to where it
5 refers to...and I need you to finish that sentence.
6 MR. TZEMENAKIS: Okay, so, the undertaking would be to
7 provide the reference to the subsequent study that
8 “made it...”. Sorry, to provide the reference of the

9 subsequent study where the conclusion “It is unclear
10 whether this antibody reactivity may confer clinical
11 benefits” is rebutted. That’s what I understood Dr.
12 Pelech to say.
13 747 Q. Is that a fair statement, Dr. Pelech?
14 A. Yes.
15 MR. WILSON: That’s fine. We’ll provide that
16 undertaking.
18 A. Yeah, it’s in the description of - of the actual study
19 that we did with the clinical study that we followed
20 up and - and basically we’ve tested more than twelve
21 times the number of people.
22 748 Q. Right. I’m going to let your counsel provide that to
23 us...
24 A. We’ll deal with that...
25 749 Q. ...and then we’ll take it from there.
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1 UNDERTAKING 6: To provide the reference of the subsequent
2 study where the conclusion “It is unclear whether this
3 antibody reactivity may confer clinical benefits” is
4 rebutted.
6 MR. TZEMENAKIS: The second last thing that I wanted to
7 do is I understand that, Mr. Wilson, that the VAERS
8 disclaimer screenshot was sent around to all counsel

9 by email. Can we agree to mark that as the next
10 exhibit?
11 MR. WILSON: Yes, we can agree.
12
13 EXHIBIT 21: The VAERS disclaimer screenshot which was sent
14 by email to all counsel.
15
16 MR. TZEMENAKIS: Dr. Pelech, subject to the answers to
17 undertakings, this ends my cross-examination. I
18 wanted to say thank you. This is not a light area by
19 any stretch of the imagination, but my job is to
20 ensure that the Court gets a complete picture of areas
21 where there might be space between us, or there might
22 be a divergence between us so that we can - so that we
23 can make sure there’s a fulsome record before the
24 Court, and so I’m going to turn the floor over to my
25 friend Mr. Wilson to see if he has any questions for
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1 you.
2 DR. PELECH: I was wondering if I could answer the
3 original question in terms of the evidence that in
4 fact these individuals that had tested positive with
5 antibodies in the original trial in fact had
6 protective antibodies, and we did a study - it’s not
7 in my report, but it was a study with Dr. Ralph
8 Panaflet (ph) continuing on from the study that we did

9 with the very same serum samples from the people in
10 that - that study in JCI where we actually did
11 neutralization studies with those serum samples that
12 showed antibodies and they blocked the entry of the
13 lentivirus constructs that this spike protein on them
14 into cells. So, they were actually contained
15 neutralizing antibodies in addition to just being
16 antibodies against the spike protein and nuclear
17 counts and other proteins. They actually were
18 demonstrated. But that work has not yet been
19 published.
20 750 MR. TZEMENAKIS: And just because you raised it and
21 before I turn the floor over to Mr. Wilson, I just
22 want to be clear, that’s a new study and that was done
23 before March of 2022?
24 A. Yes, it was, but it wasn’t complete and it has not
25 been published.
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1 751 Q. It’s not complete and not published. Okay, thank you,
2 sir.
3 MR. TZEMENAKIS: Mr. Wilson.
4 MR. WILSON: We have nothing by way of redirect.
5 That concludes this cross-examination subject to
6 matters rising from - any matters arising from
7 undertakings.
8 MR. TZEMENAKIS: Thank you, Mr. Wilson and Madam

9 Reporter. Thank you.
10
11 CROSS-EXAMINATION ENDS: 17:09:20 P.M.
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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Court Transcriber
ACT ID: 2887221650
May 21st, 2022
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•
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- European
Commission
I English cp
TO<lay. me European Comrmssion adopted <he deciSioo granf.ng

Top marlle~ng autllor,sallons to lhe company Janssen. a Jonnson &
P rinl friendly p<II Johnson company. fof a vaccine- against Eoota. The a11thofisatk>n was
Press contact !Jf'illltea in one month. ,eaucing lhe decision-mal<ing piocess timing in
half, further demonstrating the Commission's commitment in placing !he
protection of pubhc health as a prionty.
The new EW.a vaccine. wlllcll cons,sts ol two componerus. caQe<I

Zah<leno and Mvabea. had been In delietopment w,th the suppon of tile
Commrss10n. This cteosion follo\.•15 a recommendation from me
European Medicines Agency fEMA). Which has assessed the benefits
and llSks ol the 'laedne.
Stella Kyriakldts Commissioner In charge OI Health and >OO<I Safety.

said: -Th,'3 1$ Ille :seccnd Ebol a vacane cnat <t>& CommisSIOn aumonse.s
,n le~ than a year and cont,rms once again /t>a: ll>e EU n,mams at !he
fonll'rontortlN>glooaletrorttosave /rves from rhls = •· ~knew very
M.'&11 from th.• comnavrrus cnm thiill viruses do ncr respect bctders -
p!<lre<:llllg the h&al!h of others pm1ecrs the health of al/ •
Mariya G - l . CommtsSiOner In cilarge or ResearclJ, said:

·rooay v.e
ea.12 ce ~ to have supporred the dgvek:Jpmem ofthe Ebola vacane
with EU hndmg. "'partnership ..,,,,. the European phannac&wJca/
sector under the tnnovariwl l.ffil.cmes lnrriattvs. The lnvestment from
the EVs re.sean:h programme Hori'lon 2020 into several Innovative
Mea.cln&s lnltWNe Ebola projecrs Is now beanng trur:. This
defTICmlra= ye: agam. rt>e power of colla!>ofarion and Europeatr Rllf
leader5hip to rackte global health rhnt.ats- •
Jos. 1,xpialned by EMA when ,t cecommen<ll:d the 3PPf0>a! last February,

the abi-hty ot the immune system to respond m the virus after
vaccination wtth Zabcteno and Mvat>ea v.-as snded in a total of 3.367
actu!ts, adolescents Af>d chikt, en who paioc1pated in five clink:aJ srucnes
oonduCle<I Ill Ewope. Africa and the us.
The deveoprnent OI the vaccine is the result ol rlgornus WOi k by ..,.....al

p,o;ects lunded w1th jUst over €130 m~lioo through t h e ~
Mt~..llli!ia.tiY~ jlMI). which Is parlly Suppotte<I by !he EU's resean;h
and 1Mo'1alion progralMle, HofilQo._2220. Following a comprehensNe
app,oach. the EBOVAC 1. 2 ll J. proiecis assesse<l ll'.e safety and
to!efabihly o f the Ebola vaccine regimen rhlough cllnlGal trials m Europe
and Africa. The E!lQOAC p,oject developed a Cotnffi<lflical,on s~ategy
and~ to promote the acceptance and uptake 01 new Ebola vaccines.
finally, !he Efl0 1v'£,N project locuSed on accelerating the development
and manufacture or the vaccif\e.
Background
The authodsatioo ol a medicine unde, Ille centralised p,ocedure Is a

t,vo-stage process. Involving the Eu,opean Uedicmes fv;Jef'IOJ IEMA)
aO<l t h e ~ - EMA assesses llle benefits and risks of medicines
and makes recommenda1ions to !he CommtSSiOO, which then takes a
lll'lal iega>ly binding <lecision on whetl,er or not the me<lldne can be
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u 1-888-288-6817 Tins decision is ,ssued normally withm tile legal deadl,ne of 67 days OI
DATE: __••- ~....+--'-
1.l-..
,r;;i......~:::z..i- =~ - the saenblic oo,n,oo ot EMA m,, Zabdeno and Mvabea the date was 28
EX #: s7./ m~w.s:A D
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May). This phase Includes, among other things, the translation of the
product guidelines In all EU languages and a consultation with Member
States. In view of the public health Interest, the Commission has
accelerated this process and authorised the medicine In around a
month , In other words reducing the time taken for the decision-making
process in half.
The assessment report for the vaccines will be published on ~
~-
IMI funds large-scale collaborative research projects bringing together
academic and lndustrtal partners, as well as patients and other
stakeholders.
In November 2014, IMI responded very rapidly to the West Africa

outbreak of Ebola by allocating €280 million to a comprehensive call for
proposals lo tackle a wide range of challenges In Ebola research,
Including vaccines development, clinical trials, storage and transport, as
well as diagnostics. The fi rst projects under the IMI fl1Qla!..ll[Qg[l!!J!!M
started as earty as January 2015 and several focused on the
development of the Janssen vaccine regimen. Since 20 14, IMI has
funded 12 projects on Ebola and related diseases with a total combined
budget of over EUR 300 million.
For More Information
EU's efforts to tackle Ebola
EU support to Ebola =.c&tl
EMA& Ebola
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f7 Vaccine against Ebola

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Lipid nanoparticles for mRNA delivery

Xucheng Hou', Tai Zaks2,g, Robert langer'(Jf5•4 ,g and Yizhou Don{/4/) 1 '83
Abstract I Messenger RNA (mRNA) has emerged as a new category oftherapeutic agent to
prevent and treat various diseases. To function in vivo, mRNA requires safe, effective and stable
delivery systems that protect the nucleic acid from degradation and that allow cellular uptake
and mRNA release. Lipid nanoparticles have successfully entered the clinic for the delivery of
mRNA; in particular, lipid nanoparticle-mRNA vaccines are now in clinical use against coronavirus
disease 2019 (COVID-19), which marks a milestone for mRNA therapeutics. In this Review, we
discuss the design of lipid nanoparticles for mRNA delivery and examine physiological barriers
and possible administration routes for lipid nanoparticle-mRNA systems. We then consider key
points for the clinical translation of lipid nanoparticle-mRNA formulations, including good
manufacturing practice, stability, storage and safety, and highlight preclinical and clinical studies
of lipid nanoparticle-mRNA therapeutics for infectious diseases, cancer and genetic disorders.
Finally, we give an outlook. to future possibilities and remaining challenges for this promising
technology.
Messenger RNA (mRNA), which was discovered by pio- under clinical evaluation for the prevention and treat-
neering studies in 1947-1961 [REF.1), is a transient inter- ment ofvirus infections, cancer and genetic diseases7-t7
mediator between genes and proteins. By the late 1980s, (TABLES 1.2).
investigations ofmRNA structure and function resulted In this Review, we briefly overview representative
in the development of in vitro-transcribed (IVT) lipid nanopartides u.sed for mRNA delivery and desaibe
mRNA2. Since the first proof-of-concept animal study key steps in the preclinical development of lipid nano-
in 1990 [REf:3), DllDlerous strategies have been explored particle-mRNA formulations, including the overcoming
to ameliorate the instability and immunogenicity of ofphysiological barriers, different administration routes,
IVT mRNA2". Additionally, advanc.es in drug delivery manufacturing and safety profiles. Finally, we highlight
systems have expedited the preclinical development of important examples oflipid nanopartide--mRNA fomiu-
mRNA therapeutics5-17, providing the basis for mRNA lations in clinical studies and provide future perspectives
as a new class of drug (RG. 1 J. for lipid nanoparticles and mRNA therapeutics.
1
Division ofPhannaceutics &:
mRNA has shown therapeutic potential in a range of
Pharmacology, College of applications, including viral vaccines, protein replace- Deivelopment of Upids for mRNA deliYery
Phormocy, The Ohio State ment therapies, cancer immunotherapies, cellular In 1976, nucleic acids were encapsulated and delivered in
University. Columbus, OH, reprogramming and genome editing1"1 - 17• To achieve polymeric partides5. Later, exogenous mRNA delivery
USA.
therapeutic effects, mRNA molecules have to reach spe- into host cells was demonstrated with liposomes22.ll
2
Modema. Inc.. Cambridge.
cific target cells and produce sufficient proteins ofinter- (RG. 1}. Lipids are amphiphilic molecules that contain
MA. USA.
est However, targeted delivery and endosomal escape three domains: a polar head group, a hydrophobic tail
'David H. Koch Institute for
lntegrutive Cancer Researrh,
remain challenging for mRNA delivery systems, high- region and a linker between the two domains. Cationic
Massachusetts Institute of lighting the need for safe and effective mRNA delivery lipids, i.oni7.ahle lipids and other types oflipid have been
1echnalogy, Cambridge. MA. materials. explored for mRNA delivery (AG. 2).
USA. A variety ofmaterials have been developed for mRNA
•Department ofChemic:al delivery, including lipids, lipid-like materials, polymers Ctltionic lipids. Cationic lipids have a head group with
Engineering, Massachusetts and protein derivatives'-17• In particular, lipid nanopar- permanent positive charges11 .14 _ For example, 1,2-
Institute ofTedmology,
tides have been thoroughly investigated.and successfully di-O-octadecenyl-3-trimethylammonium-propane
Cambridge. MA. USA..
entered the clinic for the delivery ofsmall molecules'8, (DOTMA), a quaternary ammonium lipid, has been
siRNA drugs18 and mRNA19-i1 • Notably, two authorized applied for mRNA delivery in multiple cell types24,
Be-mail: tal.zalls@
modematx.com; rlanger@
coronavirus disease 2019 (COVID-19) vaccines, mRNA- and was commercialiud as Lipofectin in combination
mit.edu; dong.525@osu.ec/u 1273 (REFS19.10j and BNT162b2', use lipid nanopartides to with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine
https://doi.or@'l0. 1038/ deliver antigen mRNA. Many other lipid nanopartide- (DOPE}2-'. I,2-dioleoyl-3-trimethy)ammonium-propane
s41578-021-00358-0 mRNA formulations have been developed and are (DOTAP), a biodegradable analogue ofDOTMA, was
1078 I DECEMBER 2021 I VOLUME 6 - •.nature.com/natreYmats

AR08268 Reviews
mRNA Lipid nanoparticles
Discovery of mRNA
and its function1
1961 1961
Development
1965 1965 of liposomes251
In vitro translation of
isolated mRNA in a 1969 1969
cell-free system252
Development of liposome–
1978 mRNA formulations22,23 1978
1989 Development of cationic 1989

Free mRNA translation LNP–mRNA formulations24
post intramuscular
injection in mice3 1990 1990
Injection of vasopressin LNPs encapsulating

mRNA into rat brain as 1992 1992 small molecules
protein replacement (doxorubicin or
Development of liposome– amphotericin B) were
therapy for diabetes 1993 mRNA formulations as 1993
insipidus253 approved by the FDA18
influenza vaccine184
Injection of 1995 1995 LNPs encapsulating
carcinoembryonic antigen
daunorubicin were
mRNA into mouse muscle
1996 1996 approved by the FDA
as a cancer vaccine199
and the EMA18
2000 2000 LNPs encapsulating

First clinical trial of mRNA- verteporfin were
engineered dendritic cells approved by the FDA18
(NCT00004211) 2001 2001
Nucleoside-modified
mRNA shows reduced 2005 2005
immunogenicity182
Clinical trial of mRNA 2009 2009

therapeutics using
protamine–mRNA LNPs encapsulating
formulations 2012 2012 vincristine were
(NCT00204607) Clinical trial of LNP–mRNA approved by the FDA18
formulations for cancer
2014 immunotherapies (NCT02316457) 2014
LNPs encapsulating
• Clinical trial of LNP–mRNA formulations irinotecan were
2015 2015 approved by the FDA18
as influenza vaccines (NCT03076385)
First in-human test of • Clinical trial of LNP–mRNA formulations
for protein replacement therapies LNPs encapsulating
personalized mRNA 2017 2017 cytarabine were
cancer vaccines209 (NCT03375047)
approved by the FDA18
2018 • mRNA-1273 and BNT162b (LNP–mRNA 2018 Onpattro (LNPs
formulations) COVID-19 mRNA
vaccines obtained authorization from encapsulating siRNA),
2020 regulatory agencies in multiple 2020 the first siRNA drug,
countries was approved by the
• Clinical trial of LNP formulations FDA and the EMA18
delivering gene-editing components
for genetic disorders (NCT04601051)
Fig. 1 | Timeline of some key milestones for mRNA and lipid nanoparticle development. COVID-19, coronavirus
disease 2019; EMA, European Medicines Agency; FDA, United States Food and Drug Administration; LNP, lipid
nanoparticle251–253.
also studied for mRNA delivery25, and is part of the CD4+ regulatory T cells, leading to enhanced immu-
commercial agent MegaFectin, together with DOPE nosuppression and a reduction of clinical symptoms in
or cholesterol. DOTMA and DOTAP have both been mouse models27. DOTAP-based cationic nanoemulsions
applied either alone or combined with other materials can deliver antigen mRNA against viral, bacterial and
for mRNA delivery7–17; for example, spleen-targeted parasitic infections28–31. Moreover, DOTAP–polymer
DOTMA–mRNA lipoplexes (RNA-LPX) have been hybrid nanoparticles can deliver mRNA molecules
developed as systemic cancer vaccine26. The same for- for the treatment of cancer 32–37, infections 38–41 and
mulation has also been designed as mRNA vaccine for genetic disorders42. Incorporating carbonate apatite in
the treatment of autoimmune encephalomyelitis27. This DOTAP-based lipid nanoparticles increases the inter-
vaccine induces the proliferation of antigen-specific action between the particles and cellular membranes43.
NATure RevIewS | MATERIALS volume 6 | December 2021 | 1079
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The delivery efficiency can further be improved by con- responses45, thereby serving as immune adjuvant for
jugating fibronectin to the lipid nanoparticles, which is a mRNA vaccines 46,47. DDAB and DOPE constitute
cellular adhesion protein accelerating the endocytic the commercial product TransfectAce. The commer-
rate44. cialized agent Lipofectamine is composed of DOPE
Dimethyldioctadecylammonium bromide (DDAB), and 2,3-d ioleyloxy-N -[2-(sperminecarboxamido)
a quaternary ammonium lipid, can not only from com- ethyl]-N ,N-d imethyl-1-propanaminium trifluoro
plexes with mRNA but also stimulate innate immune acetate (DOSPA), a cationic lipid containing quaternary
Table 1 | Representative clinical trials of lipid nanoparticle–mRNA vaccines against infections and cancer
Name Disease Encoded antigen Administration ClinicalTrials.gov Phase
route identifier
Infections
mRNA-1273 SARS-CoV-2 Spike i.m. NCT04470427 III (EUA
and CMA)
BNT162b2 SARS-CoV-2 Spike i.m. NCT04368728 III (EUA
and CMA)
CVnCoV SARS-CoV-2 Spike i.m. NCT04652102 III
LNP-nCoVsaRNA SARS-CoV-2 Spike i.m. ISRCTN17072692 I
ARCT-021 SARS-CoV-2 Spike i.m. NCT04728347 II
ARCoV SARS-CoV-2 Receptor-binding i.m. ChiCTR2000034112 I
domain
mRNA-1440 Influenza H10N8 Haemagglutinin i.m. NCT03076385 I
mRNA-1851 Influenza H7N9 Haemagglutinin i.m. NCT03345043 I
mRNA-1893 Zika virus Pre-membrane i.m. NCT04064905 I
and envelope
glycoproteins
mRNA-1345 Respiratory syncytial F glycoprotein i.m. NCT04528719 I
virus
mRNA-1653 Metapneumovirus MPV and PIV3 F i.m. NCT03392389 I
and parainfluenza glycoproteins
virus type 3 (MPV/
PIV3)
mRNA-1647 Cytomegalovirus Pentameric complex i.m. NCT04232280 II
and B glycoprotein
mRNA-1388 Chikungunya virus Chikungunya virus i.m. NCT03325075 I
antigens
CV7202 Rabies virus G glycoprotein i.m. NCT03713086 I
Cancer
mRNA-5671/ Non-small-cell lung KRAS antigens i.m. NCT03948763 I
V941 cancer, colorectal
cancer, pancreatic
adenocarcinoma
mRNA-4157 Melanoma Personalized i.m. NCT03897881 II
neoantigens
mRNA-4650 Gastrointestinal Personalized i.m. NCT03480152 I/II
cancer neoantigens
FixVac Melanoma NY-ESO-1, tyrosinase, i.v. NCT02410733 I
MAGE-A3, TPTE
TNBC-MERIT Triple-negative Personalized i.v. NCT02316457 I
breast cancer neoantigens
HARE-40 HPV-positive cancers HPV oncoproteins E6 i.d. NCT03418480 I/II
and E7
RO7198457 Melanoma Personalized i.v. NCT03815058 II
neoantigens
W_ova1 Ovarian cancer Ovarian cancer i.v. NCT04163094 I
antigens
CMA, conditional marketing authorization; EUA, Emergency Use Authorization; HPV, human papillomavirus; i.d., intradermal;
i.m., intramuscular; i.v., intravenous; KRAS, Kirsten rat sarcoma 2 viral oncogene homologue; MAGE-A3, melanoma antigen family A;
NY-ESO-1, New York esophageal squamous cell carcinoma 1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2;
TPTE, putative tyrosine-protein phosphatase.
1080 | December 2021 | volume 6 www.nature.com/natrevmats
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AR08270 Reviews
Table 2 | Representative clinical trials of lipid nanoparticle–mRNA therapeutics against infections,

cancer and genetic disorders
Name Disease Encoded protein Administration ClinicalTrials. Phase
route gov identifier
Infections
mRNA-1944 Chikungunya virus Antibody against i.v. NCT03829384 I
chikungunya virus
Cancer
mRNA 2416 Solid tumours OX40L Intratumour NCT03323398 II
mRNA-2752 Solid tumours OX40L, IL-23 and IL-36γ Intratumour NCT03739931 I
MEDI1191 Solid tumours IL-12 Intratumour NCT03946800 I
SAR441000 Solid tumours IL-12sc, IL-15sushi, IFNα and Intratumour NCT03871348 I
GM-CSF
Genetic disorders
mRNA-3704 Methylmalonic Methylmalonyl-CoA mutase i.v. NCT03810690 I/II
acidaemia
mRNA-3927 Propionic acidaemia Propionyl-CoA carboxylase i.v. NCT04159103 I/II
MRT5201 Ornithine Ornithine transcarbamylase i.v. NCT03767270 I/II
transcarbamylase
deficiency
MRT5005 Cystic fibrosis Cystic fibrosis transmembrane Inhalation NCT03375047 I/II
conductance regulator
NTLA-2001 Transthyretin amyloidosis CRISPR–Cas9 gene editing i.v. NCT04601051 I
with polyneuropathy system
CoA, coenzyme A; CRISPR–Cas9, clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9;
GM-CSF, granulocyte–macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; i.v., intravenous.
ammonium and spermine. Lipofectamine protocols the pH is lower than in the extracellular environment,
have been optimized to deliver mRNA in diverse cell ionizable lipids are protonated and, therefore, become
types, including alveolar cells, cardiac muscle cells and positively charged, which may promote membrane
pluripotent stem cells48–50. 2-(((((3S,8S,9S,10R,13R,14S, destabilization and facilitate endosomal escape of the
17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- nanoparticles7,11,14 Ionizable lipids originally devel-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1 oped for DNA transfection, such as (2S)-2,5-bis(3-
H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)- aminopropylamino)-N-[2-(dioctadecylamino)acetyl]
N,N-bis(2-hydroxyethyl)-N-methylethan-1-aminium pentanamide (DOGS; Transfectam)57, N1-[2-((1S)-1-[(3-
bromide (BHEM-C holesterol) was developed by aminopropyl)amino]-4-[di(3-aminopropyl)amino]
modifying the head structure of 3β-[N-(N′,N′- butylcarboxamido)ethyl]-3,4-di[oleyloxy]-benzamide
d imethylaminoethane)-c arbamoyl]cholesterol (MVL5) 58, DC-C holesterol 59 and N 4-c holesteryl-
(DC-Cholesterol) with hydroxyl groups to improve spermine (GL67)60, have also been explored for mRNA
fusion with cellular membranes51. Lipid nanoparticles delivery25,61–63.
containing BHEM-Cholesterol have been applied to The ionizable lipid 1,2-d i linole y loxy-N,
deliver mRNA encoding clustered regularly interspaced N-dimethyl-3-aminopropane (DLin-DMA) was ini-
short palindromic repeats (CRISPR)–CRISPR-associated tially synthesized for siRNA delivery 64, and deliv-
protein 9 (CRISPR–Cas9) and tumour antigens 52,53. ery efficacy was improved by modification of
Ethylphosphatidylcholine (ePC) was synthesized by the linker and hydrophobic regions, resulting in
introducing a third alkyloxy group into phosphatidyl- 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane
cholines to eliminate their negative charge. ePC-based (DLin-K C2-D MA) 65 . Further optimization of
lipid nanoparticles have been applied for mRNA-based the amine head group of DLin-KC2-DMA led to
cancer immunotherapies54,55 and protein replacement (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl
therapies56. 4-(dimethylamino) butanoate (DLin-MC3-DMA; MC3),
which is a key delivery component of Onpattro, the
Ionizable lipids. Ionizable lipids are protonated at first United States Food and Drug Administration
low pH, which makes them positively charged, but (FDA)-approved siRNA drug18,66. MC3-b ased lipid
they remain neutral at physiological pH (refs7,11,14). nanoparticles have also been tested for mRNA ther-
The pH-sensitivity of ionizable lipids is beneficial for apeutics, such as protein replacement therapies56,67–72
mRNA delivery in vivo, because neutral lipids have and antiviral therapies73–75. Incorporation of biode-
less interactions with the anionic membranes of blood gradable lipids improves the tolerability of lipid nano-
cells and, thus, improve the biocompatibility of lipid particles, by allowing fast metabolism while retaining
nanoparticles7,11,14. Trapped in endosomes, in which mRNA delivery efficacy. The biodegradability of lipids
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R e vAR08271
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can be increased by introducing ester motifs; for exam- lipids have been synthesized as mRNA delivery
ple, introducing ester bonds in the linker and lipidic materials109–112.
tails of MC3 results in the lipid di((Z)-non-2-en-1-yl) Zwitterionic ionizable lipids can also be applied for
9-((4-(dimethylamino)butanoyl)oxy)heptadecanedio- mRNA delivery56,113–116; for example, lipids composed
ate (L319)76, which shows better delivery efficacy and of a pH-switchable zwitterion and three hydropho-
faster elimination from the liver and plasma in vivo bic tails assemble into a cone in the endosomal acidic
in comparison with MC3 (ref.76). Similarly, the biode- environment, enabling membrane hexagonal trans-
gradable lipids heptadecan-9-yl 8-((2-hydroxyethyl) formation and allowing them to leave the endosome.
(8-(nonyloxy)-8-oxooctyl)amino)octanoate (Lipid 5)77, Thus, lipid nanoparticle–mRNA formulations based on
heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(unde- zwitterionic ionizable lipids can escape the endosome,
cyloxy)hexyl)amino) octanoate (Lipid H (SM-102))78 leading to efficient protein expression and genome edit-
and ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl) ing in vivo114. In addition to functioning as a delivery
bis(2-hexyldecanoate) (ALC-0315)79 have better in vivo component, lipids can have therapeutic effects syner-
delivery efficacy and pharmacokinetics than MC3. gistic with mRNA-encoded proteins117–119. For exam-
Of note, SM-102 and ALC-0315 are the ionizable deliv- ple, lipids with a heterocyclic amine as head group can
ery components in the mRNA-1273 and BNT162b activate the stimulator of interferon genes (STING)
COVID-19 vaccines, respectively17. Biodegradable lipids signalling pathway in dendritic cells117. These lipids,
can also be made of both ester and disulfide motifs80–85. as part of an mRNA vaccine, induce potent cytolytic
Cleavage of the disulfide bonds then drives an intrapar- T lymphocyte responses and inhibit tumour growth in
ticle nucleophilic attack on the ester linker, accelerating mouse models117. Paclitaxel-conjugated lipids encapsu-
their degradation80–85. lating tumour suppressor mRNA can be applied to inte-
A combinatorial library has been designed that grate chemotherapy and gene therapy for triple-negative
contains lipid-like materials with different hydrophilic breast cancer118.
groups and multiple lipidic tails, highlighting the chem-
ical diversity of ionizable lipids86. Many lipid-like mate- Other types of lipid. In addition to cationic or ionizable
rials, such as 1,1′-((2-(4-(2-((2-(bis(2-hydroxydodecyl) lipids, lipid nanoparticle–mRNA formulations typically
amino)ethyl) (2-h ydroxydodecyl)amino)ethyl) contain other lipid components, such as phospholip-
piperazin-1-y l)ethyl)azanediyl) bis(dodecan-2-ol) ids (for example, phosphatidylcholine and phosphati-
(C12-200) 87, tetrakis(8-m ethylnonyl) 3,3′,3″,3‴- dylethanolamine), cholesterol or polyethylene glycol
(((methylazanediyl) bis(propane-3,1 diyl))bis (PEG)-functionalized lipids (PEG-lipids)7,14,17. These
(azanetriyl))tetrapropionate (306Oi10)88 and 3,6-bis(4- lipids can improve nanoparticle properties, such as
(bis(2-hydroxydodecyl)amino)butyl)piperazine- particle stability, delivery efficacy, tolerability and
2,5-dione (cKK-E12)89, have been developed to deliver biodistribution7,14,17. For example, 1,2-distearoyl-sn-
mRNA molecules in vivo 90–100. For example, cKK- glycero-3-phosphocholine (DSPC), a phosphatidylcho-
E12-based lipid nanoparticles are applied in cancer line with saturated tails, has a melting temperature of
immunotherapies94,95 and genome editing96. Replacing ~54 °C and a cylindrical geometry that allows DSPC
the lipidic chains of cKK-E12 with alkenyl amino alcohols molecules to form a lamellar phase, which stabilizes
results in 3,6-bis(4-(bis((9Z,12Z)-2-hydroxyoctadeca- the structure of lipid nanoparticles120. DSPC has been
9,12-dien-1-yl)amino)butyl)piperazine-2,5-dione (OF-02), used in the mRNA-1273 and BNT162b2 COVID-19
which improves mRNA delivery efficacy in vivo, compared vaccines17. DOPE is a phosphoethanolamine with two
with cKK-E12 (ref.101). Further altering the linkage of unsaturated tails, which has a melting temperature of
OF-02 leads to (((3,6-dioxopiperazine-2,5-diyl)bis ~30 °C and a conical shape120. DOPE tends to adopt
(butane-4,1-d iyl))bis(azanetriyl))tetrakis(ethane- an inverted hexagonal H(II) phase, which destabilizes
2,1-d iyl) (9Z,9′Z,9″Z,9‴Z,12Z,12′Z,12″Z,12‴Z)- endosomal membranes and facilitates endosomal escape
tetrakis (octadeca-9,12-dienoate) (OF-Deg-Lin) and of lipid nanoparticles90,120. Using DNA barcode-labelled
(((3,6-dioxopiperazine-2,5-diyl)bis(butane-4,1-diyl)) oligonucleotides, the distribution of different lipid
bis(azanetriyl))tetrakis (butane-4,1-diyl) (9Z,9′Z,9″Z,9‴Z, nanoparticle formulations can be analysed in a high-
12Z,12′Z,12″Z,12‴Z)-tetrakis (octadeca-9,12-dienoate) throughput manner in vivo121, for example, to quantify
(OF-C4-Deg-Lin), which allow selective delivery of targeted delivery of nucleic acids in multiple tissues121.
mRNA into the spleen102,103. The lipid-like material Based on this method, a series of phosphatidylcholines
N 1,N 3,N 5-t ris(3-(didodecylamino)propyl)benzene- containing constrained adamantyl groups has been
1,3,5-tricarboxamide (TT3) can deliver mRNA mol- explored for mRNA delivery, including analysis of
ecules encoding human factor IX104, CRISPR–Cas9 distribution in different cell types122.
(ref.105), an interleukin-12 (IL-12) replicon106 and severe Cholesterol can enhance particle stability by modu-
acute respiratory syndrome coronavirus 2 (SARS- lating membrane integrity and rigidity7,14,17. The molecu-
CoV-2) antigens107. Hexa(octan-3-yl) 9,9′,9″,9‴,9″″,9‴″- lar geometry of cholesterol derivatives can further affect
((((benzene-1,3,5-t ricarbonyl)ris(azanediyl)) tris delivery efficacy and biodistribution of lipid nanopar-
(propane-3,1-d iyl))tris(azanetriyl))hexanonanoate ticles. For example, cholesterol analogues with C-24
(FTT5), which is a biodegradable analogue of TT3, alkyl phytosterols increase the in vivo delivery efficacy
further improves the in vivo delivery efficacy of mRNA of lipid nanoparticle–mRNA formulations123. Here, the
encoding human factor VIII and base editing components108. length of the hydrophobic tails of the cholesterol ana-
In addition, a series of aminoglycoside-d erived logues, the flexibility of sterol rings and the polarity of
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Cationic lipids NH2
O
N O H NH H O
H 2N N N
DOTMA N
O O
DOSPA
O
O
O O
O O P O O
N
N O O
O
O DOTAP ePC
Ionizable lipids
HO OH
O N
OH OH N
N
O N N
N
DLin-MC3-DMA
OH
OH C12-200
HO O
N
O
O
N
NH
HN
OH N
O
O HO OH
O
ALC-0315 cKK-E12
O
HO O
N O O
O N O
O NH
O HN O
O N
O O O
Lipid H (SM-102) OF-Deg-Lin O
N O O
O
O N N N O
O N
O O
N A2-Iso5-2DC18 O O
306Oi10
O H
S O N N
HN O S
O
N S O O
N O S
N NH HN N
S TT3
O O S
BAME-O16B O
O
H
O N N O
O
H O O O O O
O O
N P
O N NH HN N O
O
O FTT5 O
9A1P9
O O
Other types of lipids

O
O
O O
O O
O P O O
O P O O H 3N
N O
O O
O
DOPE
DSPC
O
O
O O N O
45
O
O O 45
O ALC-0159
PEG2000-DMG
H
H H H OH
H
H H H Br
O
O H H
H H H H H H N
N HO N O
HO N O HO H
H
Cholesterol DC-Cholesterol ß-sitosterol BHEM-Cholesterol
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◀ Fig. 2 | Chemical structures of lipids and lipid derivatives used for mRNA delivery. PEG 2000-DMG from lipid nanoparticles, compared
306Oi10, tetrakis(8-methylnonyl) 3,3′,3″,3‴-(((methylazanediyl) bis(propane-3,1 diyl))bis with PEG2000-DSG, which may benefit cellular uptake
(azanetriyl))tetrapropionate; 9A1P9, decyl (2-(dioctylammonio)ethyl) phosphate; and endosomal escape of lipid nanoparticles128,129.
A2-Iso5-2DC18, ethyl 5,5-di((Z)-heptadec-8-en-1-yl)-1-(3-(pyrrolidin-1-yl)propyl)-2,
5-dihydro-1H-imidazole-2-carboxylate; ALC-0315, ((4-hydroxybutyl)azanediyl)
Overcoming physiological barriers
bis(hexane-6,1-diyl)bis(2-hexyldecanoate); ALC-0159, 2-[(polyethylene glycol)-2000]-
N,N-ditetradecylacetamide; β-sitosterol, (3S,8S,9S,10R,13R,14S,17R)-17-((2R,5R)-
To function in vivo, lipid nanoparticle–mRNA formu-
5-ethyl-6-methylheptan-2-yl)-10,13-dimethyl-2,3,4,7 ,8,9,10,11,12,13,14,15,16,17- lations need to overcome multiple extracellular and
tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol; BAME-O16B, bis(2-(dodecyldisulfa- intracellular barriers7,11 (Fig. 3a). First, mRNA needs to
nyl)ethyl) 3,3′-((3-methyl-9-oxo-10-oxa-13,14-dithia-3,6-diazahexacosyl)azanediyl) be protected from nuclease degradation in physiologi-
dipropionate; BHEM-Cholesterol, 2-(((((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17- cal fluids7,11. Second, the formulation should evade the
((R)-6-methylheptan-2-yl)-2,3,4,7 ,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H- interception by the MPS and clearance by renal glomer-
cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)-N,N-bis(2-hydroxyethyl)-N- ular filtration post systemic administration7,11. Third,
methylethan-1-aminium bromide; C12-200, 1,1′-((2-(4-(2-((2-(bis(2-hydroxydodecyl) lipid nanoparticle–mRNA systems need to reach target
amino)ethyl) (2-hydroxydodecyl)amino)ethyl) piperazin-1-yl)ethyl)azanediyl) bis(dodecan- tissues, followed by internalization by target cells7,11.
2-ol); cKK-E12, 3,6-bis(4-(bis(2-hydroxydodecyl)amino)butyl)piperazine-2,5-dione;
Finally, mRNA molecules must escape endosomes to
DC-Cholesterol, 3β-[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol; DLin-MC3-
DMA, (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino) reach the cytoplasm, where translation occurs7,11.
butanoate; DOPE, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; DOSPA, 2,3- Lipid nanoparticle–mRNA formulations manufactured
dioleyloxy-N-[2-(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium by rapid mixing exhibit a stable nanostructure17,130,131,
trifluoroacetate; DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane; DOTMA, in which mRNA molecules can be encapsulated in
1,2-di-O-octadecenyl-3-trimethylammonium-propane; DSPC, 1,2-distearoyl-sn- the interior core through electrostatic interactions with the
glycero-3-phosphocholine; ePC, ethylphosphatidylcholine; FTT5, hexa(octan-3-yl) lipids17,131. This structural feature protects mRNA mol-
9,9′,9″,9‴,9″″,9‴″- ((((benzene-1,3,5-tricarbonyl)yris(azanediyl)) tris (propane-3,1-diyl)) ecules from nuclease degradation and increases nano-
tris(azanetriyl))hexanonanoate; Lipid H (SM-102), heptadecan-9-yl 8-((2-hydroxyethyl) particle stability in physiological fluids17,46. Incorporating
(6-oxo-6- (undecyloxy)hexyl)amino) octanoate; OF-Deg-Lin, (((3,6-dioxopiperazine-2, PEG-lipids further decreases recognition by the MPS
5-diyl)bis(butane-4, 1-diyl))bis(azanetriyl))tetrakis(ethane-2,1-diyl) (9Z,9′Z,9″Z,9‴Z,
and clearance by renal filtration17,127. Additionally,
12Z,12′Z,12″Z,12‴Z)-tetrakis (octadeca-9,12-dienoate); PEG2000-DMG, 1,2-dimyristoyl-
rac-glycero-3-methoxypolyethylene glycol-2000; TT3, N1,N3,N5-tris(3-(didodecylamino) targeted biodistribution of lipid nanoparticle–mRNA
propyl)benzene-1,3,5-tricarboxamide. formulations can be improved by further modifying
and optimizing the nanoparticle26,27,69,114,132–135; for exam-
ple, nanoparticles can be coated with antibodies132 to
hydroxy groups impact delivery efficacy123. In addition, deliver mRNA molecules into inflammatory leukocytes
lipid nanoparticles formulated with cholesterol deriv- and epidermal growth factor receptor (EGFR)-positive
atives adopt a polyhedral shape, and not a spherical tumour cells for treating inflammatory bowel disease69
shape, with multilamellarity and lipid partitioning124. and cancer133, respectively. Organ selectivity can also be
Lipid nanoparticles containing cholesteryl oleate further achieved by adjusting the proportions of lipid compo-
show higher selectivity for liver endothelial cells than for nents, for example, to design spleen-targeted mRNA
hepatocytes125. Moreover, oxidative modifications on the vaccines26,27 or lung-targeted genome editing delivery
cholesterol tail enable lipid nanoparticles to accumulate systems114,134.
more in liver endothelial cells and Kupffer cells than in Once they reach target cells, lipid nanoparticles
hepatocytes126. can be internalized by multiple mechanisms, includ-
PEG-lipids can have multiple effects on the properties ing macropinocytosis and clathrin-m ediated and
of lipid nanoparticles14,17,72,127–129. The amount of PEG- caveolae-m ediated endocytosis10,17. The endocytic
lipids can affect particle size and zeta potential17,72. pathway depends on the properties of the nanoparticle
PEG-lipids can further contribute to particle stabil- and the cell type100,108,136. Following cellular internaliza-
ity by decreasing particle aggregation14,17,127, and cer- tion, lipid nanoparticles are usually trapped in endoso-
tain PEG modifications prolong the blood circulation mal compartments137–139. Indeed, only a small amount
time of nanoparticles by reducing clearance mediated of lipid nanoparticles may be able to escape from the
by the kidneys and the mononuclear phagocyte sys- endosome137–139. Thus, endosomal escape is crucial for
tem (MPS)14,17,127–129. Finally, PEG-lipids can be used to effective mRNA delivery. Although the mechanism has
conjugate specific ligands to the particle for targeted not yet been fully understood, positively charged lipids
delivery. The extent of these effects depend on the pro- may facilitate electrostatic interaction and fusion with
portions and properties of the PEG-lipids (such as PEG negatively charged endosomal membranes, resulting in
molar mass and lipid length)17,72,127–129. For example, the leak of mRNA molecules into the cytoplasm7,11,14,17,100.
1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene Endosomal escape can be increased by optimizing the
glycol-2000 (PEG 2000 -DMG) and 1,2-distearoyl- pKa values of ionizable lipids66,76–78,88,100,140. Furthermore,
rac-glycero-3-methoxypolyethylene glycol-2000 the properties of lipidic tails can affect endosomal escape
(PEG2000-DSG) are neutral PEG-lipids, and the length of lipid nanoparticles64,97,114,141; for example, some lipids
of their saturated alkyl chains is C14 and C18, respec- with branched tails show enhanced endosomal escape
tively 129. Lipid nanoparticle–siRNA formulations compared with their counterparts with linear tails,
containing PEG 2000-DMG have shorter circulation owing to stronger protonation at endosomal pH (ref.97).
times and higher delivery efficacy in vivo than for- In addition, modulating the type (for example, DSPC
mulations containing PEG 2000-D SG 129. This differ- and DOPE) and ratio of lipids may improve endosomal
ence may be attributed to the faster dissociation of escape90,104,116,123,136,142.
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a LNP–mRNA formulation b
Intracerebroventricular
injection
Systemic delivery Local delivery Intraocular

injection
Intranasal
administration
Inhalation
Extracellular barriers
Macrophage Intratumoural
injection
Intracardiac
injection
Dendritic cell
Intravenous
Endonuclease injection
Extravasation Secretory
protein
Cell membrane
Transmembrane
protein Intracellular
protein
Intracellular barriers
Epidermis
Endosome
Dermis
Adipose
tissue
Vein
Endosome Muscle
escape Intradermal Subcutaneous Intramuscular
injection injection injection
Fig. 3 | Delivery barriers and administration routes for lipid nanoparticle–mRNA formulations. a | Physiological
barriers for lipid nanoparticle–mRNA (LNP–mRNA) formulations post systemic and local delivery. b | Administration routes
for LNP–mRNA formulations. Panel b reprinted from ref.155, Springer Nature Limited.
Administration routes Topical administration routes have also been

Administration routes can greatly influence organ dis- explored for mRNA therapeutics. Topical adminis-
tribution, expression kinetics and therapeutic outcomes tration aims at achieving local therapeutic effects; for
of lipid nanoparticle–mRNA formulations143,144. The example, local injection of lipid nanoparticle–mRNA
administration route is often determined by the prop- formulations enables supplementation of therapeutic
erties of the nanoparticles and therapeutic indications proteins in specific tissues, such as heart49,93, eyes56,72,151
(Fig. 3b). After intravenous (i.v.) administration, many and brain67,152. Of note, administration of mRNA encod-
lipid nanoparticles can accumulate in the liver. The liver ing vascular endothelial growth factor (VEGF) has been
is inherently capable of producing secretory proteins shown to lead to functional protein expression in the
and, therefore, i.v. administration of lipid nanoparticle– skin even in the absence of lipid nanoparticles153. Indeed,
mRNA formulations can be used to produce proteins mRNA delivery by direct injection into the heart mus-
that are missing in inherited metabolic and haematologi- cle of patients undergoing coronary bypass surgery
cal disorders, or to produce antibodies to neutralize path- is currently being tested in a randomized phase II
ogens or target cancer cells39,95,145–147. These applications trial (NCT03370887)154. Moreover, lipid nanoparticle–
require protein translation without stimulation of an mRNA formulations can be administered into the lungs
immune response, which may limit the efficiency of by inhalation71, for example, MRT5005 (NCT03375047).
repeated dosing. However, i.v. administration may also Local administration can also prime systemic
lead to accumulation of lipid nanoparticles in multiple responses; for example, intradermal (i.d.), intramus-
lymph nodes throughout the body, which could increase cular (i.m.) and subcutaneous (s.c.) injection are com-
immune responses to mRNA vaccines. For example, monly used for vaccination17,155, because resident and
i.v. administration of mRNA vaccines has been shown recruited antigen-presenting cells (APCs) are present in
to induce stronger antigen-specific cytotoxic T cell the skin and muscle, which can internalize and process
responses compared with local injection26,148,149. Broad mRNA-encoded antigens17,155. Furthermore, the vascu-
distribution of mRNA vaccines in the body may lead to lar and lymphatic vessels of these tissues help APCs and
systemic adverse effects, and, thus, it may be necessary mRNA vaccines to centre the draining lymph nodes to
to develop lipid nanoparticles that allow targeted stimulate T cell immunity17,155. Indeed, both i.m. and i.d.
delivery of mRNA vaccines into tissues with abundant administration of lipid nanoparticle–mRNA vaccines
immune cells26,150. produce robust immune responses at a well-tolerated
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dose in human trials156,157. Vaccination can also be done removed by DNase digestion and the mRNA molecules
by intranasal administration, because APCs in the are capped by chemical or enzymatic methods2,4,165,166.
peripheral lymph nodes can readily endocytose adminis- Finally, mRNA is purified by microbeads-based pre-
tered lipid nanoparticle–mRNA formulations17,34,155,158–160. cipitation or chromatographic methods to remove the
In addition, lipid nanoparticle–mRNA formulations enzymes, free nucleotides, truncated nucleic acid frag-
encoding immune stimulators can be directly delivered ments and double-stranded RNA2,4,165,166. The purified
into tumour tissue by intratumoural injection106,161–163, mRNA can be dissolved in a storage buffer, filtered for
to boost a local pro-inflammatory environment, which sterilization and frozen for long-term storage2,4,165,166.
leads to immune cell activation and subsequent prim- To increase the stability and translational efficiency
ing of systemic anticancer responses106,161–163. Finally, of mRNA, various approaches have been explored to
in utero administration of lipid nanoparticle–mRNA optimize its structural elements (Box 1).
formulations can be applied to deliver mRNA to mouse Historically, lipid nanoparticle–nucleic acid for-
fetuses164, achieving protein expression in fetal livers, mulations were produced by thin-f ilm hydration,
lungs and intestines164. reverse-phase evaporation and other methods167. The
sizes of lipid nanoparticles were further homogenized
Considerations for clinical translation by extrusion techniques167. Lipid nanoparticle–mRNA
The properties of lipid nanoparticle–mRNA formula- formulations are now commonly manufactured by rapid
tions need to be carefully characterized and considered mixing; here, an ethanol phase (lipid components) and
for the desired application. Lipid nanoparticle–mRNA an aqueous phase (mRNA molecules) are mixed under
formulations may need different properties as vaccines specific conditions (that is, pH and flow rate)17,131. This
than as therapeutics to achieve optimal therapeutic technique allows reproducible and scalable production
effects, for example, distinct biodistribution profiles. of lipid nanoparticle–mRNA formulations that show
Vaccines need to interact with immune cells, whereas high encapsulation efficiency and homogeneous size
therapeutics are targeted to specific organs. Therefore, distribution17,131. mRNA is susceptible to degradation
lipid nanoparticle–mRNA formulations should be and, thus, formulation buffers should be free of any ribo
designed according to biomedical demand. To translate nuclease contaminations2,4. Lipid nanoparticle–mRNA
lipid nanoparticle–mRNA systems from bench to bed- formulations are further purified to remove organic
side, good manufacturing practice (GMP) is crucial to solvents and residual components, and the final mRNA
ensure drug quality and therapeutic effects, in addition concentration can be further increased by enrichment.
to considerations such as storage conditions and safety The filtered and frozen lipid nanoparticle–mRNA for-
profiles. mulations are then subject to a series of GMP standard
tests, including evaluation of physical parameters (such
Good manufacturing practice. The preparation of a as mRNA encapsulation, particle sizes, charges), com-
linearized DNA template is the initial step of GMP pendial testing (such as sterility, bacterial endotoxins,
production of mRNA2,4,165,166. Based on the DNA tem- particulate matter, osmolality) and other quality testing.
plate, the mRNA is then transcribed in vitro in the
presence of an RNA polymerase and ribonucleoside Stability and storage. Storage conditions of lipid
triphosphates2,4,165,166. The residual DNA template is nanoparticle–mRNA formulations are an important con-
sideration for their clinical translation, because storage
(aqueous, freezing and lyophilized storage) and the type
Box 1 | Engineering mRNA molecules of cryoprotectants (sucrose, trehalose or mannitol) affect
mRNA normally contains five structural elements, that is, a 5′ cap, a 3′ poly(A) tail,
the long-term stability of lipid nanoparticle–mRNA
a protein-coding sequence and 5′ and 3′ untranslated regions (UTRs)2,4,7,13. These formulations168. For example, the addition of 5% (w/v)
elements are crucial for initiation, translation, termination, post-transcriptional sucrose or trehalose to lipid nanoparticle–mRNA formu-
modification and decay of mRNA molecules2,4,7,13. These elements can be engineered lations, stored in liquid nitrogen, allows maintenance of
to improve the stability and translational efficiency of mRNA2,4,7,13. mRNA delivery efficacy for at least 3 months in vivo168.
• Incorporation of 5′ cap analogues allows initiation of the translation complex with Of note, the authorized COVID-19 mRNA vaccines are
the eukaryotic translation initiation factor 4E. Such 5′ cap analogues may be more both stored in freezing conditions in the presence of
resistant to decapping enzymes sucrose17. mRNA-1273 is stored at −15 °C to −20 °C and
• The 3′ poly(A) tail is involved in interactions with the poly(A)-binding protein. is directly injected after thawing17, whereas BNT162b2 is
Optimization of the length of the poly(A) tail and its composition can stabilize stored at −60 °C to −80 °C and requires thawing and dilu-
the mRNA and increase protein expression tion by saline before injection17. Recently, the European
• UTRs interact with multiple RNA-binding proteins and microRNAs, and, thus, Medicines Agency (EMA) has approved storage of
sequence engineering of 5′ and 3′ UTRs can increase the half-life and translational BNT162b2 at −15 °C to −25 °C for 2 weeks based on
efficiency of mRNA
new stability data. Although cold-chain transportation
• Codon optimization (for example, replacing rare codons with synonymous frequent can maintain vaccine activity, the development of lipid
codons) can accelerate the translation rate. Codon optimization can also form nanoparticle–mRNA formulations that do not require
favourable secondary structures, improving translational efficiency
cold or frozen storage would not only decrease pro-
• Incorporating chemically modified nucleosides can decrease immunogenicity and duction and transportation costs but also expedite the
increase translation of mRNA
process of vaccination. Therefore, it is important to inves-
• Circular RNA (circRNA) design can extend the duration of mRNA translation because tigate the factors impacting long-term storage of lipid
circRNA is resistant to nuclease-mediated degradation
nanoparticle–mRNA formulations.
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Safety profiles. The safety profile of lipid nanoparticle– availability, clinical trial phases I, II and III were initi-
mRNA formulations correlates with the lipid compo- ated, respectively15,17. Finally, mRNA-1273 obtained
nents and mRNA molecules. Lipid components may Emergency Use Authorization from the FDA and con-
activate host immune responses following systemic or ditional marketing authorization from the EMA within
local administration; for example, PEG-lipids could a year15,17. Many other lipid nanoparticle–mRNA formu-
induce hypersensitivity reactions by stimulating the lations are in clinical trials for the treatment of infectious
complement system127,169. Moreover, anti-PEG antibod- diseases, cancer and genetic disorders2,4,8,12–14 (Tables 1,2).
ies could result in fast systemic clearance of subsequently Moreover, mRNA-b ased cellular reprogramming,
administered PEGylated nanoparticles by accelerated tissue regeneration and genome editing have shown
blood clearance127,169. The accelerated blood clearance therapeutic potential in preclinical studies2,4,8,12–14.
phenomenon may change the bioavailability and biodis-
tribution of the drug encapsulated in PEGylated nano- Infectious diseases. Vaccines are the most effective
particles and, thus, cause side effects127,169. To ameliorate approach to control and eradicate epidemics. The first
safety concerns, numerous natural and synthetic poly- mRNA vaccine was made of liposomes and mRNA
mers have been investigated as alternatives to PEG, of encoding an influenza virus nucleoprotein184. This vac-
which several are under evaluation in clinical trials127,169. cine, designed in 1993, was able to induce virus-specific
Cationic and ionizable lipids have also been reported to cytotoxic T cell responses in mice184. Since then, lipid
stimulate the secretion of pro-inflammatory cytokines nanoparticle–mRNA formulations have emerged as a
and reactive oxygen species170–173. Although the immuno- potent alternative to conventional vaccine platforms,
genicity of these lipids has not yet been fully understood, owing to their unique features4,15,17. First, mRNA is a
complement system and Toll-like receptors may partic- non-infective and non-integrating agent with the abil-
ipate in innate immune activation170,173–175. Cytotoxicity ity to encode a broad range of antigens4,15,17. Second,
of lipid materials is also a safety concern, depending mRNA vaccines can combine different antigen mRNAs;
on the dose, lipid properties and cell types176,177. In vivo for example, six separate mRNAs have been incorporated
application of lipid nanoparticles has been reported to in a cytomegalovirus vaccine, five of which encode a sin-
induce liver and lung injuries in rodents170,173, which gle pentameric antigen and one encodes a glycoprotein
may be attributed to the cytotoxicity of the materials antigen185. Finally, GMP-grade lipid nanoparticle-mRNA
and the induction of pro-inflammatory factors171,178. vaccines can be manufactured for specific antigens in a
To improve the biocompatibility of lipid nanoparticles, short period of time, compared with other vaccine plat-
biodegradable lipids can be applied76–78,108,179. forms, such as recombinant proteins and inactivated
The immunogenicity of IVT mRNA is another vaccines2,4,15,17. These features make lipid nanoparticle–
safety concern, although eliciting cellular and humoral mRNA formulations a flexible and on-demand vaccine
immunity may be advantageous for vaccination. platform to rapidly respond to emerging infectious
Nevertheless, immune responses to IVT mRNA may pathogens4,15,17. However, the instability and short half-
also suppress antigen expression and negatively affect life of mRNA need to be carefully considered. In addi-
vaccine efficacy175,180,181. Moreover, immune activation is tion, safety concerns and storage conditions of lipid
undesirable for some mRNA applications, such as pro- nanoparticles need to be determined before clinical use.
tein replacement therapies and genome editing. To min- To address these concerns, the engineering of mRNA
imize the immunogenicity of mRNA, two approaches molecules (Box 1) and the design of lipid nanoparti-
are commonly used. Chemical modifications of specific cles have been optimized2,4,7–17, which has contributed
IVT mRNA nucleotides, such as pseudouridine (ψ) to the rapid development and clinical assessment15,17
and N1-methylpseudouridine (m1ψ), can reduce innate of the two COVID-19 mRNA vaccines, mRNA-1273
immune sensing of exogenous mRNA translation2,4,7,182. (NCT04470427)19,20 and BNT162b2 (NCT04368728)21.
Chromatographic purification can remove double- Both vaccines use ionizable lipid nanoparticles to deliver
stranded RNA, an analogue of viral genome, in IVT nucleoside-modified mRNA encoding the full-length
mRNA preparations, diminishing immune activa- spike protein of SARS-CoV-2 (Fig. 4). Applying a prime–
tion and increasing translational efficiency2,4,7,183. The boost vaccination method, the vaccines induce high
IVT mRNA molecules used in the mRNA-1273 and levels of antigen-specific antibodies and elicit robust
BNT162b2 COVID-19 vaccines were prepared by replac- T helper 1 cell responses19–21. Moreover, the vaccines
ing uridine with m1ψ17,19,21, and their sequences were showed similar efficacy (~95%) in phase III clinical
optimized to encode a stabilized pre-fusion spike protein trials19–21. Other COVID-19 vaccines based on lipid
with two pivotal proline substitutions17,19,21. nanoparticle–mRNA formulations are also under eval-
uation in different clinical phases (Table 1). In preclini-
Preclinical studies and clinical trials cal studies, some vaccine candidates showed protective
The features of lipid nanoparticle–mRNA formula- effects by delivering self-amplifying RNA encoding the
tions have been thoroughly preclinically and clinically spike protein40,186,187 (Box 2), a cocktail of mRNAs encod-
investigated, which has allowed the rapid development ing three viral proteins74, modified mRNA encoding
and clinical use of the COVID-19 lipid nanoparticle– the receptor-binding domain188 or spike mRNA with
mRNA vaccines. For example, the clinical-g rade engineered untranslated regions107.
COVID-19 vaccine, mRNA-1273, was produced within Lipid nanoparticle–mRNA vaccines are also being
a month after the SARS-CoV-2 genome sequence was investigated as influenza vaccines29,41,156,157,159,184,189–191,
available15,17. About 2, 5 and 6 months from sequence with some formulations in clinical trials (Table 1) .
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SARS-CoV-2
CD8+ CD4+
Spike protein T cell T cell
TCR
Spike gene MHC
class II
MHC
class I
LNP–mRNA vaccine B cell
Epitopes Proteasome
Spike mRNA
mRNA
Vaccinated cell Lysosome APC
Fig. 4 | Lipid nanoparticle–mRNA formulations as COVID-19 vaccines. histocompatibility complex (MHC) class I presents the resultant epitopes to
After intramuscular injection, lipid nanoparticle–mRNA (LNP–mRNA) CD8+ T cells2,4,7,11,17. Spike antigens can also be endocytosed by APCs. These
vaccines are internalized by somatic cells (for example, muscle cells) and tissue- antigens are degraded in the lysosomes of APCs and presented by MHC II
resident or recruited antigen-presenting cells (APCs)2,4,7,11,17. Moreover, molecules for CD4+ T cells2,4,7,11,17. In addition, secreted spike antigens can be
LNP–mRNA vaccines can centre draining lymph nodes, where various internalized by B cell receptors and processed for presentation to CD4+ T cells
immune cells reside, including naive T and B cells2,4,7,11,17. Spike antigens by MHC class II molecules2,4,7,11,17. COVID-19, coronavirus disease 2019; SARS-
expressed in the cytoplasm are degraded by proteasomes2,4,7,11,17 and major CoV-2, severe acute respiratory syndrome coronavirus 2; TCR, T cell receptor.
Haemagglutinin is an essential surface antigen of influ- protection against parasitical31 and bacterial30,198 infec-
enza viruses156,157. The mRNA-1440 and mRNA-1851 tions. In addition, lipid nanoparticle–mRNA for-
vaccines, which are composed of lipid nanoparticles mulations have been applied to produce therapeutic
and mRNA encoding haemagglutinin from H10N8 and proteins or antibodies39,75,145,146, to edit virus genomes105
H7N9 influenza viruses, respectively, have com- and to engineer immune cells136. For example, a vita-
pleted phase I clinical studies (NCT03076385 and min C-derived lipid nanoparticle allows mRNA deliv-
NCT03345043)156,157. After i.m. prime–boost vaccina- ery into primary macrophages136. Adoptive transfer
tion, humoral immune responses were evaluated by of macrophages engineered by delivering mRNA that
haemagglutination inhibition (HAI) and microneu- encodes an antimicrobial peptide considerably reduced
tralization (MN) assays. A 100-µg dose level induced bacterial burden and increased survival in mice with
78.3% (HAI) and 87.0% (MN) seroconversion for multidrug-resistant bacterial sepsis136. Furthermore,
H10N8 (refs156,157) and a 50-µg dose level resulted in the lipid nanoparticle–mRNA formulation mRNA-1944
96.3% (HAI) and 100% (MN) seroconversion for H7N9 (NCT03829384), designed to generate anti-chikungunya
(refs156,157). Lipid nanoparticle–mRNA formulations are virus antibody (CHKV-IgG) in vivo, is under clini-
further being explored for Zika virus vaccines38,190,192–194. cal evaluation. A single i.v. injection of 0.1, 0.3 and
The vaccine mRNA-1893 is a clinical candidate that 0.6 mg kg −1 lipid nanoparticle–mRNA formulation
contains lipid nanoparticles with mRNA encod- produced 2.0, 7.9 and 10.2 µg ml−1 CHKV-IgG 24 h
ing Zika virus premembrane and envelope (prM-E) post injection, respectively. The half-life of CHKV-IgG
proteins193,194. According to mRNA-1893 interim phase I was about 69 days and the dose levels were reasona-
data (NCT04064905) reported by Moderna, 10-µg and bly well tolerated, including 0.3 mg kg−1 given twice
30-µg dose levels (prime–boost regimen) induced 94% a week apart.
and 100% seroconversion, respectively, and both dose
levels were generally well tolerated. Cancer. The attempt of mRNA-based cancer immuno
A series of clinical trials of mRNA vaccines have therapies dates back to 1995, when i.m. injection of
been initiated against human metapneumovirus, cyto- mRNA encoding carcinoembryonic antigens was
megalovirus, respiratory syncytial virus, rabies virus shown to induce antigen-specific immune responses
and chikungunya virus (Table 1). Furthermore, lipid in mice 199. Various cancer vaccines based on lipid
nanoparticle–mRNA vaccines have been tested against nanoparticle–mRNA formulations are currently in clini-
other viruses in animal models, including human cal trials (Table 1). For example, FixVac, which was devel-
immunodeficiency virus28,144,181,190, Powassan virus195, oped based on the RNA-LPX formulation, is a systemic
Venezuelan equine encephalitis virus196, dengue virus73 mRNA vaccine encoding four non-mutated antigens
and Ebola virus197. of melanoma200. The interim analysis from the phase I
Apart from viral infections, lipid nanoparticle– trial (NCT02410733) showed that the metabolic activ-
mRNA vaccines have been reported to induce immune ity of the spleen increased post the sixth immunization,
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Box 2 | Self-amplifying RNA and circular RNA respectively210,211. In the monotherapy group, 14 out of
16 patients remained disease-free during the study, with
Self-amplifying RNA2,13 a median follow-up time of 8 months210,211. In the com-
Compared with regular mRNA, self-amplifying RNA (also termed replicon), which was bination group, the overall response rate in the cohort
originally derived from an alphavirus genome, has similar basic elements (5′ cap, 5′ and (human papillomavirus-negative, immune checkpoint
3′ untranslated regions, 3′ poly(A) tail) and a long coding region. The coding region
inhibitor-naive, head and neck squamous cell carci-
contains the sequences for an RNA-dependent RNA polymerase (RDRP), a promoter
and structural viral proteins (also known as subgenomic sequence). After delivery into nomas) was 50% and the median progression-f ree
the cytoplasm, self-amplifying RNA (positive-strand mRNA) functions as a translation survival was 9.8 months210,211. Using a similar lipid nan-
template for the production of the RDRP. Moreover, the positive-strand mRNA serves oparticle formulation, mRNA vaccination has also been
as a genomic template for RDRP-mediated replication. The initial replication leads to shown to elicit specific T cell responses in patients with
negative-strand RNA, which acts as template for the generation of the positive-strand gastrointestinal cancer (NCT03480152)212.
viral genome. Meanwhile, the promoter in the negative-strand RNA is recognized by mRNA vaccines can further be applied to overcome
the RDRP, leading to the transcription of capped subgenomic RNA that encodes insufficient stimulation of chimeric antigen receptor
structural viral proteins. This self-amplification process allows the mass production of (CAR) T cells in the therapy of solid tumours213. For
virions from limited amounts of virus at infection. Replacing the subgenomic sequence example, the RNA-LPX formulation can be used to
by a gene of interest enables high-level expression of desired proteins. The transient
deliver mRNA encoding claudin 6 (CLDN6), a target
replication generates double-stranded RNA (dsRNA) and, thus, self-amplifying RNA
tends to activate innate immune pathways. for CAR T cell therapy in solid tumours213. i.v. injection
of this vaccine resulted in CLDN6 expression on splenic
Circular RNA13,245,246 dendritic cells and macrophages213, promoting the acti-
Circular RNA (circRNA) is a single-stranded RNA with a closed-loop structure. circRNA
vation of adoptively transferred CLDN6-CAR T cells
does not have a free 5′ cap or 3′ poly(A) tails and is, thus, unsusceptible to degradation
by nucleases and more stable than linear RNA. Moreover, circRNA without a stop codon
and leading to suppression of large tumours in mice at a
reduces the frequency of ribosome detachment from the RNA, thereby enabling sub-therapeutic CAR T cell dose213.
continuous translation and high protein expression. Synthetic circRNA can be made by Alternatively to vaccination, a pro-inflammatory
covalently linking the 3′ and 5′ ends of a linear precursor using enzymatic or chemical tumour microenvironment can be induced by lipid
methods. Similar to linear mRNA, the chemical modification of specific nucleotides and nanoparticle–mRNA formulations delivering cytokines
chromatographic purification can minimize immunogenicity of the RNA and increase or co-stimulatory molecules33,106,161,163,214 (Table 2). For
translation. Therefore, circularization can improve the stability and half-life of mRNA in example, mRNA-2416, a lipid nanoparticle encapsulat-
a physiological environment. ing mRNA encoding human OX40L (a ligand of OX40),
is in clinical evaluation for the treatment of patients with
indicating targeted delivery of FixVac and activation solid tumours (NCT03323398)214. In this trial, mRNA-
of resident immune cells200. After the eighth immuni- 2416 was intratumourally administered every 2 weeks
zation, more than 75% of patients generated immune for up to 12 doses, with four dose levels from 1 to 8 mg
responses against at least one tumour-associated antigen, (ref. 214) . mRNA-2416 was generally well tolerated at
and CD8+ T cells played a major role in high-magnitude different does levels214. Moreover, the injected lesions
T cell responses200. Moreover, a combination of FixVac/ showed an increase in OX40L expression and enhanced
anti-programmed cell death protein 1 (PD1) antibody T cell activation214. Encouraged by these results, mRNA-
augmented the antitumour effect of FixVac, resulting in 2752, a lipid nanoparticle formulated with mRNA
a >35% tumour regression rate in immune checkpoint encoding human OX40L, IL-23 and IL-36γ, entered
inhibitor-experienced patients200. To further improve clinical evaluation (NCT03739931)163,215,216. mRNA-2752
vaccine efficacy, APC uptake and T cell activation can was designed to induce a pro-inflammatory tumour
be optimized; for example, mannose-modified lipid microenvironment and to simultaneously strengthen
nanoparticle–mRNA formulations are preferentially taken T cell expansion, as well as memory responses215,216.
up by dendritic cells150,201,202. The efficacy of cancer vaccines mRNA-2752 was intratumourally administered every
can also be boosted by co-delivery of antigen mRNA with 2 weeks for up to seven doses, alone or in combination
adjuvants32,63,94,203–206, co-stimulatory molecules148,150,207,208 with infusion of durvalumab215,216. In the 22 patients
and immune checkpoint inhibitors200–202,209–211. (monotherapy: n = 15; combination: n = 7), six had sta-
Neoantigens, generated by somatic mutations in ble disease, one had partial responses with 52% tumour
cancer cells, are usually tumour-specific and have high reduction and five showed tumour shrinkage in treated
immunogenicity4,11. Neoantigens are often different and/or untreated sites215,216. Lipid nanoparticle–mRNA
between individual patients, allowing the development formulations have also been investigated for ex vivo
of personalized vaccines4,11. For example, intranodal vac- engineering of CAR T cells217 and for the production of
cination with free mRNA encoding ten neoepitopes of antibodies, such as anti-CD20 (ref.146), anti-human epi-
13 patients with metastatic melanoma generated T cell dermal growth factor receptor 2 (HER2)95 and anti-CD3/
immunity against multiple neoepitopes in all patients209. claudin 6 (ref.147). Cancers are often accompanied by
Several personalized cancer vaccines using lipid nano- mutations in the genome and, therefore, correction of
particle–mRNA formulations have also entered clinical these mutations could be an effective approach for cancer
trials210–212. For example, mRNA-4157 is a personalized therapies. For example, restoration of the tumour sup-
cancer vaccine encoding up to 34 neoantigens210,211. pressor gene TP53 can induce tumour cell apoptosis and
A phase I study (NCT03897881) has been performed to sensitize tumour cells to chemotherapeutics in vivo118,218.
evaluate the immunogenicity of mRNA-4157 alone and Similarly, the regulation of other tumour-associated
in combination with immune checkpoint inhibitors in genes, such as PLK1 (ref.133), Bax219, Maspin37, PUMA70
patients with resected and unresectable solid tumours, and PTEN220, can delay tumour growth in vivo.
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Genetic disorders. Genetic disorders are caused by inher- mRNA can restore chloride secretion in Cftr-knockout
ited or acquired gene mutations, which can cause abnor- mice 68. Translate Bio has started a clinical trial
mal protein expression12. The supplement of therapeutic (NCT03375047) to evaluate the safety and tolerability
proteins can relieve clinical symptoms but can often not of nebulized lipid nanoparticle–mRNA formulations
provide lasting treatments or cures. Alternatively, gene (MRT5005) in patients with cystic fibrosis. In this
therapy seeks to modify malfunctioning genetic expres- phase I/II study, patients received a single dose of
sion. mRNA-based protein replacement therapies have MRT5005 at three dose levels (8, 16 and 24 mg). MRT5005
also emerged as a promising alternative to protein drugs, was well tolerated at the 8-mg and 16-mg dose levels, and
because mRNA can be translated into desired proteins no serious side events were observed at any dose level.
with in situ post-translational modifications in host The lung function was evaluated by percent predicted
cells12. Moreover, mRNA can restore different types forced expiratory volume in 1 s (PPFEV1). According
of protein, including secretory proteins, intracellular to the interim report, the three patients who received
proteins and transmembrane proteins12. the 16-mg dose showed maximal PPFEV1 increases
Clinical trials of protein replacement thera- of 11.1%, 13.6% and 22.2%, respectively, on day 8 post
pies using lipid nanoparticle–mRNA formulations nebulizing. mRNA-based protein replacement therapies
have mainly focused on inherited metabolic dis- are also being explored for heart241, liver242, lung243 and
orders thus far, including ornithine transcarbam- other organ diseases12.
ylase deficiency (NCT03767270), methylmalonic
acidaemia (NCT03810690) and propionic acidaemia Conclusions and future directions
(NCT04159103) (Table 2). These diseases are charac- Progress in mRNA technologies and lipid nanoparticle-
terized by genetic deficiency of key enzymes, leading based delivery systems has allowed the development
to an inability to process certain metabolic products12. of mRNA COVID-19 vaccines at unprecedented
The excessive accumulation of metabolites then speed, demonstrating the clinical potential of lipid
results in clinical symptoms and may lead to death12. nanoparticle–mRNA formulations and providing a pow-
Therefore, the supplement of desired enzymes by lipid erful tool against the SARS-CoV-2 pandemic. A variety
nanoparticle–mRNA formulations can slow down of lipid nanoparticles have been explored and optimized
disease progression42,221. The therapeutic potential of for mRNA delivery, providing valuable information for
mRNA-based protein replacement therapies has also the future design of mRNA therapeutics. Based
been tested in other metabolic disorders in preclini- on the lessons and experiences from clinical studies,
cal studies, including hereditary tyrosinaemia type I lipid nanoparticle–mRNA formulations can be further
(HTI) 142, acute intermittent porphyria 222,223, Fabry improved.
disease224,225, Crigler–Najjar syndrome type 1 (ref.226), The in vivo translation efficiency of mRNA mole-
α1 antitrypsin deficiency227, methylmalonic acidaemia/ cules could be further increased by RNA engineering.
aciduria228, arginase deficiency229, citrin deficiency230 To achieve effective translation, mRNA requires five
and glycogen storage disease type I (ref.231). In addi- structural elements, including the 5′ cap, 3′ poly(A)
tion, mRNA-based protein replacement therapies have tail, protein-coding sequence and 5′ and 3′ untrans-
been applied to haematological diseases (for example, lated regions (UTRs)2,4. The sequences of these ele-
haemophilia A232, haemophilia B91,104,233 and thrombotic ments regulate translation initiation, translation
thrombocytopaenic purpura234), central nervous system termination and post-t ranscriptional modification
disorders67,152 (for example, Friedreich’s ataxia67), skin of mRNA molecules2,4. Thus, sequence engineering of
diseases235,236 (for example, elastin deficiency235) and these elements could improve translation in vivo.
hearing loss237 in preclinical studies. For example, optimization of the UTRs or the cod-
Gene-editing tools further provide the opportu- ing sequences results in increased protein expression,
nity to correct mutated genes in genetic disorders. compared with wild-type controls107,244. In addition, cir-
Gene-editing components can be delivered by lipid cular RNA (circRNA) can be synthesized to optimize
nanoparticle–mRNA formulations to treat genetic dis- mRNA properties245,246 (Box 2). circRNA lacks the free
eases, including HTI92,238, hypercholesterolaemia81,96,105,239, ends necessary for nuclease-mediated degradation and,
lipoprotein metabolism disorders85 and transthyretin therefore, has a longer half-life than its linear mRNA
amyloidosis239,240, which has been demonstrated in pre- counterpart245,246.
clinical studies. Intellia Therapeutics further initiated a Moreover, the delivery efficacy of mRNA could
phase I clinical trial (NCT04601051) to study the safety, be improved, for example, by rational design of lipids
pharmacokinetics and pharmacodynamics of NTLA- through modulation of head groups and hydrophobic tails
2001 (lipid nanoparticles encapsulating gene-editing to increase cellular uptake and endosomal escape of lipid
components) in patients with hereditary transthyretin nanoparticle–mRNA formulations64,66,76–78,88,97,100,114,140,141.
amyloidosis. Furthermore, hybrid nanoparticles may integrate
mRNA-b ased protein replacement therapies are the advantages of individual components to improve
also in clinical trials for the treatment of cystic fibrosis. mRNA delivery potency. For example, pH-responsive
Patients with cystic fibrosis usually suffer from repeated polymers, such as poly (β-amino ester), can be incor-
airway infections and chronic respiratory problems porated into lipid nanoparticles to facilitate endosomal
because of the defective cystic fibrosis transmembrane escape of mRNA molecules160. Polymers, such as poly-
conductance regulator (CFTR), a chloride channel on ethyleneimine, protamine and polyaspartamide deriv-
epithelial cells12. Lipid nanoparticles encapsulating CFTR atives, are already widely used for mRNA delivery7–17.
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In addition, charge-altering releasable transporters162,247 depends on cholesterol structures. Such large data sets
and modified dendrimers 248 can effectively deliver will pave the way for a more profound understanding of
mRNA molecules in vitro and in vivo. Naturally derived the relationship between lipid nanoparticle properties
membrane lipids (for example, exosomes and cell mem- and biodistribution.
branes) can also be applied for mRNA delivery116,249,250. Finally, biodegradability and multifunctionality
Organ-specific and cell-specific delivery of lipid should be considered for the design of lipid nanopar-
nanoparticles can be achieved by modulating the ticles. Biodegradable lipids enable fast elimination of
lipid structures. For example, alteration of the alkyl lipid nanoparticles from plasma and tissues, improving
length of a lipid results in selective accumulation of their safety and tolerability. Notably, biodegradable lipids
lipid nanoparticle–mRNA formulations in the liver are part of the mRNA-1273 and BNT162b2 COVID-19
or spleen114. Alternatively, biomimetic lipids can be mRNA vaccines. In addition to serving as delivery com-
designed to achieve organ-targeted delivery. For exam- ponent, lipids may have therapeutic effects synergistic
ple, neurotransmitters are endogenous chemicals that with mRNA-encoded proteins. Such multifunctional
can cross the blood–brain barrier and participate in lipid materials include self-adjuvant lipids, which boost
neurotransmission82. Thus, neurotransmitter-derived vaccine efficacy117,119, and paclitaxel-derived lipids,
lipids can be used for mRNA delivery to the brain fol- which allow integration of chemotherapies and gene
lowing i.v. injection82. Testing and comparing the cell therapies for the treatment of cancer118.
distribution of many different lipid nanoparticle formu- In summary, mRNA has shown great therapeutic
lations remains challenging. However, barcoded nano- potential in a number of clinical trials and in clinical
particles allow in vivo high-throughput profiling of lipid applications. The development of next-generation lipid
nanoparticle distribution at the cell level121. For example, nanoparticles and other types of delivery material will
barcoding has been applied to study how the structure further enable mRNA-based therapies for a broad range
of cholesterol derivatives impact cell selectivity of lipid of diseases and improve health care in the near future.
nanoparticles, revealing that selective accumulation in
liver endothelial cells, Kupffer cells and hepatocytes125,126 Published online 10 August 2021
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α-GalCer induces antitumor immunity through of Fabry disease: preclinical studies in wild-type mice, H1N1 influenza, and Toxoplasma gondii challenges
conventional and natural killer T cells. ACS Nano 13, Fabry mouse model, and wild-type non-human with a single dose. Proc. Natl Acad. Sci. USA 113,
1655–1669 (2019). primates. Am. J. Hum. Genet. 104, 625–637 (2019). E4133–E4142 (2016).
204. Verbeke, R. et al. Co-delivery of nucleoside-modified 225. DeRosa, F. et al. Improved efficacy in a Fabry disease 249. Yang, Z. et al. Large-scale generation of functional
mRNA and TLR agonists for cancer immunotherapy: model using a systemic mRNA liver depot system as mRNA-encapsulating exosomes via cellular
Restoring the immunogenicity of immunosilent mRNA. compared to enzyme replacement therapy. Mol. Ther. nanoporation. Nat. Biomed. Eng. 4, 69–83 (2020).
J. Control. Release 266, 287–300 (2017). 27, 878–889 (2019). 250. Fang, R. H., Kroll, A. V., Gao, W. & Zhang, L. Cell
205. Islam, M. A. et al. Adjuvant-pulsed mRNA vaccine 226. Apgar, J. F. et al. Quantitative systems pharmacology membrane coating nanotechnology. Adv. Mater. 30,
nanoparticle for immunoprophylactic and therapeutic model of hUGT1A1-modRNA encoding for the 1706759 (2018).
tumor suppression in mice. Biomaterials 266, UGT1A1 enzyme to treat Crigler-Najjar syndrome type 251. Bangham, A., Standish, M. M. & Watkins, J. C.
120431 (2021). 1. CPT Pharmacomet. Syst. Pharmacol. 7, 404–412 Diffusion of univalent ions across the lamellae of
206. Tse, S.-W. et al. mRNA-encoded, constitutively (2018). swollen phospholipids. J. Mol. Biol. 13, 238–IN227
active STINGV155M is a potent genetic adjuvant of 227. Connolly, B., Isaacs, C., Cheng, L., Asrani, K. H. & (1965).
antigen-specific CD8+ T cell response. Mol. Ther. 29, Subramanian, R. R. SERPINA1 mRNA as a treatment 252. Lockard, R. E. & Lingrel, J. B. The synthesis of mouse
2227–2238 (2021). for alpha-1 antitrypsin deficiency. J. Nucleic Acids hemoglobin chains in a rabbit reticulocyte cell-free
207. Dewitte, H. et al. The potential of antigen and TriMix 2018, 8247935 (2018). system programmed with mouse reticulocyte 9S RNA.
sonoporation using mRNA-loaded microbubbles 228. An, D. et al. Long-term efficacy and safety of mRNA Biochem. Biophys. Res. Commun. 37, 204–212
for ultrasound-triggered cancer immunotherapy. therapy in two murine models of methylmalonic (1969).
J. Control. Release 194, 28–36 (2014). acidemia. EBioMedicine 45, 519–528 (2019). 253. Jirikowski, G. F., Sanna, P. P., Maciejewski-Lenoir, D.
208. Hess, P. R., Boczkowski, D., Nair, S. K., Snyder, D. & 229. Truong, B. et al. Lipid nanoparticle-targeted mRNA & Bloom, F. E. Reversal of diabetes insipidus in
Gilboa, E. Vaccination with mRNAs encoding tumor- therapy as a treatment for the inherited metabolic Brattleboro rats: intrahypothalamic injection of
associated antigens and granulocyte-macrophage liver disorder arginase deficiency. Proc. Natl Acad. Sci. vasopressin mRNA. Science 255, 996–998 (1992).
colony-stimulating factor efficiently primes CTL USA 116, 21150–21159 (2019).
responses, but is insufficient to overcome tolerance 230. Cao, J. et al. mRNA therapy improves metabolic and Acknowledgements
to a model tumor/self antigen. Cancer Immunol. behavioral abnormalities in a murine model of citrin This work was supported by the Maximizing Investigators’
Immunother. 55, 672–683 (2006). deficiency. Mol. Ther. 27, 1242–1251 (2019). Research Award R35GM119679 from the National Institute
209. Sahin, U. et al. Personalized RNA mutanome vaccines 231. Roseman, D. S. et al. G6PC mRNA therapy positively of General Medical Sciences (to Y.D.) and grant EB000244
mobilize poly-specific therapeutic immunity against regulates fasting blood glucose and decreases liver from the National Institute of Biomedical Imaging and
cancer. Nature 547, 222–226 (2017). abnormalities in a mouse model of glycogen storage Bioengineering (to R.L.). We acknowledge Y. Zhang for his
210. Bauman, J. et al. 798 Safety, tolerability, and disease 1a. Mol. Ther. 26, 814–821 (2018). help with chemical structures. All authors reviewed and
immunogenicity of mRNA-4157 in combination with 232. Chen, C.-Y. et al. Treatment of hemophilia A using edited the manuscript before submission.
pembrolizumab in subjects with unresectable solid factor VIII messenger RNA lipid nanoparticles.
tumors (KEYNOTE-603): an update. J. Immunother. Mol. Ther. Nucleic Acids 20, 534–544 (2020). Author contributions
Cancer https://doi.org/10.1136/jitc-2020- 233. Ramaswamy, S. et al. Systemic delivery of factor IX X.H., T.Z., R.L. and Y.D. contributed to conceiving the struc-
SITC2020.0798 (2020). messenger RNA for protein replacement therapy. ture, searching the literature and writing the Review. T.Z., R.L.
211. Burris, H. A. et al. A phase I multicenter study to Proc. Natl Acad. Sci. USA 114, E1941–E1950 (2017). and Y.D. reviewed and edited the manuscript.
assess the safety, tolerability, and immunogenicity 234. Liu-Chen, S., Connolly, B., Cheng, L., Subramanian, R. R.
of mRNA-4157 alone in patients with resected solid & Han, Z. mRNA treatment produces sustained Competing interests
tumors and in combination with pembrolizumab in expression of enzymatically active human ADAMTS13 Y.D. is a scientific advisory board member of Oncorus, Inc.
patients with unreshectable solid tumors. J. Clin. in mice. Sci. Rep. 8, 7859 (2018). and serves as a consultant of Rubius Therapeutics. T.Z. is an
Oncol. 37, 2523 (2019). 235. Lescan, M. et al. De novo synthesis of elastin by employee of Moderna, Inc. R.L. is a founding scientific advi-
212. Cafri, G. et al. mRNA vaccine–induced neoantigen- exogenous delivery of synthetic modified mRNA into sory board member of Alnylam and a founder and board
specific T cell immunity in patients with skin and elastin-deficient cells. Mol. Ther. Nucleic member of Moderna, Inc. A list of entities with which R.L. is
gastrointestinal cancer. J. Clin. Invest. 130, Acids 11, 475–484 (2018). involved, compensated or uncompensated is provided in the
5976–5988 (2020). 236. Blakney, A. K. et al. The skin you are in: design- supplementary information. X.H. declares no competing
213. Reinhard, K. et al. An RNA vaccine drives expansion of-experiments optimization of lipid nanoparticle self- interests.
and efficacy of claudin-CAR-T cells against solid amplifying RNA formulations in human skin explants.
tumors. Science 367, 446–453 (2020). ACS Nano 13, 5920–5930 (2019). Publisher’s note
214. Jimeno, A. et al. Abstract CT032: a phase 1/2, open- 237. Miwa, T., Saito, H. & Akita, H. Lipid nanoparticles- Springer Nature remains neutral with regard to jurisdictional
label, multicenter, dose escalation and efficacy study encapsulated brain-derived neurotrophic factor claims in published maps and institutional affiliations.
of mRNA-2416, a lipid nanoparticle encapsulated mRNA delivered through the round window niche in
mRNA encoding human OX40L, for intratumoral the cochleae of guinea pigs. Exp. Brain Res. 239, Supplementary information
injection alone or in combination with durvalumab for 425–433 (2020). The online version contains supplementary material available
patients with advanced malignancies. Cancer Res. 238. Song, C.-Q. et al. Adenine base editing in an adult at https://doi.org/10.1038/s41578-021-00358-0.
https://doi.org/10.1158/1538-7445.AM2020-CT032 mouse model of tyrosinaemia. Nat. Biomed. Eng. 4,
(2020). 125–130 (2020).
215. Bauer, T. et al. Abstract CT210: A Phase I, open-label, 239. Conway, A. et al. Non-viral delivery of zinc finger Related links
multicenter, dose escalation study of mRNA-2752, nuclease mRNA enables highly efficient in vivo GMP standard tests: https://www.accessdata.fda.gov/
a lipid nanoparticle encapsulating mRNAs encoding genome editing of multiple therapeutic gene targets. drugsatfda_docs/nda/2018/210922Orig1s000ChemR.pdf
human OX40L, IL-23, and IL-36γ, for intratumoral Mol. Ther. 27, 866–877 (2019). mRNA-1893 interim phase i: https://investors.modernatx.
injection alone and in combination with immune 240. Finn, J. D. et al. A single administration of CRISPR/ com/news-releases/news-release-details/moderna-
checkpoint blockade. Cancer Res. https://doi.org/ Cas9 lipid nanoparticles achieves robust and highlights-opportunity-mrna-vaccines-its-first-vaccines
10.1158/1538-7445.AM2019-CT210 (2019). persistent in vivo genome editing. Cell Rep. 22, mRNA-1944: https://investors.modernatx.com/node/7711/
216. Patel, M. R. et al. A phase I study of mRNA-2752, 2227–2235 (2018). pdf
a lipid nanoparticle encapsulating mRNAs encoding 241. Magadum, A., Kaur, K. & Zangi, L. mRNA-based MRT5005: https://translatebio.gcs-web.com/news-releases/
human OX40L, IL-23, and IL-36γ, for intratumoral protein replacement therapy for the heart. Mol. Ther. news-release-details/translate-bio-announces-interim-
(iTu) injection alone and in combination with 27, 785–793 (2019). results-phase-12-clinical-trial
durvalumab. J. Clin. Oncol. 38, 3092–3092 (2020). 242. Trepotec, Z., Lichtenegger, E., Plank, C., Aneja, M. K. storage of BNT162b2: https://www.pfizer.com/news/
217. Billingsley, M. M. et al. Ionizable lipid nanoparticle- & Rudolph, C. Delivery of mRNA therapeutics for the press-release/press-release-detail/ema-approves-new-
mediated mRNA delivery for human CAR T cell treatment of hepatic diseases. Mol. Ther. 27, storage-option-pfizer-biontech-vaccine
engineering. Nano Lett. 20, 1578–1589 (2020). 794–802 (2019).
218. Kong, N. et al. Synthetic mRNA nanoparticle-mediated 243. Sahu, I., Haque, A. A., Weidensee, B., Weinmann, P. &
restoration of p53 tumor suppressor sensitizes p53- Kormann, M. S. Recent developments in mRNA-based © Springer Nature Limited 2021, corrected publication 2021
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AR08284
science Products News About Q Cont.x1 Us e
About Our Landmark Trial ;
The P!'-1se 3 chnical tnat wa!. des1gnect to determine ,r the ?fizer-8tONTech COVID·19 vaccine rs safe and effective in preventing
COV!D-19 disease. Th ,s tnal began July 27, 2020 and completed enrollment of 46.33 1 part,c,pants ,n January 2021. On November
18~ Pfizer and s,oNTech announced that, afte-r c.onduc.tmg the primary efficacy anatyslS. their mRNA-basetl COVl0-19 vacone met
._. • all of the study's primary efficacy endpoints. On December Z, 2020, the Mechcines & Healthcare Products Regulatory Agency
(MHRA) ttl the U.K. authonzed the Pflz:er-SJoNTe<h COVJ0-19 Vaccme tot emergency use, markmg the first Emergency use
Authonzauon following a wotldV-J1de M~ase 3 ma1 of a vaccine 10 help fight the pandemic. Shortfy after on De<embe, t t, 2020. the
U.S. Food .and Drug Admm1st.rat1on {FDA) authorized the ?fizer-B10Nlech COVID-19 Vacone for emergency use. A mere 13 months
after mal in1uauon. the vaccine became the first FDA approved CO\IID-19 vaccine on August 23. 2021 .
For more ;nforrnahon on , he landmark study, p!P.ao;e see the dm1cal tnal protocol.
The landmark phase 3 dmical trial enrolled participants at dinicol trial Sites around the world
P. f 1p.11 I
Approximately of
overofl and of US.
participants hove
diverse backgrounds.
,
Our b iol sit es ore located !n
and the
of portieipanls ore mole

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What were the endpoints in your Phase 3 landmark study? +
Why was the landmark Phase 3 study randomized and placebo-controlled - w hy

+
not give everyone the vaccine candidate?
Who participated or was able to partic.ipate in the landmark Phase 3 study? +
What have you observed with the 12-15 year olds participating in the trial? +
How were you able to move with speed in the landmark Phase 3 trial? +
Our Purpose Soence
The Meaning of Moonshot: The Antigen #COVID19 The Antigen #COVID19 n

Lessons in Leadership to Podcast The Quest for a Podcast: Teamwork Makes Pc
Last a Lifetime Vaccine the Dream Work th
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Page 2 of 2
AR08285
ON TUESDAY, DECEMBER 31, 2019, What does finding a vaccine actually look What does finding a vaccine actually look In•
Chinese authorities alerted the World like? Who's involved? Last season, we like? Who's Involved? Last season, we he,
Health Organization to a mysterious outlined the many steps It takes for a outlined the many steps it takes for a hel
virus causing pneumonia-like illness in a vaccine to go from discovery to vaccine to go from discovery to We
small cluster of patients in the ci ty of distribution, in this episode we ask if that distribu tion, in this episode we ask if that are
Wuhan. Shortly after, the novel virus was process can safely accelerate for COVID- process can safely accelerate for COVID- do,
identified as SARS-CoV-2. 19, 19.
ee
Emergency uses of the vaccine have not been approved or licensed by FDA, but have been authorized by FDA, under an
Emergency Use Authorization /EUAJ to prevent Coronavlrus Disease 2019 /COVIO 19/ In either lndlvlduo/s 12 years of age and
older, or In Individuals 5 through 11 years of age, as appropriate. The emergency uses ore only authorized for the duration
of the dec/arat/an that circumstances exist Justifying the authorization of emergency use of the medical product under
Section S64/b)/1) of the FD&C Act unless the declaration is terminated or authorization revoked sooner.
Investors Grant Seekers Privacy Statem ent

Pfizer Hea lthcare Professionals Terms of u se
Careers
Business to Business Con tact Us
Media
Merchandise
Pa rtn ers
9 un;t ed States ~ 2022 Pfizer Inc. All rights reserved OOC®O
https://www.pfizer.com/science/coronavirus/vaccine/about-our-landmark-trial 2022-05-13
AR08286 Opinion
VIEWPOINT
Assessment of Deaths From COVID-19
and From Seasonal Influenza
•I ~
JeremySamuelFaust. As of early May 2020. approximately 65 000 people 9.5-fold to 44.1-fold greater than the peak week of
MD.MS in the US had died of coronavirus disease 2019 countedinfluenzadeathsduringthepast7influenzasea-
l-lanrard Medical (COVID-19),1 thediseasecaused by the severe acifte re- sons inthe us.With a 205-fold mean increase (95% a.
School. Brigham and
Women's Hospital.
spiratory ~ndrome coronavirus 2 (SARS-CoV-2). This 163-27.7).5.6
Division d Health number appears to be similarto the estimated number The CDC also publishes provisional counts of
Policy and Public of seasonal influenza deaths reported annually by the COVID-19 deaths but acknowledges that its reporting
Health. Department of Centers for Disease Control and Prevention (CDC) lags behind otherpublicdatasourres.7Fortheweekend-
Emeigenc.y Medcine.
Boston. Ma$adtusetts. (https://www.cdc.gov/flu/about/burden/preliminary- ingApril 11, 2020, data indicate that the number ofpro-
'- - in-season-estimates.htm). visionally reported COVID-19 deaths was 14.4-fold
calfosdelRlo. MD ThisapparentequivalenceofdeathsfromCOVID-19 greaterthan influenzadeathsduringtheapparent peak
Department of and seasonal influenza does not match frontline clini- week ofthe current season (week ending February 29,
Medcine. Division of cal conditions, especially in some hot zones ofthe pan- 2020), consistent with the ranges based on CDC
Infectious Diseases.
Emory University demic where ventilators have been in short supply and statistics.6 As the CDC continues to revise its COVID-19
Schoolof Mediate. many hospitals have been stretched beyond their lim- counts to account for delays in reporting. the ratio of
Atlanta. Georgia; and its. The demand on hospital resources during the counted COVID-19deathsto influenzadeaths islikelyto
Hubert Departmentof
Global Health. Rolins
COVID-19 crisis has not occurred before in the US, even increase.
School of Pubic Health during the worst of influenza seasons. Yet public offi- The ratios we present are more dinically consis-
of Emory University, cials continue to draw comparisons between seasonal tent with fronttine conditionsthan ratios that compare
Atlanta. Georgia. influenza and SARS-CoV-2 mortality, often in an COVID-19 fatality counts and estimated seasonal influ-
attempt to minimize the effects of the unfolding enza deaths. Based on the figure of approximately
pandemic. 60000 COVID-19deaths intheUSasoftheend ofApril
The root of such incorrect comparisons may be a 2020. this ratio suggests only a 1.0-fold to 2.6-fold
knowledge gap regarding how seasonal influenza and change from the CDC-estimated seasonal influenza
COVID-19 data are publicly reported. The CDC, like deaths calculated during the previous 7 full seasons.3
many similar disease control agencies around the From ouranalysis, we inferthateitherthe CDC's annual
world, presents seasonal influenza morbidity and estimates substantially overstate the actual number of
mortality not as raw counts but as calculated esti- deaths caused by influenza or that the arrrent number
,0 mates based on submitted International Classification ofCOVID-19 counted deaths substantially understates
z ,t of Diseases codes.2 Between 2013-2014 and 2018- the actual number ofdeaths caused bySARS-CoV-2, or
0 2019. the reported yearly estimated influenza deaths both.
j:: ranged from 23 000 to 61 000.3 Over that same time
~,._ Thereareanumberofconsiderations.Deathsfrom
ii ij ~ period, however, the number of counted influenza
deaths was between 3448 and lS 620 yearly.4 On
COVID-19 may be undercounted owingto ongoinglimi-
"m
(/)N
z ,
E
~ average, the CDC estimates of deaths attributed to
tations of test capacity or false-negative test results.
When patients present late in the course of iffness. up-
...~ :8~ influenza were nearly 6 times greater than its perrespiratorytractsamplesare lesslikely to yield posi-
~
reported counted numbers. Conversely, COVID-19 tiVetest results. Conversely, influenzacounts maybe less
..J fatalities are at present being counted and reported
~
reliable because adult influenza deaths are not report-
-, :r directly, not estimated. As a result. the more valid able to public health authorities, as is the case for
comparison would be to compare weekly counts of COVID-19 deaths. Moreover, because adult influenza
w :it: COVID-19 deaths to weekly counts of seasonal influ- deathsare not reportable. epidemiologists must relyon
~ ~
0 enza deaths. surveillancemechanismsthatattempttoaccountforpo-
During the week ending April 21, 2020, 15 45S tential underreporting.8 Similarly. some cities. such as
COVID-19counted deaths were reported in the US.5 The New York City. are beginning to report cases of both
C.O.,eij)Oi.dmg
Author, Jeremy
reported number ofcounted deaths from the previous probable and confirmed COVID-19 deaths. The inclu-
5arooe1 FclUSt. MO. MS. week. endingApril 14. was14478. By contrast. accord- sion of both probable and confirmed deaths has led to
HaJYclrd Medic.al ingtotheCDC. counteddeathsduringthepeakweekof revised mortalityf,guresthat. in effect. straddle the line
School. Brigham and the influenza seasons from 2013-2014 to 2019-2020 between counting and estimating the number of
Women's Hospital.
Division of Health
ranged from 351 (2015-2016. week 11 of2016) to 1626 COVID-19deaths.ltisalsopos.siblethatsomedeathsthat
Policy and Public (2017-2018. week 3 of 2018).6 The mean number of have been labeled as having been caused by COVID-19
Health. Departmentof counted deaths during the peak week of influenza sea- are not due to COVID-19. For example. in areas where
Emeigenc.y Mecidne.
sonsfrom2013-2020was7524(95% Cl. 558B-946.1).7 thereishigh-levelcommunityspread.suchasNewYork
10 ViringSt. Boston.
MA021l5 Gsfaust@ Thesestatisticsoncounteddeathssuggestthatthenum- City. if a patient is brought to an emergency depart-
grnaU.com). berofCOVID-19deathsfortheweekendingApril21was ment in cardiac arrest and has a known positive real-
jamaintemalmedidne.Ctlfll JAMAlntemalMeddne August2020 Voltme180,Nurrber8 1045
C 2020 American Medical Association. All rights reserved.

AR08287
Opinion Viewpoint
time reverse transcriptase polymerase chain reaction test result for At present, the Diamond Princess cruise ship outbreak is one
SARS-CoV-2, and dies, that would be considered a COVID-19 death of the few situations for which complete data are available. For this
in local death counts. Whether that death may have occurred any- outbreak, the case fatality rate as of late April 2020 was 1.8% (13
way is impossible to say. Eventually, a fuller reckoning of the bur- deaths out of 712 cases); age adjusted to reflect the general popu-
den of disease that focuses on excess mortality, including both di- lation, the figure would have been closer to 0.5%.1,9 A case fatality
rect and indirect COVID-19–related deaths, will be helpful. That rate of 0.5% would still be 5 times the commonly cited case fatality
analysis will be most complete if it also considers the possibility of rate of adult seasonal influenza.3,10
excess deaths owing to deferred care during the peak of the epi- Directly comparing data for 2 different diseases when mortal-
demic and the lack of capacity for care of patients without COVID-19 ity statistics are obtained by different methods provides inaccu-
at overwhelmed hospitals. rate information. Moreover, the repeated failure of government
Case fatality rates are another topic of confusion. Compari- officials and others in society to consider these statistical distinc-
sons of the case fatality rates of SARS-CoV-2 and influenza are pre- tions threatens public health. Government officials may rely on
mature. Estimates of case fatality rates for COVID-19 range from less such comparisons, thus misinterpreting the CDC’s data, when
than 1% in some nations to approximately 15% in others. This wide they seek to reopen the economy and de-escalate mitigation
range reflects limitations in calculating case fatality rates. These in- strategies. Although officials may say that SARS-CoV-2 is “just
clude failure to account for scarcity in testing (thereby falsely de- another flu,” this is not true.
creasing the denominator) and incomplete follow-up information for In summary, our analysis suggests that comparisons between
people who were critically ill but still alive when last assessed (thereby SARS-CoV-2 mortality and seasonal influenza mortality must be made
decreasing the numerator). Eventually, results from serologic stud- using an apples-to-apples comparison, not an apples-to-oranges
ies will help to determine a more accurate denominator for the case comparison. Doing so better demonstrates the true threat to pub-
fatality rate of SARS-CoV-2. lic health from COVID-19.
ARTICLE INFORMATION 4. Centers for Disease Control and Prevention. 8. Doshi P. Are US flu death figures more PR than
Published Online: May 14, 2020. NHSN reports. Accessed May 5, 2020. https:// science? BMJ. 2005;331(7529):1412. doi:10.1136/
doi:10.1001/jamainternmed.2020.2306 www.cdc.gov/nhsn/datastat/index.html bmj.331.7529.1412
Conflict of Interest Disclosures: None reported. 5. Worldometer. United States. Accessed April 28, 9. The COVID Tracking Project. US historical data.
2020. https://www.worldometers.info/ Accessed April 27, 2020. https://covidtracking.com/
REFERENCES coronavirus/country/us/ data/us-daily/
1. Johns Hopkins Coronavirus Resource Center. 6. National Center for Health Statistics Mortality 10. World Health Organization. Coronavirus
COVID-19 map. Accessed April 28, 2020. https:// Surveillance System, Centers for Disease Control disease 2019 (COVID-19): situation report—46.
coronavirus.jhu.edu/map.html and Prevention. Pneumonia and influenza mortality Accessed April 27, 2020. https://www.who.int/
surveillance from the National Center for Health docs/default-source/coronaviruse/situation-
2. Centers for Disease Control and Prevention. US Statistics Mortality Surveillance System. Accessed reports/20200306-sitrep-46-covid-19.pdf?sfvrsn=
influenza surveillance system: purpose and April 28, 2020. https://gis.cdc.gov/grasp/fluview/ 96b04adf_4
methods. Accessed April 12, 2020. https://www. mortality.html
cdc.gov/flu/weekly/overview.htm
7. Centers for Disease Control and Prevention.
3. Centers for Disease Control and Prevention. Provisional death counts for coronavirus disease
Disease burden of influenza. Accessed April 12, (COVID-19): daily updates of totals by week and
2020. https://www.cdc.gov/flu/about/burden/ state. Accessed April 12, 2020. https://www.cdc.
index.html gov/nchs/nvss/vsrr/COVID19/index.htm
1046 JAMA Internal Medicine August 2020 Volume 180, Number 8 (Reprinted) jamainternalmedicine.com
© 2020 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 05/13/2022

AR08288
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and age group: 1 July 2021 to 7 Jan 2022; B) COVID-19 Health Outcomes by vaccination
status, BC: 11 Dec 2021 to 10 Jan 2022; C) Age-standardized case, hospitali?.ation and critical
care rate, BC 11 Dec 2021 to 7 Jan 2022 [19].
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AR08289
AR08290
[https://covid19-sciencetable.ca/wp-
content/uploads/2022/05/2022-05-10-Current-Status.png]
The estimated number of cases per day, rate and percentage are predicted 7-day midpoint averages based
on the latest observed 7-day midpoint average of the number of cases per day and the latest observed 3-
day average of R(t). The estimated number of deaths per day is based on the latest 7-day midpoint
average.
The variants with N501Y mutation (N501Y+) include Alpha, Beta, Gamma and Omicron; the variants
with E484K mutation (E484K+) include Beta and Gamma; Omicron is the most frequent N501Y+
variant in Ontario now. The variants without N501Y mutation (N501Y-) and without E484K mutation
(E484K-) include Delta (B.1.617.2); the Wild Type was the most frequent N501Y-/E484K- variant until
April 2021, Delta is the most frequent N501Y-/E484K- variant in Ontario now.
The effective reproduction number R(t) corresponds to the average number of additional infections
AR08291
caused by 1 infection. An R(t) of greater than 1 indicates exponential growth. Change per week is the
change as compared with 7 days previously. The doubling time is the estimated time required in days
until the current number of cases or the wastewater signal doubles, the halving time is the estimated time
required in days until the current number of cases or the wastewater signal halves.
Estimates by vaccination status are age-standardized using Ontario’s current population and a single age
cut-off to take into account differences in vaccine uptake and the risk of severe disease between
children, adolescents and young adults (0-29 years) and remaining adults (30+ years). The currently
available data do not allow for a more granular age standardization. Estimates are based on (1) 7-day
averages of the proportions of fully vaccinated and unvaccinated patients hospitalized on wards and
ICUs reported in Ontario’s daily surveys, and of fully vaccinated and unvaccinated cases; (2) on
COVID-19 hospital and ICU occupancy and the 7-day average of COVID-19 cases in Ontario; and (3)
on Ontario’s age-specific vaccination data 7 days before. Hospital occupancy includes patients in ICU.
All estimates are updated daily.
Colour codes are adapted from Ontario’s original COVID-19 response framework: green – prevent;
yellow – protect; orange – restrict; red – control.
*Currently, R(t) based on cases cannot be estimated accurately because the testing capacity in Ontario is
insufficient to deal with the number of infections caused by Omicron, and the testing strategy has
changed.
Contents
Current Status in Ontario [https://covid19-sciencetable.ca/ontario-dashboard/#currentstatus]
Current COVID-19 Risk in Ontario by Vaccination Status [https://covid19-sciencetable.ca/ontario-

dashboard/#riskbyvaccinationstatus]
COVID-19 Wastewater Signals in Ontario [https://covid19-sciencetable.ca/ontario-dashboard/#wastewatersignal]
Estimated Rate of COVID-19 Cases per 1 Million Inhabitants per Day in Ontario [https://covid19-sciencetable.ca/ontario-
dashboard/#estimatedratepermillion]
Test Positivity and Number of COVID-19 Tests in Ontario [https://covid19-sciencetable.ca/ontario-

dashboard/#testpositivityandnumberoftestsinontario]
Effective Reproduction Number R(t) in Ontario [https://covid19-sciencetable.ca/ontario-dashboard/#effectivereproduction]
Percentage of Cases Caused by Different Variants in Ontario [https://covid19-sciencetable.ca/ontario-

dashboard/#percentcausedbyvariants]
Number of Public [https://covid19-sciencetable.ca/ontario-dashboard/#phuwithexponentialgrowth]Health Units With Exponential

Growth in Ontario [https://covid19-sciencetable.ca/ontario-dashboard/#phuexponentialgrowth]
Daily COVID-19 Hospital and ICU Occupancy in Ontario [https://covid19-sciencetable.ca/ontario-

dashboard/#hospitalicuoccupancy]
Daily COVID-19 Deaths in Ontario [https://covid19-sciencetable.ca/ontario-dashboard/#covid19deaths]
Oxford Stringency Index and Out-of-Home Mobility in Ontario [https://covid19-sciencetable.ca/ontario-

dashboard/#stringencyandmobility]
Mobility Indicators of Low-Risk Activities in Ontario [https://covid19-sciencetable.ca/ontario-dashboard/#mobilitylowrisk]
Mobility Indicators of High-Risk Activities in Ontario [https://covid19-sciencetable.ca/ontario-dashboard/#mobilityhighrisk]
COVID-19 Vaccination in Ontario [https://covid19-sciencetable.ca/ontario-dashboard/#vaccinationontario]
Current COVID-19 Risk in Ontario by Vaccination Status

AR08292
content/uploads/2022/05/2022-05-10-Protection-Against-Infection-Hospital-and-ICU-Admission-with-2-Vaccine-Doses.png]
[https://covid19-sciencetable.ca/wp-content/uploads/2022/05/2022-05-10-Current-COVID-19-Risk-in-Ontario-by-Vaccination-
Status.png]
AR08293
[https://covid19-sciencetable.ca/wp-content/uploads/2022/05/2022-05-10-Current-COVID-19-Risk-in-Ontario-by-Vaccination-
Status-Separate-Charts.png]
Estimates are age-standardized using Ontario’s current population and a single age cut-off to take into
account differences in vaccine uptake and the risk of severe disease between children, adolescents and
young adults (0-29 years) and remaining adults (30+ years). The currently available data do not allow
for a more granular age standardization. Estimates are based on (1) 7-day averages of the proportions of
fully vaccinated and unvaccinated patients hospitalized on wards and ICUs reported in Ontario’s daily
surveys, and of fully vaccinated and unvaccinated cases; (2) on COVID-19 hospital and ICU occupancy
and the 7-day average of COVID-19 cases in Ontario; and (3) on Ontario’s age-specific vaccination data
7 days before. Hospital occupancy includes patients in ICU. The estimated protection is 1 minus the age-
standardized rate ratio comparing people who have received at least 2 doses of a COVID-19 vacine with
people who have not yet received a COVID-19 vaccine and is expressed as a percentage. All estimates
are updated daily.
COVID-19 Wastewater Signals in Ontario
content/uploads/2022/05/2022-05-10-Province-Wide-COVID-19-Wastewater-Signal-in-Ontario.png]
AR08294
The province-wide COVID-19 wastewater signal for Ontario is a weighted mean of standardized,
biomarker-normalized concentrations of SARS-CoV-2 gene copies across 103 wastewater treatment
plants, pumping stations and sewersheds in the 34 public health units. Each series of concentrations of
N1 and N2 genes found in the wastewater of each location was standardized using the gene and location
specific standard deviation. Standardized concentrations of N1 and N2 genes were first converted to
standard deviation units and then log transformed. Restricted cubic splines with knots located every 10
days were fitted separately for each gene in each location to estimate daily log transformed standardized
values.
Fixed-effects meta-analyses were used to calculate daily inverse-variance weighted means of log
transformed estimates within each public health unit. Daily inverse-variance weighted means were then
combined in a fixed-effects analysis across public health units using population size of public health
units as analytical weight. Resulting daily weighted means were exponentiated and therefore represent
standard deviation units.
*The dotted orange line and the lighter shaded area represent incomplete data (less than 90% of data
available on a given date). The dashed red line thus represents the currently available best estimates
using the statistical approaches above to account for not yet available data, but are provisional. As such
they may be under- or over-estimates and may change when more data become available.
To account for the proportion of the wastewater that is from humans and the proportion that is rain
water, snow melt, etc., N1 and N2 gene concentrations are normalized using the seasonally stable fecal
biomarker pepper mild mottle virus (PMMoV). Samples are typically taken 3 times per week at each
location. There is a 5 to 7 day lag between the detection of SARS-CoV-2 gene copies in the wastewater,
and the diagnosis and reporting of COVID-19 cases. The wastewater signal on January 21, for example,
is reflected in reported COVID-19 cases around January 26 to 28.
[https://covid19-sciencetable.ca/wp-content/uploads/2022/05/2022-05-10-COVID-19-Wastewater-Signals-in-Ontario-North-
East.png]
[https://covid19-sciencetable.ca/wp-content/uploads/2022/05/2022-05-10-COVID-19-Wastewater-Signals-in-Ontario-South-
West-GTA.png]
See legend of previous figure for explanations of the methods used to derive region specific COVID-19
wastewater signals. North includes Algoma; North Bay Parry Sound; Northwestern; Porcupine; Sudbury
AR08295
& Districts; Thunder Bay; and Timiskaming. Central East includes Haliburton Kawartha and Pine
Ridge; Peterborough; and Simcoe Muskoka. Eastern includes Eastern Ontario; Hastings Prince Edward;
Kingston, Frontenac and Lennox & Addington; Leeds, Grenville & Lanark; Ottawa; and Renfrew
County and District. South West includes Chatham-Kent; Grey Bruce; Huron Perth; Lambton;
Middlesex-London; Southwestern; and Windsor-Essex. Central West includes Brant County;
Haldimand-Norfolk; Hamilton; Niagara Region, Waterloo; and Wellington-Dufferin-Guelph. GTA
includes Durham Region; Halton Region; Peel; Toronto; and York Region. GTA, Greater Toronto Area.
*The dotted orange line and the lighter shaded area represent incomplete data (less than 90% of data
available on a given date). The dashed red line thus represents the currently available best estimates
using the statistical approaches above to account for not yet available data, but are provisional. As such
they may be under- or over-estimates and may change when more data become available.
Ontario’s wastewater surveillance is coordinated and hosted by the Ministry of the Environment,
Conservation and Parks (MECP). Laboratory analyses are done by Carleton University, University of
Guelph, Health Sciences North Research Institute, McMaster University, National Microbiology
Laboratory, Ontario Tech University, University of Ottawa, Queen’s University, Ryerson University,
University of Toronto, Trent University, University of Waterloo, University of Western Ontario and
University of Windsor.
Estimated Rate of COVID-19 Cases per 1 Million Inhabitants per Day in Ontario
content/uploads/2022/05/2022-05-10-Estimated-Incidence_Combined.png]
AR08296
[https://covid19-sciencetable.ca/wp-content/uploads/2022/05/2022-05-10-Estimated-Incidence_Combined_by-PHU.png]
Test Positivity and Number of COVID-19 Tests in Ontario
content/uploads/2022/05/2022-05-10-Test-Positivity-and-Number-of-COVID-19-Tests-in-Ontario.png]
Effective Reproduction Number R(t) in Ontario

AR08297
content/uploads/2022/05/2022-05-10-Effective-Reproduction-Number-Rt_Combined.png]
Percentage of Cases Caused by Different Variants in Ontario
content/uploads/2022/05/2022-05-10-Distribution-of-Variant.png]
Number of Public Health Units With Exponential Growth in Ontario

AR08298
content/uploads/2022/05/2022-05-10-Number-of-Public-Health-Units-With-Exponential-Growth-in-Ontario.png]
There are 34 Public Health Units (PHUs) in Ontario. Exponential growth is defined as an effective
reproduction number R(t) >1 for all variants combined.
Daily COVID-19 Hospital and ICU Occupancy in Ontario
[https://covid19-
sciencetable.ca/wp-content/uploads/2022/05/2022-05-10-Daily-COVID-19-Hospitalizations-and-ICU-Occupancy-in-Ontario.png]
Daily COVID-19 Deaths in Ontario

AR08299
[https://covid19-
sciencetable.ca/wp-content/uploads/2022/05/2022-05-10-Daily-COVID-19-Deaths-in-Ontario.png]
Oxford Stringency Index and Out-of-Home Mobility in Ontario
[https://covid19-
sciencetable.ca/ontario-dashboard/2022-05-10-out-of-home-mobility/]
The Oxford Stringency Index is a composite measure assessing policy measures that governments have
taken to tackle COVID-19. It uses nine response indicators including workplace closures, school
closures, travel bans, and vaccination policies and ranges from 0 to 100 (100 = strictest).
Mobility Indicators of Low-Risk Activities in Ontario

AR08300
[https://covid19-sciencetable.ca/wp-content/uploads/2022/05/2022-05-10-Mobility-Indicators-of-Low-Risk-Activities.png]
Mobility Indicators of High-Risk Activities in Ontario
[https://covid19-sciencetable.ca/wp-content/uploads/2022/05/2022-05-10-Mobility-Indicators-of-High-Risk-Activities.png]
COVID-19 Vaccination in Ontario
[https://covid19-
sciencetable.ca/wp-content/uploads/2022/05/2022-05-10-COVID-19-Vaccination-in-Ontario.png]
AR08301
[https://covid19-
sciencetable.ca/wp-content/uploads/2022/05/2022-05-10-Percentage-Vaccinated-by-Age.png]
[https://covid19-sciencetable.ca/wp-content/uploads/2022/05/2022-05-10-Percentage-Vaccinated-by-PHU.png]
Data sourced from:
https://covid19.apple.com/mobility/ [https://covid19.apple.com/mobility/]
https://data.ontario.ca/ [https://data.ontario.ca/]
https://ourworldindata.org/explorers/coronavirus-data-explorer [https://ourworldindata.org/explorers/coronavirus-data-
explorer]
Public Health Case and Contact Management Solution and other case management systems (CCM plus)
https://www.bankofcanada.ca/markets/market-operations-liquidity-provision/covid-19-actions-support-economy-
financial-system/covid-19-stringency-index/ [https://www.bankofcanada.ca/markets/market-operations-liquidity-provision/covid-
AR08302
19-actions-support-economy-financial-system/covid-19-stringency-index/]
https://www.google.com/covid19/mobility/ [https://www.google.com/covid19/mobility/]
https://resources-covid19canada.hub.arcgis.com/datasets/covid19canada::provincial-daily-
totals/about/ [https://resources-covid19canada.hub.arcgis.com/datasets/covid19canada::provincial-daily-totals/about/]
Wastewater Dashboard hosted by Ontario’s Ministry of the Environment, Conservation and Parks (MECP)
Citation:
Jüni P, da Costa BR, Maltsev A, Katz GM, Perkhun A, Yan S, Bodmer NS. Ontario dashboard. Science Briefs of
the Ontario COVID-19 Science Advisory Table. 2021.
https://doi.org/10.47326/ocsat.dashboard.2021.1.0 [https://doi.org/10.47326/ocsat.dashboard.2021.1.0]
Home [https://covid19-sciencetable.ca] /
Contact /
@COVIDSciOntario [https://twitter.com/COVIDSciOntario]
Ontario COVID-19 Science Advisory Table

AR08303
European Joumal of Epidemiology (2021) 36:1237- 1240
https://doi.org/10.1007/s10654-021-00808-7
CORRESPONDENCE
Increases in COVID-19 are unrelated to levels

.. of vaccination across 68
countries and 2947 counties in the United States
;
S. V. Subramanian1.20 •Akhil Kumar3
.,,t
Received: 17 August 2021 / Accepted: 9 September 2021 / Published online: 30 September 2021
© Springer Nature B.V. 2021, corrected publication 2021
Vaccines currently are the primary mitigation strategy to p ercentage data yielding 2947 counties for the analysis.
combat COVID-19 around the world. For instance, the nar- We computed the number and percentages of counties that
rative related to the ongoing surge of new cases in the United experienced an increase in COVID-19 cases by levels of
States (US) is argued to be driven by areas with low vaccina- the percentage of people fully vaccinated in each county.
tion rates [l ]. A similar narrative also has been observed in The percentage increase in COVID-19 cases was calcu-
countries, such as Germany and the United Kingdom [2]. At lated based on the difference in cases from the last 7 days
the same time, Israel that was hailed for its swift and high and the 7 days preceding them. For example, Los Ange-
rates of vaccination has also seen a substantial resurgence les county in California had 18,171 cases in the last 7 days
in COVID-19 cases [3]. We investigate the relationship (August 26 to September 1) and 31,616 cases in the previous
between the percentage of population fully vaccinated and 7 days (August 19-25), so this county did not experience an
new COVID-19 cases across 68 countries and across 2947 increase of cases in our dataset. We provide a dashboard of
counties in the US. the metrics used in this analysis that is updated automatically
as new data is made available by the White House COVID-
19 Team (https://tiny.cc/USDashboard) .
Methods
We used COVID-19 data provided by the Our World in Data Findings

for cross-country analysis, available as of September 3, 2021
(Supplementary Table 1) [4 ]. We included 68 countries that At the country-level, there appears to be no discernable rela-
met the following criteria: had second dose vaccine data tionship between percentage of population fully vaccinated
available; had COVID-19 case data available; had popula- and new COVID-19 cases in the last 7 days (Fig. 1). In fact,
tion data available; and the last update of data was within the trend line suggests a marginally positive association such
3 days prior to or on September 3, 2021. For the 7 days that countries with higher percentage of population fully
preceding September 3, 2021 we computed the COVID-19 vaccinated have higher COVID-19 cases per 1 million peo-
cases per 1 million people for each country as well as the ple. Notably, Israel with over 60% of their population fully
percentage of population that is fully vaccinated. vaccinated had the highest COVID-19 cases per 1 million
For the county-level analysis in the US, we utilized the people in the last 7 days. The lack of a meaningful asso-
White House COVID-19 Team data [5 ], available as of ciation between percentage population fully vaccinated and
September 2, 2021 (Supplementary Table 2). We excluded new COVID-19 cases is further exemplified, for instance,
counties that did not report fully vaccinated population by comparison of Iceland and Portugal. Both countries have
over 75% of their population fully vaccinated and have more
181 S. V. Subramanian
COVJD..19 cases per 1 million people than countries such
svsubram@bspb.barvardedu as Vietnam and South Africa that have around 10% of their
population fully vaccinated.
1
Harvard Center for Population and Development Studies, Across the US counties too, the median new COVID-19
Cambridge, MA, USA
cases per l 00,000 people in the last 7 days is largely similar
2
Department of Social and Behavioral Sciences, Harvard across the categories of percent population fully vaccinated
T.H. Chan School of Public Health, Boston, MA, USA
(Fig. 2 ). Notably there is also substantial county variation in
3
Turner Fentcm Secondary School. Brampton, ON, Canada
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1238
AR08304 S. V. Subramanian, A. Kumar
Fig. 1 Relationship between cases per 1 million people (last 7 days) and percentage of population fully vaccinated across 68 countries as of Sep-
tember 3, 2021 (See Table S1 for the underlying data)
new COVID-19 cases within categories of percentage popu- as “low” transmission counties by the CDC, 26.3% (15) have
lation fully vaccinated. There also appears to be no signifi- percentage of population fully vaccinated below 20%.
cant signaling of COVID-19 cases decreasing with higher Since full immunity from the vaccine is believed to take
percentages of population fully vaccinated (Fig. 3). about 2 weeks after the second dose, we conducted sensitivity
Of the top 5 counties that have the highest percentage analyses by using a 1-month lag on the percentage population
of population fully vaccinated (99.9–84.3%), the US Cent- fully vaccinated for countries and US counties. The above find-
ers for Disease Control and Prevention (CDC) identifies 4 ings of no discernable association between COVID-19 cases
of them as “High” Transmission counties. Chattahoochee and levels of fully vaccinated was also observed when we con-
(Georgia), McKinley (New Mexico), and Arecibo (Puerto sidered a 1-month lag on the levels of fully vaccinated (Sup-
Rico) counties have above 90% of their population fully vac- plementary Figure 1, Supplementary Figure 2).
cinated with all three being classified as “High” transmis- We should note that the COVID-19 case data is of con-
sion. Conversely, of the 57 counties that have been classified firmed cases, which is a function of both supply (e.g., variation
in testing capacities or reporting practices) and demand-side
(e.g., variation in people’s decision on when to get tested)
factors.
13
AR08305
Increases in COVID‑19 are unrelated to levels of vaccination across 68 countries and 2947 counties… 1239
Fig. 2 Median, interquartile range and variation in cases per 100,000 people in the last 7 days across percentage of population fully vaccinated
as of September 2, 2021
Fig. 3 Percentage of counties that experienced an increase of cases between two consecutive 7-day time periods by percentage of population
fully vaccinated across 2947 counties as of September 2, 2021
Interpretation vaccination rates. Such course correction, especially with

regards to the policy narrative, becomes paramount with
The sole reliance on vaccination as a primary strategy to emerging scientific evidence on real world effectiveness
mitigate COVID-19 and its adverse consequences needs of the vaccines.
to be re-examined, especially considering the Delta For instance, in a report released from the Minis-
(B.1.617.2) variant and the likelihood of future variants. try of Health in Israel, the effectiveness of 2 doses of the
Other pharmacological and non-pharmacological interven- BNT162b2 (Pfizer-BioNTech) vaccine against prevent-
tions may need to be put in place alongside increasing ing COVID-19 infection was reported to be 39% [6],
13

1240
AR08306 S. V. Subramanian, A. Kumar
substantially lower than the trial efficacy of 96% [7]. It is https:// w ww. n pr. o rg/ s ecti o ns/ g oats a ndso d a/ 2 021/ 0 8/ 2 0/
also emerging that immunity derived from the Pfizer-BioN- 10296 2 8471/ h ighly- v acci n ated- i srael- i s- s eeing- a - d rama
tic-surge-in-new-covid-cases-heres-why.
Tech vaccine may not be as strong as immunity acquired 4. Ritchie H, Ortiz-Ospina E, Beltekian D, Mathieu E, Hasell J,
through recovery from the COVID-19 virus [8]. A substan- Macdonald B, Giattino C, Appel C, Rodés-Guirao L, Roser M.
tial decline in immunity from mRNA vaccines 6-months Coronavirus pandemic (COVID-19). 2020. Published online at
post immunization has also been reported [9]. Even though OurWorldInData.org. Retrieved from: https://ourwor ldindata.org/
coronavirus.
vaccinations offers protection to individuals against severe 5. White House COVID-19 Team. COVID-19 community profile
hospitalization and death, the CDC reported an increase report. 2020. HealthData.gov. https://healt hdata.gov/Health/
from 0.01 to 9% and 0 to 15.1% (between January to May COVID-19-Community-Profile-Report/gqxm-d9w9.
2021) in the rates of hospitalizations and deaths, respec- 6. Ministry of Health Israel. Two-dose vaccination data. Govern-
ment of Israel; 2021. https://w ww.g ov.i l/B lobFo lder/r eport s/v acci
tively, amongst the fully vaccinated [10]. ne-efficacy-safety-follow-up-committee/he/files_publications_
In summary, even as efforts should be made to encour- corona_two-dose-vaccination-data.pdf.
age populations to get vaccinated it should be done so with 7. Thomas SJ, Moreira ED, Kitchin N, Absalon J, Gurtman A,
humility and respect. Stigmatizing populations can do more Lockhart S, Perez JL, et al. Six Month safety and efficacy of the
BNT162b2 Mrna Covid-19 vaccine. MedRxiv. 2021. https://doi.
harm than good. Importantly, other non-pharmacological org/10.1101/2021.07.28.21261159.
prevention efforts (e.g., the importance of basic public 8. Gazit S, Shlezinger R, Perez G, Lotan R, Peretz A, Ben-Tov A,
health hygiene with regards to maintaining safe distance or Cohen D, Muhsen K, Chodick G, Patalon T. Comparing sars-
handwashing, promoting better frequent and cheaper forms cov-2 natural immunity to vaccine-induced immunity: reinfections
versus breakthrough infections. MedRxiv. 2021. https://doi.org/
of testing) needs to be renewed in order to strike the bal- 10.1101/2021.08.24.21262415.
ance of learning to live with COVID-19 in the same manner 9. Canaday DH, Oyebanji OA, Keresztesy D, Payne M, Wilk D,
we continue to live a 100 years later with various seasonal Carias L, Aung H, Denis KS, Lam EC, Rowley CF, Berry SD,
alterations of the 1918 Influenza virus. Cameron CM, Cameron MJ, Wilson B, Balazs AB, King CL,
Gravenstein S. Significant reduction in humoral Immunity among
healthcare workers and nursing home residents 6 months AFTER
Supplementary Information The online version contains supplemen- COVID-19 BNT162b2 mRNA vaccination. MedRxiv. 2021.
tary material available at https://d oi.o rg/1 0.1 007/s 10654-0 21-0 0808-7. https://doi.org/10.1101/2021.08.15.21262067.
10. McMorrow M. (rep.). Improving communications around vac-
cine breakthrough and vaccine effectiveness. 2021. Retrieved
References from https://context-cdn.washingtonpost.com/notes/prod/default/
documents/8a726408-07bd-46bd-a945-3af0ae2f3c37/note/57c98
604-3b54-44f0-8b44-b148d8f75165.
1. Vaccinations CDC. CDC COVID data tracker. Centers for Disease
Control and Prevention. 2021. https://covid.cdc.gov/covid-data-
Publisher's Note Springer Nature remains neutral with regard to
tracker/#vaccinations.
jurisdictional claims in published maps and institutional affiliations.
2. Nicolas E. Germany mulls restrictions for unvaccinated as cases
soar. EUobserver; 2021. https://euobserver.com/coronavirus/
152534.
3. Estrin D. Highly vaccinated Israel is seeing a dramatic
surge in New COVID cases. Here's why. NPR; 2021.
13
AR08307
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VAERS - Data
AR08308
en Espanol (dataSpanish.html)
VAE
(index.html)
Vaccine Adverse Event Reporting System
www.vaers.hhs.gov 'I '"\
'
f
VAERS Home (index.html)
.,I
VAERS Home(index.html) ·, Home (index.html) / VAERS Data I en Espanol (dataSpanish.htm1:
About VAERS (aboulhtml)
Report an Adverse Event

" - +
VAERSData
(reportevent.html) VAERS data is accessible by downloading raw data in comma-separated value (CSV) files for import into a database,
spreadsheet, or text editing program, or by using the CDC WONDER on line search tool. Information provided to VAERS
VAERS Data (data.html)
which identifies a person who received the vaccine or vaccines will not be made available to the public. De-identified
VAERS Data Sets (data.html) VAERS data are available 4-6weeks after the report is received. VAERS data change as new reports are received, so your
results may change if you repeat the same search at a later date. To learn more about interpretingdata see Guide to
Guide to Interpreting Data
lnterpretingVAERS Data (data/dataguide.html).
(data/dataguide.html)
Resources (resources.html) + Options for AccessingVAERS Data

Submit Follow-Up Information
VAERS data is available in two ways:
(au to upload.html)
Frequently Asked Questions Search data with an easy-to-use, menu-driven tool Produce tables, maps, charts, and data extracts of
vaccine adverse events.
(faq.html)
Search CDC Wonder
Contact Us (contact.html)
Privacy (privacy.html)
Download raw data for import into a database, spreadsheet, or text editing program.
Download VAERS Data I
Disclaimer
VAERSaccepts reports of adverse events that occur following vaccination. Anyone. including Healthcare providers. vaccine
manufacturers. and the public can submit reports to the system. While very important in monitoring vaccine safety,
VAERS .-eports alone cannot be used to determine if a vaccine caused or contributed lo an adverse event or illness.
Vaccine providers are encouraged to report any clinically significant health problem followingvaccination to VAERS even if they are
not sure if the vaccine was the cause. In some situations, reporting to VAERS is required of healthcare providers and vaccine
manufacturers.
VAERS reports may contain information that is incomplete. inaccurate. coincidental. or unverifiable. Reports to VAERS
can also be biased. As a result, there are limitations on how the data can be used scientifically. Data from VAERS reports should always
be interpreted with these limitations in mind.
The strengths ofVAERS are that it is national in scope and can often quickly detect an early hint orwarningof a safety problem with a
vaccine. VAERS is one component of CDC's and FDA's multifaceted approach to monitoring safety after vaccines are licensed or
authorized for use. There are multiple, complementary systems that CDC and FDA use to capture and validate data from different
https://vaers.hhs.gov/data.html Page 1 of 2
Pl'M Centers for Disease Control and Prevention
liiilil COC 24/2: SoVtng ll\les. Protecilng Peopl&'M Search
Disclaimer
VAERS accept s ,.eports of adverse events that occ11r following vaccination. Anyone, iocloding heal thcare provide rs, vaccine manufacturers, and t h e public, can sub111it report s to t h e
system, W hile very Important in monitoring vaccine safety, VAERS reports al one cannot be used to dete r mine if a vaccine caused or contributed to an adver se event or
illn ess, Vaccine providers are encouraged to report any clinically significant health problem following vaccination to VAER5 even if t hey are not su,·e if the vaccine was the cause. In some
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data can be used ,cientiflcally. Dat a fron, VAERS reports should always be Interpreted w ith these hm1tatlons in mind.
The strengths of VAERS are that 1t is national in scope Md can often quickly detect an early hint or warning of a safety problem with a vaccine. VAERS 1s one component of CDC's and FDA's
multifaceted approach to monitoring safety after vaccines are licensed or authorized for use. There are multiple, complementary systems that CDC and FDA use to capt ure and validate data
fronJ differef:\lsource.§_,. VAER5 is designed t.o rapidly det ect unusual or unexpected patterns of adverse events, also referred to as "safety signals." rr a possible safet y signal is found in VAERS,
furt~r a11alys1, 1s performed with other safety systems, such as the CDC's Vaccine Safety Datalink (VSD) and Clinical Immunizat ion Safety As;essment (CJSA) Project, or 1n the FDA BEST
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fal se VAERS report Is a viol ation of Federal l aw (18 U.S. Code § 1001) pu11ishable by fine and i mprisonmen t,
I have read and under~tand the disclaimer.

AR08309
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S u m ma ry
Calendar week Year Measure Names Measure Values SUM(lst additional dose (61) SUM ( First Dose [ 3.,7]} S'UM(Second Dose [4,71) SUM(Single Dose [ 51) SUM(Total Doses)
43,0 0 2021 .00 2nd additiona l dose [6) o.oo 15, 410,955.0 0 214, 579, 199.00 178,421, 221 15,678,286.00 424,089,661,00
43.00 2021.00 1st adda;onal dose (6) 15,410,955.00 15,410,955.00 214, 579, 199.00 178,421,221 15,678,286.00 424,089,661.00
43,0 0 2021 .00 S ingle Dose [5) 15,678, 286.00 15, 410,955.0 0 214, 579, 199.00 178,421, 221 15,678,286.00 424,089,661,00
43,0 0 2021 .00 Second Dose ( 4, 7) 178, 421,22 1.0 0 15, 410,955.0 0 214, 579, 199.0 0 178,421, 221 15,678, 286.00 424,089 ,661.00
43,0 0 2021 ,00 First Dose [3, 7) 2 14, 579,199,0 0 15, 410,955.0 0 214, 579, 199.00 178,421, 221 15,678,286.00 424,089,661.00
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AR08311
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AR08312
m.RNA-1273 or mRNA-Omicron boost in vaccinated macaques
elicits comparable B cell expansion, ;neutralizing antibodies and

f
protection against Omicron
.,t
Authors:
Matthew Gagne1.9, Juan I. Moliva1.9, Kathryn E. Foulds1.9, Shayne F. Andrew1.9, Barbara J.
Flynn 1•9, Anne P. Wemer1•9, Danielle A. Wagner\ I-Ting Teng1, Bob C. Lin1, Christopher
Moore 1, Nazaire Je~-Baptiste1, Robin Carroll1, Stephanie L. Foster, Mit Patel2, Madison Ellis2,
Venkata-Viswanadh Edara2 , Nahara Vargas Maldonado2, MahnazMinai3 , Lauren McCormick 1,
Christopher Cole Honeycutt\ Bianca M. Nagata3, Kevin W. Bock3, Caitlyn N. M. Dulan1,
Jamilet Cordon1, John-Paul M. Todd1, ElizabethMcCarthy1, LaurentPessaint4, Alex VanRy4,
Brandon Narvaez", Daniel Valentin4, Anthony Cook4, Alan Dodson4, Katelyn Steingrebe4,
Dillon R Flebbe1, Saule T. Nurmukhambetova1, Sucheta Godbole 1, Amy R Henry1, Farida
Laboune1, Jesmine Roberts-Torres 1, Cynthia G. Lorang1, Shivani Amin1, Jessica Trost\ Mursal
Naisan1, Manjula Basappa1, Jacquelyn Willis1, Lingshu Wang 1, Wei Shi 1, Nicole A. Doria-
Rose1, Adam S. Olia1, Cuiping Liu1, Darcy R Harris 1, Andrea Carfi5, John R Mascola1, Peter D.
Kwong\ Darin K. Edwards5, Hanne Andersen4, Mark G. Lewis4, Kizzmekia S. Corbett\ Martha
C. Nason7, Adrian B. McDermott1, Mehul S. Suthar2, Ian N. Moore8, Mario Roederer1, Nancy J.
Sullivan1, Daniel C. Douek1•10, and Robert A. Seder1•10, 11
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bioRxiv preprint doi: https://doi.org/10.1101/2022.02.03.479037; this version posted February 4, 2022. The copyright holder for this preprint
AR08313
Affiliations:
1
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, Maryland, 20892, United States of America

2
Department of Pediatrics, Emory Vaccine Center, Yerkes National Primate Research Center,
Emory University School of Medicine, Atlanta, Georgia, 30322, United States of America
3
Infectious Disease Pathogenesis Section, Comparative Medicine Branch, National Institute of
Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, 20892,
United States of America

4
Bioqual, Inc., Rockville, Maryland, 20850, United States of America
5
Moderna Inc., Cambridge, MA, 02139, United States of America
6
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public
Health, Boston, Massachusetts, 02115, United States of America

7
Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892, United States of
America
8
Division of Pathology, Yerkes National Primate Research Center, Emory University School of
Medicine, Atlanta, Georgia, 30329, United States of America
9
These authors contributed equally to this manuscript.
10
Correspondence: ddouek@mail.nih.gov and rseder@mail.nih.gov
11
Lead contact
2
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1 Summary
2 SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to antibody
3 neutralization following immunization with ancestral spike-matched vaccines. It is unclear
4 whether boosting with Omicron-specific vaccines would enhance immunity and protection.
5 Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41
6 with mRNA-1273 or mRNA-Omicron. Neutralizing antibody titers against D614G were 4760
7 and 270 reciprocal ID50 at week 6 (peak) and week 41 (pre-boost), respectively, and 320 and 110
8 for Omicron. Two weeks after boost, titers against D614G and Omicron increased to 5360 and
9 2980, respectively, for mRNA-1273 and 2670 and 1930 for mRNA-Omicron. Following either
10 boost, 70-80% of spike-specific B cells were cross-reactive against both WA1 and Omicron.
11 Significant and equivalent control of virus replication in lower airways was observed following
12 either boost. Therefore, an Omicron boost may not provide greater immunity or protection
13 compared to a boost with the current mRNA-1273 vaccine.
14
15 Keywords
16 SARS-CoV-2; Omicron; COVID-19; mRNA vaccine; boost; antibody; B cells; T cells; original
17 antigenic sin; immune memory
18
19 Introduction
20 The COVID-19 mRNA vaccines BNT162b2 and mRNA-1273 provide highly effective
21 protection against symptomatic and severe infection with ancestral SARS-CoV-2 (Baden et al.,
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22 2021b; Dagan et al., 2021; Pilishvili et al., 2021; Polack et al., 2020). More recently, protective
23 efficacy has declined due to both waning vaccine-elicited immunity (Baden et al., 2021a;
24 Bergwerk et al., 2021; Goldberg et al., 2021) and antigenic shifts in variants of concern (VOC)
25 including B.1.351 (Beta) and B.1.617.2 (Delta) (Planas et al., 2021; Wang et al., 2021a; Wang et
26 al., 2021b). Importantly, the introduction of a boost after the initial vaccine regimen enhances
27 immunity and vaccine efficacy against symptomatic disease, hospitalization and death across a
28 broad range of age groups (Andrews et al., 2022; Bar-On et al., 2021; Barda et al., 2021; Garcia-
29 Beltran et al., 2022; Pajon et al., 2022). However, the timing and selection of a boost is a major
30 scientific and clinical challenge during this evolving pandemic in which emerging VOC have
31 distinctive patterns of transmission and virulence and against which vaccine-elicited antibody
32 neutralization is reduced.
33
34 The most recent VOC, B.1.1.529, henceforth referred to by its WHO designation of Omicron,
35 was first identified in South Africa in November 2021 and was associated with a dramatic
36 increase in COVID-19 cases (Cele et al., 2021; Maslo et al., 2021). Omicron is highly
37 contagious, with a significant transmission advantage compared to Delta, which until recently
38 was the dominant VOC worldwide (Viana et al., 2022). It remains unclear, however, if this
39 advantage is due to differences in cell entry, enrichment in respiratory aerosols, or the ability to
40 evade immunity conferred by vaccination or prior infection. Compared to the ancestral strain,
41 Omicron contains more than 30 mutations in the spike (S) gene, including S477N, T478K,
42 E484A, Q493R, G496S, Q498R, N501Y and Y505H in the receptor binding motif (RBM) alone.
43 Neutralizing antibody titers in sera of individuals recently recovered from previous infection or
44 shortly after immunization with two doses of an mRNA-based COVID-19 vaccine are
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45 dramatically reduced to Omicron as compared to the ancestral strains Wuhan-Hu-1, USA-
46 WA1/2020 (WA1) and D614G. Numerous studies using both live virus and pseudovirus
47 neutralization assays report a 60- to 80-fold reduction for convalescent sera and a 20- to 130-fold
48 reduction for vaccinee sera (Edara et al., 2021a; Hoffmann et al., 2021; Muik et al., 2022;
49 Schmidt et al., 2021). mRNA-1273 vaccine efficacy against breakthrough cases of Omicron in
50 the first few months after immunization has been estimated as 30% in California, USA and 37%
51 in Denmark (Hansen et al., 2021; Tseng et al., 2022) and a complete loss of protection within six
52 months (Accorsi et al., 2022). Multiple reports have suggested that Omicron has reduced
53 virulence compared to prior VOC in humans, mice and hamsters (Davies et al., 2022; Halfmann
54 et al., 2022; Suryawanshi et al., 2022). It is possible that reduced virulence of Omicron may
55 result from preferential replication in the upper airway compared to the lungs, perhaps due to
56 altered cellular tropism not reliant on expression of transmembrane serine protease 2
57 (TMPRSS2) (Meng et al., 2022; Willett et al., 2022). However, the effect of any reduction in
58 intrinsic viral pathogenicity may be somewhat offset in the context of reduced vaccine efficacy
59 and enhanced virus transmission in human populations worldwide. Together these data reinforce
60 the value of boosting to limit the extent of infection from Omicron.
61
62 Variant-matched boosts have been suggested as a strategy to enhance neutralizing and binding
63 antibody titers to the corresponding VOC beyond the levels conferred by existing FDA-approved
64 boosts, which are homologous to the original ancestral WA1-matched primary vaccine regimen.
65 We previously showed that boosting mRNA-1273 immunized nonhuman primates (NHP) with
66 mRNA-1273 or a boost matched to the Beta VOC spike (mRNA-1273.351 or mRNA-1273.Beta)
67 resulted in significant enhancement of neutralizing antibody responses across all VOC tested and
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68 an expansion of S-specific memory B cells with ~80-90% expressing WA1 and Beta. Moreover,
69 both vaccines provided substantial and similar protection against Beta replication (Corbett et al.,
70 2021a). These NHP data were confirmed in a study in humans which compared an mRNA-1273
71 boost to mRNA-1273.Beta ~6 months after participants had received the standard two-dose
72 mRNA-1273 vaccine regimen (Choi et al., 2021). Following either boost, neutralizing titers were
73 substantially increased against D614G and several variants including Beta and were comparable
74 between boost groups. Of note, the level of neutralizing antibodies to Beta after either boost were
75 about 10-fold higher than after the initial vaccination suggesting affinity maturation or epitope
76 focusing of the B cell response. Together, these data suggest that the variant Beta boost did not
77 uniquely enhance immunity or protection compared to existing ancestral strain-matched boosts.
78 However, as Omicron contains more mutations in S compared to Beta and demonstrates even
79 more substantial escape from vaccine-elicited neutralizing antibodies than does Beta, it is unclear
80 whether an Omicron-specific boost would provide an additional protective benefit against
81 Omicron infection beyond that of WA1-matched boosts.
82
83 The nonhuman primate (NHP) model has been useful for demonstrating immune correlates,
84 mechanisms and durability of vaccine-elicited protection against SARS-CoV-2 and been largely
85 predictive for what has been observed in humans in terms of protective efficacy (Corbett et al.,
86 2021b; Gagne et al., 2022; Gilbert et al., 2021). Here, we vaccinated NHP with 100µg mRNA-
87 1273 at weeks 0 and 4, which is a similar dose and schedule as used in humans. Animals were
88 then boosted about ~9 months later with 50µg of either a homologous dose of mRNA-1273 or
89 mRNA-1273.529, which is matched to Omicron S (henceforth referred to as mRNA-Omicron).
90 For the duration of these 9 months, we collected sera, bronchoalveolar lavage (BAL) and nasal
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91 washes to analyze the kinetics of antibody binding and neutralization as well as the frequency of
92 S-specific B cells for WA1 and Omicron as well as Beta and Delta. Four weeks after boost, NHP
93 were challenged with Omicron. Viral replication in upper and lower airways and lung
94 inflammation were measured to compare boost-elicited protection against Omicron.
95
96 Results
97 Kinetics of serum antibody responses following mRNA-1273 immunization and boost
98 Indian-origin rhesus macaques (n=8) were immunized with 100µg of mRNA-1273 at weeks 0
99 and 4 (Fig. S1). Sera were collected at weeks 6 (peak) and 41 (memory) to measure
100 immunoglobulin G (IgG) binding to WA1 S and a panel of VOC (Fig. 1A). At week 6, we
101 observed a clear hierarchy of binding titers with WA1>Delta>Beta >Omicron. Geometric mean
102 titers (GMT) to WA1 and Omicron were 8x1019 and 3x1015 area under the curve (AUC).
103 Antibody titers waned markedly by week 41, with GMT of 2x1012 and 2x108 AUC for WA1 and
104 Omicron, reflecting a 7-log decline for each strain. Similar antibody kinetics and hierarchy of
105 potency were observed when measuring binding to the receptor binding domain (RBD) of the
106 same variants, with titers to Omicron of 7x1011 AUC at week 6 and 8x107 AUC at week 41 (Fig.
107 1B). Nine months after the second dose of mRNA-1273 (week 41), NHP were boosted with
108 50µg of homologous mRNA-1273 or heterologous virus challenge-matched mRNA-Omicron
109 (n=4/group). S-binding titers were restored to the same level as observed at week 6 following
110 either a homologous or heterologous boost, and titers to Omicron were still lower than all other
111 variants.
112
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113 Neutralizing antibody titers were then assessed using a live virus assay (Fig. 1C and Table S1).
114 At week 6, neutralizing titers were highest to D614G followed by Delta, then Beta and Omicron.
115 Titers to all variants markedly declined by week 41, including a drop in reciprocal 50%
116 inhibitory dilution (ID50) titers for D614G from 5560 at week 6 to 330 at week 41 and for
117 Omicron from 110 at week 6 to 33 at week 41. However, following either boost, neutralizing
118 titers to D614G and Delta were increased similar to week 6 and titers to Beta and Omicron were
119 greater than they had been at week 6 (Beta: P=0.05 and 0.035; Omicron: P=0.041 and 0.01 for
120 mRNA-1273 and mRNA-Omicron, respectively). We substantiated these findings using a
121 lentiviral pseudovirus neutralization assay similar to the one used to assess immune responses in
122 human clinical trials (Fig. 1D). Following either boost, pseudovirus neutralizing titers were
123 greater to Beta and Omicron than they had been at the week 6 time-point, including an increase
124 in Omicron titers from 320 GMT to 2980 GMT in the mRNA-1273 boost group and 1930 GMT
125 in the mRNA-Omicron boost group (Beta: P=0.022 and <0.0001; Omicron: P=0.049 and 0.002
126 for mRNA-1273 and mRNA-Omicron, respectively).
127
128 The increase in neutralizing titers to all VOC tested after the third dose could suggest continued
129 antibody maturation (Gaebler et al., 2021). To extend this analysis, we measured antibody
130 avidity over time following immunization (Fig. 1E). Serum antibody avidity to WA1 S-2P
131 increased from a geometric mean avidity index of 0.43 to 0.61 from weeks 6 to 41 (P=0.0016), a
132 comparable increase to our previous findings (Corbett et al., 2021a; Gagne et al., 2022).
133 Similarly, avidity to Omicron S-2P rose from 0.44 to 0.67 (P<0.0001). Following the boost, no
134 further change was observed (P>0.05 for both boost groups).
135
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136 Collectively, these data show that boosting with the homologous mRNA-1273 or mRNA-
137 Omicron leads to comparable and significant increases in neutralizing antibody responses against
138 all VOC including Omicron.
139
140 mRNA-1273 and mRNA-Omicron boosting increase mucosal antibody responses to Omicron
141 Upper and lower airway antibody response are critical for mediating protection against SARS-
142 CoV-2 and were assessed following immunization. Nasal washes (NW) and bronchoalveolar
143 lavage fluid (BAL) were collected at weeks 8 (four weeks after the initial mRNA-1273
144 immunizations), 39 (pre-boost) and 43 (two weeks after the boost). At all timepoints, BAL and
145 NW IgG S-binding titers followed the hierarchy of WA1>Delta>Beta>Omicron (Fig. 2A-B), the
146 same trend detected in our serological assays. In BAL, immediately prior to the boost, GMT
147 were 6.8x106, 4.0x106, 1.3x106 and 2.5x104 AUC for WA1, Delta, Beta and Omicron,
148 respectively. These titers correlated with a 2-fold reduction for Delta compared to WA1, a 5-fold
149 reduction for Beta, and a 275-fold reduction for Omicron. Following either boost, titers were
150 increased by 3-4 logs for all variants. In NW, titers decreased from ~1011 for WA1, Delta and
151 Beta at week 8 to 1.3x106, 3.7x105 and 1.9x105 for WA1, Delta and Beta, respectively. GMT to
152 Omicron similarly declined from 8.8x108 to 8.7x103 AUC and were lower than WA1 and all
153 other variants. Consistent with the findings in the BAL, either boost increased nasal antibody
154 titers ~6-7 logs, with GMT of ~1012 for WA1, Delta and Beta and ~1010 for Omicron.
155
156 In a number of prior NHP studies, we have not been able to detect antibody neutralizing titers
157 using pseudo- or live-virus assays from NW or BAL. However, based on its high sensitivity, we
158 have used the angiotensin converting enzyme 2 receptor (ACE2) inhibition assay to measure
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159 antibody function as a surrogate for neutralization capacity (Corbett et al., 2021a; Gagne et al.,
160 2022). While the antigen for determination of binding titers was wildtype S, our ACE2 inhibition
161 assay used stabilized S-2P (Table S2). In the BAL, 25-50% median binding inhibition was
162 observed for all variants at week 8, except for Omicron S-2P in which binding inhibition was
163 low to undetectable (Fig. 2C). ACE2 binding inhibition declined to a median of <15% for all
164 variants by week 39 and then increased after either the homologous or mRNA-Omicron boost to
165 levels above those at week 8. Of note, although ACE2 inhibition of Omicron S-2P increased
166 following the boost, it remained lower than all other variants. In the upper airway, ACE2
167 inhibition was low to undetectable at week 39 following the initial vaccine regimen for all
168 variants. However, after either boost, there was an increase across all variants including Omicron
169 to values higher than the initial peak at week 8 (Fig. 2D). Thus, boosting with either vaccine was
170 important for enhancing mucosal antibody binding and neutralization responses.
171
172 Similar expansion of cross-reactive S-2P-specific memory B cells following boosting
173 The observation of rapid and significant increases in binding and neutralizing antibody titers to
174 Omicron in both blood and mucosal sites after homologous or heterologous mRNA boost
175 suggests an anamnestic response involving the mobilization of cross-reactive memory B cells.
176 Thus, we measured B cell binding to pairs of fluorochrome-labeled S-2P probes with different
177 VOC including Omicron at weeks 6, 41 and 43 (2 weeks post-boost) (Fig. S2). Of the total S-2P
178 specific memory B cell responses at week 6, 63% were dual-specific and capable of binding both
179 WA1 and Omicron probes, with 33% binding WA1 alone and only 4% which bound Omicron
180 alone (Fig. 3A, 4A). By week 41, the total S-specific memory B cell compartment had declined
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181 ~90% as a fraction of all class-switched memory B cells (Fig. S3A), although the dual-specific
182 population remained the largest fraction within the S-binding pool (Fig. 4A).
183
184 Two weeks after boosting, there was an expansion of the total S-specific memory B cell
185 compartment similar to that observed at week 6. Following an mRNA-1273 boost, 24% of all S-
186 2P-specific memory B cells were specific for WA1 alone and 71% were dual-specific for WA1
187 and Omicron. After the mRNA-Omicron boost, 81% were dual-specific for WA1 and Omicron.,
188 with 12% specific for WA1 only (Fig. 4A). Of note, we did not observe a population of
189 Omicron-only memory B cells before or after the boost that was clearly distinct from background
190 staining (Fig. 3A). These data suggest a marked expansion of cross-reactive dual-specific WA1-
191 and Omicron-positive B cells for either boost, with mRNA-1273 also expanding WA1-only B
192 cell responses. The increase in cross-reactive B cells for WA1 and Omicron is consistent with the
193 comparable and high-level of neutralizing titers against D614G and Omicron by either boost
194 (Fig. 1C-D). To extend these data, serologic mapping of antigenic sites on Omicron and WA1
195 RBD was performed. This analysis revealed that boosting with either mRNA-1273 or mRNA-
196 Omicron elicited serum antibody reactivity with similar RBD specificities (Fig S4).
197
198 To further explore the effect of boosting on anamnestic B cell responses, we phenotyped the
199 activation status of S-binding memory B cells (Fig. 4E). WA1 S-2P- and/or Omicron S-2P-
200 binding memory B cells predominantly had an activated memory phenotype immediately after
201 both the second and third doses.
202
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203 It has recently been shown that individuals in South Africa with or without prior vaccination had
204 increased neutralizing antibody titers to Delta and Omicron following Omicron infection (Khan
205 et al., 2022). Thus, we determined whether there was cross-reactivity of B cells for Delta and
206 Omicron following vaccination. Indeed, 68% of all Delta S-2P and/or Omicron S-2P memory B
207 cells were also dual-specific at week 6 and the remainder of S-binding memory B cells largely
208 bound Delta alone (Fig. 3B, 4B). Following a third dose, the frequency of dual-specific cells
209 increased to 76% for mRNA-1273 and 85% for mRNA-Omicron, consistent with our findings on
210 cross-reactive B cells using WA1 and Omicron S-2P probes.
211
212 To complete the analysis and demonstrate cross-reactivity of B cells across other variants, we
213 assessed the frequencies of memory B cells specific for WA-1 and Delta or Beta. We have
214 previously reported that dual-specific WA1 S-2P and Delta S-2P memory B cells accounted for
215 greater than 85% of all memory B cells which bound either spike after two immunizations with
216 mRNA-1273 (Gagne et al., 2022). Here we confirmed and extended these findings and show that
217 after either boost, ~95% of all WA1- and/or Delta-binding memory B cells are dual-specific (Fig.
218 3C, 4C). Similar findings were obtained with WA1 and Beta S-2P probes, in which the dual-
219 specific population was 85% at week 6 and 90% following either boost (Fig. 3D, 4D). Of note
220 following the mRNA-Omicron boost, very few B cells were detected that only bound WA1
221 epitopes when co-staining for Delta or Beta. Overall, the data show that cross-reactive cells were
222 expanded following a boost with either mRNA-1273 or mRNA-Omicron while only mRNA-
223 1273 was capable of boosting memory B cells specific for WA1 alone (Fig. S3).
224
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225 S-2P-specific T cell responses in blood and BAL following vaccination
226 We have previously shown that mRNA-1273 immunization elicits TH1, TFH and a low frequency
227 of CD8 responses to S peptides in NHP (Corbett et al., 2020; Corbett et al., 2021a; Corbett et al.,
228 2021c; Gagne et al., 2022; Jackson et al., 2020). Consistent with the prior studies we show that
229 mRNA-1273 elicits TH1, TFH and low-level CD8 T cell responses at the peak of the response
230 (week 6) that decline over time (Fig. S5 and S6). Boosting with either mRNA-1273 or mRNA-
231 Omicron increased TFH responses which could be important for expanding the S-specific
232 memory B cell population following the boost (Johnston et al., 2009; Nurieva et al., 2009;
233 Tangye et al., 2002). We also detected TH1 and CD8 T cells in BAL at week 8 that decreased to
234 undetectable levels at week 39. Such responses were increased with either mRNA-1273 or
235 mRNA-Omicron (Fig. S5).
236
237 Boosting with mRNA-1273 or mRNA-Omicron provides equivalent protection in the lungs
238 against Omicron challenge
239 To determine the extent of protection provided by a homologous mRNA-1273 or challenge
240 virus-matched mRNA-Omicron boost following the two-dose mRNA-1273 immunization series,
241 we obtained a new viral stock of Omicron, which was sequenced and confirmed to contain the
242 canonical mutations present in the dominant Omicron sub-lineage BA.1 (Fig. S7).
243
244 Four weeks after administration of either boost, we challenged these NHP and 8 control NHPs
245 with 1x106 plaque forming units (PFU) via both intratracheal (IT) and intranasal (IN) routes. The
246 control NHP had previously been administered 50µg of control mRNA formulated in lipid
247 nanoparticles at the time of boost and had never been vaccinated.
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248
249 BAL, nasal swabs (NS) and oral swabs (OS) were collected following challenge. Copy numbers
250 of SARS-CoV-2 subgenomic RNA (sgRNA) were measured to determine the extent of viral
251 replication. As sgRNA encoding for the N gene (sgRNA_N) are the most abundant transcripts
252 produced due to the viral discontinuous transcription process (Kim et al., 2020), the sgRNA_N
253 qRT-PCR assay was chosen for its enhanced sensitivity. On day 2 post-infection in the BAL,
254 unvaccinated NHP had geometric mean copy numbers of 1x106 sgRNA_N per mL whereas the
255 vaccinated NHP had 3x102 and 2x102 for the mRNA-1273 and mRNA-Omicron cohorts,
256 respectively (Fig. 5A). By day 4, all vaccinated NHP had undetectable levels of sgRNA_N while
257 copy numbers in the unvaccinated group had only declined to 3x105 per mL (mRNA-1273 vs
258 control on days 2 and 4: P<0.0001; mRNA-Omicron vs control on days 2 and 4: P<0.0001).
259
260 In the nose, sgRNA_N copy numbers at days 1 to 4 were low for most animals and were not
261 different between the control and vaccinated cohorts, so protection following vaccination could
262 not be determined (Fig. 5B). At day 4, 5/8 controls had detectable virus in the nose as compared
263 to 3/8 vaccinated NHP, with no clear difference between the boost cohorts. However, by day 8,
264 4/8 controls still had detectable sgRNA_N including 2 animals with increased copy numbers
265 while none of the vaccinated NHP had detectable sgRNA.
266
267 In assessing sgRNA_N in the throat, it is noteworthy that 2 days after challenge, only 1/8
268 vaccinated NHP (in either boost group) had detectable virus in the throat compared to 6/8 control
269 NHP (Fig. 5C).
270
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271 We also measured the amount of culturable virus using a tissue culture infectious dose assay
272 (TCID50). No virus was detected in the BAL of any vaccinated NHP, while 8/8 and 7/8 control
273 NHP had detectable virus 2 and 4 days after challenge, respectively (Fig. 5D). In the NS, 1/8
274 boosted animals had culturable virus at any timepoint. In the unvaccinated control animals, 2/8
275 and 3/8 NHP had culturable virus in the nose 2 and 4 days after challenge, respectively (Fig. 5E).
276
277 Viral antigen and pathology in the lungs after challenge
278 To assess lung pathology in NHP, 2 of the animals in each group were euthanized on day 8
279 following Omicron challenge, and the amount of viral antigen (SARS-CoV-2 N) and
280 inflammation in the lungs were assessed (Fig. 6). N antigen was detected in variable amounts in
281 the lungs of both control animals. When present, viral antigen was often associated with the
282 alveolar capillaries and, occasionally, nearby immune cells. There was no evidence of viral
283 antigen in the lungs of the vaccinated NHP.
284
285 Animals from both boost groups displayed histopathologic alterations that were classified as
286 minimal to mild or moderate. Inflammation was largely characterized by mild and patchy
287 expansion of alveolar capillaries, generalized alveolar capillary hypercellularity, mild and
288 regional type II pneumocyte hyperplasia and, less frequently, scattered collections of immune
289 cells within some alveolar spaces. In contrast, unvaccinated animals were characterized as
290 having a moderate to severe pathology. Lung sections from controls included features
291 characterized by moderate and often diffuse alveolar capillary expansion, diffuse
292 hypercellularity, moderate type II pneumocyte hyperplasia and multiple areas of perivascular
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293 cellular infiltration. Together, these data indicate that protection against Omicron was robust in
294 the lungs regardless of boost selection.
295
296 Discussion
297 Omicron has become the dominant global variant of SARS-CoV-2 due to its transmission
298 advantage relative to Delta and its ability to evade prior immunity (Grabowski et al., 2022; Viana
299 et al., 2022). Vaccine efficacy against infection with Omicron has declined and boosting with a
300 third dose of an mRNA COVID-19 vaccine matched to the prototype strain has been shown to
301 restore immunity and protection (Accorsi et al., 2022; Garcia-Beltran et al., 2022; Hansen et al.,
302 2021; Pajon et al., 2022; Tseng et al., 2022). Here, we immunized NHP with 2 doses of mRNA-
303 1273 (100µg) and boosted them ~9 months later with 50µg of either mRNA-1273 or mRNA-
304 Omicron prior to challenge with Omicron virus. The principal findings were: (1) 9 months after
305 the two-dose regimen, neutralizing and binding antibody titers to Omicron had declined
306 substantially in blood and mucosal airways; (2) after the boost, neutralizing antibody titers to
307 ancestral strains were restored and those to Omicron were increased compared to the peak
308 response after the initial prime and boost; (3) both boosts expanded cross-reactive memory B
309 cells but only the homologous boost was capable of expanding B cells specific for epitopes
310 unique to the ancestral strain; and (4) both boosts provided complete protection in the lungs and
311 limited protection in the upper airway after Omicron challenge.
312
313 Following either mRNA-1273 or mRNA-Omicron boost, there was essentially complete
314 protection in the lower airway with no culturable virus by day 2 and no detectable sgRNA_N by
315 day 4. These data are comparable to our previous findings of equivalent upper and lower airway
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316 protection following Beta challenge in NHP boosted with either mRNA-1273 or mRNA-
317 1273.Beta 1-2 months after immunization with 2 doses of mRNA-1273 (Corbett et al., 2021a). In
318 contrast to the lower airway, there were no clear and consistent differences in sgRNA_N copy
319 number at days 2 or 4 in the upper airway of vaccinated or control NHP. Of note, more of the
320 control animals had detectable sgRNA at day 4 and increased sgRNA at day 8 as compared to
321 the boosted animals. We would also note that the amount of Omicron replication as assessed by
322 sgRNA or culturable virus in the control animals is demonstrably different than in our prior
323 studies in which NHP were challenged with WA1, Delta or Beta (Corbett et al., 2020; Corbett et
324 al., 2021c; Gagne et al., 2022). These findings compliment a growing body of evidence for
325 reduced overall severity of Omicron infection in animal models of COVID-19 compared to other
326 variants (Bentley et al., 2021; Halfmann et al., 2022; Suryawanshi et al., 2022). Overall, the
327 findings here of high-level protection in the lungs recapitulate observations in mRNA-1273-
328 vaccinated humans of reduced disease severity following infection with Omicron (Abdullah et
329 al., 2021; Sigal, 2022; Wolter et al., 2022).
330
331 Neutralizing antibodies to Omicron in the blood or ACE2 binding inhibitory antibodies in the
332 airway mucosa were low after the first 2 doses of mRNA-1273 at weeks 6-8 and low to
333 undetectable ~9 months later. Importantly, either mRNA-1273 or mRNA-Omicron boosts were
334 able to significantly increase neutralizing antibody titers against Omicron and Beta beyond their
335 initial peak consistent with a rapid recall B cell response. This also implies that neutralizing
336 antibody titers at extended times after vaccination may not be a reliable surrogate either for
337 vaccine efficacy in the lower airway or for predicting responses following a boost or infection as
338 they may not reflect the recall capacity of the underlying memory B cell population.
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339
340 The observation that boosting with either mRNA-1273 or mRNA-Omicron resulted in the
341 expansion of a similarly high frequency of cross-reactive B cells likely stems from the principle
342 of original antigenic sin, otherwise termed antigenic imprinting, whereby prior immune memory
343 is recalled by a related antigenic encounter (Davenport and Hennessy, 1957; Davenport et al.,
344 1953). Recall of prior immunity may be either deleterious or beneficial as exemplified by the
345 impact of the circulating influenza A subtypes at the time of an individual’s first exposure after
346 birth on patterns of disease susceptibility to subsequent pandemic influenza A outbreaks (Gostic
347 et al., 2016; Worobey et al., 2014). The current worldwide distribution and evolution of SARS-
348 CoV-2, however, is quite different from that of influenza A. Whereas multiple subtypes of
349 influenza A circulate with different levels of co-dominance, SARS-CoV-2 distribution has
350 generally become rapidly dominated by a single variant — currently Omicron — before
351 replacement by another that, for various reasons, is more transmissible. The question therefore is
352 whether there is added value from boosting with a heterologous vaccine matched to the dominant
353 circulating variant, or whether cross-reactive B cell recall immunity elicited by boosting with the
354 original vaccine is sufficient to reduce infection and disease severity. As we have now shown in
355 two different NHP studies, boosting animals with either mRNA-1273.Beta (Corbett et al., 2021a)
356 or mRNA-Omicron provided no advantage over mRNA-1273 in recalling high titer neutralizing
357 antibodies across all variants tested and protecting from virus replication after challenge. These
358 considerations apply to the large numbers of individuals with prior immunity from vaccination or
359 infection with current and previous variants who may not necessarily benefit from a change in
360 vaccine design.
361
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362 Looking to the future, however, if Omicron, or a closely antigenically related variant, remains
363 the dominant circulating variant for some years to come, then it is possible that a change in the
364 initial vaccine regimen would be warranted, particularly in immunologically naïve populations
365 such as children as they reach the age of eligibility for approved COVID-19 vaccines.
366 Importantly, it would need to be established that a switch in COVID-19 vaccine design to match
367 the current dominant variant would not jeopardize responses against variants which may be
368 antigenically distant from Omicron but close to the prototype. Indeed a recent study has shown
369 that immunization of mice with an Omicron mRNA vaccine elicited strong neutralization against
370 Omicron but not to other variants, consistent with data from primary Omicron infection (Lee et
371 al., 2022; Roessler et al., 2022; Suryawanshi et al., 2022). Thus, a combination or bivalent
372 vaccine to generate B cells specific for the current variant as well as cross-reactive to other
373 variants might ensure greater breadth of neutralization.
374
375 In summary, our findings highlight two important factors that will impact management of this
376 pandemic. The first is the design of the vaccine and whether it should be changed based on the
377 currently circulating variant. At present, boosting with mRNA-1273 provides robust increases in
378 neutralizing antibodies and appears to be sufficient to prevent severe disease after exposure from
379 all known variants (Baden et al., 2021a; Bruxvoort et al., 2021a; Bruxvoort et al., 2021b;
380 Chemaitelly et al., 2021; Corbett et al., 2020; Corbett et al., 2021c; Gagne et al., 2022; Pilishvili
381 et al., 2021; Tang et al., 2021). Variant-matched vaccines may be preferable in the future if new
382 variants were to emerge that were even further antigenically distant such that cross-reactive
383 epitopes are rendered ineffective or if there were differences in the durability of neutralizing
384 antibody titers elicited by different boosts. Second, as neutralizing antibody titers wane with time
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385 after vaccination, their ability to serve as a surrogate for vaccine efficacy or to predict clinical
386 outcomes against severe disease after infection with VOC may become diminished. Thus the
387 determination of when to administer a boost may depend on the recall capacity of the underlying
388 memory B cell population. These considerations will become clear as human clinical data are
389 made available.
390
391 Limitations of the study
392 There are several limitations to this study. First, NHP models may not fully recapitulate clinical
393 data in humans regarding the extent of viral replication necessary for the enhanced transmission
394 of Omicron compared to prior variants. Even if a significant component of Omicron’s growth
395 advantage is due to immune escape, the role of viral replication kinetics cannot be ruled out.
396 Here, viral titers were low in the lungs and low to undetectable in the upper airway. Second,
397 neutralizing antibody titers in NHP are 5- to 10-fold greater than in humans that received the
398 same dose and regimen of mRNA-1273 with a boost (Edara et al., 2021a; Pajon et al., 2022).
399 Third, a second dose of mRNA-Omicron may elicit a population of B cells specific only for
400 Omicron. Finally, since we sought to compare two different mRNA boosts, we did not have an
401 unboosted group to determine whether the boost enhanced protection. As all the boosted NHP
402 were completely protected in the lungs, we were unable to determine an immune threshold for
403 protection.
404
405 Materials and methods
406 Resource availability
407 Lead contact
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408 Further information and requests for resources should be directed to and will be fulfilled by the
409 lead contact, Robert A. Seder (rseder@mail.nih.gov).
410
411 Materials availability
412 This study did not generate new unique reagents.
413
414 Data and code availability
415 • All data reported in this paper will be shared by the lead contact upon request.
416 • This paper does not report original code.
417 • Any additional information required to reanalyze the data reported in this paper is
418 available from the lead contact upon request.
419
420 Experimental model and subject details
421 Preclinical mRNA and lipid nanoparticle production
422 A sequence-optimized mRNA encoding prefusion-stabilized SARS-CoV-2 S protein containing
423 2 proline stabilization mutations (S-2P) (Pallesen et al., 2017; Wrapp et al., 2020) for WA1 and
424 Omicron were synthesized in vitro and formulated (Hassett et al., 2019). Control mRNA
425 “UNFIX-01 (Untranslated Factor 9)” was synthesized and similarly formulated into lipid
426 nanoparticles as previously described (Corbett et al., 2021a).
427
428 Rhesus macaque model and immunizations
429 All experiments conducted according to NIH regulations and standards on the humane care and
430 use of laboratory animals as well as the Animal Care and Use Committees of the NIH Vaccine
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431 Research Center and BIOQUAL, Inc. (Rockville, Maryland). All studies were conducted at
432 BIOQUAL, Inc. Four- to eight-year-old rhesus macaques of Indian origin were stratified into
433 groups based on sex, age and weight. Eight macaques were immunized with mRNA-1273 at
434 weeks 0 and 4 with a dose of 100μg delivered intramuscularly in 1mL of formulated lipid
435 nanoparticles diluted in phosphate-buffered saline (PBS) into the right quadricep as previously
436 described (Corbett et al., 2020; Corbett et al., 2021c; Gagne et al., 2022). At week 41 (~9 months
437 after the second immunization), the eight macaques were split into two groups of 4 and boosted
438 with 50μg mRNA-1273 or 50μg of mRNA-Omicron. Animals in the control group were
439 immunized with 50μg control mRNA at the time of the boost.
440
441 Method details
442 Cells and viruses
443 VeroE6-TMPRSS2 cells were generated at the Vaccine Research Center, NIH, Bethesda, MD.
444 Isolation and sequencing of EHC-083E (D614G SARS-CoV-2), Delta, Beta and Omicron for
445 live virus neutralization assays were previously described (Edara et al., 2021b; Edara et al.,
446 2021c; Vanderheiden et al., 2020). Viruses were propagated in Vero-TMPRSS2 cells to generate
447 viral stocks. Viral titers were determined by focus-forming assay on VeroE6-TMPRSS2 cells.
448 Viral stocks were stored at -80°C until use.
449
450 Sequencing of Omicron virus stock
451 We used NEBNext Ultra II RNA Prep reagents and multiplex oligos (New England Biolabs) to
452 prepare Illumina-ready libraries, which were sequenced on a MiSeq (Illumina) as described
453 previously (Corbett et al., 2021c; Gagne et al., 2022). Demultiplexed sequence reads were
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454 analyzed in the CLC Genomics Workbench v.21.0.3 by (1) trimming for quality, length, and
455 adaptor sequence, (2) mapping to the Wuhan-Hu-1 SARS-CoV-2 reference (GenBank no.
456 NC_045512), (3) improving the mapping by local realignment in areas containing insertions and
457 deletions (indels), and (4) generating both a sample consensus sequence and a list of variants.
458 Default settings were used for all tools.
459
460 Omicron challenge
461 Macaques were challenged at week 45 (4 weeks after the second boost) with a total dose of 1 ×
462 106 PFU of SARS-CoV-2 Omicron. The viral inoculum was administered as 7.5 ×105 PFUs in
463 3mL intratracheally and 2.5 ×105 PFUs in 1mL intranasally in a volume of 0.5mL distributed
464 evenly into each nostril.
465
466 Serum and mucosal antibody titers
467 Quantification of antibodies in the blood and mucosa were performed as previously described
468 (Corbett et al., 2020). Briefly, total IgG antigen-specific antibodies to variant SARS-CoV-2 S-
469 and RBD-derived antigens were determined in a multiplex serology assay by MSD V-Plex
470 SARS-CoV-2 Panel 23 for S and MSD V-Plex SARS-CoV-2 Panel 22 for RBD) according to
471 manufacturer’s instructions, except 25μl of sample and detection antibody were used per well.
472 Heat inactivated plasma was initially diluted 1:100 and then serially diluted 1:10 for blood S-
473 and 1:4 for RBD-binding. BAL fluid and nasal washes were concentrated 10-fold with Amicon
474 Ultra centrifugal filter devices (Millipore Sigma). Concentrated samples were diluted 1:5 prior to
475 5-fold serial dilutions.
476
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477 S-2P antigens
478 While S antigens were used for binding ELISAs, S-2P antigens were used for ACE2 inhibition
479 assays and B cell probe binding. S-2P constructs were made as follows. Biotinylated S probes
480 were expressed transiently for WA1, Delta, Beta and Omicron strains and purified and
481 biotinylated in a single in-process step (Teng et al., 2021; Zhou et al., 2020). S-2P for WA1 and
482 Omicron were made as previously described (Olia et al., 2021).
483
484 S-2P-ACE2 binding inhibition
485 ACE2 binding inhibition was performed using a modified Meso Scale Discovery (MSD)
486 platform assay. Briefly, after blocking MSD Streptavidin MULTI-ARRAY 384 well plates with
487 Blocker A (MSD), the plates were coated with 1 µg/ml of biotinylated SARS-CoV-2 variant S-
488 2P (WA1, Beta, Delta or Omicron) and incubated for 1 hour at room temperature (RT). The
489 plates were washed 5 times with wash buffer (1x PBS containing 0.05% Tween-20). Diluted
490 samples were added to the coated plates and incubated for 1 hour at RT. MSD SULFO-TAG
491 Human ACE2 protein was diluted 1:200 and added to the plates. After 1 hour incubation at RT,
492 the plates were washed 5 times with wash buffer and read on MSD Sector S 600 instrument after
493 the addition of Gold Read Buffer B (MSD). Results are reported as percent inhibition. BAL fluid
494 and nasal washes were first concentrated 10-fold with Amicon Ultra centrifugal filter devices
495 (Millipore Sigma) and then diluted 1:5 in Diluent 100 (MSD).
496
497 Focus reduction neutralization assay
498 FRNT assays were performed as previously described (Edara et al., 2021b; Edara et al., 2021c;
499 Vanderheiden et al., 2020). Briefly, samples were diluted at 3-fold in 8 serial dilutions using
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500 DMEM (VWR, #45000-304) in duplicates with an initial dilution of 1:10 in a total volume of
501 60µl. Serially diluted samples were incubated with an equal volume of WA1, Delta, Beta or
502 Omicron (100-200 foci per well based on the target cell) at 37oC for 45 minutes in a round-
503 bottomed 96-well culture plate. The antibody-virus mixture was then added to VeroE6-
504 TMPRSS2 cells and incubated at 37oC for 1 hour. Post-incubation, the antibody-virus mixture
505 was removed and 100µl of pre-warmed 0.85% methylcellulose overlay was added to each well.
506 Plates were incubated at 37oC for 18 hours and the methylcellulose overlay was removed and
507 washed six times with PBS. Cells were fixed with 2% paraformaldehyde in PBS for 30 minutes.
508 Following fixation, plates were washed twice with PBS and permeabilization buffer (0.1% BSA,
509 0.1% Saponin in PBS) was added to permeabilized cells for at least 20 minutes. Cells were
510 incubated with an anti-SARS-CoV S primary antibody directly conjugated to Alexaflour-647
511 (CR3022-AF647) overnight at 4°C. Foci were visualized and imaged on an ELISPOT reader
512 (CTL). Antibody neutralization was quantified by counting the number of foci for each sample
513 using the Viridot program (Katzelnick et al., 2018). The neutralization titers were calculated as
514 follows: 1 - (ratio of the mean number of foci in the presence of sera and foci at the highest
515 dilution of respective sera sample). Each specimen was tested in duplicate. The FRNT-50 titers
516 were interpolated using a 4-parameter nonlinear regression in GraphPad Prism 9.2.0. Samples
517 that do not neutralize at the limit of detection (LOD) at 50% are plotted at 20 and was used for
518 geometric mean and fold-change calculations. The assay LOD was 20.
519
520 Lentiviral pseudovirus neutralization
521 Neutralizing antibodies in serum or plasma were measured in a validated pseudovirus-based
522 assay as a function of reductions in luciferase reporter gene expression after a single round of
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523 infection with SARS-CoV-2 spike-pseudotyped viruses in 293T/ACE2 cells (293T cell line
524 stably overexpressing the human ACE2 cell surface receptor protein, obtained from Drs. Mike
525 Farzan and Huihui Mu at Scripps) as previously described (Gilbert et al., 2021; Shen et al.,
526 2021). SARS-CoV-2 S-pseudotyped virus was prepared by transfection in 293T/17 cells (human
527 embryonic kidney cells in origin; obtained from American Type Culture Collection, #CRL-
528 11268) using a lentivirus backbone vector, a spike-expression plasmid encoding S protein from
529 Wuhan-Hu-1 strain (GenBank no. NC_045512) with a p.Asp614Gly mutation, a TMPRSS2
530 expression plasmid and a firefly Luc reporter plasmid. For pseudovirus encoding the S from
531 Delta, Beta and Omicron, the plasmid was altered via site-directed mutagenesis to match the S
532 sequence to the corresponding variant sequence as previously described (Corbett et al., 2021a). A
533 pre-titrated dose of pseudovirus was incubated with eight serial 5-fold dilutions of serum
534 samples (1:20 start dilution) in duplicate in 384-well flat-bottom tissue culture plates (Thermo
535 Fisher, #12-565-344) for 1 hour at 37ºC prior to adding 293T/ACE2 cells. One set of 14 wells
536 received cells and virus (virus control) and another set of 14 wells received cells only
537 (background control), corresponding to technical replicates. Luminescence was measured after
538 66-72 hours of incubation using Britelite-Plus luciferase reagent (Perkin Elmer, #6066769).
539 Neutralization titers are the inhibitory dilution of serum samples at which relative luminescence
540 units (RLUs) were reduced by 50% (ID50) compared to virus control wells after subtraction of
541 background RLUs. Serum samples were heat-inactivated for 30-45 minutes at 56ºC prior to
542 assay.
543
544 Serum antibody avidity
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545 Avidity was measured as described previously (Francica et al., 2021) in an adapted ELISA assay.
546 Briefly, ELISA against S-2P was performed in the absence or presence of sodium thiocyanate
547 (NaSCN) and developed with HRP-conjugated goat anti-monkey IgG (H+L) secondary antibody
548 (Invitrogen) and SureBlue 3,3′,5,5′-tetramethylbenzidine (TMB) microwell peroxidase substrate
549 (1-Component; SeraCare) and quenched with 1 N H2SO4. The avidity index (AI) was calculated
550 as the ratio of IgG binding to S-2P in the absence or presence of NaSCN.
551
552 Epitope mapping
553 Serum epitope mapping competition assays were performed, as previously described (Corbett et
554 al., 2021a), using the Biacore 8K+ surface plasmon resonance system (Cytiva). Briefly, through
555 primary amine coupling using a His capture kit (Cytiva), anti-histidine antibody was
556 immobilized on Series S Sensor Chip CM5 (Cytiva) allowing for the capture of his-tagged
557 SARS-CoV-2 S-2P on active sensor surface.
558
559 Human IgG monoclonal antibodies (mAbs) used for these analyses include: RBD-specific mAbs
560 B1-182, A19-46.1, A20-29.1, A19-61.1, S309, A23-97.1 and A23-80.1. Negative control
561 antibody or competitor mAb was injected over both active and reference surfaces. Following
562 this, NHP sera (diluted 1:50) was flowed over both active and reference sensor surfaces. Active
563 and reference sensor surfaces were regenerated between each analysis cycle.
564
565 For analysis, sensorgrams were aligned to Y (Response Units) = 0, using Biacore 8K Insights
566 Evaluation Software (Cytiva) beginning at the serum association phase. Relative “analyte
567 binding late” report points (RU) were collected and used to calculate fractional competition (%
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568 C) using the following formula: % C = [1 – (100 * ( (RU in presence of competitor mAb) / (RU
569 in presence of negative control mAb) ))]. Results are reported as fractional competition. Assays
570 were performed in duplicate, with average data point represented on corresponding graphs.
571
572 B cell probe binding
573 Kinetics of S-specific memory B cells responses were determined as previously described
574 (Gagne et al., 2022). Briefly, cryopreserved PBMC were thawed and stained with the following
575 antibodies (monoclonal unless indicated): IgD FITC (goat polyclonal, Southern Biotech), IgM
576 PerCP-Cy5.5 (clone G20-127, BD Biosciences), IgA Dylight 405 (goat polyclonal, Jackson
577 Immunoresearch Inc), CD20 BV570 (clone 2H7, Biolegend), CD27 BV650 (clone O323,
578 Biolegend), CD14 BV785 (clone M5E2, Biolegend), CD16 BUV496 (clone 3G8, BD
579 Biosciences), CD4 BUV737 (clone SK3, BD Biosciences), CD19 APC (clone J3-119,
580 Beckman), IgG Alexa 700 (clone G18-145, BD Biosciences), CD3 APC-Cy7 (clone SP34-2, BD
581 Biosciences), CD38 PE (clone OKT10, Caprico Biotechnologies), CD21 PE-Cy5 (clone B-ly4,
582 BD Biosciences) and CXCR5 PE-Cy7 (clone MU5UBEE, Thermo Fisher Scientific). Stained
583 cells were then incubated with streptavidin-BV605 (BD Biosciences) labeled WA1, Beta, Delta
584 or Omicron S-2P and streptavidin-BUV661 (BD Biosciences) labeled WA1 or Delta S-2P for 30
585 minutes at 4°C (protected from light). Cells were washed and fixed in 0.5% formaldehyde
586 (Tousimis Research Corp) prior to data acquisition. Aqua live/dead fixable dead cell stain kit
587 (Thermo Fisher Scientific) was used to exclude dead cells. All antibodies were previously
588 titrated to determine the optimal concentration. Samples were acquired on an BD FACSymphony
589 cytometer and analyzed using FlowJo version 10.7.2 (BD, Ashland, OR).
590
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591 Intracellular cytokine staining
592 Intracellular cytokine staining was performed as previously described (Donaldson et al., 2019;
593 Gagne et al., 2022). Briefly, cryopreserved PBMC and BAL cells were thawed and rested
594 overnight in a 37°C/5% CO2 incubator. The following morning, cells were stimulated with
595 SARS-CoV-2 S protein (S1 and S2, matched to vaccine insert) peptide pools (JPT Peptides) at a
596 final concentration of 2 μg/ml in the presence of 3mM monensin for 6 hours. The S1 and S2
597 peptide pools were comprised of 158 and 157 individual peptides, respectively, as 15 mers
598 overlapping by 11 amino acids in 100% DMSO. Negative controls received an equal
599 concentration of DMSO instead of peptides (final concentration of 0.5%). The following
600 monoclonal antibodies were used: CD3 APC-Cy7 (clone SP34-2, BD Biosciences), CD4 PE-
601 Cy5.5 (clone S3.5, Invitrogen), CD8 BV570 (clone RPA-T8, BioLegend), CD45RA PE-Cy5
602 (clone 5H9, BD Biosciences), CCR7 BV650 (clone G043H7, BioLegend), CXCR5 PE (clone
603 MU5UBEE, Thermo Fisher), CXCR3 BV711 (clone 1C6/CXCR3, BD Biosciences), PD-1
604 BUV737 (clone EH12.1, BD Biosciences), ICOS Pe-Cy7 (clone C398.4A, BioLegend), CD69
605 ECD (cloneTP1.55.3, Beckman Coulter), IFN-g Ax700 (clone B27, BioLegend), IL-2 BV750
606 (clone MQ1-17H12, BD Biosciences), IL-4 BB700 (clone MP4-25D2, BD Biosciences), TNF-
607 FITC (clone Mab11, BD Biosciences), IL-13 BV421 (clone JES10-5A2, BD Biosciences), IL-17
608 BV605 (clone BL168, BioLegend), IL-21 Ax647 (clone 3A3-N2.1, BD Biosciences) and CD154
609 BV785 (clone 24-31, BioLegend). Aqua live/dead fixable dead cell stain kit (Thermo Fisher
610 Scientific) was used to exclude dead cells. All antibodies were previously titrated to determine
611 the optimal concentration. Samples were acquired on a BD FACSymphony flow cytometer and
612 analyzed using FlowJo version 10.8.0 (BD, Ashland, OR).
613
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614 Subgenomic RNA quantification
615 sgRNA was isolated and quantified by researchers blinded to vaccine history as previously
616 described (Corbett et al., 2021c), except for the use of a new probe noted below. Briefly, total
617 RNA was extracted from BAL fluid and nasal swabs using RNAzol BD column kit (Molecular
618 Research Center). PCR reactions were conducted with TaqMan Fast Virus 1-Step Master Mix
619 (Applied Biosystems), forward primer in the 5’ leader region and gene-specific probes and
620 reverse primers as follows:
621
622 sgLeadSARSCoV2_F: 5’-CGATCTCTTGTAGATCTGTTCTC-3’
623
624 N gene
625 N2_P: 5’-FAM- CGATCAAAACAACGTCGGCCCC-BHQ1-3’
626 wtN_R: 5’-GGTGAACCAAGACGCAGTAT-3’
627
628 Amplifications were performed with a QuantStudio 6 Pro Real-Time PCR System (Applied
629 Biosystems). The assay lower LOD was 50 copies per reaction.
630
631 Median Tissue Culture Infectious Dose (TCID50) assay
632 TCID50 was quantified as previously described (Corbett et al., 2021c). Briefly, Vero-TMPRSS2
633 cells were plated and incubated overnight. The following day, BAL samples were serially
634 diluted, and the plates were incubated at 37 °C/5.0% CO2 for four days. Positive (virus stock of
635 known infectious titer in the assay) and negative (medium only) control wells were included in
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636 each assay setup. The cell monolayers were visually inspected for cytopathic effect. TCID50
637 values were calculated using the Reed–Muench formula.
638
639 Histopathology and immunohistochemistry
640 Routine histopathology and detection of SARS-CoV-2 virus antigen via immunohistochemistry
641 (IHC) were performed as previously described (Corbett et al., 2020; Gagne et al., 2022). Briefly,
642 seven to nine days following Omicron challenge animals were euthanized and lung tissue was
643 processed and stained with hematoxylin and eosin for pathological analysis or with a rabbit
644 polyclonal anti-SARS-CoV-2 anti-nucleocapsid antibody (GeneTex, GTX135357) at a dilution
645 of 1:2000 for IHC. Tissue sections were analyzed by a blinded board-certified veterinary
646 pathologist using an Olympus BX43 light microscope. Photomicrographs were taken on an
647 Olympus DP27 camera.
648
649 Quantification and statistical analysis
650 Comparisons between groups, or between timepoints within a group, are based on unpaired and
651 paired t-tests, respectively. All analysis for serum epitope mapping was performed using
652 unpaired, two-tailed t-test. Binding, neutralizing and viral assays are log-transformed as
653 appropriate and reported with geometric means and corresponding confidence intervals where
654 indicated. There are no adjustments for multiple comparisons, so all p-values should be
655 interpreted as suggestive rather than conclusive. All analyses are conducted using R version 4.0.2
656 and GraphPad Prism version 8.2.0 unless otherwise specified.
657
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658 P values are stated in the text, and the sample n is listed in corresponding figure legends. For all
659 data presented, n=4 for individual boost cohorts and n=7-8 for controls and vaccinated NHP at
660 pre-boost timepoints.
661
662 Acknowledgments
663 We would like to thank G. Alvarado for experimental organization and administrative support.
664 The VRC Production Program (VPP) provided the WA1 protein for the avidity assay. VPP
665 contributors include C. Anderson, V. Bhagat, J. Burd, J. Cai, K. Carlton, W. Chuenchor, N.
666 Clbelli, G. Dobrescu, M. Figur, J. Gall, H. Geng, D. Gowetski, K. Gulla, L. Hogan, V. Ivleva, S.
667 Khayat, P. Lei, Y. Li, I. Loukinov, M. Mai, S. Nugent, M. Pratt, E. Reilly, E. Rosales-Zavala, E.
668 Scheideman, A. Shaddeau, A. Thomas, S. Upadhyay, K. Vickery, A. Vinitsky, C. Wang, C.
669 Webber and Y. Yang.
670
671 This project has been funded in part by both the Intramural Program of the National Institute of
672 Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human
673 Services and under HHSN272201400004C (NIAID Centers of Excellence for Influenza
674 Research and Surveillance, CEIRS) and NIH P51 OD011132 awarded to Emory University. This
675 work was also supported in part by the Emory Executive Vice President for Health Affairs
676 Synergy Fund award, COVID-Catalyst-I3 Funds from the Woodruff Health Sciences Center and
677 Emory School of Medicine, the Pediatric Research Alliance Center for Childhood Infections and
678 Vaccines and Children’s Healthcare of Atlanta, and Woodruff Health Sciences Center 2020
679 COVID-19 CURE Award.
680
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681 Author contributions
682 M.R., N.J.S., D.C.D. and R.A.S. designed experiments. M.G., J.I.M, K.E.F., S.F.A., B.J.F.,
683 A.P.W, D.A.W., B.C.L., C.M., N.J-B., R.C., S.L.F., M.P., M.E., V-V.E., N.V.M., M.M., L.M.,
684 C.C.H., B.M.N., K.W.B., C.N.M.D., J.C., J-P.M.T., E.M., L.P., A.V.R., B.N., D.V., A.C., A.D.,
685 K.S., D.R.F., S.T.N., S.G., A.R.H., F.L., J.R-T., C.G.L, S.A., D.K.E., H.A., M.G.L., K.S.C.,
686 M.C.N., A.B.M., M.S.S., I.N.M., M.R., N.J.S., D.C.D. and R.A.S. performed, analyzed, and/or
687 supervised experiments. M.G., J.I.M., K.E.F., S.F.A., D.A.W., I.N.M. and D.C.D. designed
688 figures. I-T.T., J.T., M.N., M.B., J.W., L.W., W.S., N.A.D-R., A.S.O., C.L., D.R.H., A.C.,
689 J.R.M. and P.D.K. provided critical reagents. M.G., J.I.M., D.C.D. and R.A.S. wrote manuscript.
690 All authors edited the manuscript and provided feedback on research.
691
692 Declaration of interests
693 K.S.C. is an inventor on U.S. Patent No. 10,960,070 B2 and International Patent Application No.
694 WO/2018/081318 entitled “Prefusion Coronavirus Spike Proteins and Their Use”. K.S.C. is an
695 inventor on U.S. Patent Application No. 62/972,886 entitled “2019-nCoV Vaccine”. L.W., W.S.,
696 J.R.M., M.R., N.J.S. and D.C.D are inventors on U.S. Patent Application No. 63/147,419 entitled
697 “Antibodies Targeting the Spike Protein of Coronaviruses”. L.P., A.V.R., B.N., D.V., A.C.,
698 A.D., K.S., H.A. and M.G.L. are employees of Bioqual. K.S.C, L.W. and W.S. are inventors on
699 multiple U.S. Patent Applications entitled “Anti-Coronavirus Antibodies and Methods of Use”.
700 A.C. and D.K.E. are employees of Moderna. M.S.S. serves on the scientific board of advisors for
701 Moderna and Ocugen. The other authors declare no competing interests.
702
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893 Tangye, S.G., Ferguson, A., Avery, D.T., Ma, C.S., and Hodgkin, P.D. (2002). Isotype switching by
894 human B cells is division-associated and regulated by cytokines. J Immunol 169, 4298-4306.
895 Teng, I.-T., Nazzari, A.F., Choe, M., Liu, T., de Souza, M.O., Petrova, Y., Tsybovsky, Y., Wang, S.,
896 Zhang, B., Artamonov, M., et al. (2021). Molecular probes of spike ectodomain and its
897 subdomains for SARS-CoV-2 variants, Alpha through Omicron. bioRxiv, 2021.2012.2029.474491.
898 Tseng, H.F., Ackerson, B.K., Luo, Y., Sy, L.S., Talarico, C.A., Tian, Y., Bruxvoort, K.J., Tubert, J.E.,
899 Florea, A., Ku, J.H., et al. (2022). Effectiveness of mRNA-1273 against SARS-CoV-2 omicron and
900 delta variants. medRxiv, 2022.2001.2007.22268919.
901 Vanderheiden, A., Edara, V.V., Floyd, K., Kauffman, R.C., Mantus, G., Anderson, E., Rouphael, N.,
902 Edupuganti, S., Shi, P.Y., Menachery, V.D., et al. (2020). Development of a Rapid Focus
903 Reduction Neutralization Test Assay for Measuring SARS-CoV-2 Neutralizing Antibodies. Curr
904 Protoc Immunol 131, e116.
905 Viana, R., Moyo, S., Amoako, D.G., Tegally, H., Scheepers, C., Althaus, C.L., Anyaneji, U.J., Bester,
906 P.A., Boni, M.F., Chand, M., et al. (2022). Rapid epidemic expansion of the SARS-CoV-2 Omicron
907 variant in southern Africa. Nature.
908 Wang, L., Zhou, T., Zhang, Y., Yang, E.S., Schramm, C.A., Shi, W., Pegu, A., Oloniniyi, O.K., Henry,
909 A.R., Darko, S., et al. (2021a). Ultrapotent antibodies against diverse and highly transmissible
910 SARS-CoV-2 variants. Science.
911 Wang, R., Zhang, Q., Ge, J., Ren, W., Zhang, R., Lan, J., Ju, B., Su, B., Yu, F., Chen, P., et al.
912 (2021b). Analysis of SARS-CoV-2 variant mutations reveals neutralization escape mechanisms
913 and the ability to use ACE2 receptors from additional species. Immunity 54, 1611-1621 e1615.
914 Willett, B.J., Grove, J., MacLean, O.A., Wilkie, C., Logan, N., Lorenzo, G.D., Furnon, W., Scott, S.,
915 Manali, M., Szemiel, A., et al. (2022). The hyper-transmissible SARS-CoV-2 Omicron variant
38
AR08350
916 exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism.
917 medRxiv, 2022.2001.2003.21268111.
918 Wolter, N., Jassat, W., Walaza, S., Welch, R., Moultrie, H., Groome, M., Amoako, D.G., Everatt,
919 J., Bhiman, J.N., Scheepers, C., et al. (2022). Early assessment of the clinical severity of the
920 SARS-CoV-2 omicron variant in South Africa: a data linkage study. Lancet.
921 Worobey, M., Han, G.Z., and Rambaut, A. (2014). Genesis and pathogenesis of the 1918
922 pandemic H1N1 influenza A virus. Proc Natl Acad Sci U S A 111, 8107-8112.
923 Wrapp, D., Wang, N., Corbett, K.S., Goldsmith, J.A., Hsieh, C.L., Abiona, O., Graham, B.S., and
924 McLellan, J.S. (2020). Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.
925 Science 367, 1260-1263.
926 Zhou, T., Teng, I.T., Olia, A.S., Cerutti, G., Gorman, J., Nazzari, A., Shi, W., Tsybovsky, Y., Wang,
927 L., Wang, S., et al. (2020). Structure-Based Design with Tag-Based Purification and In-Process
928 Biotinylation Enable Streamlined Development of SARS-CoV-2 Spike Molecular Probes. Cell Rep
929 33, 108322.
39
AR08351
A S IgG binding B RBD IgG binding Boost:

mRNA-1273
22 22 WA1
20
Delta
20
Beta
18 18 Omicron
AUC (Log10)
AUC (Log10)
16 16 mRNA-Omicron
14 14 WA1
Delta
12 12 Beta
Omicron
10 10
8 8
6 6
0 6 40 41 43 0 6 40 41 43
Weeks post-immunization Weeks post-immunization
C Live virus neutralization D Lentiviral pseudovirus neutralization Boost:

mRNA-1273
Reciprocal ID50 titer (Log 10)
Reciprocal ID50 titer (Log 10)
4 4 D614G
Delta
Beta
Omicron
3 3
mRNA-Omicron
D614G
2 2 Delta
Beta
Omicron
1 1
0 6 40 41 43 0 6 40 41 43
Weeks Post-immunization Weeks Post-immunization
E Serum antibody avidity Boost:

mRNA-1273
0.8 WA1
Omicron
0.7
mRNA-Omicron
Avidity index
0.6 WA1
Omicron
0.5
0.4
0.3
0 6 40 41 43
Weeks Post-immunization
Figure 1
AR08352
Figure 1 Kinetics of serum antibody responses following mRNA-1273 immunization and
boost
(A-E) Sera were collected at weeks 6, 40 or 41, and 43 post-immunization.
(A-B) IgG binding titers to (A) variant S and (B) variant RBD expressed in AUC.
(C-D) Neutralizing titers to (C) live virus and (D) lentiviral pseudovirus expressed as the
reciprocal ID50.
(E) Avidity index for WA1 S-2P- and Omicron S-2P-binding serum antibodies.
Circles represent geometric means (A-D) or arithmetic means (E). Error bars represent 95%
confidence intervals (CI). Assay LOD indicated by dotted lines. Break in X-axis indicates a
change in scale without a break in the range depicted. Responses to variants are color-coded as
WA1 or D614G (black), Delta (blue), Beta (red) and Omicron (green). Arrows represent
timepoints of immunizations. Following the boost at week 41, mRNA-1273-boosted NHP
indicated by solid lines and mRNA-Omicron-boosted NHP indicated by dashed lines. 4 NHP per
boost group.
See also Figure S1 for experimental schema and Table S1 for detailed neutralizing titers.
AR08353
A BAL IgG S-binding

16
WA1 16
Delta 16
Beta 16
Omicron
AUC (Log10)
12 12 12 12
8 8 8 8
4 4 4 4
0 0 0 0
Week 8 39 43 8 39 43 8 39 43 8 39 43
B Nasal wash IgG S-binding

16
WA1 Delta Beta Omicron
16 16 16
AUC (Log10)
12 12 12 12
8 8 8 8
4 4 4 4
0 0 0 0
Week 8 39 43 8 39 43 8 39 43 8 39 43
C BAL S-2P-ACE2 binding inhibition

D614G Delta Beta Omicron
100 100 100 100
% Inhibition
75 75 75 75
50 50 50 50
25 25 25 25
0 0 0 0
Week 8 39 43 8 39 43 8 39 43 8 39 43
D Nasal wash S-2P-ACE2 binding inhibition

D614G Delta Beta Omicron
100 100 100 100
% Inhibition
75 75 75 75
50 50 50 50
25 25 25 25
0 0 0 0
Week 8 39 43 8 39 43 8 39 43 8 39 43
mRNA-1273 (x2) mRNA-1273 boost mRNA-Omicron boost Control
Figure 2
AR08354
Figure 2 Kinetics of mucosal antibody responses following mRNA-1273 immunization and
boost
(A-D) BAL (A, C) and NW (B, D) were collected at weeks 8, 39 and 43 post-immunization.
(A-B) IgG binding titers to WA1, Delta, Beta and Omicron expressed in AUC.
(C-D) D614G, Delta, Beta and Omicron S-2P-ACE2 binding inhibition in the presence of
mucosal fluids. All samples diluted 1:5.
Circles indicate individual NHP. Boxes represent interquartile range with the median denoted by
a horizontal line. Dotted lines are for visualization purposes and denote 4-log10 increases in
binding titers (A-B) or 0 and 100% inhibition (C-D). 8 controls and 8 vaccinated NHP, split into
2 cohorts post-boost.
See also Table S2 for list of mutations in variant-specific S-2P-ACE2 inhibition assays.
AR08355
Week 0 Week 6 Week 41 Boost Week 43

A mRNA-1273 (x2)
&'()
&'()
! "#$ %
! "#$ %
mRNA-1273
!" #
* !+ ,-. /
* !+ ,-. /
$ %&'()*
mRNA-Omicron
! "#$ %
! "#$ %
B mRNA-1273 (x2)
&'()
&'()
! "#$ %
! "#$ %
mRNA-1273
! "#$%
* !+ ,-. /
* !+ ,-. /
& ' ()*+,
mRNA-Omicron
! "#$ %
! "#$ %
C mRNA-1273 (x2)
&'()
&'()
! "#$ %
! "#$ %
mRNA-1273
!" #
* !+ ,-. /
* !+ ,-. /
$ %&'
(
mRNA-Omicron
! "#$ %
! "#$ %
D mRNA-1273 (x2)
&'()
&'()
! "#$ %
! "#$ %
mRNA-1273
!" #
* !+ ,-. /
* !+ ,-. /
$ %&
'
mRNA-Omicron
! "#$ %
! "#$ %
Figure 3
AR08356
Figure 3 Memory B cell specificities following immunization and boosting
(A-D) Representative flow cytometry plots showing single variant-specific (top left and bottom
right quadrant) and dual-variant specific (top right quadrant) memory B cells at weeks 0, 6, 41
and 43 post-immunization. Event frequencies per gate are expressed as a percentage of all class-
switched memory B cells. Cross-reactivity shown for (A) WA1 and Omicron S-2P, (B) Delta and
Omicron S-2P, (C) WA1 and Delta S-2P and (D) WA1 and Beta S-2P. 4-7 NHP per group.
See also Figure S2 for B cell gating strategy.

AR08357
Week 6 Week 41 Boost Week 43
A
! "#$ %
&'()0 12'3 ! "#$ %
&'()0 12'3
&'()
&'()
mRNA-1273 (x2)
! "#$ %
! "#$ %
mRNA-1273
! " #$%
&' () * +, - .
! " #$%
&' ( )* +, - $
* !+ ,-. /
* !+ ,-. /
! "# .%
&' ( )* +,-$
mRNA-Omicron
! "#$ %
! "#$ %
B
! "#$ %
&'()0 12'3 ! "#$ %
&'()0 12'3
&'()
&'()
mRNA-1273 (x2)
! "#$ %
! "#$ %
mRNA-1273
! "#$%&'() * +, -./ 0
! "#$%&'() * +, -./&
* !+ ,-. /
* !+ ,-. /
! "#$%0'() * +, -./&
mRNA-Omicron
! "#$ %
! "#$ %
C mRNA-1273 (x2)
mRNA-1273
! " #$%&'( )*+,
! " #$%
&' ( )*+$
! "# ,%&'( )*+$
mRNA-Omicron
D mRNA-1273 (x2)
mRNA-1273
! " #$%&'
( )* +
! " #$%
&' ( )* $
! "# +%&'
( )* $
mRNA-Omicron
E
! "#$ %
&'()0 12'3 ! "#$ %
&'()0 12'3
&'()
&'()
mRNA-1273 (x2)
! "#$ %
! "#$ %
mRNA-1273
WA1 x Omicron S2P

!"# $%&'( )*+,- . '/ 012-3!"# 456!"# $%
7
* !+ ,-. /
* !+ ,-. /
8*((9 ' %
:*; '- . '/ 012-3! " #4%
6!"# $%
7
<=)*>?)'@-. '/ 012-3! " #4%
6! " #$57
mRNA-Omicron
! "#$ %
! "#$ %
&'( )*+,- . '/ 012-3! " #456! " #$57
Figure 4
AR08358
Figure 4 Similar expansion of cross-reactive S-2P-specific memory B cells following
boosting
(A-D) Pie charts indicating the proportion of total S-binding memory B cells that are cross-
reactive (dark gray) or specific for the indicated variants (black or light gray) for all NHP
(geomean) at weeks 6, 41 and 43 post-immunization. Where applicable, memory B cells specific
only for WA1 or Delta are represented by the light gray segment. Cross-reactivity shown for (A)
WA1 and Omicron S-2P, (B) Delta and Omicron S-2P, (C) WA1 and Delta S-2P and (D) WA1
and Beta S-2P.
(E) Pie charts indicating the proportion of total S-2P-binding memory B cells (geomean) that
have a phenotype consistent with resting memory (pattern), activated memory (black), tissue-like
memory (dark gray) or CD27-negative resting memory (light gray) B cells at weeks 6, 41 and 43
post-immunization. Analysis shown here for memory B cells that bind to WA1 and/or Omicron
S-2P. 4-7 NHP per group.
See also Figure S3 for frequencies of cross-reactive S-2P memory B cells, Figure S4 for serum
epitope reactivity and Figures S4 and S5 for T cell responses after boosting.
AR08359
sgRNA_N sgRNA_N sgRNA_N

A BAL
B nasal swabs
C oral swabs
Post-challenge Post-challenge Post-challenge

8 8 8
RNA Copies/swab (Log10)
RNA Copies/swab (Log10)

RNA Copies/mL (Log10)
6 6 6
4 4 4
2 2 2
Day 2 4 8 1 2 4 8 2
D Viral titers E Viral titers

BAL nasal swabs
Post-challenge Post-challenge
6 6
TCID50/swab (Log10)
TCID50/mL (Log10)
mRNA-1273 boost
5 5
mRNA-Omicron boost
4 4 Control
3 3
2 2
Day 2 4 2 4
Figure 5
AR08360
Figure 5 Boosting provides equivalent protection in the lungs against Omicron challenge
(A-E) BAL (A, D), NS (B, E) and OS (C) were collected at the indicated times following
challenge with 1x106 PFU Omicron.
(A-C) Omicron sgRNA_N copy numbers per mL of BAL or per swab.
(D-E) Viral titers per mL of BAL or per swab.
Circles indicate individual NHP. Boxes represent interquartile range with the median denoted by
a horizontal line. Assay LOD indicated by dotted lines. 8 controls and 4 vaccinated NHP per
boost cohort.
See also Figure S7 for Omicron challenge stock sequence.

AR08361
A Viral
Antigen Inflammation
MC6
mRNA-1273
MA6
DGW
mRNA-Omicron
DH0
A17
Control
TLM
B
id
id
Rm
Rm
Lc
Lc
Rc
Rc
MC6 - - - + + +
mRNA-1273
MA6 - - - +/- +/- +/-
DGW - - - +/- +/- +/-

mRNA-Omicron
DH0 - - - + +/- +
A17 +/- + + + ++ ++
Control
TLM + + +/- ++ ++ ++
Figure 6
AR08362
Figure 6 Viral antigen and pathology in the lungs after challenge
(A-B) 2 NHP per group were euthanized on day 8 post-challenge and tissue sections taken from
lungs.
(A) Left. Representative images indicating detection of SARS-CoV-2 N antigen by
immunohistochemistry with a polyclonal anti-N antibody. Antigen-positive foci are marked by a
red arrow. Right. Hematoxylin and eosin stain (H&E) illustrating the extent of inflammation and
cellular infiltrates. Images at 10x magnification with black bars for scale (100µm).
(B) SARS-CoV-2 antigen and inflammation scores in the left cranial lobe (Lc), right middle lobe
(Rmid) and right caudal lobe (Rc) of the lungs. Antigen scoring legend: - no antigen detected; +/-
rare to occasional foci; + occasional to multiple foci; ++ multiple to numerous foci; +++
numerous foci. Inflammation scoring legend: - minimal to absent inflammation; +/- minimal to
mild inflammation; + mild to moderate inflammation; ++ moderate to severe inflammation; +++
severe inflammation. Horizontal rows correspond to individual NHP depicted above (A).
FULL TEXT LINKS
I PM·c Full~
Meta-Analysis > Am J Ther. 2021 Jun 21;28(4):e434-e460. doi: 10.1097/MJT.0000000000001402.
Ivermectin for Prevention and Treatment of COVID-

19 Infection: A Systematic Review, Meta-analysis,
and Trial Sequential Analysis to Inform Clinical
Guidelines
Andrew Bryanf-1 , Theresa'A. Lawrie 2 , Therese Dowswell 2 , Edmund J Fordham 2 , Scott Mitchell 3 ,
Sarah R Hill 1 , ~Tony C Tham 4
Affiliations
PMID: 34 145166 PMCID: PMC8248252 DOI: 10.1097/MJT.0000000000001402
Free PMC article
Expression of concern in
Expression of Concern for Bryant a, Lawrie TA, Dowswell T, Fordham EJ, Mitchell S, Hill SR,
Tham TC. lvermectin for Prevention and Treatment of COVID-19 Infection: A Systematic
~ ~
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Review, Meta-Analysis, and Trial Sequential Analysis to Inform Clinical Guidelines. Am J i2 ~ $

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Ther. 2021 ;28(4): e434-e460. ~
AR08363
Manu P. ~~~
t- ..- ~
Am J Ther. 2022 Feb 17;29(2):e232. doi: 10.1097/MJT.0000000000001482. i-, ".l \
PMID: 35142702 No abstract available. .. ~
~0 ~
AR08364
Abstract
Background:
Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic
ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical
trials.
Areas of uncertainty:
We assessed the efficacy of ivermectin treatment in reducing mortality, in
secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19
infection.
Data sources:
We searched bibliographic databases up to April 25, 2021. Two review authors sifted
for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of
the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for
mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion.
Therapeutic advances:
Meta-analysis of 15 trials found that ivermectin reduced risk of death
compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19-0.73; n = 2438; I2
= 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the
same DerSimonian-Laird method that underpinned the unadjusted analysis. This was also robust
against a trial sequential analysis using the Biggerstaff-Tweedie method. Low-certainty evidence
found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence
interval 79%-91%). Secondary outcomes provided less certain evidence. Low-certainty evidence
suggested that there may be no benefit with ivermectin for "need for mechanical ventilation," whereas
effect estimates for "improvement" and "deterioration" clearly favored ivermectin use. Severe adverse
events were rare among treatment trials and evidence of no difference was assessed as low certainty.
Evidence on other secondary outcomes was very low certainty.
Conclusions:
Moderate-certainty evidence finds that large reductions in COVID-19 deaths are
possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers
progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to
have a significant impact on the SARS-CoV-2 pandemic globally.
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.

AR08365
Figures
FIGURE 2. Risk-of-bias
FIGURE 1. Study flow FIGURE 3. Death due to
summary: review authors'
diagram from search… any cause.
judgments…
FIGURE 4. Death due to FIGURE 5. Death due to FIGURE 6. Death due to

any cause,… any cause,… any cause,…
All figures (15)
Comment in
AR08366
Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review,
Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines. American Journal
of Therapeutics, 28, e434-e460, July 2021.
Bryant A, Lawrie TA, Fordham EJ.
Am J Ther. 2021 Aug 27;28(5):e573-e576. doi: 10.1097/MJT.0000000000001442.
PMID: 34469921
Free PMC article.
No abstract available.
Meta-Analyses Do Not Establish Improved Mortality With Ivermectin Use in COVID-19.

Rothrock SG, Weber KD, Giordano PA, Barneck MD.
Am J Ther. 2021 Dec 7;29(1):e87-e94. doi: 10.1097/MJT.0000000000001461.
PMID: 34994351
No abstract available.
Related information
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NCI CPTAC Assay Portal
AR08367
AR08368
Health Canada is reminding Canadians not to use ivermectin to prevent or
treat COVID-19. Canadian poison centres have seen an increase in reports
concerning ivermectin over the summer.
There is no evidence that ivermectin works to prevent or treat COVID-19,

and it is not authorized for this use. To date, Health Canada has not
received any drug submission or applications for clinical trials for
ivermectin for the prevention or treatment of COVID-19.
Ivermectin has been authorized by Health Canada for human use, as a

prescription antiparasitic drug for the treatment of parasitic worm
infections. Prescription drugs should be taken only under the advice and
supervision of a healthcare professional. Patients taking prescription drugs
without being examined and monitored by a healthcare practitioner may
not receive the appropriate treatment to maintain and protect their health.
They may also put themselves at risk for drug interactions or harmful side
effects. Canadians should never consume health products intended for
animals because of potential serious health risks, including seizures, coma
and even death.
Recently, Health Canada became aware that ivermectin had been

advertised in Canada for the treatment of COVID-19. It is illegal in Canada
to sell or advertise a drug in a false, misleading or deceptive manner. The
Department took action and directed advertisers to remove the non-
compliant advertisements.
Health Canada continues to monitor the situation. In the event of

additional cases of illegal marketing activities involving ivermectin products
as a treatment for COVID-19 are identified, the Department will take action
to mitigate the risk to Canadians.
AR08369
As part of its ongoing commitment to openness and transparency, Health
Canada posts a summary of health product advertising complaints as well
as health product advertising incidents related to COVID-19 addressed by
the Department.
Original Advisory (August 31, 2021):
Health Canada has received concerning reports of the use of veterinary

ivermectin to prevent or treat COVID-19. Canadians should never consume
health products intended for animals because of the potential serious
health dangers posed by them.
In this light, Health Canada is advising Canadians not to use either the
veterinary or human drug versions of Ivermectin to prevent or treat COVID-
19. There is no evidence that ivermectin in either formulation is safe or
effective when used for those purposes. The human version of ivermectin
is authorized for sale in Canada only for the treatment of parasitic worm
infections in people.
The veterinary version of ivermectin, especially at high doses, can be

dangerous for humans and may cause serious health problems such as
vomiting, diarrhea, low blood pressure, allergic reactions, dizziness,
seizures, coma and even death. Ivermectin products for animals have a
higher concentrated dose than ivermectin products for people.
The Department is aware of multiple reports of patients in the U.S. who

have required medical support and been hospitalized after using
ivermectin intended for horses.
Health Canada is closely monitoring all potential therapeutic treatments for

COVID-19, including treatments being studied in international clinical trials.
To date, Health Canada has not received any drug submission or clinical
trial application for ivermectin for the prevention or treatment of COVID-19.
AR08370
For drugs that have the potential to be helpful in treating COVID-19, Health
Canada encourages drug manufacturers to conduct clinical trials. This
would provide an opportunity for the healthcare community to collect
information on the effectiveness of the treatment and its associated risks.
Should a manufacturer provide a submission to Health Canada related to

the use of ivermectin to prevent or treat COVID-19, Health Canada would
conduct a scientific evaluation of the evidence to determine the drug's
quality, safety and effectiveness.
Health Canada will continue to monitor the situation and will take
appropriate and timely action should new information become available,
including any information regarding the illegal advertising or sale of
ivermectin. Health Canada will also communicate any new safety
information to healthcare professionals and consumers.
Health Canada has previously warned Canadians about products making

false and misleading claims to treat or cure COVID-19. For information on
Health Canada authorized vaccines and treatments, visit Canada.ca.
What you should do

If you are concerned or are experiencing symptoms after having used
ivermectin to prevent or treat COVID-19, call your local poison
centre right away.
If you have purchased ivermectin for the prevention or treatment of
COVID-19, stop using it and discard it:
Follow municipal or regional guidelines on how to dispose of
chemicals and other hazardous waste; or
Return the product to the point of sale for proper disposal.
Consult a healthcare professional if you have used ivermectin and have
health concerns.
AR08371
Report any health product adverse events to Health Canada.
Submit a complaint to Health Canada should you have any information
regarding the illegal advertising or sale of ivermectin or any other
health product using its online complaint form.
Report marketing that is false or misleading or does not meet
regulatory requirements.
Additional information
Background
Details
Media and public enquiries
Date modified:
2021-10-19
5/12/22, 6:27 PM Why You Should Not Use lvermectin to Treat or Prevent COVID-19 I FDA
AR08372
Why You Should Not Use lvermectin to Treat or Prevent COVID-19
Espanol (/consumers/articulos-en-espanol/por-que-no-debe-utilizar-ivermectina-para-tratar-o-prevenir-ekovid-19)
Portugues (/consumers/consumer-updates/por-que-voce-nao-deve-usar-iverrnectina-para-tratar-ou-prevenir-covi~l9)
cp)t (/corisumers/consumer-updates/weishenmebuyinggaishiyongyiweijunsuzhiliaohuoyufang2019xinguanfeiyan)
Tagalog (/consumers/consumer-updates/bakit-hindi-ka-dapat-gumamit-ng-ivermectin-upang-gamutin-o-maiwasan-ang-covi~19)
Tieng V~t (/consumers/consumer-updates/tai-sao-ban-khong-nen-su-dung-ivermectin-de-dieu-tri-hoac-ngall-ilgua-covid-19)
~~ Oj (/consumers/consumer-updates/kobideu-19-covid-19Ieukhilyohago-yebanghagi-wihayeo-ibeomegtineul-sayonghaji-malaya-haneun-iyu)
COVID-19. We've been living with it for what sometimes seems like forever. Given the number of deaths that
have occurred from the disease, it's perhaps not surprising that some consumers are turning to drugs not
approved or authorized by the Food and Drug Administration (FDA).
One of the FDA's jobs is to carefully evaluate the scientific data on a drug to be sure that it is both safe and
effective for a particular use. In some instances, it can be highly dangerous to use a medicine for the prevention
or treatment of COVID-19 that has not been approved by or has not received emergency use authorization
from the FDA.
There seems to be a growing interest in a drug called ivermectin for the prevention or treatment of COVID-19 in
humans. Certain animal formulations of ivermectin such as pour-on, injectable, paste, and "drench," are
approved in the U.S. to treat or prevent parasites in animals. For humans, ivennectin tablets are approved at
very specific doses to treat some parasitic :worms, and there are topical (on the skin) formulations for head lice
and skin conditions like rosacea.
However, the FDA has received multiple reports of patients who have required medical attention, including
hospitalization, after self-medicating with ivermectin intended for livestock.
Here's What You Need to Know about lvermectin

• The FDA has not authorized or approved ivermectin for use in preventing or treating COVID-19 in
humans or animals. Ivermectin is approved for human use to treat infections caused by some parasitic
https://www.fda..gov/consumers/consumer-upda.tes/why-you-should-not-use-ivermeclin-treat-or-prevent-<:0vid-19 1/3
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AR08373
worms and head lice and skin conditions like rosacea.
Currently available data do not show ivermectin is effective against COVID-19. Clinical trials
(https://www.clinicaltrials.gov/ct2/results?cond=COVID-
19&term=ivermectin&cntry=&state=&city=&dist=&Search=Search) assessing ivermectin tablets for the
prevention or treatment of COVID-19 in people are ongoing.
Taking large doses of ivermectin is dangerous.
If your health care provider writes you an ivermectin prescription, fill it through a legitimate source such
as a pharmacy, and take it exactly as prescribed.
Never use medications intended for animals on yourself or other people. Animal ivermectin products are
very different from those approved for humans. Use of animal ivermectin for the prevention or treatment
of COVID-19 in humans is dangerous.
What is Ivermectin and How is it Used?

Ivermectin tablets are approved by the FDA to treat people with intestinal strongyloidiasis and onchocerciasis,
two conditions caused by parasitic worms. In addition, some topical forms of ivermectin are approved to treat
external parasites like head lice and for skin conditions such as rosacea.
Some forms of animal ivermectin are approved to prevent heartworm disease and treat certain internal and
external parasites. It’s important to note that these products are different from the ones for people, and safe
only when used in animals as prescribed.
When Can Taking Ivermectin Be Unsafe?

The FDA has not authorized or approved ivermectin for the treatment or prevention of COVID-19 in people or
animals. Ivermectin has not been shown to be safe or effective for these indications.
There’s a lot of misinformation around, and you may have heard that it’s okay to take large doses of ivermectin.
It is not okay.
Even the levels of ivermectin for approved human uses can interact with other medications, like blood-thinners.
You can also overdose on ivermectin, which can cause nausea, vomiting, diarrhea, hypotension (low blood
pressure), allergic reactions (itching and hives), dizziness, ataxia (problems with balance), seizures, coma and
even death.
Ivermectin Products for Animals Are Different from Ivermectin Products

for People
For one thing, animal drugs are often highly concentrated because they are used for large animals like horses
and cows, which weigh a lot more than we do— up to a ton or more. Such high doses can be highly toxic in
humans. Moreover, the FDA reviews drugs not just for safety and effectiveness of the active ingredients, but
also for the inactive ingredients. Many inactive ingredients found in products for animals aren’t evaluated for
use in people. Or they are included in much greater quantity than those used in people. In some cases, we don’t
know how those inactive ingredients will affect how ivermectin is absorbed in the human body.
Options for Preventing and Treating COVID-19
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The most effective ways to limit the spread of COVID-19 (https://www.cdc.gov/coronavirus/2019-
ncov/prevent-getting-sick/prevention.html) include getting a COVID-19 vaccine when it is available to you and
following current CDC guidance.
Talk to your health care provider about available COVID-19 vaccines and treatment options. Your provider can
help determine the best option for you, based on your health history.
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AR08375
A majority of uninfected adults show preexisting antibody

reactivity against SARS-CoV-2
Abdelilah Majdoubi, ... , Adrian B. McDerm.otf, Pascal M. Lavoie
I
JC/ Insight. 2021 ;6(8):e146316. https://doi.org/10.1172/jci.insight.14~316.
Research Article COVl~ 19 Immunology
Graphical abstract
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AR08376 RESEARCH ARTICLE
A majority of uninfected adults show

preexisting antibody reactivity against
SARS-CoV-2
Abdelilah Majdoubi,1,2 Christina Michalski,1,2 Sarah E. O’Connell,3 Sarah Dada,1,2 Sandeep Narpala,3
Jean Gelinas,4,5 Disha Mehta,4,6 Claire Cheung,1,2 Dirk F.H. Winkler,7 Manjula Basappa,3
Aaron C. Liu,1,2,8 Matthias Görges,1,6 Vilte E. Barakauskas,9 Mike Irvine,1 Jennifer Mehalko,10
Dominic Esposito,10 Inna Sekirov,9,11 Agatha N. Jassem,9,11 David M. Goldfarb,1,2,12 Steven Pelech,7,13
Daniel C. Douek,3 Adrian B. McDermott,3 and Pascal M. Lavoie1,2
BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada. 2Department of Pediatrics, University
1
of British Columbia, Vancouver, British Columbia, Canada. 3Vaccine Research Center, National Institute of Allergy and
Infectious Diseases, NIH, Bethesda, Maryland, USA. 4Department of Anesthesiology, Surrey Memorial Hospital (SMH),
Surrey, British Columbia, Canada. 5Department of Anesthesiology & Pain Medicine, University of Alberta, Edmonton,
Alberta, Canada. 6Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia,
Vancouver, British Columbia, Canada. 7Kinexus Bioinformatics Corporation, Vancouver, British Columbia, Canada. 8Vaccine
Evaluation Centre, BC Children’s Hospital Research Institute, Vancouver, British Columbia. 9Department of Pathology and
Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 10National Cancer Institute RAS
Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical
Research Inc., Frederick, Maryland, USA. 11British Columbia Centre for Disease Control (CDC) Public Health Laboratory,
Vancouver, British Columbia, Canada. 12Division of Medical Microbiology, Department of Pathology and Laboratory
Medicine, and 13Department of Medicine, University of British Columbia, Vancouver, Canada.
Preexisting cross-reactivity to SARS-CoV-2 occurs in the absence of prior viral exposure. However,
this has been difficult to quantify at the population level due to a lack of reliably defined
seroreactivity thresholds. Using an orthogonal antibody testing approach, we estimated that about
0.6% of nontriaged adults from the greater Vancouver, Canada, area between May 17 and June 19,
2020, showed clear evidence of a prior SARS-CoV-2 infection, after adjusting for false-positive
and false-negative test results. Using a highly sensitive multiplex assay and positive/negative
thresholds established in infants in whom maternal antibodies have waned, we determined that
more than 90% of uninfected adults showed antibody reactivity against the spike protein, receptor-
binding domain (RBD), N-terminal domain (NTD), or the nucleocapsid (N) protein from SARS-
CoV-2. This seroreactivity was evenly distributed across age and sex, correlated with circulating
coronaviruses’ reactivity, and was partially outcompeted by soluble circulating coronaviruses’
spike. Using a custom SARS-CoV-2 peptide mapping array, we found that this antibody reactivity
Authorship note: AM, CM, and SEO broadly mapped to spike and to conserved nonstructural viral proteins. We conclude that most
are co–first authors.
adults display preexisting antibody cross-reactivity against SARS-CoV-2, which further supports
Conflict of interest: SP is the majority investigation of how this may impact the clinical severity of COVID-19 or SARS-CoV-2 vaccine
owner of Kinexus Bioinformatics responses.
Corporation.
Copyright: © 2021, Majdoubi et

al. This is an open access article
published under the terms of the
Creative Commons Attribution 4.0
International License. Introduction
Submitted: November 23, 2020 Coronavirus disease 2019 (COVID-19) was declared a global pandemic on March 11, 2020, and has result-
Accepted: March 12, 2021 ed in almost 100 million confirmed cases and 2.1 million deaths worldwide as of January 24, 2021. Almost
Published: March 15, 2021 all individuals infected with SARS-CoV-2 seroconvert within 2–3 weeks, with the spike and nucleocapsid
(N) proteins eliciting the strongest responses (1, 2). While much attention has focused on defining immune
Reference information: JCI Insight.
2021;6(8):e146316. reactivity in individuals after infection, other data indicate that many individuals show preexisting SARS-
https://doi.org/10.1172/jci. CoV-2 cross-reactive T and B cells without prior exposure to the virus (3–5). However, the extent of preex-
insight.146316. isting SARS-CoV-2 antibody reactivity at the population level has been difficult to estimate, due to a lack
1
of assay sensitivity (6) and clearly definable background thresholds to identify meaningful seroreactivity
among individuals who have been unexposed to the virus (7).
There are 4 circulating coronaviruses predating COVID-19 that cause up to 30% of seasonal upper
respiratory tract infections (8). The spike proteins of β-coronaviruses HKU1 and OC43 exhibit approxi-
mately 40% sequence similarity, whereas the α-coronaviruses NL63 and 229E exhibit approximately 30%
structural similarity with SARS-CoV-2 (9). The common occurrence of circulating coronaviruses year after
year and their structural similarity with SARS-CoV-2 raises the possibility that the former may stimulate
cross-reactive responses toward SARS-CoV-2 and that this heterotopic immunity may impact clinical sus-
ceptibility to COVID-19 and/or modulate responses to the SARS-CoV-2 vaccine (10, 11).
The main objective of this study was to estimate the extent of the preexisting seroreactivity against
SARS-CoV-2 in the general adult population and its relationship to circulating coronaviruses. To confirm
that SARS-CoV-2 antibody reactivity in uninfected adults was genuinely cross-reactive and not due to wide-
spread unreported, asymptomatic SARS-CoV-2 circulation, we similarly assayed sera collected prior to the
emergence of SARS-CoV-2 and from infants before and after maternal antibodies have waned. In addition,
we used a SPOT peptide array to map this antibody reactivity on the SARS-CoV-2 proteome.
Results
Study population. In total, 276 healthy adults were recruited for this cohort between May 17 and June 19,
2020. The demographic characteristics and geographical area of residence of participants are shown in
Supplemental Table 1 (supplemental material available online with this article; https://doi.org/10.1172/
jci.insight.146316DS1) and Supplemental Figure 1, respectively. The majority (n = 196; 71%) were health
care workers. Less than half had traveled outside of British Columbia (BC) since January 1,2020, to
the USA, Europe, Iran, the Caribbean, Australia, Mexico and Japan. Two individuals had a history of
PCR-confirmed COVID-19.
Prevalence of prior SARS-CoV-2 infection in the study population. To estimate the proportion of individuals
who had been previously infected with SARS-CoV-2, we used a multiplex assay to profile antibody reac-
tivity against 4 viral antigens: the whole SARS-CoV-2 spike protein, its N-terminal domain (NTD) and
receptor-binding domain (RBD), and the N protein. Clustering analysis based on antibody reactivity for
these 4 antigens identified that 3 individuals (CW087, CW0150, FH0037) and 5 control sera from conva-
lescent COVID-19 patients (controls A, B, C, D and E) clustered together, separately from the rest of the
cohort (Figure 1). The antibody reactivity profile of these 8 distinct sera showed high reactivity against all
4 SARS-CoV-2 antigens, whereas all other individuals showed variable antibody reactivity against either
spike, RBD, or the N protein (Supplemental Figure 2).
The 3 individuals (CW087, CW0150, FH0037) who clustered with the 5 control sera included the 2
individuals who had a history of PCR-confirmed COVID-19, plus an asymptomatic woman who was not
aware she had COVID-19 initially but later identified that she had been in contact with a COVID-19 case
about 90 days prior to serology testing for this study (Supplemental Table 2).
All sera from the cohort who displayed above-the-mean antibody reactivity for at least 1 of the 4 SARS-
CoV-2 antigens (i.e., for a total of 222 out of 276 individuals) were further tested with a commercial diag-
nostic commercial chemiluminescent (CLIA) assay, which recognizes the spike protein S1 antigen (Supple-
mental Figure 3). With this assay, the same 3 individuals (CW087, CW0150, FH0037), plus the 5 control
sera mentioned above, tested positive. Therefore, based upon these data, it appeared that 3 of 276 partici-
pants (1.1%) showed clear evidence of a previous infection with SARS-CoV-2. After adjusting for bias by
using point estimates of specificity and sensitivity of the CLIA assay, we estimated that the prevalence of a
previous SARS-CoV-2 infection was 0.60% (95%CI, 0%–2.71%) in this cohort.
Antibody reactivity to circulating coronaviruses. The multiplex assay also included quantification of anti-
body reactivity against the spike proteins of circulating coronaviruses (OC43, HKU1, NL63, 229E). All
individuals showed high antibody reactivity against the spike proteins from these circulating coronaviruses
(Supplemental Figure 2). We used correlation analyses to understand the relationship between the antibody
reactivity against SARS-CoV-2 and circulating coronaviruses. Among the 273 seronegative individuals, we
detected significant correlations between antibody reactivity to SARS-CoV-2 spike, as well as spike proteins
from HKU1, NL63, and 229E, but not OC43 (Supplemental Table 3 and Supplemental Figure 4).
Specificity of SARS-CoV-2 antibody reactivity in uninfected individuals. Next, we conducted competition
experiments to exclude the possibility that the antibody reactivity against SARS-CoV-2 in uninfected
JCI Insight 2021;6(8):e146316 https://doi.org/10.1172/jci.insight.146316 2

Figure 1. Hierarchical clustering of individual based on serum SARS-CoV-2 antibody reactivity profiles. COVID-19 diagnosis identifies convalescing
individuals who had a positive viral test by PCR. This figure combines data from 276 study participants plus the 5 COVID-19 convalescent control sera.
Color scale represents antibody reactivity as a Z score.
individuals was due to nonspecific binding in the multiplex assay and to assess whether this antibody
reactivity may represent cross-reactive antibody responses to circulating coronaviruses. To these ends, we
determined whether the antibody reactivity against antigens in the multiplex assay could be outcompeted
using either a cocktail of free SARS-CoV-2 RBD and full-length spike proteins — or the spike proteins
from all 4 other circulating coronavirus spike proteins (OC43, HKU1, NL63, and 229E) pooled (Figure
2). Antibody reactivity was measured on serial dilutions from selected COVID-19 convalescent and unin-
fected sera selected on the basis of a high reactivity to full-length SARS-CoV-2 spike protein, its RBD, or
its low reactivity to both of these antigens. As expected, the high SARS-CoV-2 spike and RBD antibody
reactivity in COVID-19 convalescent sera was efficiently outcompeted by free SARS-CoV-2 spike and
RBD proteins, but not by other free circulating coronavirus spike proteins (Figure 2, A and B).
Moreover, antibody reactivity to SARS-CoV-2 spike and RBD was partially outcompeted by cir-
culating coronavirus spikes in uninfected individuals — this latter finding supports the argument that
at least some of this SARS-CoV-2 antibody reactivity represented cross-reactivity toward circulating
coronaviruses. Conversely, reactivity to circulating coronavirus spike proteins was efficiently outcom-
peted by spike protein from circulating coronaviruses but not by SARS-CoV-2 spike and RBD proteins
(Figure 2, C and D). Therefore, this experiment confirms that SARS-CoV-2 spike and RBD antibody
reactivity in uninfected individuals is saturatable, essentially excluding nonspecific binding in the mul-
tiplex assay. Interestingly, competition of SARS-CoV-2 spike antibody reactivity was higher in unin-
fected individuals with higher detectable SARS-CoV-2 spike or RBD antibody reactivity compared
with individuals who showed low reactivity against these 2 antigens (Figure 2E). Unexpectedly, anti-
body reactivity against SARS-CoV-2 RBD in uninfected individuals was not efficiently competed by a
fixed amount of SARS-CoV-2 RBD.
Seroreactivity thresholds defined in sera from immunologically naive infants. To unequivocally distinguish unin-
fected individuals who could have SARS-CoV-2 antibody reactivity, we defined the background of antibody
reactivity of sera in the multiplex assay. We reasoned that infants would be immunologically naive, with the
exception of maternal antibodies that are expected to wane gradually after birth; thus, their sera can be used
to define antibody reactivity thresholds in uninfected adults in the multiplex assay. Using this assay, we mea-
sured antibody reactivity of sera from 45 infants less than 6 months of age and repeated this measurement in
the same infants approximately 8 months later, after BC’s lockdown period (Figure 3); the study included 21
infants in whom the first sera were obtained before the pandemic (i.e., before January 2020). In infant sera,
reactivity to circulating coronaviruses was uniformly detected in the first set of blood samples, albeit at much
lower levels than adults. In the second infant sample sets taken after July 1, 2020, antibody recognition of
circulating coronaviruses had decreased to approximately 1000-fold lower levels compared with adults, con-
sistent with a waning of maternal antibodies (Supplemental Figure 5). When comparing antibody reactivity
of SARS-CoV-2 in the second postnatal infant sera, levels were up to 100-fold higher in uninfected adults
compared with infants, regarding the different SARS-CoV-2 antigens (Figure 3).

Figure 2. Specificity of SARS-CoV-2 antibody reactivity. (A and B) Competition of SARS-CoV-2 spike and RBD antibody reactivity by SARS-CoV-2 spike
and RBD proteins (A) or by circulating coronaviruses (cCoVs) spike proteins (B). (C and D) Competition of cCoVs spike antibody reactivity by SARS-CoV-2
spike and RBD proteins (C) or cCoVs spike proteins (D). (E) Competition of SARS-CoV-2 spike antibody reactivity by SARS-CoV-2 spike and RBD proteins
or cCoVs spike proteins, in COVID-19 convalescent sera (seropositive, n = 5), or sera from uninfected individuals who showed highest SARS-CoV-2 spike (n
= 10) and high RBD (n = 9), or lowest SARS-CoV-2 spike and RBD antibody reactivity (all low; n = 10). All values represent the ratios of antibody reactivity
in competed samples over the antibody reactivity measured in absence of competing proteins (dash line). One sample in the RBD-high group failed, and
these data are not shown. In E, data are represented as boxes (25th to 75th percentile, line at median) and whiskers (minimum to maximum); comparisons
were made using 2-tailed paired t tests.

Thus, these second infant samples allowed us to define effective thresholds for SARS-CoV-2 antibody
reactivity in uninfected adults (Figure 3). Based on infants’ sera, we estimate that between 90% and 99% of
adults show positive antibody reactivity for SARS-CoV-2 spike, RBD, or the N antigen. Prepandemic sera
showed similar antibody reactivity, therefore excluding the possibility that the reactivity in adults after the
first pandemic wave is due to undiagnosed exposures to the virus in the study population. This baseline,
preexisting SARS-CoV-2 cross-reactivity in uninfected adults was evenly distributed according to age, sex,
travel history, or whether participants were healthcare workers (HCW), and the data were independent of
participants’ reporting “COVID-19-like” symptoms (Supplemental Figure 6).
Further characterization of SARS-CoV-2 antibody reactivity in uninfected adults. To map this antibody reac-
tivity on the viral proteome, we used a SPOT array assay where peptides broadly covering the SARS-
CoV-2 proteome were directly synthesized on a cellulose membrane (Supplemental Figure 7). To enrich
for high-affinity antibodies, sera from individuals who showed high spike or RBD antibody reactivity
were compared with infant samples. As shown in Figure 4, we detected high antibody reactivity against
nonstructural proteins, particularly the nonstructural protein 2 (nsp2) and nsp15 encoded in the replicase
polypeptides ORF1a and ORF1b. RBD-high samples showed the strongest antibody reactivity encom-
passing RBD, as well as the S1 and the S2 peptides, indicating a diverse anti–SARS-CoV-2 antibody
reactivity linked to a high RBD antibody cross-reactivity. This cross-reactivity was also detected in ran-
domly selected prepandemic sera, which demonstrated preexisting recognition prior to the SARS-CoV-2
pandemic. Importantly, we detected no antibody reactivity against any viral peptides in infants’ sera.
Discussion
In this study, we estimated that 0.60% (95%CI, 0%–2.71%) of the study population showed clear evidence
of a prior infection with SARS-CoV-2. The combination of a highly specific commercial CLIA assay and
a highly sensitive multiplex assay allowed us to distinguish individuals who have been infected with SARS-
CoV-2 from those who have not. This prevalence of SARS-CoV-2 infections was identical to the 0.55%
prevalence reported by the BC CDC on 885 residual sera obtained from an outpatient laboratory network
in the Lower Mainland of BC between May 15 and May 27, 2020. Data from the BC CDC represent a
wider geographical catchment and do not specifically target HCW (12). The current study confirms that
COVID-19 transmission in BC after the first wave was low, even among HCW, contrasting with a high sero-
prevalence reported among HCW in other studies (13–15), which may be attributed to the very low number
of total tested cases in BC during the first wave.
The main finding in this study is that, at a population level, the vast majority of adults show anti-
body reactivity against SARS-CoV-2 antigens. BC reported its first COVID-19 case on January 29,
2020, with the first documented case of community transmission on March 5, 2020. The first pandemic
wave peaked between the third week of March and late April 2020 (11). As of May 17, only 2445 diag-
nosed COVID-19 cases (approximately 49 of 100,000 population) had been reported in BC after the
first wave, which was the lowest rate in Canada and one of the lowest rates in North America. Because
of a relatively low number of COVID-19 cases in BC after the first wave, it is extremely unlikely that
this antibody reactivity results from a direct exposure to SARS-CoV-2. Moreover, findings of similar
antibody reactivity in prepandemic adult sera and from sera obtained from infants younger than 1 year
of age confirms that we are detecting genuine cross-reactivity rather than reactivity to SARS-CoV-2
from asymptomatic COVID-19 cases.
Our findings are consistent with another study in which prepandemic sera exhibited cross-reactive IgG
antibody reactivity with conserved epitopes in SARS-CoV-2 proteins (S2 and N) (5). The higher prevalence
of preexisting antibody reactivity in uninfected adults in our cohort compared with this previous study may
be explained by the high sensitivity of our assay and evidence of positive seroreactivity in those individuals
informed by the infant sera. However, whereas these previous studies have quantified cross-reactivity in
selected sera, to the best of our knowledge, the current study is the first to determine SARS-CoV-2 antibody
reactivity at the population level. The fact that we measured antibody reactivity between infected and unin-
fected individuals in the same population and time period in the current study also eliminates recruitment
or sampling biases and is another major strength of this study.
The presence of preexisting SARS-CoV-2 antibody reactivity in uninfected individuals in the current
study is consistent with the detection of T cell reactivity against SARS-CoV-2 in about 40% of uninfected
individuals (3, 4). This raises an important question: what is the antigenic source of this antibody reactivity?

Figure 3. Thresholds of antibody reactivity based on infants’ sera. Comparison of antibody reactivity (AU/mL) in
infants sampled before 6 months of age (darker blue) and again about 8 months later (lighter blue; n = 45), in SARS-
CoV-2–uninfected (orange; n = 273), in SARS-CoV-2–infected (convalescent) adults (red; n = 8), and in prepandemic
sera (yellow; n = 99). Infants sampled before the pandemic (January 1, 2020) are represented by the larger circle
symbols, whereas infants sampled after January 1, 2020, are shown using the small circle symbols. Boxes represent
median with 25th and 75th percentiles with positive/negative antibody reactivity thresholds for SARS-CoV-2 spike
calculated at the 99th percentile for value distribution (10.00 AU/mL), RBD (10.00 AU/mL), and N protein (10.00 AU/
mL) as 10(mean log[antibody reactivity] + SD log [antibody reactivity] × 2.33) in infants’ sera. Antibody detection for NTD was low and inconsis-
tent between experiments; therefore, the data are not presented and reactivity thresholds were not calculated.
Competition experiments and correlatives analyses indicate that it may, in part, be attributable to cross-re-
activity against circulating coronaviruses. Most humans become infected with circulating coronavirus-
es by their second year of age (16). On the one hand, correlations between SARS-CoV-2 and antibody
reactivity against either HKU1, N63L, or 229E, but not OC43, could reflect seasonal variations in recent
exposure to common coronaviruses (10, 17). On the other hand, the high antibody reactivity to SARS-
CoV in individuals in this study likely represents cross-reactivity due to the higher (>75%) sequence sim-
ilarity between SARS-CoV and SARS-CoV-2 (18, 19), rather than a previous exposure to SARS-CoV.
The data presented in this study shed light on another important question: what region of the virus
does this preexisting antibody reactivity bind to? We found in our peptide mapping experiments that it is
broadly distributed across the viral proteome, including whole spike, and proteins encoding the viral repli-
cation complex. The binding to ORF polypeptides could be a sign of infection by circulating coronaviruses
that share conserved sequences with SARS-CoV-2. High antibody reactivity against nonstructural ORF
proteins was reported in another study using a VirScan peptide mapping approach on prepandemic sera
(6). However, due to a lower sensitivity of the assay, antibody reactivity against spike was not detected in
the latter study. Here, we confirm that this preexisting antibody reactivity involves structural external ele-
ments of the virus in both epitope mapping and competition experiments.
It is unclear whether this antibody reactivity may confer clinical benefits — for instance, modulating
the severity of a SARS-CoV-2 infection. Data indicate that a past circulating coronavirus infection may
decrease the severity of a subsequent SARS-CoV-2 infection (20). Others have linked preexisting seroreac-
tivity against circulating coronaviruses to increased SARS-CoV-2 pseudovirus neutralization in vitro (5),
although this remains debated. Individuals with high RBD reactivity showed the most structurally diverse
antibody reactivity against spike epitopes, which may enhance viral clearance in addition to the improved
neutralizing activity specific to RBD-specific antibodies. Indeed, strong antibody response to RBD have
been linked to improved clinical outcomes from COVID-19 (21). However, reactivity against RBD in the
multiplex assay was not competed by soluble RBD in uninfected individuals, despite that this reactivity
was almost completely abrogated in COVID-19 convalescent sera. The latter finding is consistent with
another study that showed that preexisting antibody reactivity against SARS-CoV-2 in prepandemic sera
could be efficiently competed by a soluble S1 (that contains the RBD domain) but not a soluble S2 subunit
of the spike protein (5). Notably, we were also unable to detect ACE2 receptor binding inhibition from

Figure 4. Mapping of SARS-CoV-2 antibody reactivity in sera from uninfected individuals. Serum antibody binding to 15-mer peptides distributed across
the SARS-CoV-2 proteome or an IgG-binding peptide (positive control), from 5 randomly selected prepandemic samples, adults showing high level of
spike or RBD reactivity (n = 20 each), or infants (n = 5). Values represent signals on a scale from 0 to 10, after subtracting background. The column labeled
C shows the immunoreactivity signal in the absence of sera, but with the addition of anti–human IgA, IgM, and IgG horse-radish peroxidase–coupled
secondary antibody. In the spike protein, labels indicate the N-terminal (NTD), C-terminal (CTD), or receptor-binding (RBD) domains, receptor-binding motif
(RBM), heptad repeat sequence (HR1), central helix (CH), or connector domain (CD); N, nucleocapsid protein; M, membrane protein; ORF, open-reading
frame polypeptide proteins; nsp, nonstructural proteins.
sera of uninfected individuals (not shown), which could indicate that the preexisting antibody reactivity
against SARS-CoV-2 in uninfected adults represents an excess of low-affinity antibodies that have poor
overall viral neutralizing potential. This may not be surprising given that viral neutralization improves
generally with affinity maturation, an antigen-driven process that requires cognate interaction by B cells,
in collaboration with follicular T cells. Similarly, preexisting, highly variable low-avidivity SARS-CoV-2
CD4 memory T cells cross-reactive to circulating coronaviruses appeared less protective in uninfected
adults (22). More studies are needed to understand the origin of preexisting SARS-CoV-2 antibodies and
their impact on COVID-19 severity.
In conclusion, this study reveals common preexisting, broadly reactive SARS-CoV-2 antibodies in
uninfected adults. These findings warrant larger studies to understand how these antibodies affect the sever-
ity of COVID-19, as well as the quality and longevity of responses to SARS-CoV-2 vaccines.
Methods
Study design. Prospective cross-sectional study after the first pandemic wave in BC.
Participants. Adults over 18 years of age from the greater Vancouver metropolitan area were included if they
did not have active COVID-19, did not require self-isolation as per BC provincial public measures, or had recov-
ered from COVID-19 at least 14 days prior to the study visit and blood collection. Blood was drawn in gold-top
serum separator tubes with polymer gel (BD Biosciences, catalog 367989); after at least 30 minutes of clotting at
room temperature, the blood sample was then centrifuged at 1400g for 10 minutes at room temperature to obtain
serum aliquots that were frozen at –80°C within 4 hours of collection. Adult prepandemic sera were all obtained
before January 1, 2020. Infants’ sera were collected before discharge from hospital at birth (first sample) and after
June 11, 2020 (second sample), as part of a study examining antibody responses to respiratory viruses.

Recruitment. Greater Vancouver is the main urban center in BC and the third largest metropolitan
area in Canada, with a population of 2.5 million. Study participants were invited by an email sent to clin-
ical departments of the BC Children’s & Women’s (C&W) Hospitals (the largest pediatric referral center
in BC, located in Vancouver, and where no cases of COVID-19 were admitted during the pandemic’s
first wave) and its affiliated BC Children’s Research Institute (BCCHR). The study was also advertised to
hospitalists, anesthesiologists, and critical care physicians at SMH (located approximately 27 km from
Vancouver). To minimize recruitment bias, all adults who responded to the invitation email and returned
their signed consent form were enrolled sequentially and invited to give a blood sample, without triaging.
Blood samples were collected between May 17 and June 19, 2020.
Study size. Since there were little population seroprevalence data available at the time and none in BC or
Canada, no a priori sample size calculation was performed. The recruitment period was, therefore, defined
by convenience over a 3-week period of enrollment, in order to obtain baseline data.
Multiplex antibody assay. A highly sensitive multiplex (10-plex) assay (Meso Scale Diagnostics, catalog
K15369U) where each antigen is “spotted” into a single well of a 96-well plate (23) was used to measure
antibody profiles against 4 SARS-CoV-2 antigens: the trimeric (whole) S-2P native spike protein, its RBD,
its NTD (24), and N protein; the trimeric SARS-CoV spike protein; and spike proteins from circulating
β-coronaviruses (HKU1, OC43) and α-coronaviruses (229E, NL63) , plus BSA, a negative control. Briefly,
after blocking wells with 5% BSA, sera were added at 4 dilutions (1:100, 1:800, 1:3200, and 1:10,000)
and incubated with shaking for 2 hours. Sulfo-tag–labeled anti-IgG detection antibodies were added, and
the electrochemiluminescence signal was read using the MSD Sector 600 instrument (Meso Scale Diag-
nostics). Initial AUC of the electrochemiluminescence values for antibody detection were well above the
BSA background for all sera for SARS-CoV-2 antigens, except for 1 sera for the RBD and N antigens and
10 sera for the NTD antigen. Samples were rescreened again in a second set of experiments after Meso
Scale Diagnostics provided standards. Results are presented as dilution-corrected interpolated values from
a standard curve with assigned AU/mL. Assignment of AU/mL of serum was performed by Meso Scale
Diagnostics and is designed such that values are comparable with an International Standard Serum (ISS),
so that bridging to a WHO International Standard will be possible in the future.
Competition experiments. Eight 2-fold dilutions of sera prediluted in a ratio of 1:50 assay diluent were add-
ed to an equal volume of assay diluent (control) or to assay diluent mixes containing 5 μg/mL SARS-CoV-2
spike and 5 μg/mL RBD proteins (SARS-CoV-2 RBD-spike cocktail), or 5 μg/mL spike proteins from all 4
circulating coronaviruses (HKU1, OC43, 229E, NL63; circulating coronaviruses [cCoVs] cocktail) (25), for
an on-plate assay dilution of 1:100 through 1:12,800. The dilution series was incubated for 30 minutes at
room temperature and then analyzed using the multiplex antibody assay protocol, as mentioned previously.
CLIA antibody assay. Total antibody (IgA, IgG, and IgM) against recombinant spike (S1) protein was
determined using the VITROS 5600 analyzer (Ortho-Clinical Diagnostics) according to manufacturer
instructions. This is a Health Canada and FDA-licensed qualitative assay with reported performance and
in-house validation indicating sensitivities > 7 days after onset range between 96% and 100%, and specific-
ities from 99% to 100% (26, 27).
SPOT peptide array. Forty-one 15-mer peptides selected based on their reactivity on convalescent samples
and immunogenicity, and that were distributed over the entire SARS-CoV-2 proteome, were synthesized on
a cellulose trioxatridecanediamine membrane using a MultiPep synthesizer (CEM) (28). Additionally, each
membrane contained a human-IgG binding peptide as positive control (29). These in-house–made mem-
branes were incubated with a 1:400 dilution of sera and incubated for 2 hours at room temperature. A copy
of the array was also incubated with Tris buffered saline with Tween 20 only, as a negative control. After
washing, membranes were incubated with secondary antibody (HRP-conjugated goat anti–human IgA +
IgG + IgM polyclonal antibody, Jackson ImmunoResearch Inc., catalog 109-035-064) at a 1:30,000 dilution
for another 2 hours, and detection was carried out using enhanced chemiluminescence detection, with 8
images captured over an exposure time of 50 seconds. The grayscale of images represented as numeric
values between 0 and 10 were used before applying a uniform background correction of 1.
Variables. The following information was collected from participants by questionnaire: age; sex; the first
3 digits of their postal code; HCW status (and whether they worked at C&W or SMH); history of travel
outside BC since January 1, 2020; and history of COVID-19 symptoms and testing. SARS-CoV-2–exposed
cases were defined by a positive result on the commercial CLIA assay, validated for sensitivity by antibody
profiling on the multiplex assay.

Statistics. The seroprevalence from a SARS-CoV-2 exposure was adjusted for bias due to false-positive
and false-negative tests using the Greenland method (30). Differences in proportions were calculated using
a Fisher’s exact test, with significance threshold at P < 0.05. Hierarchical clustering of antibody levels
(based on the multiplex assay) was performed on log-transformed, Z score–normalized serology data, using
the complete linkage agglomeration method and Euclidean distance measures. Spearman correlations
between antibody levels and metavariables were adjusted for multiple testing using the Benjamini-Hoch-
berg FDR = 0.05. There were no missing data. For competition experiments, same-sample groups were
compared using 2-tailed paired t tests. Analyses were conducted in R version 4.0.2, R Studio version 3.6.2,
and GraphPad Prism version 8.4.
Study approval. Written informed consent was obtained from all participants. The study procedures were
approved by the University of British Columbia (UBC) C&W Research Ethic Board (H20-01205; H18-01724).
Author contributions
AM, CM, and SD coordinated the study sample accrual and blood processing in Vancouver. JG and DM
coordinated recruitment at SMH. CC collated the data and helped with data analysis. SEO performed
the multiplex assay, with help from SN and MB. MG provided important input into the study design.
JM and DE expressed and provided the soluble proteins for the multiplex assays and competition experi-
ments. ACL, IS, and ANJ revised the manuscript. MI supervised the statistical analyses. VEB and DMG
supervised the commercial CLIA testing of samples. DFHW and SP performed the SPOT peptide array
analysis. PML and ABM supervised the study in Vancouver and at the NAID/NIH, respectively. AM, CM,
SD, DCD, and PML wrote the manuscript’s first draft. All authors contributed to the study design, data
analysis, and reviewing the manuscript, and they accept the article submission in its final form. The order
of co–first authors was determined based on their earlier involvement at the study design stage.
Acknowledgments
We thank Lauren Muttucomaroe, Esther Alonso-Prieto, and Lisa-Marie Candeias for help with recruitment;
Linda Warner and Stuart Turvey for lending essential staff resources; Kim Schmidt and Kiara Gibbons for
advertising the study; and study participants who have generously donated their time and blood samples. AM is
supported by a Mining for Miracles postdoctoral award from the British Columbia Children’s Hospital (BCCH)
Foundation. CC is supported by BCCHRI Research Institute and UBC Faculty of Medicine Summer Student
Research Program Studentships. AL is supported by a UBC Four Year Fellowship. PML holds a salary award
from the BCCH Foundation through the Investigator Grant Award Program. ANJ and MG acknowledge
funding from the Michael Smith Foundation for Health Research. This study was funded by the BC Children’s
Hospital Foundation (to PML), the Intramural Research Program of the Vaccine Research Centre (VRC) at
the National Institute of Allergy and Infectious Diseases (NIAID), NIH (to ABM and DCD). These funders
did not play a role in the design, planning, execution, analysis, or publication of the study. The study was also
funded in part by the Government of Canada via its COVID-19 Immunity Task Force.
Address correspondence to: Pascal M. Lavoie, BC Children’s Hospital Research Institute, 4th Floor,
Translational Research Building, 950 West 28th Avenue, Vancouver, British Columbia V5Z 4H4, Canada.
Phone: 604.875.2135; Email: plavoie@bcchr.ca.
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Dis. 2020;222(1):9–16.
11. Callow KA, et al. The time course of the immune response to experimental coronavirus infection of man. Epidemiol Infect.
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12. Skowronski D, et al. Low SARS-CoV-2 sero-prevalence based on anonymized residual sero-survey before and after first wave
measures in British Columbia, Canada, March-May 2020 [preprint]. https://doi.org/10.1101/2020.07.13.20153148. Posted on
medRxiv July 15, 2020.
13. Stubblefield WB, et al. Seroprevalence of SARS-CoV-2 among frontline healthcare personnel during the first month of caring for
COVID-19 patients — Nashville, Tennessee [published online July 6, 2020]. Clin Infect Dis https://doi.org/10.1093/cid/ciaa936.
14. Houlihan CF, et al. Pandemic peak SARS-CoV-2 infection and seroconversion rates in London frontline health-care workers.
Lancet. 2020;396(10246):e6–e7.
15. Garcia-Basteiro AL, et al. Seroprevalence of antibodies against SARS-CoV-2 among health care workers in a large Spanish ref-
erence hospital. Nat Commun. 2020;11(1):3500.
16. Zhou W, et al. First infection by all four non-severe acute respiratory syndrome human coronaviruses takes place during child-
hood. BMC Infect Dis. 2013;13:433.
17. Killerby ME, et al. Human coronavirus circulation in the United States 2014-2017. J Clin Virol. 2018;101:52–56.
18. Ou X, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-
CoV. Nat Commun. 2020;11(1):1620.
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20. Sagar M, et al. Recent endemic coronavirus infection is associated with less-severe COVID-19. J Clin Invest. 2021;131(1):143380.
21. Mulligan MJ, et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature. 2020;586(7830):589–593.
22. Bacher P, et al. Low-avidity CD4+ T cell responses to SARS-CoV-2 in unexposed individuals and humans with severe COVID-19.
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23. Johnson M, et al. Evaluation of a novel multiplexed assay for determining IgG levels and functional activity to SARS-CoV-2.
J Clin Virol. 2020;130:104572.
24. Wrapp D, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367(6483):1260–1263.
25. Klumpp-Thomas C, et al. Standardization of ELISA protocols for serosurveys of the SARS-CoV-2 pandemic using clinical and
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26. FDA. EUA Authorized Serology Test Performance. https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-
emergency-use-authorizations-medical-devices/eua-authorized-serology-test-performance. Accessed March 15, 2021.
27. Garnett E, et al. Clinical validation and performance evaluation of the automated vitros total anti-SARS-CoV-2 antibodies assay
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[ Lhave read and understand the disclaimer. I

AR08386
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DATE: 1--(-:-( lb , d"'O qs?:
EX #: ,2 I INITIALS: ~ ·D
AR08387
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AR08388

FEDERAL COURT
BETWEEN:
NABIL BEN NAOUM
Demandeur
et
Défendeur

AND BETWEEN:
Demandeur
et
Défendeur

AND BETWEEN:
AND AEDAN MACDONALD
Applicants
and
Respondent
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AND BETWEEN:
Applicants
and
Respondent
_________________________________________________________________
CROSS-EXAMINATION OF DR. BYRAM BRIDLE

May 24, 2022
_________________________________________________________________
James Elford For the Respondent
Keith Wilson For Dr. Bridle
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INDEX
PAGE
Exhibits ................................................... 4
DR. BYRAM BRIDLE

Cross-Examination by Mr. Elford ....................... 9
Proceedings Adjourned ................................ 245
Reporter’s Certification ............................. 246
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EXHIBITS
PAGE
1. “A Majority of Uninfected Adults, Show Pre-existing
Antibody Activity against SARS-CoV-2.PDF,” published
in JCI Insight, 2021, by Majdoubi, et al. 73
2. Public Health Impact of COVID-19 Vaccines in the United
States Observational Study, BMJ2022; 37e069317 106
3. WWW.Alberta/Stats/COVID-19-Alberta-Statistics.htm#
vaccine-outcomes 118
4. SAGE 56 Minutes: Coronavirus (COVID-19) Response, 10
September 2020 135
5. “Circulating Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2) Vaccine Antigen Detected in
the Plasma of mRNA – 1273 Vaccine Recipients,” in NIH,
2021, by Ogata, et al. 170
6. “Fact Check.Org COVID-19 Vaccine-Generated Spike
Protein is Safe, Contrary to Viral Claims,”
(May 20, 2022) 190
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EXHIBITS
PAGE
7. “BNT162b2 vaccination induces SARS-CoV-2 specific
antibody secretion into human milk with minimal
transfer of vaccine mRNA,” published in Semantic
Scholar, by Low, et al. 210
8. “VAERS, Event Details 1168901-1, (Screen Capture)
May 24th, 2022.PDF,” from the Vaccine Adverse Even
Reporting System 220
9. “VAERS, Event Details 0913971-1 (Screen Capture)
May 24th, 2022.PDF,” document from the Vaccine
Adverse Event Reporting System 223
10. Statement – on – Ivermectin – 01 – 14 – 2021 230
11. Page 168 from PDF, entitled, “Coronavirus Disease
2019 (COVID-19) Treatment Guidelines.PDF” from NIH 240
12. “Correction: Ivermectin Prophylaxis Used for
COVID-19: A Citywide, Prospective, Observational
Study of 223,128 Subjects Using Propensity Score
Matching,” article from Cureus, Lucy Kerr, et al. 245
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1 MAY 24, 2022
2 CROSS-EXAMINATION
5 MR. WILSON: I’d just like to clarify at the outset, the
6 aides to cross, my understanding is this morning, um,
7 at 7:48 a.m., we received 25 aides to cross. Is that
8 correct, Mr. Elford?

9 MR. ELFORD: I don’t know the exact number, sir.
10 MR. WILSON: Okay. Does that number sound close to you,
11 sir?
12 MR. ELFORD: It sounds a little high, but it might be
13 correct. And some of them may be duplicative of ones
14 that were sent previously, as you recall, before the
15 last cross-examination prep-date that we had had, that
16 unfortunately, was moved to today. I’d also provided
17 a number of aides to cross, that I understand, you’re

18 - your witnesses had the opportunity to review now.
19 MR. WILSON: So, in the previous - not yet, Dr. Bridle,
20 just wait please. In the previous exchange, there was
21 approximately 39 aides to cross. Does that sound
22 about right, Mr. Elford?
23 MR. ELFORD: That sounds approximately correct. Yes.
24 MR. WILSON: Okay. So, we’re dealing with plus or minus,
25 around 60 aides to cross. I just want to go on the
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1 record, because of the way in which the e-mail came
2 in, and the later position requested by the Crown, or
3 the Attorney General, which was that, we were asked
4 not to share aides to cross significantly in advance
5 of the cross, you know, just a few minutes before they
6 would start. So, we - we’ve made that our practice.
7 Of course, we all know that with the rescheduling that
8 occurred with Dr. Bridle, that that e-mail was in his

9 inbox for an extended period of time. He did not look
10 at them. We didn’t get clearance for him to look at
11 them, until late on Friday, and we’re now here Tuesday
12 morning, after the May long weekend.
13
14 So, I just want to be clear, and Dr. Bridle’s not very
15 happy about the situation with being - having this
16 many aides to cross put to him. Just so everybody’s
17 clear, we all understand that the process is that, if

18 a witness doesn’t feel they’ve had sufficient time to
19 review something, to answer a question, they won’t
20 answer it and they will be given sufficient time. So,
21 with that understanding of the ground rules, we’re
22 prepared to proceed. But to be clear, Dr. ...
23 MR. ELFORD: Now, and that’s - and that’s....
24 MR. WILSON: Dr. Bridle hasn’t - he hasn’t reviewed...
25 MR. ELFORD: My apologies.
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1 MR. WILSON: ...any of the aides to cross. So....
2 MR. ELFORD: Okay. Thank you for clarifying that. And
3 I’m fine giving him the time he need. We’ll take the
4 time it takes to get this done. I do note that we
5 weren’t asked until late last week to provide that
6 agreement, we did, but I also appreciate that, you
7 know, this is - there’s a lot of wheels on the go.
8 So, we’ll go with what we can do today, and if it

9 needs to continue later, than we will do so. All
10 right.
11 MR. WILSON: Thank you, Mr. Elford. I appreciate your
12 cooperation.
13 MR. ELFORD: All right. Thank you very much, sir. Good
14 morning, Dr. Bridle. I understand that you’re here to
15 be questioned today. I, of course, will be
16 questioning you. My name is James Elford. I’m with
17 the Attorney General of Canada and I’m going to ask

18 that Madam Court Reporter now have you swear or
19 affirm, so, that we may proceed. That’s all, when
20 you’re ready to proceed.
21
22 DR. BYRAM BRIDLE, affirmed, testified:
23 COURT REPORTER: Okay. Sir, do you solemnly affirm the
24 evidence you’re about to give today shall be the
25 truth, the whole truth and nothing but the truth?
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1 DR. BRIDLE: On my Bible, I swear that to be true.
2 COURT REPORTER: Okay. Can you please state your full
3 name and then spell it for the record?
4 DR. BRIDLE: Sure. It’s Dr. Byram W. Bridle. Byram is
5 B-Y-R-A-M. And last name Bridle is spelled B-R-I-D-L-
6 E.
7 COURT REPORTER: Thank you very much. Counsel, we’re on
8 the record, whenever you’re ready.

9 MR. ELFORD: Great. Thank you very much, Madam Court
10 Reporter. Again, good day, Dr. Bridle.
11 DR. BRIDLE: Hello.
12
13 CROSS-EXAMINATION BY MR. ELFORD
14
15 1 MR. ELFORD: And so - so, I’ll be, of course, questioning
16 you today on your Expert Report, and your affidavit.
17 And I’m just going to start with some introductory

18 questions, just to - just to lay some background here.
19 Now, you’ve been sworn or affirmed prior to this
20 cross-exa - so, just - just recently here? You were
21 just sworn? Pardon me. Strike that. Let me start
22 again. You were just sworn or affirmed prior to this
23 cross-examination starting right now?
24 A. Is that a question?
25 2 Q. Yes, sir. I can pose that as a question if - if you’d
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1 like. Would you agree with me that you are now under
2 oath, having just been sworn or affirmed, prior to
3 this cross-examination start?
4 A. Yes.
5 3 Q. Excellent. Now, you’d agree with me you were - your
6 sworn affidavit, sworn March 11th, 2022 in the Brian
7 Peckford, et al, and Canada Proceedings in the Federal
8 Court of Canada.
9 A. Yes.
10 4 Q. And you’d agree with me that it attaches your Export
11 Report, dated March 10th, 2022, as Exhibit B?
12 A. Yes.
13 5 Q. And sir, can you please advise me where you’re
14 physically located right now?
15 A. I’m in the basement of my house at 99 Kingsmill
16 Avenue, Guelph, Ontario.
17 6 Q. Okay. And sir, can you confirm with me that you’re

18 the only person in the room?
19 A. I am the only person in the room. My wife is
20 upstairs.
21 7 Q. Okay. Thank you. And sir, will you also confirm that
22 during any breaks in this cross-examination, you will
23 not communicate with any party outside of this virtual
24 meeting, or take instructions from anyone, other than
25 properly framed objections by your legal counsel?
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1 A. I agree to that.
2 8 Q. Thank you, sir. Now, sir, you have that affidavit,
3 your report, and the exhibits attached to your report,
4 available to you, during this cross - cross-
5 examination. Correct?
6 A. Ah, yes. So, with that said, I have - I’ve printed
7 out some documents. Again, I - I received everything
8 at the last second and ran out of ink to print things.

9 So, I have some documents printed. But I do have a
10 second screen here, so, that I can pull them up
11 electronic versions of the documents, if that’s okay.
12 9 Q. Sir, that’s fine, but what I actually asked you was
13 could you confirm that you have your affidavit, your
14 report, and the exhibits attached to those in front of
15 you for this cross-examination?
16 A. Electronic versions. Yes.
17 10 Q. Thank you, sir. And so, additionally, you’ve informed

18 me that you have some of the aides cross-examination
19 printed out, are the rest available to you
20 electronically?
21 A. They are now. Yeah. They’re in a few places. Um,
22 the file names were so long, that I couldn’t put them
23 all into one folder, because they - they were too long
24 to be transferred. So, they’re in - yes. I do have
25 them, but they are in multiple different files, at the
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1 moment. So, I will need some time to access them.
2 11 Q. Yes. Thank you for clarifying that, sir. Now, would
3 you also confirm for me, that you have no other notes,
4 documents, aside from your affidavit and the
5 documents, we just discussed in front of you? Either
6 on your desk or electronically?
7 A. Ah, well, yeah. No, other than the documents, like,
8 like for example, I have the - and you can see, I

9 don’t have - it’s not even black, because I was
10 running out of ink, but there’s the Exhibit C, from
11 Dr. Dawn Bowdish’s. So, I have some of these
12 documents printed out and then the rest, I will be
13 using as electronic files on my computer. And those
14 are the only documents that I have here.
15 12 Q. Okay. So, you’ve shown me a document from Dr. Dawn
16 Bowdish’s Expert Report and Affidavit.
17 A. Yes.
18 13 Q. So, then, I take it then, you’ve had an opportunity to
19 review the Affidavit and Expert Report of Dr. Dawn
20 Bowdish?
21 A. Yes, that’s correct.
22 14 Q. And you’ve had an opportunity to review the Affidavit
23 and Expert Report of Dr. Jason Kinderchuk?
24 A. Yes.
25 15 Q. Okay. Have you had the opportunity to review the
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1 affidavits and Export Reports of any other experts,
2 provided by the Attorney General of Canada in this
3 litigation?
4 A. I was able to partially review - uh, just give me one
5 moment here, so, I can see the name. I partially
6 reviewed the affidavit for - from Celia Larinko (ph).
7 16 Q. Okay. And sir, what parts were you able to review of
8 that affidavit?
9 A. Okay. Let me pull it up. Up until paragraph - up to
10 and including paragraph 52.
11 17 Q. Thank you, sir. And does that include the exhibits
12 that form part of that affidavit...
13 A. No.
14 18 Q. ...up to....
15 A. No. Just the - the text. Up to - including -
16 including paragraph 52.
17 19 Q. Okay. Thank you, sir. If you wouldn’t mind just

18 letting me - I appreciate it was obvious where I was
19 going, but if you wouldn’t mind letting me finish the
20 question, then you can answer, it’ll just make it
21 clear what you’re responding to. So, I was going to
22 ask you, you read the exhibits attached to that
23 affidavit up to paragraph 52, and if you read them
24 beyond, and I understand you hadn’t?
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1 20 Q. Okay. Great. Thank you very much, sir. So, just to
2 go back and for clarity, then before you today, you
3 don’t have any other notes or documents besides your
4 affidavit, the Export Report, and the exhibits to
5 that, and the aides to cross-examination you were
6 provided, and the affidavits of Dr. Jason Kindrachuk
7 with his Export Report, the affidavit of Dr. Dawn
8 Bowdish, with her Export Report, and the affidavit of

9 Celia Larinko (ph)?
11 21 Q. Thank you. And would you please confirm for me that
12 during the cross-examination, you won’t be viewing, or
13 referring to any notes or other notes, either paper or
14 electronically, other than your affidavit, or as
15 requested, documents that are presented to you during
16 the cross-examination?
17 A. I - yes, I understand that.

18 22 Q. So, that’s an agreement? Or do you understand?
19 A. Yes. Yes, I agree.
20 23 Q. Thank you very much, sir. And before we begin, there
21 are no changes or - let me rephrase that. Strike
22 that. Are there any changes that you wish to make to
23 your affidavit or Export Report, before we proceed?
24 A. I - I could - based on reading Dr. Kindrachuk’s
25 report, I agree with him that in the one section, let
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1 me open up my affidavit, so, that I can refer you to
2 the exact location.
3 24 Q. Thank you, sir.
4 A. Yes. So, in my - so, it would be Exhibit B, the
5 Expert Report that I wrote on page 2, Section 2, which
6 is entitled, “SARS-CoV-2 is not a problem of pandemic
7 portions.”
8 25 Q. So, for clarity then, was that a reference to your

9 Export Report or his?
10 A. My Export Report.
11 26 Q. Okay. And maybe for further clarification, could you
12 just explain what you agree specifically with Dr.
13 Kindrachuk on?
14 A. Ah, yes. So, he had mentioned - so, I have a sentence
15 - so, the third paragraph of Section 2, a sentence
16 that says, “It is likely that this infection fatality
17 rate will drop even further, as the extent of

18 unnoticed infections is further elucidated. Indeed, a
19 recent study found that up to 90 per cent of randomly
20 tested healthy adults in British Columbia had been
21 exposed to SARS-CoV-2.” And he had indicated that
22 that - so, I - I had ind - so, I had put that - so, I
23 want to clarify that I had put that there to indicate
24 that that 90 per cent, as he’s pointed out as well, is
25 referring to naturally acquired immunity, but not
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1 necessarily due to infection with SARS-CoV-2. He had
2 correctly pointed out that in this study, which was
3 done very early in the declared pandemic, that it - it
4 included that about 0.6 per cent of healthy adults, at
5 that time, had evidence of having been infected with
6 SARS-CoV-2 Coronavirus 2. So, I just want to clarify
7 that point. And - and - and I agree with him on that
8 point, that that study - that based on that study, the

9 inclusion would be that at that time, at that early
10 time point, there was evidence of 0.6 per cent of
11 healthy adults in British Columbia, having had been
12 exposed to SARS-CoV-2 Coronavirus 2 without knowing
13 it. In other words, there were about approximately
14 0.6 per cent of healthy British Columbian adults had
15 evidence of an asymptomatic infection with SARS-CoV-2
16 Coronavirus 2. So, it’s not a - a correction, but
17 just a clarification on that point.

18 27 Q. Okay. So, for clarity then, your referring to
19 paragraph 5 of your Expert Report, is that correct?
20 Where you make this statement regarding this specific
21 study?
22 A. Yes. Yes. Paragraph 5, if you start at the top of
23 page 3. Yes.
24 28 Q. Okay. And it specifically - it’s the “Indeed a recent
25 study found that up to 90 per cent of randomly tested
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1 healthy adults in British Columbia had been exposed to
2 SARS-CoV-2. This suggests that the denominator for
3 determining the true IFR is substantially higher than
4 previously appreciated, which would mean the IFR is
5 less than 0.15 per cent.”
6 A. Ah, yes.
7 29 Q. Okay.
8 A. But what I want - what I want to clarify is that that

9 second sentence is still - still remains 100 per cent
10 correct. I just want...
11 30 Q. Okay.
12 A. ...to clarify that that - with that 90 per cent,
13 that’s total - that’s the total proportion of healthy
14 adults in British Columbia that had evidence of
15 naturally acquired immunity, of which, 0.6 per cent
16 had direct evidence of asymptomatic infection with
17 SARS Coronavirus 2.
18 31 Q. Okay. So, you’re saying that 90 per cent of randomly
19 tested healthy adults in British Columbia, at the
20 beginning of the pandemic, had naturally acquired
21 immunity?
22 A. Yes.
23 32 Q. Okay. And this is the naturally acquired immunity
24 that prevents infection with SARS-CoV-2?
25 A. Yes. And, again, to clarify there’s two types of
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1 naturally acquired immunity. One can acquire it
2 either by direct infection with SARS Coronavirus-2 or
3 cross - what we call cross-reactive immunity due to
4 infection with other Coronaviruses, ‘cause it’s
5 important to point out that at the beginning of the
6 pan - declared pandemic, we were told this is a
7 completely novel agent to which everybody was naive,
8 and this is clear evidence that that’s not true. This

9 is not a fundamentally different virus. It shares a
10 lot of similarities to other Coronavirus viruses, and
11 that’s exactly what this data demonstrates.
12 33 Q. Okay. And so, just you’re saying then that 0.6 per
13 cent of the individuals in this study, and - and
14 please correct me if I’m wrong on that number, had
15 asymptomatic SARS at that time.
16 A. There was - there was evidence of - yeah, asymptomatic
17 infection, specifically, SARS-CoV-2, yes.

18 34 Q. And that’s not prior infection, that’s asymptomatic
19 infection?
20 A. Yes. The remainder - so, that would put it at about,
21 you know, a little over 89 per cent had evidence of
22 cross-reactive immunity, due to prior infections with
23 other Coronaviruses.
24 35 Q. Okay. I’m sorry. I thought you said, “asymptomatic.”
25 So, you’re saying, it’s prior infection?
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1 A. No. The - the remaining 8 - 89 per cent would have
2 been - had immunity, evidence of natural acquired
3 immunity due to prior infection with other
4 Coronaviruses.
5 36 Q. Okay. Sorry, sir. I was just asking about the 0.6
6 per cent, which I understood you said there was clear
7 evidence in this study, showing that they had had
8 asymptomatic SARS-CoV-2 infections?

9 A. Yeah. Well, like, again, that can be definitively
10 concluded they - they weren’t aware of illness, but
11 yet, tested positive. Yes.
12 37 Q. Okay. Thank you, sir. Are there any other changes
13 that you would like to make to your affidavit or
14 Export Report, besides this one?
15 A. No thank you.
16 38 Q. Thank you, sir. Well, what I would like to do first,
17 is start off with a discussion of your CV, which is

18 Exhibit A to your affidavit, sir. If you wouldn’t
19 mind turning to that, please.
20 A. Okay.
21 39 Q. And let me know when you have it up.
22 A. Okay. I have it up.
23 40 Q. Okay. Thank you very much, sir. So, what I’d like to
24 start off with is to clarify, you are a viral
25 immunologist, correct?
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2 41 Q. Okay. And you’d agree that most of your work that’s
3 set out in your CV before 2020, focused on vaccines
4 against cancer?
5 A. Vaccines against cancer and post-immune responses to
6 viruses. And actually, I guess for complete accuracy
7 in the record, I - I’ve also - I’d also published in
8 the area of, you know, transplantation.

9 42 Q. Uh-hmm. I think you did one of your degrees with that
10 as the thesis, is that not correct?
12 43 Q. Okay. And you said post-immune response to - to which
13 viruses specifically, sir?
14 A. Ah, generally.
15 44 Q. Okay.
16 A. So - so, yeah, I use all kinds of different models,
17 including our - the viruses that we use in our cancer

18 research. We’ve used them as models. I have an
19 infectious disease model for influenza, influenza
20 virus. There’s a number of different infectious
21 models that we’ve utilized.
22 45 Q. Okay. And these are models that you’ve worked with?
23 A. Sorry. You got cut off at the last moment there.
24 46 Q. Oh, I’m sorry. And these are models that you’ve
25 worked with?
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1 A. Yes.
2 47 Q. Okay. And if we turn to your affidavit at page 10,
3 under User Profile Section, there’s a little section
4 called, “Research Interest.”
5 A. Ah, okay. I’m just going there. Page 10, you said?
6 48 Q. Uh-hmm.
7 A. Okay. On....
8 49 Q. On - the page set - it’s the PDF page of your

9 affidavit, sir. So, I’m just trying to make it as easy for
10 you to find as possible. And if I’m wrong, just let me
11 know.
12 A. Okay.
13 50 Q. So, just - just let me know, if you’ve got it there
14 yet.
15 A. Okay. Yes. “Research Interest.” Yes.
16 49 Q. Excellent. Thank you. Now, you know what, I think
17 that I might be wrong. I think it might be page 10 of

18 your actual CV. My apolo - oh, no. Sorry. It’s page
19 8 of your CV, 16, upper right-hand corner. So, sorry
20 about that, sir. That was - must have been a mistype
21 on my part. Anyways, if you wouldn’t mind just
22 reading what it says there under “Research Interest.”
23 And just, onto the record, please.
24 A. Okay. “In an effort to destroy malignant cells with
25 minimal bystander damage to normal tissues, I combine
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1 two approaches: (1) Cancer immunotherapy, which
2 directs the power of the immune system against tumors;
3 and, (2) oncolytic virotherapy that utilizes viruses
4 that replicate in and kill only cancerous cells. The
5 exquisite specificity and systemic targeting
6 capability of these two approaches holds promise that
7 some day cancer patients might be effectively treated
8 without the toxicities associated with many

9 conventional therapies. My extensive work with
10 oncolytic viruses has also led to the discovery of a
11 novel mechanism for the negative regulation of complex
12 cytokine networks. This has led to a keen interest in
13 basic aspects of innate anti-viral immunity. In
14 summary, my specific interests include: vaccines,
15 oncolytic viruses, immunological tolerance,
16 autoimmunity (to kill cancerous, but not normal self),
17 tumour biology, host anti-viral response, and antigen

18 presentation.”
19 51 Q. Okay. And so, this is the research that you were
20 referring to, when you talked about your work with
21 viruses, is that correct?
23 52 Q. Thank you, sir. Now, you don’t list any research on
24 Coronaviruses prior to 2020 in your curriculum vitae,
25 do you?
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1 A. No.
2 53 Q. Okay. And that includes no research in relation to
3 the original SARS or to MERS, correct?
4 A. Ah, yeah. Well, it depends on what you call research.
5 I haven’t done any formal laboratory research. I’ve
6 done lots of literature-based research. I need to as
7 part of my teaching program.
8 54 Q. Okay.
9 A. I teach in the areas of immunology, virology, and
10 cancer biology.
11 55 Q. Okay. So, as part of teaching, but not researching
12 your role as....
13 A. Not - not laboratory-based research. No.
14 56 Q. Thank you, sir. If you wouldn’t mind just letting me
15 finish the question. I don’t want to cut you off.
16 So, that you don’t know what question you’re
17 answering. I - I appreciate it may seem clear, what

18 I’m going to ask you, but....
19 A. Sure.
20 57 Q. It’s just much clearer once I ask and then you can
21 respond. Thank you very much, sir. And you don’t
22 have any research, this is on your CV, prior to 2020
23 related to mRNA vaccines, do you?
24 A. Ah, again, I’d say the same thing. Not formal
25 laboratory-based research, but again, I’m very
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1 familiar with the field of development of mRNA
2 vaccines. I’ve been following extensively for a long
3 time, as I have all vaccine technologies because I’m a
4 vaccinologist. So, it forms the basis of a lot of the
5 knowledge base that I use and development of my own
6 vaccines and my vaccine research program. And, again,
7 for my teaching.
8 58 Q. Thank you, sir. Now, you - the work you have listed
9 in your CV, that’s pre-clinical work, correct?
10 A. The - uh, no. It’s - I - I do emphasize pre-clinical
11 research, but I’ve also been involved in conducting
12 quite a bit of translational research, and I haven’t
13 directly - I haven’t directly been involved hands-on
14 with human clinical trial research, at this point, but
15 I did have a vaccine technology that I passed along
16 that was advanced into four human clinical trials.
17 But my - with my hands-on work, it focuses on what we

18 call discovery, pre-clinical, and translational
19 research.
20 59 Q. Okay. Now, what’s translational research?
21 A. That - that’s kind of the - between the pre-clinical
22 and the clinical. It - that’s the research that’s
23 required to really start looking at the safety of a -
24 a - a novel therapy, and the efficacy. And it’s done
25 in different animal models. So, it’s - it’s literally
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1 - it’s referred to as translational research, because
2 that’s where researchers attempt to translate
3 promising pre-clinical findings into clinical
4 applications through clinical trial work. So, it
5 involves things like working with alternative species.
6 So, for example, most of the pre-clinical research
7 that’s done in the world is done with rodent models.
8 So, either mice or rats. But with translational

9 research, other animal models are used. So, for - for
10 example, if one wants to go in a clinical trial,
11 typically one would be expected to conduct safety and
12 toxicity testing, and at least two different animal
13 models, non-human primates are often used. So, for
14 example, I have experience running with the
15 collaboration with the Public Health Agency of Canada.
16 I’ve run a non-human primate trial, in the context of
17 COVID-19 vaccines. I’ve also, in the context of my

18 cancer vaccine research, I’ve run - I ran a Canadian
19 Breast Cancer Foundation Funded Translational Study,
20 also known as a veterinary clinical trial in cats with
21 memory carcinomas, which is the equivalent of breast
22 cancers in humans. So, that’s the type of work. It’s
23 - it’s really trying to bridge the pre-clinical work
24 and trying to optimize those positive findings and
25 translate them into an effective therapy for testing
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1 in human clinical trials.
2 60 Q. Okay. So, they’re - you’re - you’re talking about
3 animal clinical trials then?
4 A. Yes.
5 61 Q. And that includes that one product that you were
6 advancing, you had done the animal clinical trials and
7 then hand it - hand it off to someone else to take....
8 A. To conduct the human clinical trials. That’s correct.

9 62 Q. Okay. Thank you, sir. And I’m sorry, I just - I -
10 I’m not trying to step on you, I suggest you’re -
11 you’re answering incorrectly, other than to suggest
12 that you are maybe jumping on my question before I
13 finish asking it. And, again, I just want to make
14 sure that what I’m asking you is clear. And I
15 appreciate it’s difficult. It’s not how people talk.
16 So, it’s - it’s a little awkward.
17 A. I guess I’m - I guess I’m unsure with the annotation

18 at the end and the pause. I - I assumed you were
19 finished. I’m sorry, if...
20 63 Q. No.
21 A. ...you weren’t done your question.
22 64 Q. Not a problem, sir. I’m letting you know. I’ll try
23 and pause less then. Okay. You don’t have any
24 experience or training running a human clinical trial
25 then?
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1 A. With - with the hands-on running? No. But I’m
2 familiar with the process.
3 65 Q. Okay. But you don’t list any experience training -
4 seeking regulatory approval in Canada for a vaccine,
5 do you?
6 A. No. Ah, well, again, so, that’s - that - it’s -
7 again, it depends. Through the Veterinary Biologics
8 Division, I have.
9 66 Q. Okay. But not with humans?
10 A. Not with humans.
11 67 Q. Okay. And you don’t list any experience or training
12 in the application of regulations and guidelines for
13 drug development, regulation, and post-market
14 monitoring, including vaccines in your CV, do you?
15 A. No.
16 68 Q. Okay. You don’t have any direct first-hand experience
17 with the regulatory process regarding new drugs or

18 vaccines, including vaccines, with Health Canada or
19 the US FDA?
20 A. Ah, again, it depends on what you mean by experience.
21 Again, I’m familiar with the process through
22 literature searches, because it’s part of what I have
23 to teach, but I haven’t actually done the process
24 hands-on for any of the experimental therapies that
25 I’ve been working with.
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1 69 Q. Okay. Thank you, sir. So, I want to just move along
2 here. Your work list in the CV, we’ve cov - we’ve
3 covered it. Your work focuses on animal studies and
4 cell cultures then?
5 A. Ah, well, I guess, yes. Generally speaking. Yes. I
6 - I do a lot of cell culture work and I also do a lot
7 of animal studies. There are other kinds of studies,
8 as well, I mean beyond just the cell culture, ’cause

9 there’s lots of laboratory-based studies. For
10 example, I work with x-vivo analysis of living
11 tissues. That type of thing. A lot of molecular
12 biology. So, my - my research methods involve far
13 more than just animal modelling and cell culture.
14 70 Q. Okay. Thank you, sir. I’m just going to ask you to
15 turn now, if you will, to the section called,
16 “Editorial Activities.” And I’ll just get you a page
17 number in a moment. I’m going to look it up this

18 time, because I want to make sure I get you to the
19 right page. Okay.
20 A. Okay.
21 71 Q. And the page I have is PDF page 53 and that’s 53 in
22 the upper right-hand corner, as well, please.
23 A. This, “Community and Volunteer Activities?”
24 72 Q. Ah, no, sir. It’s Editorial Activities.
25 A. Sorry. You said it was page 53 of the PDF?
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1 73 Q. It is on mine. Maybe you have a slightly different
2 version, for some reason, but if you look in the upper
3 right-hand corner, it’s page 53.
4 A. I - I don’t have numbers in the upper-hand corner.
5 Mine are on the bottom of the page.
6 74 Q. Okay. It’s 45 then, sir.
7 A. Okay. Ah, there, I have a list of post-doctoral
8 fellows that I have advised.

9 75 Q. Yeah, but it’s below that. If you go down, it says,
10 “Editorial Activities” in large blue letters on the
11 left-hand side, please.
12 A. Okay. I have that on page 47 of the PDF for me. The
13 “Editorial Activities.”
14 76 Q. Oh. Um, and that’s at - the - the number at the
15 bottom?
16 A. At the bottom is 45.
17 77 Q. Yes. That’s the one I’m talking about, sir.

18 A. Okay.
19 78 Q. Yeah. Not a problem. Don’t worry. We’ll get through
20 this. So, now, I noticed that you have a number of
21 editorial activities listed here and they all seem to
22 end in December of 2025 - or sorry. My apologies.
23 Not all of them, but a number of them do. Why is
24 that, sir?
25 A. Oh, that’s because in the Canadian - so, first of all,
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1 this is a - this is a very partial list that I
2 actually haven’t updated for quite some time. But
3 they’re listed for 2025 to put them into - because
4 they’re ongoing, essentially. So, for the Canadian,
5 this - this version of my CV is known as the “Canadian
6 Common CV” and the purpose of the Canadian Common CV
7 is - is just that, to have a common template to be
8 used by granting agencies to try and minimize the

9 amount of work that we have to do as faculty members.
10 I mean, despite this, I’m expected to maintain a huge
11 number of different, fundamentally different CVs, but
12 this is the one that I try and keep most
13 comprehensive, but this is - this is just a very
14 partial list of my review activities. But that in
15 short, the reason why I have them as 2025 is because
16 one has to put - enter a start date for an activity
17 and an ending date, and I haven’t ended my, you know,

18 willingness to review for these journals that are
19 listed here. So, come, 2025, I would extend the date
20 further. So, it’s just pulled out of a - pulled out
21 of a hat, just to make it clear that it’s an ongoing
22 activity.
23 79 Q. Great. Thank you, sir. That clarifies it. And so,
24 your work with infectious disease only began after the
25 emergence of SARS-CoV-2, correct?
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1 A. That is incorrect.
2 80 Q. Okay. And it - so, you’re saying that it began
3 earlier?
4 A. Oh yes. As - as I said, I’ve been doing research - I
5 run - I run an animal model on for influenza virus. I
6 also have been working for years with a model looking
7 at virus-induced cytokine storms. And trying to
8 figure out why those occur and look for potential ways
9 to treat that issue. So, and I’ve been working with a
10 number of infectious disease models for quite a few
11 years now.
12 81 Q. Great. Thank you, sir. And you don’t have any
13 experience or training as an obstetrician or a
14 gynecologist in your CV, correct?
15 A. Not formally as a gynecologist or obstetrician, but I
16 understand the reproductive organs, especially as it
17 applies to cancer biology and immunology very well. I

18 have to. So, for example, I’ve published multiple
19 papers on treatment of ovarian cancers. I also do
20 work in the area of cervical cancers. So, I - I
21 understand the reproductive tract and reproductive
22 organs very well. The bio - and, you know, the
23 biology, but no, I’m not a clinician and I don’t treat
24 diseases of the reproductive tract.
25 82 Q. Okay. And that’s through your work on cats?
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1 A. Um, well, again, no. Not - no, also, we deal with
2 infectious diseases. So, for example, is part of my
3 safety studies, one of the tissues that I evaluate on
4 a regular basis when working with female animals, is
5 potential toxicities or damage to the ovaries, for
6 example. That’s one of the tissues that we would
7 routinely include. Sometimes the - the uterus as
8 well. And in males, I - I’ve done some work, for

9 example, with prostate cancers. And if we’re doing
10 infectious disease work in male animals, we would
11 also, the - the testicles for example, would be an
12 obvious place that we would look, as part of our
13 pathological assessment.
14 83 Q. Okay, but you don’t have any training in the area of
15 obstetrician or gynecological work?
16 A. As a clinical obstetrician, no. I’m not a clinical
17 obstetrician or gynecologist.
18 84 Q. Or at all in obstetrician or gynecology?
19 A. Asked and answered. That will be the third time.
20 85 Q. Thank you, sir. If that’s your position, I
21 understand. I’m going to move on. And going back for
22 a moment to infectious disease then, but your work on
23 - on SARS-CoV-2, of course, didn’t start till 2020.
24 A. That’s correct. Just - yeah. For everybody, yes, it
25 would be limited to 2020.
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1 86 Q. Yeah. And you don’t have any training or experience
2 in infectious disease, epidemiology in your CV,
3 correct?
4 A. Ah, well, again, I’m not formally trained as an
5 epidemiologist, but I understand a lot of the issues
6 around public health. The way I like to explain this,
7 is - is along the lines of a Venn diagram, right. One
8 can, you know, a Venn diagram is when you have

9 circles, circles of influence essentially is how it’s
10 often viewed, and there can be overlaps, overlaps in
11 expertise. So, for example, I’m an expert - I have
12 expertise is virology and immunology, as well as
13 cancer biology, but that’s not particularly relevant
14 to the discussion today. So, virology overlaps with
15 the field of epidemiology, because it’s critically
16 involved in a public health issues. And immunology
17 obviously overlaps, as well, to some degree, and I

18 mean, we look, one of the big - one of the primary
19 tools used by epidemiologists when it comes to public
20 health measures is our vaccines, for example, and
21 monoclonal antibodies, et cetera, et cetera, in which
22 I - in which I’ve got great expertise. So, as a
23 vaccinologist, especially, I have a, you know, quite a
24 good understanding of epidemiology and public health.
25 I have to. I have to, because both of these fields
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1 overlap. So, it’s not a complete overlap. An
2 epidemiologist will have additional training, which I
3 have not received, but my training in viral - in both
4 virology and immunology overlap.
5 87 Q. Okay. Thank you, sir. What I had asked though was do
6 you have any training or experience in infectious
7 disease and epidemiology, not whether or not you had
8 understanding. So....
9 A. Yes. So, I have education. I’ve had courses during
10 my university training, and have done literature
11 research on that basis.
12 88 Q. Okay.
13 A. Yes.
14 89 Q. So, you’re....
15 A. I’ve received formal university training. I - I mean,
16 I guess if you’re asking if I hold a degree in
17 epidemiology, no, I don’t. But I have received - I’ve

18 sat in on lectures about epidemiology and multiple
19 courses throughout my university training. And,
20 again, I’ve done plenty of literature res -
21 literature-based research on the topic. Um, and
22 again, based on the virology and immunology training,
23 as well, I’ve received some formal training, as it
24 relates to epidemiology. Again, because there’s
25 overlap. So, I’ve had many courses that - that have
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1 overlapped with epidemiology that involve formal
2 epidemiology-based lectures.
3 90 Q. But you don’t consider yourself an epidemiologist?
4 A. I - I am not a - I don’t hold a degree in
5 epidemiology. No. I - I consider myself to have
6 expertise in the field of epidemiology where it
7 overlaps with virology and immunology.
8 91 Q. Okay. So, you agree then that you’re not an expert in

9 epidemiology.
10 A. I’m an expert in the areas of epidemiology that
11 overlap with immunology and virology.
12 92 Q. Now, sir, you are an Associate Professor at the
13 Department of Pathobiology at the Ontario Veterinary
14 College at the University of Guelph, correct?
16 93 Q. Okay. And you’d agree that the Department of
17 Pathobiology describes itself on its website as

18 “...dedicated to the advancement of knowledge in
19 veterinary and comparative pathology, veterinary
20 infectious diseases, and immunology.”
21 A. I don’t have that page memorized. I’m sorry. I can’t
22 confirm or refute that statement.
23 94 Q. Okay. Give me a moment, please. So, sir...
24 A. Yes.
25 95 Q. ...I’m sharing with you a webpage. If you look up
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1 here at the website address, it says,
2 “OVC.uguelph.ca/pathobiology/” and then it appears to
3 be the page for the University of Guelph Ontario
4 Veterinary College. Do you see that, sir?
5 A. I do.
6 96 Q. Okay. And you would agree that this is the website
7 for the Department of Pathobiology?
8 A. I do.
9 97 Q. Okay. And you’d agree that under the words,
10 “Pathobiology,” it says, “The Department of
11 Pathobiology is dedicated to the advancement of
12 knowledge in veterinary and comparative pathology,
13 veterinary infectious diseases and immunology.”
14 A. Yeah. That’s correct.
15 98 Q. Great. Thank you. Madam Court Reporter, please stop
16 the screenshare. Great. Thank you. Okay. So, you’d
17 agree with me then, going back to my last question,

18 that the Department of Pathobiology has described
19 itself on its website as, “...dedicated to the
20 advancement of knowledge in veterinary and comparative
21 pathology, veterinary infectious diseases, and
22 immunology.”
23 A. Ah, yeah, they’ve stated that. That isn’t the
24 limitations of what we - what we do within the
25 department, by any stretch. Those are the official -
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1 so, what one has to understand is the Ontario College
2 or the - what’s it called? Ontario - I just blanked.
3 The organization that - that certifies the programs
4 that can be offered by colleges and universities, they
5 have certain requirements for something to be listed
6 as a program, for example, there’s a limited number of
7 faculty members required. So, one good example, when
8 it comes to laboratory and medicine, we’ve had one

9 faculty member, that - that teaches in that program,
10 but it can’t be listed on the website as an official
11 program, because there’s just one faculty member. My
12 understanding is there has to be a minimum, I believe,
13 of three faculty members for something to classify as
14 a formal program. And so, we have many programs that
15 are offered where only one faculty member deep
16 perhaps, and - and so, that’s - so, that’s why the
17 immunology, for example, is listed, because we have

18 four immunologists, and - and I would point out, as
19 well, that that’s not listed as veterinary immunology,
20 but rather immunology, general immunology. And yeah,
21 so, just keep that - so, that’s important to keep in
22 mind. So, yes, those are the formally approved
23 programs that can be listed, of which there’s many
24 other programs offered within our department, that
25 just don’t fall under that official categorization of
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1 a [quote] “program.” So - so, for example, a good way
2 for the court to understand this is somebody could,
3 for example, can do training in my laboratory in the
4 area of - of cancers, and human cancers, but they
5 would go down officially listed as - the program would
6 be listed as “Immunology.” Somebody who would be
7 doing the Laboratory Animal Medicine Program, for
8 example, their official degree would be in the area of

9 one of the pathologies, even though they did
10 laboratory animal medicine. So, that’s what it is.
11 It's a formal designation, but it’s not a limitation
12 by any stretch, or of what we do within the
13 department. We are - what we - the research that we
14 do and the teaching that we do, is far broader, than
15 what’s listed there.
16 99 Q. Okay. And this is at the Ontario Veterinary College?
18 100 Q. Okay. Thank you, sir. And you’re not part of the
19 regulatory college, or a regulated profession,
20 correct?
21 A. Ah, pro - professional regulated? Prof - sorry.
22 Could you clarify your question?
23 101 Q. I’ll break it down for you, sir. You’re not part of a
24 regulatory college, correct?
25 A. No.
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1 102 Q. Okay. And you’re not part of a regulated profession,
2 correct?
3 A. Ah, I don’t understand that question. My profession
4 is highly regulated.
5 103 Q. Okay. Ah, let me rephrase that. You’re not part of a
6 self-regulated profession?
7 A. Again, I’m not quite sure I understand the question.
8 I do a lot of self-regulation within my profession.

9 I’m - I’m sorry. I don’t...
10 104 Q. Okay.
11 A. ...understand the question.
12 105 Q. Let me try to do this again. There’s no governing
13 body that a viral immunologist, let’s say, that says,
14 “You can or can’t be a viral immunologist that engages
15 in investigations into professional misconduct, which
16 engages in training, which engages in the assertion or
17 the assessment of competence.” There’s nothing like

18 that, that you’re a member of, correct?
19 A. Uh, that I’m a - again, it’s un - unclear. Those are
20 things that can be influenced at the university level,
21 at the administrative level, and I serve on various
22 administrative committees. So, I’m sorry. I - that -
23 that doesn’t clarify it for me. I’m not - I’m not
24 sure how to answer the question. It - you know, I - I
25 don’t just have free reign in my position, and nor
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1 does anybody else, and any of my colleagues. So, I’m
2 - I’m sorry. It’s unclear to me.
3 106 Q. No. I - I understand that, sir. Um. You’d agree
4 with me, you’re not regulated by a college similar to
5 the College of Physicians and Surgeons?
6 A. I - I’m not familiar with how the College of
7 Physicians and Surgeons operate because I am not a
8 physician, but my college, again, I’m part of - like

9 you said, the Ontario Veterinary College, and they
10 regulate many of our activities.
11 107 Q. Okay.
12 A. So, I assume that there could be similarities, but I
13 can’t state definitely whether there are or not.
14 108 Q. And I understand that they do regulate certain
15 activities, including attending campus recently,
16 whether - dependant on one’s vaccination status.
18 109 Q. And I understand that you were unable to access campus
19 for a while?
21 110 Q. Okay. And that is distinct from the sabbatical you
22 have listed on your CV that took place between January
23 2021 to December 2021?
25 111 Q. Okay. So, separately they granted you a sabbatical to
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1 conduct as - as you state, “research-related
2 activities, including service to the research
3 community during the declared COVID-19 pandemic.” And
4 that is what the sabbatical was for?
6 112 Q. Okay. Did you find it difficult to conduct research,
7 when you did not have access to the labs or university
8 facilities?
9 A. Well, okay. So, there’s two ways for me to answer
10 that question. For me, for my person - I’m very much
11 a hands-on researcher. I don’t just direct my - my
12 research team.
13
14 So, in other words, I do lots of hands-on research
15 with the animals for example, and like to be able to
16 teach, like - like show, demonstrate for my trainees,
17 certain techniques. So, certainly my ability has been

18 dramatically impacted. You know, I’ve been unable to
19 do any of the - the work that I do. In fact, there’s
20 certain techniques, in fact, that are used within my
21 research program that are unique to my research
22 program and for which I’m the only person on campus
23 who has been authorized to do the procedure. And in
24 fact, I’ve been asked, in the past, when there have
25 been other people who had needed to do the procedure,
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1 as part of their program, I have been asked to
2 actually do the training for others. So, that aspect,
3 obviously, has been dramatically impacted.
5 And I mean has it impacted - negatively impacted the
6 ability for my research team to conduct the research?
7 Yeah.
8
9 On that basis, but I have still been able to do it,
10 because what I’ve done is I’ve had to pay a lot of
11 money to make sure I have senior researchers,
12 including an associated faculty member, associated
13 with my research team now, to provide the frontline
14 hands-on support to my research team.
15
16 But has it had a negative impact overall? Yes. I -
17 what I would say though is I have been - I - I’ve had

18 record productivity over the past two years, despite
19 that, I’ve published more papers in the last two years
20 of my career, than in any two-year period, prior to
21 that, by - by quite a margin. In fact, I - I’ve out-
22 performed the average publication productivity of
23 everybody within my college. Not - not every
24 individual, I’m saying the average, the average
25 productivity for a faculty member by college, I’ve
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1 vastly exceeded that productivity, in terms of
2 research publications over the past two years, but
3 yes...
4 113 Q. Okay.
5 A. ...it has had a negative impact.
6 114 Q. Okay. And some of the research you’ve done is
7 attached to your affidavit as exhibits that you’re -
8 this is the research that you’re referring to, just

9 right now, correct?
10 A. Ah, yeah. That’s some of it. Yes. I have - yes. I
11 can - I have some publications that I - that were
12 published within the last two years, attached as
13 exhibits. That’s correct.
14 115 Q. Okay.
15 A. I - I have published a lot more than those.
16 MR. ELFORD: Okay. Thank you, sir. And Now, this is a
17 question for your counsel, Mr. Wilson, when we had Dr.

18 Pelech on, you were asked to confirm what he was being
19 tendered as an expert in, and I’m going to ask you the
20 same question with respect to Dr. Bridle, please.
21 MR. WILSON: Sure. Immun - immunology, vaccinology,
22 virology, with some expertise in cardiology, and
23 women’s productive health, and public health, and all
24 of the categories and sub-categories of subject
25 matter, that are at issue in this litigation and may
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1 be of benefit to the courts. I should also add, uh, I
2 forgot to mention epidemiology, given Dr. Bridle’s
3 excellent description of the overlapping and inertia
4 nature of the work that medical experts do.
5 116 Q. So, then he’s also being tendered as an expert in
6 epidemiology and just for clarity, sir, and - and
7 counsel, please don’t misunderstand. I just want to
8 make sure I understand here. And Dr. Bridle, you then

9 agree with the characterization and the way your
10 expertise, with respect to women’s health, was
11 described by your counsel? You - you agree that
12 you’re an expert, as he described?
13 A. Yes.
14 117 Q. Okay. Thank you. I’d like to move on then to Exhibit
15 B. So, when you’ve got that, just let me know, sir.
16 A. Exhibit B, my Expert Report. Yes. I have that opened
17 now.
18 118 Q. Okay. Thank you very much, sir. And if we could
19 please turn to paragraph 2 of that report. Let me
20 know when you’re there.
21 A. Okay. So, just to clarify, you don’t mean .2 after
22 the summary? You mean...
23 119 Q. No, I don’t, sir.
24 A. ...[inaudible].
25 120 Q. Oh, I’m sorry. I interrupted you this time.
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1 A. Oh, no problem. So, you mean page - on page 5,
2 paragraph 2, starting from Section 1? If I have the
3 right paragraph, I’m looking at Section 1.2, “In early
4 2021, Health Canada provided....”
5 121 Q. Yes, sir. That is what I was trying to refer you to.
6 A. Okay.
7 122 Q. So, it sounds like we’re on the same page.
8 A. Yes.
9 123 Q. Great. So, um, I note at this paragraph, you state,
10 “In early 2021, Health Canada provided authorization
11 for interim use for several [quote] ‘Designated C-19
12 drugs’ [end quote] that were akin to vaccines,
13 although the definition of vaccine had to be changed
14 to officially recategorize them as such.” Do you
15 recall writing that, sir?
16 A. Yes.
17 124 Q. Okay. But you agree with me that the definition in

18 Health Canada or in Canada of vaccines has not
19 changed?
20 A. Not officially. No, this is - this was the United
21 States Centres for Disease Control, which changed the
22 definition.
23 125 Q. Okay. So, when you say that officially, you mean, no,
24 it did not change in Canada, it changed in the US?
25 A. Yes.
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1 126 Q. Okay. Thank you, sir. And, uh, just to be clear, the
2 definition you’re talking about that changed in the
3 United States was the definition set out on US CDC
4 website, webpage, called, “Immunization: The Basics?”
5 A. Ah, yes, I believe so.
6 127 Q. Okay. And the definition on that webpage, sir, for
7 vaccines was changed from, “A product that stimulates
8 a person’s immune system to produce immunity to a

9 specific disease, protecting the person from that
10 disease. Vaccines are usually administered through
11 needle injections, but can also be administered by
12 mouth, or sprayed into the nose.” So, that was the
13 first one, correct?
15 128 Q. Okay. And it was changed to [quote], “A preparation
16 that is used to stimulate the body’s immune response
17 against disease, vaccines are usually administered

18 through needle injections, but some can be
19 administered by mouth, or sprayed into the nose,” [end
20 quote].
22 129 Q. Okay. I just want to clarify, are you claiming that
23 for the US - for COVID-19 vaccines to be recognized as
24 vaccines, in the United States, this particular US CDC
25 webpage had to be changed?
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1 A. Yes.
2 130 Q. Okay.
3 A. And again, I would also point out, because the one
4 thing that’s missing from this discussion, which
5 applies to Health Canada is the interchangeable use
6 with the term, “Immunization,” which means to confirm
7 immunity. So, again, from that - that’s the
8 perspective to applies to Health Canada.

9 131 Q. Did you....
10 A. ’Cause the - the key is the definition for immunity.
11 132 Q. Okay. Are you referring to a definition of immunity
12 in the Food and Drug Act or its regulations here in
13 Canada?
14 A. Yes. Yes. So, the fact that vaccination and
15 immunization are interchangeable. Yes.
16 133 Q. Which section of either that Act or the Regulation are
17 you referring to, please?

18 A. Ah, I’m sure specifically about the Act. I’d have to
19 go back through the Act. I’m talking about the
20 interchangeable use of vaccine and - vaccination and
21 immunization.
22 134 Q. Okay, but you’re saying that that is the Food and Drug
23 Act or its regulations here in Canada?
24 A. I would have to look at the Food and Drug Regulations
25 Act...
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1 135 Q. Okay.
2 A. ...to - to confirm that.
3 136 Q. But you - you don’t know that information currently?
4 A. Ah, I can’t recall offhand. No.
5 137 Q. Okay. And regardless, that wasn’t what you were
6 referring to when you wrote in your Export Report, “In
7 early 2021, Health Canada provided authorization for
8 interim use of several [quote] ‘designated C-19 drugs’

9 [end quote] that were akin to vaccines, although the
10 definition of a vaccine had to be changed to
11 officially recategorize them as such.”
12 A. That was based primarily on the US definition change.
13 Yes.
14 138 Q. But you agree with me that Health Canada didn’t change
15 the definition of vaccine?
16 A. Ah, yeah. I can’t confirm that they did.
17 139 Q. Well, you can’t confirm that they did? Or you believe
18 that they did and you can’t confirm? Or you don’t
19 know that they did, and you can’t confirm? Could you
20 please clarify exactly what you mean, sir?
21 A. Yeah. No. They didn’t change their definition, but
22 they use immunization and vaccination interchangeably.
23 140 Q. Okay. Okay.
24 A. The Government of Canada routinely does that. They
25 usually ref - in fact, they often refer it - they
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1 often use the term “Immunization.”
2 141 Q. Okay. And where’s that?
3 A. The - well, the Government of Canada, lots of places
4 with the Government of Canada. Do you - do you want
5 me to give you an example? I could - I could look one
6 up, if you’d like.
7 142 Q. Well, I - I....
8 A. Like, the Government - the Government of Canada uses

9 the term “immunization” and “vaccination”
10 interchangeably...
11 143 Q. Okay.
12 A. ...on multiple websites.
13 144 Q. Okay. But you’re not referring to the Food and Drug
14 Act or its regulations?
15 A. Again, I’d have to look up again the Food and Drug Act
16 and regulations to confirm.
17 145 Q. So, you don’t know whether it does? Or you’re

18 just....
19 A. I can’t - I can’t recall. As you can appreciate, I -
20 I keep up-to-date with all of the literature, and I’ve
21 been reading hundreds of papers and articles. I can’t
22 - I don’t have them all memorized. I - I would - I
23 don’t want to state definitively one way or the other,
24 until I’ve had an opportunity to look.
25 146 Q. Okay. Thank you, sir. And just for - your - your
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1 concern then is that the - was the removal in the US
2 CDC page to the word, “immunity?” That’s your
3 concern, correct?
4 A. Yes. Yes. That’s the concern and that’s the concern
5 I have in Canada, as well, because they use the term
6 “immunization” interchangeably with “vaccination,” and
7 to immunize is to confer immunity and - and the term
8 “immunity” has a very specific meaning. And that is,

9 I get - I get - so, for example, in Canada, we have
10 the Canadian Immunization Guide, which includes
11 information about the CO - you know, COVID-19 [quotes]
12 “vaccines.”
13 147 Q. Okay, sir. And as I understand, that’s because you’re
14 of the view that the traditional meaning of the word,
15 “vaccine,” is - is the one that confers immunity?
16 A. That is correct and that’s what the term,
17 “immunization,” implies.
18 148 Q. And so, any vaccine....
19 A. [inaudible].
20 149 Q. Oh, sorry.
21 A. Yeah. Which again, I - I will point out, is used
22 interchangeably by the Government of Canada in many
23 places, including, again, what they don’t refer to it
24 as, when they talk about - when the Government of
25 Canada talks about the COVID-19 vaccines, their guide
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1 is not the Canadian Vaccination Guide, it’s the
2 Canadian Immunization Guide.
3 150 Q. And so, it’s your view that any vaccination that fails
4 to produce immunity, as you assert the COVID-19
5 vaccines failed to do, is not a vaccine?
6 A. Ah, that’s correct. Yes. And it’s not just based on
7 that. It’s - it’s based on traditional patent law as
8 well. So, if - if medical products did not meet the

9 strict definition of conferring immunity, and by that,
10 we’re talking about inferring sterilizing, or near
11 sterilizing immunity, they would not be allowed to be
12 - to claim the product as a vaccine, under patent law.
13 Again, a vaccine, it’s - it’s very clear under the -
14 as - well, again, based on immunization, it’s very
15 clearly implied, both the Canadian definition and in
16 the original US definition, that a vaccine is to
17 confer immunity and immunity has a very specific

18 definition. It means that a person is protected from
19 the disease and cannot transmit the causative agent to
20 another individual. And so, I mean I’m a
21 vaccinologist, and I - I love vaccines, right? And I
22 - I teach the value of vaccines. So, a classic
23 example of what we call vaccines are the childhood
24 vaccination series, for example, that are required for
25 children to attend school. They are - once they’re
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1 done, we don’t acquire another shot, you know, another
2 booster for the rest of our lives. They confer, long-
3 lasting immunity, and protect people from disease, and
4 don’t transmit. In fact, so the Court understands,
5 ’cause I know I’m supposed to be helping the Court,
6 you know, make their decision, so, just so, the Court
7 understands, the best way to think of it are the
8 vaccines used for travel. So, that - that’s an

9 example of something that falls under the traditional
10 definition of an immunization, meaning a vaccine that
11 confers immunity, where if somebody wants to travel to
12 a - to an exotic location, where there’s a pathogen
13 that’s endemic that is not present in Canada, a
14 physician would often advise the individual to receive
15 a vaccine/immunization, and once that is complete, the
16 physician will wish them well on their trip, and the
17 person will actually pay a lot of money to go on

18 vacation, or a business trip, whatever it is, the
19 endemic location. They will actively go to the
20 location, where the pathogen is an endemic. They know
21 they can potentially engage that pathogen, be exposed
22 to the pathogen. They’re fine with it. The physician
23 is fine with it. And the Canadians are fine with it,
24 because that person will not acquire the disease and
25 they will be at an extremely low risk of being able to
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1 bring that pathogen back into Canada. So, that’s -
2 that’s the classic definition. The definition that -
3 if one does not accept the concept of immunity, but
4 rather inducing immune responses that can potentially
5 dampen the severity of a disease, I - I just recently
6 wrote an article about this. I have been compelled
7 under that type of definition to teach that yogurt
8 represents a - a vaccine, or sauerkraut, anything that

9 would involve, for example, probiotic bacteria,
10 because yogurt, there’s all kinds of publications that
11 show the benefit, the immunological benefits of
12 consuming things like yogurt and sauerkraut, and
13 inducing immune responses that can be of benefit in
14 the context of various diseases. So - so, no, I - I -
15 I have a real problem with the fact that if a product
16 - and - and I’m glad you brought this up, because it’s
17 an important, because when we talk about vaccines

18 today, at any point, and if I use the term “vaccines,”
19 in the context of the current COVID-19 inoculations, I
20 always intend to use that term “vaccines” in quotation
21 marks, or one could insert the term, “inoculations” in
22 instead, because these don’t - the current COVID-19
23 inoculations don’t function any - in any way shape or
24 form, anything like a traditional vaccine technology,
25 for which one could interchangeably use the term,
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1 “immunization,” which means to confer immunity.
2 151 Q. Okay. And so, I just want to clarify then, you said,
3 uh, yogurt could be a vaccine, based on this
4 definition?
5 A. Absolutely.
6 152 Q. Because - and that’s despite it, these - these
7 benefits you’ve described not relating to a specific
8 disease that it would prevent?

9 A. It - yeah, exactly.
10 153 Q. Okay. You don’t think vaccines need to be directed
11 towards a particular disease? Or a virus that, for
12 example, induces a disease?
13 A. Ah, yeah. I - I think - yeah. If that - if that -
14 for a vaccine to function, the only way to achieve
15 sterilizing and near sterilizing immunity would be to
16 direct and you would want as - to bring in as many
17 immunological effector mechanisms as possible. So,

18 any immunological mechanisms, as well as mechanisms
19 that will fall under the arm of the immune system that
20 we call the adaptive immune response. So, that would
21 be t-cells and b-cells, which produce the antibody -
22 you know, antibodies that we’ve been hearing about.
23 And those ideally functioned, based off of - those are
24 known, the hallmark of those responses are
25 specificity, what we call exquisite specificity. So,
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1 an ideal vaccine, yes, should induce sterilizing or
2 near sterilizing immunity, and that’s almost certainly
3 going to acquire induction of adaptive immune
4 responses. So, that’s why - yeah. So, to clarify,
5 I’m not comfortable defining a yogurt, or sauerkraut,
6 as a vaccine.
7 154 Q. Okay.
8 A. But I’m never - I’m not going to teach that to my

9 students. No. There - there’s clear characteristics.
10 A vaccine has to confer sterilizing and near
11 sterilizing immunity, such that it prevents the
12 disease and prevents transmission of the causative
13 agent, and if it’s going to be considered a vaccine of
14 any kind of quality, that - the duration of protection
15 has to be long-lasting.
16 155 Q. Okay.
17 A. And by long-lasting, I mean like akin to the childhood

18 vaccine regiment, where you don’t - where memory -
19 immunological memory can last years and doesn’t
20 require boosting months later. I mean in Canada,
21 we’re - we’re now talking about fifth doses in their
22 elderly, in less than one year. That is not the
23 characteristic of a vaccine. Again, that confer -
24 that one would - would use the term, “immunization.”
25 For a physician to immunize a patient, they have to -
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1 they would have to administer a product that fits the
2 characteristics that I just described.
3 156 Q. Okay. And so, a vaccine that has less than 50 per
4 cent efficacy against infection, wouldn’t match your
5 definition of near immunizing or near sterilizing
6 immunity?
7 A. No. No. Exactly. So, I - I assume you’re talking
8 about - like, for example, a classic example are the

9 annual flu vac - you know, vaccines, which often have
10 a less than 50 per cent effectiveness. Maybe in a
11 good year, they’ll have 50 per cent effectiveness.
12 And that’s exactly why they’re not mand - mandatory,
13 because they don’t come close to conferring, again,
14 any - anything for which we imply - so, for example,
15 in Ontario, we have an implied requirement for school
16 kids to attend school, right? To get - to receive
17 what we call a childhood vaccine schedule. Anything

18 that falls under that category, where people are - in
19 - in the past have been very strongly encouraged and -
20 and through the use of any kind of documentation, such
21 as, you know, an immunization card, those fit the
22 category, fit the description of what I just
23 mentioned. And no, 50 per cent effectiveness at
24 preventing infection, doesn’t cut it.
25 157 Q. Okay. And so, you don’t consider flu vaccination to
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1 be vaccines?
2 A. It’s - it’s attempting to use the - the concept, but
3 no. It’s - it’s - you can’t use the term - again, the
4 Government of Canada routinely interchanges
5 vaccination and immunization and - and immunization is
6 to confer immunity.
7 158 Q. Okay. Thank you, sir, but my question is....
8 A. So - so - so, you see the difficulty that I have. If

9 one is going to use them interchangeably, that means -
10 that means also the verse is true, vaccination has to
11 match the definition then of immunization. So - so,
12 yes. They - they induce immune responses, but they do
13 not induce sterilizing, or sterilizing immunity. And
14 that’s one of the reasons why I would - I, personally,
15 would never support, as an expert, mandating, for
16 example, flu vaccines. No. Because they - they - you
17 have to understand, the whole, okay. To - to help the

18 Court understand, as well, here’s a good way to look
19 at it. Again, a vaccination/immunization, it’s one of
20 two ways to achieve immunity in an individual. The -
21 remember, the - the whole goal, when there’s an
22 infectious disease, ideally is to achieve what we
23 call, “herd immunity.” That - that’s the purpose.
24 There’s two ways. One can either become naturally
25 infected, clear the infection, and therefore,
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1 naturally acquire immunity to the infectious agent, or
2 we can use vaccines, as tools, to trick the immune
3 system into thinking it was infected. So, hopefully,
4 it amounts an immune response, that’s hopefully, at
5 least, close to the gold standard of - of quality,
6 which is the natural immune response. And - but we’re
7 often a long way from that, because we’re still trying
8 to understand the basics of natural immunity. But

9 nevertheless, that’s the goal, to try to achieve that
10 gold standard, such that a person doesn’t have to get
11 sick in order to achieve immunity, and risk any of the
12 potential consequences of that illness. But in both
13 cases then, when a person is exposed, whether it’s
14 with natural - after natural infection, so, exposed a
15 second time, or after vaccination, exposed the first
16 time to the pathogen, in both cases, the person’s
17 immune system is going to view it as the second -

18 second infection, and they’re going to respond
19 robustly enough and quickly enough that they can clear
20 the pathogen without experiencing disease. That -
21 that’s the goal.
22
23 And so, immunity is the goal, and herd immunity
24 requires just that, immunity. So, we’ve been talking
25 at Annasian in Canada about our goal to achieve herd
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1 immunity, right? And we were told that these
2 inoculations were the way to achieve herd immunity.
3 Again, it’s the term “immunity,” and immunity has a
4 specific connotation. It means you’re protected from
5 the disease and can’t transmit it. So, this is why
6 it’s very important for immunization to meet that
7 requirement to achieve immunity, because otherwise,
8 vaccines can’t be used as tools to achieve herd

9 immunity, and that’s exactly what they were designed
10 for. And what I mean by that is herd immunity means
11 that you don’t have to have everybody immune to a
12 pathogen, but rather you need the majority of a
13 population, some majority. It - it depends on - on
14 how dangerous and transmissible the infectious
15 pathogen is. It could be as little as a small
16 majority, in, you know, 50-some odd per cent. It
17 could mean up to 80 per cent. But not everybody - and

18 - and then the idea being that if you have people who
19 can’t mount an immune response properly, right, or are
20 high risk, because remember the traditional approach
21 to infectious diseases wasn’t you isolate everybody,
22 but rather you isolate the high-risk demographic, and
23 allow the low-risk demographic to achieve herd
24 immunity, whether it be by natural infection and/or
25 vaccination. And then those who are high-risk, or
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1 can’t be vaccinated, or don’t respond properly to
2 vaccination, or don’t respond properly to natural
3 infection, will be protected, because we would have
4 achieved herd immunity. And herd immunity only works
5 if the person that has mounted the immune response,
6 has mounted an immune response that does confer
7 sterilizing - sterilizing immunity, such that they
8 don’t get sick themselves, and can’t transmit the

9 virus. As soon as a vaccine - so, for example, if a
10 vaccine has less than 50 per cent, say it’s 50 per
11 cent effective, or - you’re not going to be able to
12 achieve herd immunity. So, for these current COVID-19
13 inoculations, and I mean, it’s become obvious by our
14 Public Health data, we can never, ever, ever, with the
15 current COVID-19 inoculations, we can’t - we can’t
16 ever achieve herd immunity with them, because they are
17 far too leaky. They don’t come close to conferring

18 sterilizing or near sterilizing immunity. So, the
19 whole goal of herd immunity, which is what these were
20 for, cannot be met with these inoculations. So,
21 that’s why the concept of immunity is - is a very
22 important one. A very important one for the - for the
23 Court to understand.
24 159 Q. Thank you, sir. That was very interesting, but my
25 question was, you - does this mean you do not consider
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1 by your definition, that flu vaccines are not
2 vaccines?
3 A. They can’t be used for immunization. No.
4 160 Q. Okay. But do you consider them vaccines, yes or no?
5 A. The - yeah, not by - not by the definition that I just
6 said. No.
7 161 Q. Okay. And so, you don’t consider....
8 A. They don’t - they don’t - they don’t....

9 162 Q. [inaudible].
10 A. Sorry. Could I - could I - could I qualify that for a
11 moment? Because having given it some thought, I need
12 to point out, whe - when you ask the question about
13 flu vaccine, there’s a difference here. The fl - the
14 flu vaccine, so - so, I would go back out and correct
15 my statement. I would say it depends; it depends on
16 how it performs from year-to-year. These are - the
17 flu vaccines, remember, are made on an annual basis.

18 We have a completely new flu vaccine every single
19 year. And I should clarify, I’m not going to say that
20 no, they don’t qualify as vaccines. They, in fact,
21 do. And sometimes, in some years, they’re very good,
22 and the reason being that in some individuals, they -
23 they do confer, sterilizing or near sterilizing
24 immunity, and can protect a person from being infected
25 with the - with the agent. The problem - the flu is
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1 very different. Influenza viruses are very different
2 from many other viruses, in that they mutate extremely
3 rapidly. So, the reason why we need a new flu vaccine
4 every year is because the - the viruses change so much
5 from year-to-year. So, the flu vac - and like a lot
6 of viruses, so, for example, the Coronavirus, it's a
7 SARS Coronavirus 2, it mutates. It mutates by
8 intentionally incorporating errors into its genetic

9 material, as it replicates its genetic code.
10 Influenza viruses do that as well, but in addition,
11 influenza viruses can exchange large chunks of genetic
12 material with other influenza viruses, which means you
13 can have very huge changes in the nature of the virus.
14 So, in many cases, those can qualify as vaccines, but
15 the reason for the low effectiveness is because the
16 virus has changed so much. Once a virus has mutated
17 or changed too much, it doesn’t matter whether you

18 have naturally acquired or vaccine-induced immunity,
19 you are going to have to update that immunity at that
20 point in time. So, yes, the flu vaccines can function
21 very well as vaccines, but they’re going to have a
22 very limited timeframe, in which they confer
23 sterilizing and near sterilizing immunity because the
24 virus is going to change so much, that it’s just a
25 matter of time before that virus can start evading
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1 that previously, highly-protected immunity.
2 163 Q. Okay. And that’s shorter than the time limit that you
3 had suggested about childhood vaccines?
4 A. Ah, yes. So - so, for the flu, yeah. The - the
5 duration of immunity might be fine, but if the virus
6 changes too much, right, that immunity is going to
7 become irrelevant.
8 164 Q. Okay. Let’s move on, sir. Let’s talk about

9 paragraphs 3 to 5 of your Expert Report. And just for
10 clarity, when I say paragraphs, I mean the paragraph
11 number associated with the paragraph. They’re just be
12 on the left-hand side, indented a bit. Okay.
13 A. Yes.
14 165 Q. Great. And specifically, at paragraph 5, and we
15 talked about this earlier, but you wrote, “Indeed a
16 recent study found that up to 90 per cent of randomly
17 tested healthy adults in British Columbia had been

18 exposed to SARS-CoV-2. This suggested that the
19 development for determining the true IFR is likely
20 substantially higher than previously appreciated,
21 which would mean the IFR is less than 0.15 per cent.”
22 Do you recall that?
23 A. Yes, I do.
24 166 Q. Okay. And earlier you had told me that based on your
25 understanding, this study had determined that 0.6 per
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1 cent of the study population showed clear evidence of
2 a prior infection with SARS-CoV-2?
3 A. That is correct. Yes. I included that as proof of
4 principal that even at the very beginning of the
5 declared pandemic, there was already emerging evidence
6 of people having acquired immunity, as a result of
7 direct infection with SARS-CoV-2 without having been
8 aware of it.
9 167 Q. Okay. Did the author specifically state in this study
10 that it was from asymptomatic infection?
11 A. Ah, I - I - I’d have to look at the paper. I don’t -
12 I don’t recall - I mean, as you can appreciate again,
13 I don’t have every one of the hundreds of papers that
14 I’ve read memorized. We - we could look, if you’d
15 like, but I - I can’t recall.
16 168 Q. Okay. I just wanted to know where you got the
17 information that this is from asympt - asymptomatic

18 infections.
19 A. Oh, because the people hadn’t been aware. Again,
20 remember these were healthy - healthy adults.
21 169 Q. Okay.
22 A. There - there has been no indication of - of any
23 obvious illness. Again, you know, so, in theory they
24 could have had mild signs or symptoms that they didn’t
25 really pay attention to. It’s - it’s hard to say.
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1 But there was no obvious, you know, overt moderate or
2 serious illness, associated with it. And, in fact,
3 you know, I - I’m in complete agreement actually with
4 - with the portion of the report by Jason Kindrachuk
5 on this, right. Where he - he also talks about the
6 fact that because - because - as you can appreciate,
7 asymptomatic, if an asymptomatic individual has - were
8 to have any viral load at all, because they’re

9 asymptomatic, it means they’re healthy. It means
10 they’re not sick. And - and so, these people can’t be
11 easily identified, unless you’re screening. And the
12 best way for screening for this, is - is certainly not
13 what we’ve been doing with the PCR testing, or - or
14 the antigen testing, that - that requires the vir - an
15 active virus to be present in an individual, but
16 rather the ea - the - the best way to determine this,
17 would be through antibody testing, a process we call,

18 “Seroconversion.” So, what happens - seroconversion,
19 “Sero,” refers to serum, which is the - the liquid
20 portion of our blood. And so what it is, is
21 seroconversion means that antibodies become - start
22 circulating in the blood of an individual after
23 they’ve been infected. So, if you find antibodies
24 against the pathogen, like SARS-CoV-2, in the blood,
25 there’s only two ways that those antibodies could be -
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1 could have been generated, either by natural infection
2 or by vaccination. And so, if somebody is
3 symptomatic, or is asymptomatic, but had been
4 infected, you would expect to see this seroconversion,
5 antibodies present. So, we actually set-up in Canada
6 a task force to monitor seroconversion throughout the
7 declared pandemic. Unfortunately, it was shut down
8 and we - we do not - we have not generated those data,

9 which would have been extremely helpful, especially
10 when it came to plugging in assumptions for the
11 epidemiology models, because we had no idea then - or
12 the epidemiologist had no idea what to plug in, in
13 terms of assumptions for naturally acquired immunity,
14 but if we had that data, we would have a better idea
15 of how many asymptotic infections have actually
16 occurred. And so, that’s the whole point here. Just
17 like Jason Kindrachuk also recognized that

18 asymptomatic infections are very difficult to identify
19 because the way we’ve been approaching it, you would
20 have to have somebody who is being tested for a
21 reason, other than being sick. They’d have to be
22 tested for the presence of the SARS Coronavirus 2, or
23 would have to be involved in an active study
24 investigating this, in order to be identified. So,
25 the reality is, we have no idea how - to what degree
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1 there has been asymptomatic infections. And again,
2 Dr. Jason Kindrachuk mentioned this in his report, and
3 I agree with him. And so, that - that’s the basis of
4 this is that there was this re-estimation of the
5 infection fatality rate, bringing it to approximately
6 0.15 per cent in this. And yet, we still don’t have a
7 good appreciation for how extensive asymptomatic
8 infections have occurred. And it’s - it’s probably

9 even, you know, exaggerated, in particular, in
10 children, because they seem to have particularly
11 robust innate immune responses that can quickly deal
12 with the virus before it causes any disease.
13 170 Q. Okay. Thank you, sir. Now, what I want to ask you
14 about is your comment that the study confirmed that
15 the - it’s not - you said - I believe you said 90 per
16 cent of individuals have pre-existing immunity, or how
17 - what - how did you term it again?

18 A. Yeah. Yeah. Pre-existing immunity and that pre-ex -
19 pre-existing immunity or naturally acquired immunity
20 can occur one of two ways. It can be due to....
21 171 Q. Sorry, sir. We’ll be here a while, if I - if we go
22 down this. And if you want to answer - you answer how
23 you want, and I don’t want to tell you how not to
24 answer, but I do have further questions and - and -
25 and a lot more. So, I just want to mention that to
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1 you. I don’t want to tell you how to answer...
2 A. Oh.
3 172 Q. ...or not to answer, but...
4 A. Okay.
5 173 Q. ...I do, however....
6 A. If you can answer - you can ask fewer questions, if
7 time is an issue. It doesn’t matter to me. I....
8 174 Q. Well, I’m [inaudible], sir.

9 A. Okay.
10 175 Q. I’m just letting you know, so, you can choose, if - if
11 you want to answer additional information, I haven’t
12 asked. I mean, it’s your answer, sir. I can’t tell
13 you, but I’m just saying, I have a - a number of them,
14 just so that you’re aware, because I appreciate you’re
15 a very busy man.
16 A. Okay. Thanks. And - and just so you’re aware, as a
17 scientist, I like to give very thorough answers. I’m

18 - I’ll give the answer that is required for the Court
19 to understand the - the nature of the - the issue.
20 Um, so, I’m sorry, I - I don’t have any recollection
21 of what the question was that you just asked.
22 176 Q. Not a problem.
23 A. If you could ask it again?
24 177 Q. So, I just wanted to confirm that how you had
25 described - give me a second - I’m going to move my -
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1 you had described this as natural immunity. And this
2 is a natural immunity that meets your definition of
3 immunity, correct?
4 A. They - okay. So, that - that - that would be - these
5 would be naturally acquired immune responses. In
6 order for it to be - somebody to be immune, they would
7 have to be protected from the disease, and they would
8 have to also be protected against the transmission of

9 the causative agent, sufficient amount of the
10 causative agent to cause disease in another
11 individual. So - so, thank you. I would clarify this
12 to mean the - the - the authors use “immunity,” but
13 you’re correct, I - I would say these are natural
14 acquired immune responses that were detected.
15 178 Q. Okay. So, you’re not saying now that the - that you
16 were talking about this study proving that individuals
17 have natural immunity?

18 A. They have naturally acquired immune responses is what
19 it - is what this study shows.
20 179 Q. Okay. But that - that’s not what you said initially.
21 So, you’re just clarifying or correcting your earlier
22 comment?
23 A. That - yes, I am.
24 180 Q. Okay. ’Cause you would agree with me that what the
25 study actually concludes, at one point, and I’ll quote
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1 you here, and I can take you to it, is, “It is unclear
2 whether this antibody re-activity may confer clinical
3 benefits. For instance, modulating the severity of
4 the SARS-CoV-2 infection.” Would you agree with me
5 that it says that? If you don’t recall, we can go
6 look at it.
7 A. No, no. Absolutely. Yeah. This study was not
8 designed to look at protection against disease or

9 transmission. It was only looking at seroconversion.
10 It was only demonstrating evidence of a large propor -
11 ’cause again, the - the - the question being addressed
12 by these authors was - we were told at the beginning
13 of the pandemic, that this is a completely novel
14 virus, for which no - no - for which nobody has been
15 exposed and so, therefore, people are completely
16 lacking immune responses to this virus. What this
17 study clearly shows is that was absolutely 100 per

18 cent false, that in fact, about 90 per cent of healthy
19 adults had evidence of naturally acquired immune
20 responses to the virus, of which a tiny fraction
21 seemed to be due to infection with the SARS
22 Coronavirus 2, itself, and the vast majority due to
23 infection with other coronaviruses. And - and again,
24 that fits the virology. When we were told that people
25 had no - no pre-existing immune responses to this
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1 virus, that made no sense to those of us, who
2 understand virology. This is not such a complete
3 different virus. If you look in its sequence, it - it
4 is very similar to other coronaviruses. It is a
5 coronavirus, in fact, Jason Kindrachuk goes through
6 the virology and the similarities and the different
7 viruses, and that’s based on similarity in terms of
8 genetic sequence. And there’s - there are large

9 swaths of the amino acids sequence in this - in this
10 virus, that matches that of other coronaviruses and
11 that’s - what that means is if anybody is mounted
12 immune response against any of those - the pieces that
13 are shared between the viruses, then they’re going to
14 have, what we call, “Cross-reactive immunity.” It’s a
15 natural acquired immunity, conferred by infection with
16 - from another, but similar virus that cross-reacts,
17 that can also - where antibodies can also recognize

18 this SARS Coronavirus 2. So, that - that’s just to
19 clarify, that’s what this paper is showing. Robust,
20 pre-existing, naturally acquired immune responses
21 against SARS Coronavirus 2, but they did not - they
22 cannot comment based - based on how this study was run
23 on the clinical outcome of those immune responses.
24 181 Q. Okay. Great. What I’m going to do, sir, you talked a
25 little bit about it. Let’s put it on as an exhibit.
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1 So, to do that, what I’d like you to do is - and I
2 believe Madam Court Reporter, you should have a copy
3 of this, this would be one of the ones that came to
4 you a while back, and I’d like you to open up the
5 document, and - and I’ll read the title to you. It’s
6 a PDF. It’s called, “A Majority of Uninfected Adults,
7 Show Pre-existing Antibody Activity against SARS-CoV-
8 2.PDF.”
9 A. I think this is the one I printed out. Yes, I do.
10 182 Q. Okay. And this appears to be an article published in
11 “JCI Insight” in 2021 with Majdoubi, M-A-J-D-O-U-B-I,
12 et al, as - as authors and it appears to have been
13 published March 15th, 2021. And is this the article
14 that you were referring to when you were talking about
15 the 90 per cent randomly tested in paragraph 5 of your
16 Expert Report, sir?
17 A. Yes. That’s correct.

18 MR. ELFORD: Okay. Great. Madam Court Reporter, do you
19 have a copy of that?
20 COURT REPORTER: Yes, I do.
21 MR. ELFORD: Okay. Great. I’d like to enter that as
22 Exhibit 1, please.
23 COURT REPORTER: Okay. I’ll enter that as Exhibit 1.
25 MR. ELFORD: Thank you very much, Mr. Wilson.
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2 EXHIBIT 1: Published article titled, “A Majority of
3 Uninfected Adults, Show Pre-existing Antibody Activity
4 against SARS-CoV-2.PDF,” published in JCI Insight,
5 2021, by A. Majdoubi, et al.
7 MR. ELFORD: Now, I noticed it’s 12:30, and I suspect
8 this is probably a good time to take a bit of a break.

9 How’s that sound to everybody? We can go enjoy some
10 yogurt and maybe take about 10 to 15? How’s everyone
11 feel about that?
12 MR. WILSON: Ah, just hang on. Dr. Bridle, how much time
13 do you need?
14 DR. BRIDLE: I - I’m fine with what everybody else agrees
15 on.
16 MR. WILSON: Mr. Elford?
17 MR. ELFORD: Fifteen minutes?

18 MR. WILSON: Okay.
19 MR. ELFORD: Does that work for you, sir? I have 10:34,
20 so, we’ll come back at 12:50, or Dr. Bridle’s time, 11
21 - or 10:50, our time, is that sufficient?
22 MR. WILSON: Before we go off the record, I just wanted
23 to clarify that when I was asked to describe the list
24 of categories for which we’re establishing or
25 presenting Dr. Bridle as an expert at approximately
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1 10:06 a.m., MST, he testified in response to your
2 question on a matter that he’s a virologist, and I had
3 forgotten to mention earlier when I gave the list,
4 that that is also an area where we’re presenting him
5 as an expert is virology. So, I just wanted to
6 confirm that his answer to your question aligns with
7 what we’re presenting him as.
8 MR. ELFORD: Great. Thank you, sir, for your

9 clarification.
11 MR. ELFORD: Then - oh, pardon me. Sorry?
12 MR. WILSON: We can go off the record and we’ll see you
13 all in about 15 minutes.
14 MR. ELFORD: Sure. Yes. We’ll go off the record.
15 Excellent.
16
17 OFF RECORD
18
19 MR. ELFORD: Great. We’re back on the record. And....
20 MR. WILSON: Mr. Elford.
21 MR. ELFORD: Yes, sir?
22 MR. WILSON: Sorry to interrupt. I - I - I had a sick
23 child last night, so, I’m running on about three hours
24 sleep and when I read the words from my notes from Dr.
25 Bridle’s testimony at 10:06 a.m. MST, I didn’t
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1 verbalize the word that I had written. The word that
2 I had written is “He had said, “I am a
3 vaccinologist.’” I misread that, just before the
4 break and said, “Virologist.” Of course, as I noted
5 earlier at about 9:30 a.m., that we’re seeking - we
6 will be presenting him to the Court as an - as an
7 expert in immunology, vaccinology, virology, with some
8 expertise in cardiology, women’s productive health,

9 and public health. So, I just wanted to correct my
10 mis - misspeaking, just before the break. Thank you
11 very much.
12 MR. ELFORD: You’re welcome, sir. I’m sorry to hear that
13 your child is sick. I hope that they recover swiftly.
15
16 CROSS-EXAMINATION (CONTINUED) BY MR. ELFORD:
17
18 183 MR. ELFORD: Okay. So, now that we’re - we’ve completed
19 that, I would like to move along here to paragraph 9
20 of your affidavit, sir. Just let me know when you’re
21 there. Or not your affidavit. I’m sorry. Your
22 Export Report.
23 A. Just to doublecheck, did you say, “Paragraph 9?”
24 184 Q. Yes, sir.
25 A. Okay. I’m there.
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1 185 Q. Now, paragraph 9, you state that transmission of the
2 Delta variant is not substantially effected by a
3 vaccination. Do you agree with me on that?
4 A. Yes.
5 186 Q. Okay. And you would also agree with me that people
6 who are not infected with the SARS-CoV-2 virus can’t
7 transmit it?
8 A. Ah, sorry. Could you repeat that question? People

9 who are not infected?
10 187 Q. Yes, sir. I’ll repeat it for you. You would agree
11 with me that people who are not infected with the
12 SARS-CoV-2 virus cannot transmit it to other
13 individuals?
14 A. Ah, generally speaking, that’s not entirely true. So,
15 for example, just off the top of my head, if somebody
16 who was infected and for example, sneezed or coughed
17 on somebody’s hand, for example, that was - and

18 delivered a high enough threshold dose that that could
19 be delivered to somebody else to get them infected,
20 that would be one potential way, right. So, whoever’s
21 the - the individual’s not infected, but they - they -
22 they could infect somebody else through, you know,
23 their hand, then touching something else that somebody
24 gets exposed to, or it could be, again, full mites
25 (ph), full mites (ph), which are like inanimate
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1 objects, haven’t proven to be a particular - like a
2 huge problem, but if somebody were to, again, you
3 know, sneeze on somebody’s mug and deliver the - the
4 virus and then somebody were to immediately take a
5 drink from that, that’s one potential - one potential
6 way. So, generally speaking, no, but there - there
7 are - in biology, there - there’s always exceptions to
8 the rule. So, I can think - I can think of multiple

9 biological scenarios, where it would be theoretically
10 possible for an uninfected person to transmit.
11 188 Q. Okay. Thank you, sir. But my - my question is aimed
12 at, if someone is not infected with the SARS-CoV-2
13 virus, and it’s not replicating within them and being
14 injected in some manner from them, they aren’t going
15 to transmit it, other than in these third-party
16 manners that you’re speaking of?

18 189 Q. Okay. And then based on your - you agree that
19 vaccination can effect transmission of the Delta
20 variant? You just say it’s not substantial?
21 A. Yes. Yes. The - again, Public Health data suggested
22 that - yeah. It was - not - not as substantial
23 effect, at best, a minor effect.
24 190 Q. Okay. We don’t....
25 A. Which is exactly the reason why we’re using multiple
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1 booster doses, and it’s also the reason why - well, of
2 course, we have the Omicron variant thrown in there as
3 well, but we’re seeing fully in vaccinated workplaces
4 and other locations, you know, COVID-19 is - has run
5 wild through these populations.
6 191 Q. Okay. We, of course, were talking about the Delta
7 variant there.
8 A. Yup. Yup.
9 192 Q. Okay. And you cite to - one document, that’s cite 6,
10 and it’s entitled, “Shedding of Infectious SARS-CoV-2
11 Despite Vaccination.” You - you recall citing that
12 document, sir?
13 A. Yes.
14 193 Q. And do you recall that study?
15 A. Ah, I - I would have to see the study again, like for
16 - in order to - if - like, so, yeah. I can confirm
17 that I cited it. I’d have to see the study again, if

18 I’m going to answer any specific questions, because,
19 again, I - I don’t have the paper memorized.
20 194 Q. No. I appreciate that, sir. I’m just looking around
21 here. Well, you should have a copy of it. I’d ask
22 you to turn to it. It is -it should be entitled,
23 “Shedding of Infectious SARS-CoV-2 Despite
24 Vaccination.PDF.”
25 A. Okay. Just give me one moment. It looks like it’s
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1 one that I printed out. Okay. Yes. I have it.
2 195 Q. Okay. And you’d agree with me that this study is just
3 looking at - well, first off, you’d agree with me that
4 this is a pre-print?
5 A. Yes.
6 196 Q. Okay. And you’d agree with me that this isn’t a study
7 about whether or not individuals can get infected with
8 the Delta variant, where they’re vaccinated, but

9 rather it’s looking at viral loads in individuals who
10 are vaccinated and unvaccinated with respect to the
11 Delta variant?
12 A. Yes. Yeah. I agree. A viral load is very important.
13 A threshold dose has to be delivered to another
14 individual, which would be able to overcome their
15 innate immunological barriers to disease.
16 197 Q. Okay.
17 A. Yes.
18 198 Q. But it’s not about whether or not someone could get
19 infected?
20 A. Ah, it didn’t directly assess infection of other
21 individuals. No. It was showing the potential for
22 infection...
23 199 Q. Okay. Great.
24 A. ...based on shedding of - of infectious viral
25 particles.
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1 200 Q. Great. And you acknowledge, of course, there’s more
2 than one study on how vaccination could impact Delta
3 transmission?
4 A. Ah, yes.
5 201 Q. Okay. I’d like to have you turn - you should have
6 this document. It’s called, “Public Health Impact of
7 COVID-19 Vaccines in the US Observational Study.”
8 A. Okay. Just give me one moment. I think I have that

9 printed. Okay. I have it.
10 202 Q. Okay. And, sir, this - you’d agree with me that this
11 is a - a study printed in the BMJ in 2022 and it has
12 cite BMJ 2022; 377: e069317. And it was published
13 April 27th, 2022.
14 A. Yes.
15 203 Q. Okay. And so, as this was published after your report
16 came out, you don’t refer to this study in your
17 report?
18 A. Ah, no. I - I’ve got a - an issue, some issues with
19 this report.
20 B.
21 204 Q. Okay.
22 A. So, for - for example, like many of the things dealing
23 with - a lot of - again, so, what’s important to note
24 is these authors are primarily experts in
25 epidemiology/public health. And again, so, they don’t
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1 have the - the in-depth training in immunology and
2 virology and - and therefore, and this is what I find
3 with a lot of studies done be - being performed by the
4 epidemiologists and public health experts is that they
5 - they’re largely lacking in both comprehensive and
6 transparent data. First - first of all, I point out,
7 if you look at the title, this is an observational
8 study. So, that’s what we call level three evidence.

9 So, it’s generally, you know, it’s not the best
10 scientific evidence available. And there - there’s a
11 couple of key things that are problematic here. So, I
12 - I have a - I have a problem with a lot of the
13 epidemiological studies, if I’m to be perfectly honest
14 with you, in that they - they don’t account for
15 natural acquired immunity. And, again, this is very,
16 very important, ’cause we’re talking about the impact
17 of vaccination and we’re talking about transmission of

18 - of disease, and yet, they - they don’t count at all
19 for pre-existing immunity. It’s really quite
20 incredible. Because as I’ve said, there’s tw - they
21 have a goal, the goal in preventing transmission and
22 the goal of vaccination is to confer immunity, and
23 yet, there’s not assessment of immunological status.
24 And so, by that, I mean, I - I already mentioned this,
25 serological testing should be done. Um, what we’re -
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1 what these groups are doing is they’re dividing the
2 vaccinated groups down, and - and these finely defined
3 groups, where there will be, you know, one dose, or
4 two doses, or booster doses, they even define how long
5 after receipt, before they’re categorized as such, you
6 know, after receipt of - of the - the [quote]
7 “vaccine,” um, but there’s no subdividing the - when
8 it comes to [quote] “unvaccinated.” Unvaccinated does

9 not mean, not immune, right? And - and it’s crazy in
10 these studies. You have to iden - since the goal is
11 immunity, you have to identify the immunological
12 status. I’ll also point out, even when it comes to -
13 to vaccinating an individual, vaccination does not
14 equal immunity. It doesn’t eq - it certainly - it
15 doesn’t even equal induction of an immune response.
16 And this is important, because when you’re dealing
17 with an outbred population, like people, the response

18 to a vaccine follows a normal curve, a bell-shaped
19 curve. And what that means is, the majority of people
20 will respond moderately well to a vaccine, you’ll have
21 relatively few on the - the one tail, that will be -
22 what - or what we call the high responders, and
23 they’ll respond quite robustly to a vaccine. But
24 importantly, on the other end, are the - are - is the
25 minor subset of the population that we call the low-
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1 responders, or non-responders, where they don’t
2 respond at all. Um, and this isn’t being accounted
3 for, like, from an immunological perspective, this is
4 an egregious mission. We have to know the
5 immunological status, even of the vaccinated, because
6 there - there are - there are people who all have
7 received a COVID-19 inoculation, who are not even -
8 who have not even mounted an immune response, where

9 they have been - they - they’re either a non-
10 responder, or there was some mistake. We - there’s
11 examples during this declared pandemic of people
12 having received saline accidently instead of the - the
13 vaccine, for example. That would be a technical
14 reason for them not mounting an immune response. And
15 again, the whole purpose is immunity, not
16 certification of having received a jab, and so,
17 immunity has to be properly assessed, both on those

18 who did receive the jab, and those who didn’t. So,
19 that’s a major - a couple major things. And the other
20 one, if you go to the limitations of the study, on
21 page 5, you’ll see that given the limited numbers of
22 variables, that were known to effect mortality and
23 incidents, this is under limitations of study, it says
24 here, “We did not control for masking physical
25 distancing,” but this is the thing, “...are other
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1 potential confounding variables in this study.”
2 Right. “And as a result, we cannot rule out the
3 possibility of temporal confounding,” which I agree,
4 which means overtime, time. And the time it was
5 somebody could be transmitting. And, for example,
6 this - so, this is a key one for me. And see, this is
7 - this is what I - this is the given example of what I
8 meant by a lack of transparency in the data, presented

9 in a lot of these papers, right. So, cor -
10 comorbidities were not available. It’s incredible how
11 many public health agencies, or public health
12 databases are not recording key things. We - we’ve
13 known about the - the key risk factors from very, very
14 early on in this declared pandemic. And yet, we still
15 aren’t recording them. It - it’s crazy. So, you see
16 this demographics comorbidities were not available.
17 The number one risk factor for getting - ’cause we’re

18 - ’cause what the purpose of these kind of papers is
19 try and show that the vaccine somehow might dampen,
20 they don’t function - they don’t confer immunity,
21 anywhere close to, you know, sterilizing or near
22 sterilizing immunity, we already discussed that, but
23 there’s papers are often trying to argue that they can
24 protect against severe disease. Well, the number one
25 risk factor for severe COVID-19 are comorbidities,
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1 including things like, obesity is probably one of the
2 major ones, but there’s many other, many other
3 illnesses. In fact, the vast majority of the people
4 who have died from COVID-19 in Canada have had
5 multiple comorbidities. Um, so, to exclude
6 comorbidities from the analysis, is - is not
7 acceptable. We can’t properly interpret this because
8 comorbidities are the number one correlate for severe

9 disease, not vaccination. And, for example, um, if -
10 if somebody had - to - to - like to exclude that, you
11 also have to keep in mind, people who have a lot of
12 comorbidities, also often can’t be vaccinated. So,
13 yet, they’re the ones that are greatest risk of being
14 in - infected potentially and suffering severe
15 disease, or potentially even fatal disease. So, as an
16 example of that, we - we don’t actually have the
17 information available in Canada, but many countries

18 have indicated, for example, that terminally ill
19 patients are not receiving these COVID-19
20 inoculations. One of the key reasons is, um, and -
21 and - and – and they don’t even have to be terminally
22 ill, a lot of frail elderly are not receiving these
23 vaccines, because they’re what we call “highly
24 reactogenic.” These lipid nanoparticles that are
25 used, especially in the mRNA vaccines, which are the
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1 ones that have primarily been used in the frail
2 elderly, cause a lot of inflammation and a highly
3 reactive genetic medical product in a frail elderly
4 person, or somebody who is already destined to die
5 because of some medical condition, can put them over
6 the top. So, in many cases, they’re not even
7 administered. And – and yet, that isn’t encountered
8 for in this. So, I – I would say, as soon as I see

9 that comorbidities aren’t included as a – as a
10 variable, the data becomes very difficult to
11 interpret. So, I mean I’ll just leave it at that, but
12 there’s an example of multiple things with this study
13 that, you know, so, yes, I acknowledge the study and
14 that it’s here, but I – I’ve got some major issues
15 with it as a – as a person who’s qualified to review
16 this. And I should just point out for the Court,
17 because then the question might become, “Well, what –

18 what is my opinion matter?” So, just to point out, I
19 – I – I’m a professional reviewer, as part of my job
20 as a – as an academic faculty member, and I – I’ve
21 actually been – it’s considered to be very prestigious
22 to be invited to be a member of the Canadian
23 Institutes of Health Research, CHR, that’s our
24 federally-funded medical research granting agency, and
25 I – I’ve been invited and accepted as a member of
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1 their College of Reviewers, and I have been invited, I
2 was asked to serve a three-year term on their grant
3 review panel for virology and viral pathogenesis, as
4 well as cancer biology and therapeutics. I’ve also
5 received only the top ten per cent of reviewers in any
6 competition, grant competition, received citations,
7 and I’ve received a citation, uh, three citations now
8 for being one of the top – in the top ten per cent of
9 reviewers. So, I know what I’m do – so, in other
10 words, I know what I’m talking about when I look at
11 these articles and I have some major issues with this
12 particular paper.
13 205 Q. Thank you, sir. Um, do you remember what my question
14 was?
15 A. Um, yup. Yup. About this paper and about the – the
16 messaging here.
17 206 Q. No. What I asked you is, you don’t refer to this
18 study in your report. Um....
19 A. Well, yeah. And I’m explaining why.
20 207 Q. Okay.
21 A. As a scientist, I – I – I’m always – as a scientist,
22 what you have to understand, I – I – I’m not following
23 the duty of a scientist, if I do not provide a
24 rational for my answer. So, yes, I do not include it
25 and I’ve just given multiple reasons why.
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1 208 Q. Sure. I had only asked if you’d included it or not,
2 but anyways, I’m going to say that you appeared to
3 have answered my – my second question, but you can
4 clarify whether this is the case. I was going to ask
5 you, have you had an opportunity to review this study?
6 And it sounds like you did.
7 A. Yes. I did have an opportunity to review this one.
8 209 Q. When did you do that?

9 A. I can’t remember the exact date, but it was this
10 weekend. So, again, while – while we’re on record,
11 I’d like to point out as well, because there was some
12 questions about the number of documents, so, I – I
13 received 80, 80 files to review. I’ll point out that
14 I received – I was originally scheduled to be cross-
15 examined, I can’t remember the exact date, but about a
16 couple weeks ago, and received two of the critical,
17 um, affidavits, just a couple working days before.

18 Also, spanning then a weekend, in which I was expected
19 to review that. And then, yeah, I was given official
20 permission – I honour – I honoured the court process,
21 and I did that, open any files. I received permission
22 late on Friday night of the Long Weekend. And so –
23 so, yeah, I do just want to point out to the Court,
24 that I have reviewed some of these documents, so, that
25 we can make the best use of today. Um, but I’ve had
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1 to – it’s costing me a lot of family time and I’ve got
2 a couple of – of children. Um, so – so, I just want
3 that made known, the grand total are 80 documents.
4 And I received 25, precisely 25 this morning, and was
5 still trying to get them into subfolders. As I
6 mentioned, the file sizes were so long, it went over
7 the character limit, when I tried to put them all into
8 the same subfolder. Um, so, I can’t give you the

9 exact answer, but it was sometime this weekend, that I
10 – that I looked at this particular paper.
11 210 Q. I just wasn’t sure if it was a while ago, or not. I
12 want to move on, sir. Um, so, just to continue on
13 something you – you mentioned, you take issue with –
14 you said epidemiologists and their approach, lacking
15 an understanding of virology, I think. It was a while
16 ago. Could you remind me of what you specifically
17 said? Just – and I mean you can answer how you’re

18 gonna answer, but if you just make it quick, I’ll be
19 able to get to my next question.
20 A. Yeah. Vir – vir – virological and immunological
21 principals, the – the mechanisms underlying the
22 disease and disease severity. And so, again, those
23 have to be accounted for when looking at these
24 studies. They can’t be oversimplified, right. They
25 have to be overlayed on the – the biological,
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1 mechanistic complexity.
2 211 Q. Yeah. And you said epidemiologists don’t do that?
3 A. Well, not – not altogether. No. I’m not going to say
4 that, I mean there’s epidemiologists who hold advanced
5 training in virology and immunology. Um, this is a
6 problem – so, I’ll clarify. This is a problem that I
7 have with this particular paper. No. Epidemiologists
8 do great work and great studies, and can. But in this

9 particular one, they – what I’m pointing out is that
10 these epidemiologists, again, I don’t see any evidence
11 from their qualifications that they are experts in
12 virology and/or immunology. And that’s why it’s very
13 important that – that the expertise, when dealing with
14 these problems, we have to have experts, and there
15 might not be an ind – it doesn’t have to be an
16 individual expert, it can be a team, and this is a
17 collection of – of scientists here. But there has to

18 be generally speaking, expertise when putting together
19 a paper like this, that spans virology, deep expertise
20 in virology, deep expertise in immunology, as well as
21 the epidemiology and public health. If – if you
22 exclude the virology and immunology, the – these
23 papers tend to become too shallow to be able to
24 interpret properly.
25 212 Q. Okay. And so, they need that deep experience, that
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1 training, to be able to produce a product on these
2 subject matters, that’s of value, is what you’re
3 saying?
4 A. Generally speaking, yes. And some of the epidemiology
5 papers can achieve that, for sure. This one, I can
6 only comment specifically on this one. I can’t
7 comment specifically on any others.
8 213 Q. Yeah. And that’s because you haven’t seen any

9 indication they have that – that training you’re
10 talking about...
11 A. Yes.
12 214 Q. ...on this paper?
13 A. Yeah. At the end of the day, it doesn’t even really
14 matter, what – what it is, I – this paper, I’ve got
15 the – I’ve pointed out the specific problems that I
16 have with this paper. At the end of the day, it’s –
17 it’s really irrelevant who the authors are, or what

18 their expertise is, I mean, I’m assessing the science
19 that’s presented to me in this paper.
20 215 Q. Okay. In any case....
21 A. And I – and I find it lacking.
22 216 Q. Okay. And that’s because epidemiologists, just by
23 virtue of their role, don’t have some sort of cross-
24 over knowledge with, let’s say, viral immunology that
25 they could rely on to give this sort of opinion. Is
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1 that – is that your position?
2 A. No. No. They also like with the Venn diagram, would
3 have to have overlap in order to understand
4 epidemiology and public health, they’d have to have
5 some – some knowledge of vaccines and virology.
6 217 Q. Okay. Well, I want to just turn to the discussion
7 section of the paper, in the first paragraph of it.
8 A. Okay.
9 218 Q. Okay. And you agree that the authors write, “Using
10 data from 2,558 counties, representing nearly 300
11 million people in 80 per cent of the US population, we
12 found that increasing the vaccination coverage in
13 counties, was associated with the reduced incident of
14 COVID-19 related mortality and cases. We observed
15 decrease in transmit and mortality and case incident
16 associated with higher levels of vaccination coverage,
17 across the areas of both Alpha and Delta variant

18 predominance. This effect was robust to various sens
19 – sensitivity analysis, which improves prediction and
20 confidence in these findings.”
21 A. Ah, yes. I see that. Can I – can I make two
22 comments?
23 219 Q. I mean, sir, it’s your answer.
24 A. Okay. So, uh, as I already pointed out, they didn’t
25 account for – and they admitted it, limitations of the
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1 study, that they didn’t account for a number of
2 potential confounding variables. And as I’ve pointed
3 out, one would be comorbidities. So, for example, in
4 the - what they’re calling the....
5 220 Q. Sir, you did answer this earlier. Did you want to
6 answer that? I can ask the next question, or you can
7 continue. I leave it to you.
8 A. Yeah. Thanks. I’ll continue. And so, they didn’t

9 account for that. So, for example, if there were more
10 in the [quotes] “unvaccinated” population, if there
11 were more comorbidities, for example, that could
12 explain the difference. And again, they didn’t look
13 at – to compare, again, to compare vaccinated versus
14 unvaccinated, makes no sense. One needs to compare
15 immune versus non-immune. And specifically what one
16 needs to compare is those who have mounted an immune
17 response due to vaccination versus those who have

18 mounted immune response due to natural infection
19 versus those who have no evidence of an immune
20 response, whatsoever, against SARS Coronavirus 2.
21 That’s the proper kind of analysis. And the final
22 thing that I want to say here, is you note at the end
23 of the first sentence, they use that term, “cases.”
24 So, this is a common problem with the public health
25 data that is being, you know, published with, and it’s
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1 certainly in Canada on the public health databases,
2 which is our provincial and federal government
3 databases, when it comes to public health. Is this
4 idea of cases, I – I – I need to take a moment here.
5 Because it’s very important to the case, that the
6 Court understands, because cases has a – again, a very
7 specific meaning. We’re talking about cases of COVID-
8 19. And so, I want to clarify because there’s a lot

9 of misunderstanding right now about what – what a case
10 means. So, first of all, when we’re talking about
11 cases, there’s no delineation of the severity, right.
12 Whether it’s mild, moderate, severe, sever non-lethal,
13 or sever and lethal. Um, but more importantly, when
14 we’re talking about cases, it’s assumed, we’re talking
15 about cases of COVID-19. But the data that are being
16 generated in these public health databases, that are
17 being used, such as the one used from these 2,558

18 counties, they often are not cases – they are not
19 confirmed cases of COVID-19, and the vast majority of
20 the scenarios, they are positive test results, by
21 using the RT PCR tests. And this – this is very
22 nuance. So, when the pandemic was declared in Canada,
23 we did absolutely the right thing. We went to the
24 National Microbiology Laboratory of Canada in Winnipeg
25 and they ran a study to identify where the cut-off
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1 should be for the PCR test in Canada. And what I mean
2 by that is we’ve been using the R – so, the RT PCR
3 test, it’s a very exquisite, very elegant scientific
4 method, but it has to be used appropriately and
5 contextually. And we haven’t been doing that. We
6 have been using it as a gold standard test, without
7 being properly calibrated. This test must be
8 calibrated. It must be properly calibrated to be able

9 to provide reliable data. And what I mean by that is
10 you have to use the gold standard virology assay, a
11 functional assay, that actually tells you whether a
12 PCR result is indicative of replication competent
13 viral particles or not, because the only infectious
14 bioparticles are those that are replication competent.
15 And simply having genetic material, from the virus,
16 doesn’t mean that somebody is potentially infectious
17 and can transmit the virus. I mean our – the cells in

18 our immune system will hold onto this virus and pieces
19 of virus for weeks, even months. There’s been
20 evidence of macrophages, a type of white blood cell,
21 holding onto the virus or components thereof, or – or
22 the message mRNA from the vaccines for – for months.
23 So, it’s all about whether it’s indicative of the
24 potential to transmit. And so, what you do is - what
25 would always be done, is you would run – you take a
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1 sample, these nasopharyngeal swabs that we’re all
2 familiar with. You would take that from people and
3 you would split the sample in two. Instead, we’re
4 just doing – you know, have it split one way and it
5 goes for the PCR test. You split it in two. Half the
6 sample – with half the sample, you’d run the PCR test
7 and with the other half the sample, you would run the
8 gold standard virology assay, which is the – where you

9 apply the sample to cells in a culture dish, that are
10 stripped of all their antiviral mechanisms, such that
11 if there is any replication competent viral particles
12 present, they will infect the cells, replicate, and
13 cause what we call cytopathic effect. They’ll kill
14 the cells. So, you simply look under a microscope
15 before adding the sample, you see all the healthy
16 cells, and then you add the sample. If there’s
17 replication competent viral particles, they’ll infect

18 the cells and kill them. So, then you look under the
19 microscope and if you see a whole bunch of – of dead
20 cells now, you know that there were replication
21 competent viral particles. And what the National
22 Microbiology Laboratory of Canada found was that –
23 they found – and what this PCR test is, it’s an
24 iterative test, where you run a number of cycles, and
25 each time you amplify the amount of genetic material
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1 that you’re trying to target. In this case, it would
2 be pieces of the genetic material from SARS
3 Coronavirus 2. And so, you determine cycle, the cycle
4 threshold is what it’s called. The number of cycles
5 at which you get a positive result, where you get a
6 piece of DNA that you can – that you can visualize.
7 That’s a positive result. And what they found is if
8 they get positive results at the cut-offs above 24

9 cycles, they had no evidence of replication competent
10 viral particles in the gold standard virology assay.
11 So, the proper thing to do, at that point, so, if the
12 National Microbiology Laboratory were running our PCR
13 tests, they would say, “Okay. Any sample that tests
14 at a cycle threshold above 24 is deemed negative. We
15 have no evidence that there’s replication competent
16 viral particles in those samples.” Anything that
17 tests positive that a threshold of 24 or lower, we’re

18 going to call positive. Now, this – now, so, this
19 allows you then to understand cases. In Ontario, for
20 example, without doing this calibration, we have been
21 putting – we have set the cut-off, Public Health
22 Ontario have set the cut-off at 38 cycles. Now, when
23 you compare that to the National Microbiology
24 Laboratory at 24, that means that we have been
25 defining a substantial, but unknown, we don’t know the
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1 number because we can’t see the cycle numbers, and
2 they....
3 221 Q. Dr. Bridle, I had asked you about the paper.
4 A. Yes. And I have to get through this. This is
5 extremely important.
6 222 Q. Well, I’m – I’m...
7 A. This is dealing with cases.
8 223 Q. ...not clear how it responds to the question and....

9 A. You’re going to see, but I have to define cases. You
10 – you’ve asked me to comment on a sentence, in which
11 you read, “cases,” and we have to be able to
12 understand what I mean by “case,” because you’re going
13 to see that what – what I define as a case, and what
14 others have defined as cases in the database here, are
15 two completely different things.
16 224 Q. Okay.
17 A. And that is why I come to a completely different

18 conclusion.
19 225 Q. And this is in your experience, as a virologist, that
20 you have this [inaudible] cases?
21 A. Well, yeah. As a virologist, immunologist, I use PCR,
22 RT PCR testing all the time in my laboratory. Yes. I
23 – I understand...
24 226 Q. Yeah. And as...
25 A. ...it.
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1 227 Q. ...from your experience in public health then, as
2 well?
3 A. Par – pardon me? We’re talking about the RT PCR test,
4 at the moment.
5 228 Q. Well, you’re describing to me about how cases are
6 counted, sir. I’m just trying to understand are you
7 saying that this – your – your views on case comes
8 from your experience as a public health expert?

9 A. It comes from my expertise as a virologist,
10 immunologist, cancer biologist, and my overlap in the
11 areas with public health. I – I – I understand the
12 cases, how cases define for cancer, a case of cancer,
13 case of an infectious disease, a case of all kinds of
14 immunological diseases.
15 229 Q. Okay. And so....
16 A. Can – can I – could I please finish answering?
17 Because this is absolutely – okay. I’m going to

18 explain it this way.
19 230 Q. This wasn’t in your aff – your Export Reports, or so,
20 it seems like it’s...
21 A. You’ve asked me...
22 231 Q. ...going beyond the scope of...
23 A. ...a question.
24 232 Q. ...the question.
25 MR. WILSON: Gentlemen, gentlemen. Let’s just slow this
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1 down. Firstly, the reason that this has come up, it’s
2 my understanding that this is an aide to cross. Is
3 that correct, Counsel?
4 MR. ELFORD: It is, sir.
5 MR. WILSON: All right.
6 MR. ELFORD: And I asked him a question about it...
7 MR. WILSON: Right.
8 MR. ELFORD: ...and now I’m finding out his theory on

9 cases, which I don’t recall seeing...
10 MR. WILSON: And....
11 MR. ELFORD: ...his Export Report, if I understand.
12 MR. WILSON: You....
13 MR. ELFORD: It comes from his expertise as a public
14 health, uh, uh, a person with expertise in public
15 health now.
16 MR. WILSON: It’s the action of the Attorney General in
17 presenting this report as an aide to cross, that

18 purportedly makes it relevant. And I believe you were
19 asking whether he had relied on it and – and his views
20 about the report, and now he’s answering. But we need
21 to all remember, that these are incredibly complex
22 matters. And, as lawyers, we might like little simple
23 answers to things, but this is a complex, multi-
24 disciplinary topic, and I think you’ve raised the
25 question. You’re obviously seeking to use the report
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1 to someway to try and impeach this witness. I think
2 he’s entitled to give a full answer.
3 MR. ELFORD: Well, sir, I actually only asked him if he
4 agreed as to the content. This is his desire to speak
5 about this issue, that wasn’t in his report, but I –
6 and I – frankly, I’ve been trying to give your – your
7 witness here, as much leeway as I can, to speak about
8 issues that he feels are related to the question. But

9 I’m really lost as to how these issues about PCR
10 testing are now related to what we’ve been discussing.
11 So....
12 MR. WILSON: Well, I can help you with that.
13 MR. ELFORD: I’m willing to give some more leeway to a
14 certain point. Well....
15 MR. WILSON: The – the issue is you’re wanting to rely on
16 the data in this report to reach some certain
17 conclusion or advanced proposition, and what Dr.

18 Bridle’s doing is explaining what the data says, and
19 he’s saying to you, “In order to understand that, you
20 have to understand what they’re using as a case.” And
21 the case has two elements, as you’ve heard from other
22 witnesses, it has a positive test result, and a
23 clinical evaluation, and what Dr. Bridle’s explaining
24 is, let’s stop and pause on the positive test result,
25 and say, okay, well what is a positive test, and what
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1 did this study conclude as a positive test? And what
2 does he believe is a legitimate positive test? So,
3 it’s...
4 MR. ELFORD: Well, the difficulty....
5 MR. WILSON: ...highly relevant.
6 MR. ELFORD: The difficulty I have is he’s not
7 referencing how they – how the authors of this study
8 consider a positive test, we’re talking about Ontario.

9 This took place in the United States. I’m – I’m not –
10 I appreciate what you’re saying, but I’m not following
11 as to how all this goes to the specific use of the
12 word, “case,” in this specific article, which is the
13 aide to cross. So, I’m – I’m just trying to follow
14 that.
15 MR. WILSON: I – I’m – I’m – I think it’s proper to let
16 the Doctor finish his answer and I think it will
17 become clear to all of us.

18 MR. ELFORD: Well, I certainly hope so. Thank you very
19 much, sir.
21
23
24 DR. BRIDLE: Okay. Thank you. Can you clarify or do I –
25 do I need to start over, or is it on the record?
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1 233 Q. No. Continue with your answer about tests.
2 A. Okay. I’ll try. The interruption to that line of
3 thought is a bit frustrating, but I’ll continue. So,
4 with respect to the Ontario data, that – that’s –
5 that’s using an – an example. I’m talking about –
6 about it here, but because we’re more familiar with
7 the Canadian situation. That’s why I’m using the
8 example, but the same thing implies here. So, cases,

9 so, where was I?
10
11 So, as I was mentioning, um, so, the National
12 Microbiology Laboratory, if they were doing the
13 testing, they would say that a PCR test above a
14 threshold of 24 would be negative, yet, we and – and
15 in the United States, this is data from the CDC,
16 they’ve been using the same thing, approximately 38
17 cycles, in fact, in some places in the United States,

18 they’ve gone to a size 45 cycles with some of their
19 test labs, and what’s important to note is every test
20 lab should be doing this calibration, using this gold
21 standard virology assay to be able to show why they’ve
22 determined their positive and negative cut-off.
23
24 And so, the point is, when one sets the cut-off at 35
25 instead of 38, or 40, or 45, whatever the lab is using
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1 in the United States, but they’re very high, the
2 standard that was set was 38, that means that you have
3 a huge number of positive tests that are almost
4 certainly not indicative of somebody having
5 replication competent viral particles that could
6 potentially be passed onto somebody else. And my
7 point is, is that indeed, so this is – so therefore,
8 this is my definition of a case. A case of COVID-19,

9 because COVID-19 is the disease, right, so, it’s not –
10 so, it’s actually a disease, so, there has to be signs
11 and symptoms in order for it to be defined as a
12 disease. So, one needs a positive PCR test result,
13 but a result that is positive, using a PCR test that
14 has been appropriately calibrated, such as a
15 laboratory can show the gold standard assay that
16 proves why they off-set that cut-off that they’re
17 using, and it has to be married to a clinical

18 diagnosis. There has to be a clinical expert who
19 defines that a disease is present. If there’s signs
20 and/or symptoms that are conducive with a diagnosis of
21 COVID-19, both have to be present. And what I want to
22 point out is that in this database, the vast majority
23 of the data is simply based on positive PCR tests.
24 And so, there’s going to be a lot of false positives.
25 And unknown amount of false positives, but in – in
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1 papers that I’ve looked at, if you adjust that cut-
2 off, guess what, you lose sometimes the majority of
3 the positive cases. And these cases, many of them are
4 not linked to assessments having been made by a – a
5 clinician. And so, that is – so, now, we get down to
6 this, because that’s the whole point is, they’re
7 talking about cases. It’s all based on – all – all of
8 these data are based on the case numbers. And as you

9 can see, I have a huge problem with simply defining
10 cases as somebody having a positive PCR test result.
11 I’m sorry. That does not – that does not prove COVID-
12 19, the presence of COVID-19, the disease in the
13 individual.
14 234 Q. Okay. So then, for clarity, unless a – any study then
15 that uses the term, “cases,” that does not have the
16 standard that you set-out underlying it, in terms of
17 it’s – the case count it uses, than you’re saying is

18 unreliable?
19 A. Yeah. I would – yes. Yes. The vast majority of our
20 public health data, when it comes to cases are
21 unreliable. I agree. Yes.
22 MR. ELFORD: Okay. Thank you. I’d like to mark this
23 document as an exhibit. Now, Madam Court Reporter,
24 you have “Public Health Impact of COVID-19 Vaccines in
25 the United States Observational Study?”
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1 COURT REPORTER: Do you want to do that as Exhibit 2?
2 MR. ELFORD: Yes, please.
5 EXHIBIT 2: Public Health Impact of COVID-19 Vaccines in
6 the United States Observational Study, BMJ2022;
7 37e069317
8
9 235 MR. ELFORD: And – oh, one thing here. Hold on. Well,
10 you’re familiar with the study, since you read it.
11 Now, do you recall if the study uses the same
12 definition for positive case for all groups? So,
13 vaccinated, partially vaccinated, unvaccinated?
14 A. In terms of cases of COVID-19? Yes.
15 236 Q. Okay. And so, you’d agree the study then uses the
16 same definition for a case of all the groups?
17 A. Well, uh, actually, let me just look at the methods

18 here.
19 237 Q. Take your time.
20 A. So, actually, no. I can’t state that definitively.
21 It just says that they included – we use the CDC’s
22 managed case surveillance data set. Uh, uh, okay.
23 What I can comment on, so, I can’t comment on that
24 data set, ’cause I haven’t seen that data set and I
25 don’t – so, therefore, I don’t know what – what
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1 proportion of the data set used in – improperly
2 calibrated PCR tests, and I don’t know what proportion
3 we’re associated with a proper clinical diagnosis.
4 Um, but what I can say here is they – to document new
5 cases, jurisdictions may use the date that a case was
6 reported to the health department, a person took a
7 COVID-19 test, a laboratory confirmed a COVID-19 test
8 as positive, or a person was diagnosed as having

9 COVID-19 by a clinician, but then that doesn’t
10 indicate whether or not that was in conjunction with a
11 COVID-19 test, but what it does specifically say then
12 is there’s two groups in which it could be a self-
13 administered COVID-19 test, or a laboratory confirmed
14 COVID-19 test, as positive. So, what – what – what
15 this is telling me and it actually causes me even more
16 concern, because it seems like there were multiple
17 categories of ways of defining people as COVID

18 positive and like I said, one could even be diagnosed
19 as by a clinician, which doesn’t suggest that it also
20 had to have a positive test result. I would – I would
21 assume it does, but it certainly indicates that it’s –
22 so, see this – so see this exactly highlights the
23 problem. I would assume that if a clinician has
24 diagnosed the person as having COVID-19, I would tend
25 to accept that better, if it’s been a COVID-19
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1 positive test result, that goes along with the
2 diagnosis, that was properly calibrated. Then I would
3 take that, but you see, they’re accepting even self-
4 administered tests, if they have a positive test, then
5 they had COVID-19. I mean a person self-administering
6 a test and then – and then declaring that person as,
7 you know, we confirm they have COVID-19, I can’t – I
8 can’t emphasize enough, COVID-19 is a disease. A

9 positive test result on its own is an aide to
10 diagnosis, and no more than an aide to diagnosis. So,
11 no, in fact, what I can confirm now, looking at the
12 materials and methods is they – they – they didn’t
13 have a consistent definition across the population
14 they studied here. And they had completely
15 inappropriate definitions of what a case of COVID-19
16 is.
17 238 Q. Okay. Now, I’d like to move onto paragraph 12 and

18 Figure 6. Just let me know when you’re there, please.
19 A. Okay.
20 MR. WILSON: Counsel, are you referring to his report?
21 Or the....
22 MR. ELFORD: I’m referring – I’m referring to his Export
23 Report. My apologies.
24 MR. WILSON: Okay. So, that would be....
25 MR. ELFORD: Dr. Bridle, I’m referring to your Export
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1 Report.
2 A. Oh, okay. So, that’s – so....
3 239 Q. Yes. My apologies to you.
4 A. ’’cause at paragraph 6, it starts to read, “April
5 1....”
6 240 Q. Paragraph 12, Figure 6.
7 A. Or paragraph 12.
8 241 Q. Paragraph 12, Figure 6.

9 A. Okay. I’ve got the right document here. Uh, okay.
10 Yes. Data from Alberta Public Health?
11 242 Q. Uh-hmm.
12 A. Yes. I’m there. I’m there.
13 243 Q. Okay. And you’d agree that this information includes
14 statistics that are only lab-confirmed cases of infection
15 with SARS COVID 2?
16 A. Okay. Sorry. Could you – what – what – what do you
17 mean by “lab confirmed?”

18 244 Q. Ah, PCR testing.
19 A. Ah, okay. So, these – these data go back to March of
20 2001. So, again, this – my – my answer is more
21 complicated than just PCR. This presumably the
22 majority of these cases was based on just a PCR,
23 positive PCR test result. Yes. Um, some of them, an
24 unknown proportion because it’s not disclosed, would
25 have been accompanied with a clinical diagnosis by a
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1 physician. But again, that’s based on signs and
2 symptoms and I wouldn’t accept that as a proof of a
3 positive case, unless the PCR test was positive,
4 using, again, an appropriate calibrated version of the
5 PCR test. But the other thing to keep in mind,
6 especially historically, beginning of this declared
7 pandemic, some of the cases that were identified, were
8 based purely on observations of symptoms and/or signs

9 that – that – that were – were conducive to a
10 diagnosis of COVID-19. There wasn’t even any
11 laboratory testing involved. So, we know that at the
12 beginning, when we were trying to get all – all –
13 everything in order, and trying to get proper testing
14 up and running. So, in other words, the cases that
15 represented historically on these curves, represent a
16 mixture of – of different definitions of a case, but
17 yes, the vast majority would be based on PCR

18 positivity.
19 245 Q. Okay. And you’re aware that Alberta changed its
20 recommendations regarding who should get PCR testing
21 on December 23rd, 2021, correct?
22 A. The - um, I – I’m aware that they made a change. Yes.
23 I – I’m not sure what the exact change was.
24 246 Q. Okay. And you didn’t look up what the exact change
25 was when you prepared the paragraph 12, did you?
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1 A. No. I wasn’t aware of the change at that time. I
2 just became aware of the change recently.
3 247 Q. Okay. And so, you’d agree that they restricted the
4 access to PCR testing around Jan – excuse me – around
5 December 23rd and – and – and so on.
6 A. Ah, again, I’m not familiar with the specifics for
7 Alberta because I live in Ontario, but I’m – I’m – I
8 know that in Ontario there was some slowdown in

9 testing around the Christmas period, but I don’t know
10 the details in Alberta.
11 248 Q. All right. So, if I told you that then, you couldn’t
12 disagree that that’s what occurred?
13 A. I couldn’t disagree.
14 249 Q. Okay. There is a document that you were sent called,
15 “Alberta Changes, COVID-19 Testing Criteria
16 Notification, Policies in Mid-Surging Cases,” screen
17 capture May 20th, 2022. If you wouldn’t mind going to

18 that.
19 A. Okay. Yeah. It’s – so, this was something I received
20 this morning. So, I haven’t looked at this yet.
21 Okay. See, it’s...
22 250 Q. Please take your time reading it, sir.
23 A. ...it appears to be a Glo – Global News article.
24 251 Q. Yeah. Take your time reading it, please.
25 A. Okay. I finished reading it.
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1 252 Q. Okay. So, you’d agree with me that there’s at least
2 some indication that there was a change?
3 A. Yes. Yeah. They were overwhelmed with the testing
4 because the vaccines were clearly doing a poor job of
5 controlling Omicron.
6 253 Q. Okay.
7 A. Yeah.
8 254 Q. Well, I want to move onto another question because I’m

9 realizing the time here. So, I apologize. I’ve had a
10 lot of questions for you and you’ve been patient
11 answering them in – in fulsome manner, but I want to
12 move onto some public statistics. And I know you have
13 your issue with them, and you can let me know what
14 they are.
15 A. Okay.
16 255 Q. I am just going to locate here. Okay. So, if you
17 could open up the document, “Alberta.ca_Stats_COVID-19

18 Alberta Statistics_Vaccine Outcome Screenshot on May
19 20th, 2022.PDF.” And let me know when you have that.
20 A. Okay. So, again, this is a document that I haven’t
21 seen yet. It was just sent this morning, but I have
22 it open now.
23 256 Q. Yeah. Great. Take a look at it, please. Just let me
24 know when you’re done, please.
25 A. Okay. I – I’ve glanced through everything. There’s a
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1 lot of data here. Yes. Was there something specific
2 you wanted me to look at in more detail?
3 257 Q. Yeah. We’ll get to it. So, at paragraph 15 – or 13,
4 excuse me, so, one, three, please go to that in your
5 Expert Report.
6 A. Okay. Yes.
7 258 Q. You talk a little bit about the data from Alberta and,
8 sir, I’m going to share my screen with you.

9 A. Okay.
10 259 Q. Okay. So, you can see that. And if you take a look
11 at the top here. This appears to be an Alberta
12 government website, www.Alberta.ca/stats/covid-19-
13 alberta-statistics.htm - html - or sorry – htm –
14 excuse me – [number sign] vaccine – outcomes.
15 A. Yes.
16 260 Q. And does the document you have appear to be a copy of
17 this document?
18 A. Yes, it does.
19 261 Q. Yeah. And I’ll take you to where it says, “COVID-19
20 data included in the interactive data – data
21 application rather, up-to-date as of end of day May
22 16th, 2022, unless stated otherwise.”
23 A. Ah, let me check.
24 262 Q. Take your time, sir.
25 A. Yes, that’s what it says.
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1 263 Q. Okay. And so, you’d agree with me that what you have
2 been provided appears to be a copy of this webpage?
3 A. Yes.
4 264 Q. Okay. And you’re comfortable with that then?
5 A. Yes.
6 265 Q. Okay. So, lets go down to some of the data on this.
7 And I’d like to start with total hospitalizations,
8 please.
9 A. Okay.
10 266 Q. And if you’ll notice across the top, it has three
11 doses, hospitalized, three doses, hospitalized, rate
12 per 1K. Two doses, hospitalized, and then two doses
13 hospitalized, rate per 1K. Unvaccinated and
14 hospitalized and then unvaccinated and hospitalized
15 per 100K. And that’s across the top and then it’s
16 broken down on the left-hand side by years. Do you
17 see that, sir?

18 A. Yes.
19 267 Q. And would you agree with me that looking at the rate
20 per 100K that unvaccinated and hospitalized is higher
21 than with two doses and hospitalized and three doses
22 and hospitalized, across all age groups?
23 A. Ah, I would agree that’s what this graph is showing.
24 I don’t – I don’t agree with these data. These data
25 are highly inaccurate. And I’ll explain why. So –
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1 so, first of all, I don’t know how they’ve been
2 manipulated, because if you go up to the table above,
3 go up to that again for a moment, Table 1. You’ll see
4 that the per cent hospitalized unvaccinated is only 19
5 per cent. So, and my understanding is that that’s
6 fairly close to the number that the proportion that
7 are unvaccinated in the province, although I can’t
8 confirm it, but in all the provinces, it’s somewhere

9 around 80, or low 80 per cent, you know, 81, 82,
10 somewhere around there. Um, but more so than that, if
11 you go back down for a moment.
12 268 Q. Yes, sir. Right here?
13 A. Yeah. So, yeah. I’ve got several major issues with
14 these data. And this is what I was referring to. So,
15 this is actually an excellent example of the non-
16 transparency of the public health data. So, this
17 gives me an opportunity to explain what I mean by

18 that. So, first of all, as I’ve already mentioned,
19 this is dealing with cases. And again, the cases have
20 been dramatically over-estimated, but to an unknown
21 degree, because the PCR test has not been properly
22 calibrated. And further, different provinces have
23 disclosed different – different types of information
24 and so, see, what – what Alberta doesn’t disclose here
25 that other provinces have, such as Ontario, um, and
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1 it's frustrating because Ontario although has
2 disclosed the data, have not overlayed it on data like
3 this to better explain what’s going on, but there’s
4 two – in terms of these outcomes, because presumably
5 this – this gets to the idea that – that, you know,
6 the vaccines don’t have to confer, we’re still trying
7 to achieve herd immunity with vaccines that can never
8 achieve herd immunity, but that they – they – they

9 might blunt severity of disease, and therefore,
10 looking at severe outcomes. So, in Ontario, right
11 now, right at this very day, more than 50 per cent,
12 well, well over, like in fact, I think it’s about
13 three quarters, it’s somewhere there, about two-thirds
14 anyways, it’s – it’s well over 50 per cent of all
15 cases in hospital that are associated with COVID-19
16 are not due to COVID-19. The people are not in the
17 hospital due to COVID-19, but rather, due to some

18 other clinical condition, but they have a positive PCR
19 test result. And then when it comes to the ICU
20 admissions, the Ontario data shows, again, over 50 per
21 cent of everybody that’s in the ICU that where they’re
22 showing cases of COVID-19, they aren’t actually there.
23 More than half of them are not there, because of
24 COVID. They’re there because of some other clinical
25 condition. They might have appendicitis and need to
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1 get the appendix taken out, but they have a positive
2 PCR test result. And when it comes to deaths, when
3 one looks at the deaths, it varies from day-to-day,
4 but a substantial proportion of deaths that have been
5 attributed to COVID-19 are not due to COVID-19, they
6 were due to some other clinical condition, but the
7 person happened to have a positive PCR test result.
8 So, you can see how this is where this comes into play
9 and why I had to explain so much about cases and how
10 they’re defined, because where – where – these numbers
11 are based on that PCR test, but they’re not accounting
12 for the fact that that PCR test, a large proportion,
13 but unknown proportion of people is a false positive.
14 These people do not have replication competent SARS-
15 CoV-2. A large proportion have not been even
16 necessarily clinically diagnosed with COVID-19.
17 They’re in the hospital, but have a positive test

18 result. And an unknown proportion of these are going
19 to be in the hospital for some other clinical
20 condition. But like I said, had – had a concurrent,
21 competent positive result on the PCR test. And in
22 fact, and the other thing is, just so then when one
23 looks at how people are showing this in a more
24 transparent way, so, a good example would be – so,
25 British Columbia, for example, I’ve seen their public
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1 health data recently. And of Public Health – the
2 Public Health Agency in Manitoba and the Public Health
3 Agency in Ontario, are – well, I – I say the two – the
4 two in B – in British Columbia and – well, in all
5 three of those provinces, when one looks at cases,
6 they are happening disproportionately among those,
7 especially who are boosted, it suggests that if one is
8 boosted, one will have more than a two-fold chance of

9 being diagnosed with COVID-19, um, but what’s of
10 greater concern, one who looks at BC and Manitoba and
11 the pie charts that they have, it shows the proportion
12 that have been boosted, for example, and then the
13 proportion that have all these severe outcomes,
14 including deaths, and death, those who are boosted are
15 disproportionately represented among the deaths.
16 269 Q. Okay. Thank you, sir. I’d like to mark this document
17 as an exhibit. Madam Court Reporter, can we stop

18 sharing the screen, please?
20 MR. ELFORD: Thank you, sir. So, that’s, I believe,
21 Exhibit 3?
22 COURT REPORTER: Yeah. Exhibit 3.
23 MR. ELFORD: Thank you very much.
24
25 EXHIBIT 3: www.Alberta/Stats/COVID-19-Alberta-
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1 Statistics.htm#vaccine-outcomes
2 270 Q. I’d like to move onto paragraph 16 of your Expert
3 Report, sir. Please let me know when you’re there.
4 A. What paragraph number again?
5 271 Q. Sixteen, sir. One, six.
6 A. Thank you.
7 272 Q. You’re welcome.

9 273 Q. Okay, sir. I’ll be referring to Appendix “A,” as
10 well. Just so you’re aware. So, hopefully you have
11 access to that as well. But I think that’s your
12 article, so, you should be familiar with it.
13 A. Yes.
14 274 Q. Okay. So, at paragraph 16, you say that, “The Pfizer
15 vaccine should not have been authorized in Canada.”
16 And you rely on Appendix “A” to set-out the scientific
17 basis in that regard, is that correct?

19 275 Q. And – but this document, or this paper, hasn’t been
20 published, has it?
21 A. Not yet. No.
22 276 Q. It was submitted to “Viral Immunology” though?
23 A. Yes.
24 277 Q. Okay. And that’s why what we’re looking at here is a
25 peer-reviewed only copy?
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1 A. Yes.
2 278 Q. And you wrote this with a number of co-authors,
3 correct?
5 279 Q. And some of these co-authors include Dr. Steven
6 Pelech? That’s one of them at least.
7 A. I – sorry. Is that – is that a question?
8 280 Q. Yes, sir. It is. I can phrase it as a question. Is

9 Dr. Steven Pel – or is – it just says, “Steven Pelech”
10 here, but I assume Dr.’s implied. But is Steven
11 Pelech a co-author on this paper with you?
12 A. Yes.
13 281 Q. Okay. And so are Deanna McLeod and Ilidio – I think
14 it’s pronounced Martins?
15 A. Yes, that is correct.
16 282 Q. And they – is it Mr. Martins?
17 A. The – the – well, Doctor.

18 283 Q. Oh, it’s a doctor.
19 A. Yes.
20 284 Q. But they work at Kaleidoscope Strategic.
21 A. Yes.
22 285 Q. Which is a publisher?
23 A. Yes.
24 286 Q. Okay. Um, cancer papers, is that correct?
25 A. Ah, that’s what – that’s one of the thing – that’s
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1 what they emphasize I believe. I actually can’t
2 really comment. I’m – I’m not, you know, part of that
3 company. Yeah. So, I – I – I can’t really – I’m
4 sorry. I can’t really give details on the company. I
5 know that’s one of the things, that they support
6 publishing on. I don’t know if that’s exclusively
7 what they – what they focus on.
8 287 Q. Okay. And I see Chris Shaw is on here. And he’s at

9 the Department of Ophthalmology & Visual [sic]
10 Sciences?
11 A. Ah, I know he’s at the University of British Columbia.
12 Um, if – if that’s – if that’s the University of
13 British Columbia, then yes, I assume that’s his
14 department.
15 288 Q. Okay. And I see another author is Claudia Chaufam?
16 A. Yes.
17 289 Q. Yes. C-H-A-U-F-A-M for Madam Court Reporter. She may

18 know how to spell it already, but I – I wouldn’t have
19 offhand. And if you need any of the spellings, Madam,
20 please, just let me know afterwards. And so, you’d
21 agree that Claudia’s research is in the drivers of
22 social and health and equalities, and lackal [sic] –
23 at a local national and global level, correct?
24 A. Ah, again, I – yeah. She’s the one who can comment
25 best on her areas of expertise. I don’t want to limit
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1 anybody based on, you know, it’s – I can only comment
2 really on my and defend my own expertise.
3 290 Q. Okay. Fair enough, sir. Fair enough. I – I’ve just
4 got a few more questions of clarification here. And
5 Julian Northee’s (ph) research is in crop sciences,
6 he’s another co-author?
7 A. Again, I – I confirm he’s a co-author. Again, I’m – I
8 – I would let him comment on his areas of expertise.

9 291 Q. Okay, but a couple of your colleagues from the
10 Department of Pathobiology at the College of
11 Veterinary Medicine, which I may have just got the
12 name wrong there. They’re – they worked with you on
13 this paper, as well, right?
14 A. Ahhh....
15 292 Q. [inaudible] Neil A. Carol (ph)?
16 A. Oh, yes. Yes. One’s at the Ontario Veterinary
17 College, one is in a different college.

18 293 Q. Oh, okay.
19 A. [inaudible].
20 294 Q. I see. I see. Well, Neil, you’d agree with me though
21 that Dr. Carol’s research is in immunoregulation,
22 immunotoxicology, and immunogenetics of livestock and
23 fish species?
24 A. Ah, so, he’s a well-trained immunologist and he has
25 training in toxicology. Again, I know, but again, I –
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1 I would - beyond that, I would have him, you know,
2 comment on his own expertise.
3 295 Q. Okay. You haven’t looked at his staff page then...
4 A. No.
5 296 Q. ...to see how he describes – so, if I told you that he
6 described himself as an immuno – as his research being
7 immunoregulation, immunotoxicology, and immunogenetics
8 of livestock and fish species, you couldn’t disagree?

9 A. Ah, I couldn’t disagree. I can’t confirm it either.
10 297 Q. That’s fine, sir. I appreciate you are just
11 clarifying to the extent of your knowledge. But you’d
12 agree that – or maybe you can’t, but if I describe to
13 you Bonnie A. Mallard’s (ph) work as genetic
14 regulation of the immune system and implications to
15 disease resistance, particular emphasis is given to
16 preventative methods to improve disease resistant of
17 livestock, such as genetic selection of livestock for

18 enhanced immune responsiveness, other areas of
19 interest include, xenotransplantation and part of
20 immune responses, would you – would you be able to
21 agree or disagree that that’s an accurate description
22 of her expertise?
23 A. Ah, again, I know her as a very well-trained
24 immunologist, in terms of the specifics beyond that,
25 again, I – you know, every individual is welcome to
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1 put forward what their areas of expertise are.
2 298 Q. Okay. No. Fair enough, sir. Fair enough. You – you
3 know what you know. Um, so, are you – you – you’ve
4 indicated in the past you have some – some experience
5 with vaccine approval, but not with human vaccine
6 approval, but I didn’t really understand the extent of
7 it. But I’m going to ask you if any of the authors
8 have any experience with Health Canada’s Vaccine

9 Regulatory approvals for human use in Canada?
10 A. My understanding is that those who are associated with
11 Kaleidoscope – sorry. I can’t even remember the – the
12 name of the company. Ah, Deanna McLeod and – and the
13 other one. Um, that company is – my understanding is,
14 helps to some degree in – in helping companies get –
15 go through that process. My – my understanding is
16 that they help write up some of the documentation for
17 companies to go through that process, but again,

18 that’s as far as I know. I – I don’t have any
19 additional details. Again, when it comes to the
20 others, I don’t want to limit their scope of knowledge
21 in any way. I – I can only comment on my own
22 experience. I – I really don’t want to go on record
23 as stating what other people’s breadth or narrowness
24 of expertise and experiences.
25 299 Q. Okay. Are you able to say if whether any of the
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1 authors were involved in Health Canada’s approval of
2 the Pfizer vaccine in Canada?
3 A. Ah, none of the authors were involved in approving the
4 Pfizer – sorry, did you say the Pfizer vaccine?
5 300 Q. Yes, sir.
6 A. Um, no. None of them were involved in the approval of
7 the Pfizer vaccine.
8 301 Q. And none of them....

9 A. But that’s – to the best of my knowledge.
10 302 Q. To the best of your knowledge. I understand. And so,
11 none of the authors reviewed all the information
12 available to Health Canada, that they were reviewing
13 and approving the Pfizer vaccine in Canada?
14 A. No. Unfortunately those materials have not been made
15 transparent to the scientific community in Canada. It
16 would have been nice if they would.
17 303 Q. Okay. How are you doing, sir? Do you need another
18 break? Or are you good to keep going?
19 A. I’m fine. Thank you.
20 MR. ELFORD: Okay. You’re welcome. Mr. Wilson, I know
21 you have a sick child. Do you need a – to go check on
22 them? I don’t want to keep you from....
23 MR. WILSON: No.
24 MR. ELFORD: Do you need a break?
25 MR. WILSON: Thank you for your – your concern. I’m
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1 fine. Thank you.
2 MR. ELFORD: Okay. Thank you. So, at paragraph 17 and
3 18 of your affidavit, sir, if you could turn to those.
4 A. Okay.
5 304 Q. You discuss asymptomatic transmission under the
6 heading, “Asymptomatic Transmission is Negligible.”
7 A. Again, is that a question?
8 305 Q. No. It’s a pause, ’cause I’m trying to...

9 A. Oh, okay.
10 306 Q. ...see where I’m going next, but thank you for asking.
11 So, at paragraph 18, you write, “In the United
12 Kingdom, the Scientific Advisory Group for
13 emergencies, recommended that prioritizing rapid
14 testing of symptomatic people is likely to have a
15 greater impact on identifying positive cases and
16 reducing transmission than frequent testing of
17 asymptomatic people in an outbreak area.

18 Consequently, they have asked their government to
19 their testing policy, by moving away from asymptomatic
20 testing.” Do you recall writing that?
21 A. Ah, yes. And I – I see there’s a word missing. That
22 should have been, “...asked their government to change
23 their testing policy.”
24 307 Q. Yeah. Okay. I understand, sir. It’s a – I wasn’t
25 going to ask you if you missed it. So, that’s –
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1 that’s your review of what stage, the scientific
2 Advisory Group for Emergencies recommended. Is that –
3 is that – is my understanding correct?
4 A. Ah, that’s – yup. Well that’s the citation there.
5 Yes.
6 308 Q. Okay. And I’m going to ask you to open up a document
7 that was sent to you.
8 A. Okay.
9 309 Q. SAGE, 56 minutes, Coronavirus, [open parenthesis],
10 COVID-19, [end parenthesis] response, 10, September,
11 2020. Just let me know when you’re there.
12 A. Okay. Yeah. Just give me one moment. I think this
13 is one that’s printed. Ah, no. It looks like I
14 haven’t printed it. Okay. Let me just open up here.
15 Okay. Oh, maybe I do. SAGE 56 minutes, you said?
16 310 Q. Yes. SAGE, 56 Minutes, Coronavirus, [open
17 parenthesis], COVID-19 [end parenthesis] response, 10,

18 September, 2020.PDF.
19 A. Okay. Yes. I just realized; I don’t think I – yeah.
20 I was looking for that title.
21 311 Q. No. That wouldn’t be the title. That’s the PDF, sir.
22 A. Okay.
23 312 Q. It would be very similar though. It would be
24 basically the same, but without the “PDF.”
25 A. Okay. Yeah. Okay. One moment. I think I did see
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1 it. Okay. Yes. This one, I’ve printed it out, but I
2 haven’t looked at it yet, but I have it in front of
3 me.
4 313 Q. Okay. Well, is this the document that you were
5 relying on for the facts or – or – or for your
6 assertions, I should say, or however you’d like to
7 characterize it, about SAGE at paragraph 18.
8 A. Um, let me just see here. No. It appears they used a

9 different document.
10 314 Q. Okay. And what document was that then?
11 A. Uh, let me see here. Uh, I have to confirm it looks
12 like with my endnote software, it may have truncated
13 the – the website address potentially.
14 315 Q. Okay. So, you don’t....
15 A. ’Cause it’s – ’cause it’s now saying, “The file can’t
16 be found.”
17 316 Q. Okay. So, we – we don’t know what you’ve cited to

18 therefore that?
19 A. Uh, give me – give me one second. I can try it this
20 way. Okay. It – it does appear to be the same
21 document.
22 317 Q. Okay.
23 A. To confirm.
24 318 Q. Yeah. Take you time to confirm and let me know when
25 you can confirm that.
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1 A. Okay. Yes. I can confirm that. It appears to be...
2 319 Q. Okay.
3 A. ...point number 5 in the summary, that I’ve quoted
4 specifically.
5 320 Q. Okay. Thank you for confirming that. Can I get you
6 to turn to point 35, please, on page 7 of this
7 document?
8 A. Okay.
9 321 Q. And if – if you wouldn’t mind reading out loud points
10 35 and 36, please.
11 A. Okay. Point number 35 says, “Given that asymptomatic
12 transmission is known to occur SAGE reiterated the
13 importance of maintaining social distancing and other
14 COVID-secure measures.” Point 36 states, “There is a
15 risk of mixed messaging to the public and that while
16 only people with symptoms and certain other groups are
17 encouraged to get tested. Asymptomatic people outside

18 these groups still present a transmission risk. It is
19 important to that – to – it is important to that -
20 risk of - [Okay. So they must have missed a word] it
21 is important to – that risk of asymptomatic
22 transmission are reflected in public communication and
23 engagement.”
24 322 Q. Okay. Thank you, sir. So, this would appear to be
25 important context to SAGE’s comments about
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1 asymptomatic testing that you – or symptomatic,
2 asymptomatic testing that you refer to in paragraph
3 18, would you agree?
4 A. Ah, they seem to be wanting to take a safe approach
5 that way. Yes. I – I – yeah. I disagree as an
6 expert in this context – in the – so, it’s a matter of
7 – it’s a matter of degree. So, for example, with –
8 with the – the – the one expert, Jason Kindrachuk, we

9 agree that the – that asymptomatic transmission is a
10 minor contributor. It’s how we define “minor.” So, I
11 view it as it’s a – it’s certainly theoretically
12 possible, but is it highly probable? No. And there’s
13 immunological and virological reasons for that. An
14 organization like this is wanting to, you know, put in
15 those messages, I guess, to be on the safe side. I
16 don’t know if it’s a liability thing, but the
17 scientific side, I – I disagree. I mean, this is how

18 we’ve mislabelled children. And so, I – I want to
19 explain. I’ll give you one example for the sake of
20 time, to explain, again, the ratio – provide the
21 rational for why I disagree. So, children – children,
22 I like to use an example, because they’re on the
23 extreme low-risk spectrum, when it comes to COVID-19.
24 And they have been mislabelled as – and we’ve masked
25 them and made them distance, so they were taken out of
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1 their schools, and so on, and so forth, and – and now
2 being made to receive these COVID-19 inoculations,
3 because they were deemed to be asymptomatic,
4 transmitters, potential asymptomatic – a – a large
5 proportion of them. And it’s because for two reasons,
6 they’re not prone to severe disease, and that’s
7 because they physically, in their lungs, do not
8 express the – nearly the same concentration of

9 receptors that the virus needs to infect cells, as
10 adults do. So, they’re prone to much lessor severity
11 of disease. And therefore, have more potential to be
12 asymptomatic. They’re innated immune systems seem to
13 be ideal for rapidly clearing the virus. And so,
14 they’ve been labelled as asymptom – there’s a lot more
15 children who are asymptomatic, but that test positive,
16 again, by the PCR test for the SARS-CoV-2. But this
17 is where I’ve looked at the literature for – you know,

18 very extensively, when it comes to children. And
19 what’s interesting is, when you look at the papers
20 that have identified children as being potential
21 asymptomatic spreaders, transmitters, of SARS-CoV-2,
22 in other words, arguing that they can potentially
23 transmit sufficient - not be sick, but have – but sort
24 of be spilling over with this highly pathogenic virus,
25 yet not be very sick themselves, but be able to
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1 transmit a threshold dose that would make an adult,
2 for example, sick, is based on the PCR testing. And
3 in those – in those publications, when you look at the
4 – where – where they disclose the results of the PCR
5 testing, they show, they plot on the – on these brass,
6 they plot ca – they show individuals as dots, and it
7 shows the – the cycle threshold, at which they tested
8 positive, and interestingly, if one were – and of

9 course, the positive is placed at – usually in the
10 ballpark of 38 cycles, so, if it was in Ontario, it’d
11 be 38 cycles, and interestingly if one redraws the –
12 the positive threshold at 24, like our National
13 Microbiology Laboratory would have suggested, if they
14 were running the diagnostic test, the vast majority,
15 the vast majority, and – and some of the publications
16 of what – 100 per cent of the cases, get removed, as
17 actually negative. So, you see, so, that’s the basis

18 here again. It comes down to – and this is why I had
19 to be very careful beginning to make sure things are
20 very well-defined. And when we’re talking about
21 cases, and – and what’s interesting here is a lot of
22 the data, that – that – that relates to the, say,
23 symptomatic transmission is based on the PCR test and
24 a failure to demonstrate replication competent viral
25 particles through the use of what we use, called the
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1 plaque assay, a fully functional assay. They use
2 other assays, but not the plaque assay, we call it.
3 And – and it – with most of these studies, they don’t
4 actually show transmission. It’s – it’s dealing with
5 the potential for transmission, based on the
6 identification of viral particles, and we don’t even
7 know if those reach an amount that would be able –
8 allow a child, or an asymptomatic individual to be

9 able to deliver a threshold dose, which typically
10 requires active signs and symptoms of illness, like
11 coughing and sneezing, in order to deliver the large
12 threshold dose that’s required to infect somebody
13 else.
14
15 So, yes. So, I acknowledge that they have stated
16 that, that they have put these conditions on their
17 initial statement, but their initial statement still

18 stands. I view it as those add – those additional
19 statements near the end, are sort of a liab – kind of
20 to – to fulfill, you know, liability issues. And at
21 the end of the day, the data, as I have looked at it,
22 as an expert, looking at the sum total of data on
23 asymptomatic transmission, I will agree 100 per cent,
24 yes, it is theoretically possible that it can occur.
25 I – it – it has occurred, but does it occur at a - at
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1 a – a rate that would contribute significantly to the
2 spread of COVID-19, among our population? No. I
3 don’t believe it does.
4 323 Q. Okay. And going back to paragraphs 17 and 18, you
5 said you’ve reviewed the sum total of data, or the sum
6 total of data that you’ve reviewed leads you to this
7 conclusion. That’s – that’s what you said, correct?
8 A. Yes.
9 324 Q. Okay. And I notice here, other than the citation to
10 SAGE, and in another study here by Civic (ph) about
11 viral loads and shedding, the only study reference
12 here about actual data of individuals is a study from
13 Mohan China (ph) that found no evidence of
14 asymptomatic transmission, is that correct?
15 A. Yes.
16 325 Q. Okay. And this is the Cao Study, C-A-O, right?
17 A. Ah, let me confirm. Yes. That’s correct.

18 326 Q. And so, you’d agree with me that this study involved
19 finding 3,000 asymptomatic cases and no positive cases
20 amongst their 1,174 close contacts?
21 A. Yes.
22 327 Q. Okay. And this was, of course, during the early days
23 of the pandemic, because - during the Wuhan explosion
24 in, you know, say spring to early summer of 2020,
25 correct?
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1 A. Ah, give me just one moment to confirm.
2 328 Q. Please, take your time.
3 A. Yes. That is correct.
4 MR. ELFORD: Okay. Thank you. I’d like to enter the
5 “SAGE 56 Minutes: Coronavirus (COVID-19) Response,” as
6 an exhibit, please.
8 MR. ELFORD: Thank you.

9 COURT REPORTER: Exhibit Number 4.
10 MR. ELFORD: Number 4. Thank you very much, Madam Court
11 Reporter.
12
13 EXHIBIT NUMBER 4: SAGE 56 Minutes: Coronavirus (COVID-
14 19) Response, 10 September 2020.
15
16 MR. ELFORD: Well, I notice we’re about 12:23 here. And
17 I suspect we can all use a little bit of a break. I

18 know it’s getting into lunch. For me, I’m not going
19 still eat anything, but it doesn’t hurt to have a
20 break. Um, I can go longer, but I – I think that
21 probably makes sense as a time. How about you, Mr.
22 Wilson? What do you think?
23 MR. WILSON: Yeah. I could use a – a break as well.
24 MR. ELFORD: Okay. Dr. Bridle, I imagine you wouldn’t
25 mind a break to – it might be a bit late for lunch. I
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1 don’t know if you’ve had anything.
2 DR. BRIDLE: Yeah. That’s fine for me. Yes. How long?
3 MR. ELFORD: I’m gonna suggest 30 minutes for myself, but
4 I mean, you know, its up to everyone else. I don’t
5 know what they’re situation is and I don’t want to
6 push it through, but I would like to get done today,
7 if possible. And I do have some more questions.
8 DR. BRIDLE: Thirty minutes is good with me.

9 MR. WILSON: Likewise.
10 MR. ELFORD: Madam Court Reporter?
11 COURT REPORTER: That’s fine. Thank you.
12 MR. ELFORD: Well, you’ve been very patient with us,
13 Madam Court Reporter. So, thank you.
14 COURT REPORTER: No problem. I’ll take us off the
15 record.
16 MR. ELFORD: Okay. Thank you very much.
17
18 OFF RECORD
19
20 COURT REPORTER: We’re back on.
21 MR. ELFORD: Excellent. Thank you very much. Welcome
22 back to everyone.
23
25
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1 Dr. Bridle, if I could have you please turn to paragraph 30
2 of your Affidavit. Just let me know when you’re
3 there.
5 329 Q. Sir, I said, “Affidavit,” I mean Expert Report, sir.
6 Are you at your Affidavit or Expert Report?
7 A. Expert Report. Yeah. I knew what you meant.
8 330 Q. Thank you very much. Well, I’m glad you did, because
9 my question for you is this. Now, you write, “It has
10 been demonstrated that there is no difference for the
11 potential for unvaccinated and fully vaccinated people
12 to transmit the Omicron variant of SARS-CoV-2,”
13 correct?
14 A. Ah, did – did you say, “Omicron variant of SARS-CoV-
15 2?”
16 331 Q. Yes. That’s what you wrote there, correct?

18 332 Q. And for that you – you refer to citation 34, correct?
19 A. Ah, yes. That is correct.
20 333 Q. Okay. And citation 34 is – I’m going to try to get
21 this name correct, Franco-Paredes, P-A-R-E-D-E-S on
22 the second name, “C,” and it’s 2020 [sic] and it’s an
23 article called, “Transmissibility of SARS-CoV-2 Among
24 Fully Vaccinated Individuals.” It’s in The Lancet,
25 Infectious Diseases, 22, parathesis 116. Is that
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1 correct?
2 A. You had said, “2020,” it’s 2022. Year 2022, but other
3 than that, yes, it’s all correct.
4 334 Q. Okay. My mistake. I thought I had said the right
5 year, but obviously not. There’s – you know. And
6 there’s only three or four of them, at this point,
7 right?
9 335 Q. Three or four of them that we talked about.
10 A. Yes.
11 336 Q. Thankfully I’ve got a copy of it here. I’m just going
12 to locate it and give you the name. So, you should
13 have received a copy of it. And it’s,
14 “Transmissibility of SARS-CoV-2, among fully
15 vaccinated individuals.PDF.” And just let me know
16 when you’ve located that, please, sir.
17 A. Okay. Okay. This is one – yeah. I’ve got it. Okay.

18 I’ve got it in front of me.
19 337 Q. Okay. Thank you, sir. So, is this the document you
20 refer to at citation 34?
21 A. Yeah.
22 338 Q. Okay. And so, this is correspondence rather than a
23 study?
24 A. Yes.
25 339 Q. And it doesn’t actually make reference to Omicron in
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1 it, does it?
2 A. The – ah, let me remind myself. Just give me a second
3 here. Yeah. No. You’re correct. It doesn’t
4 specifically state Omicron.
5 340 Q. And looking at the citation, they all appear to be
6 from 2021, correct?
7 A. Ah, yes. So, yeah. You’re correct. I – based on the
8 year, yeah. I had made the initial assumption it was

9 Omicron. It looks like it’s referring to Delta.
10 341 Q. Okay. Thank you.
11 A. Delta variant.
12 342 Q. Um, I’m going to just ask that we go off the record
13 for a moment, if that’s possible.
14 MR. WILSON: That’s fine.
15
16 OFF RECORD
17
19 MR. ELFORD: Great. Now, now, we’re back on the record.
20
22
23 MR. ELFORD: If I could get you to turn to paragraph 32
24 of your – your Expert Report, please.
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1 343 Q. Great. And so, you write in that paragraph, and it’s
2 sort of split into a couple of mid-paragraphs. One’s
3 entitled, “Natural infection.” And the last sentence
4 says, “Indeed, most people who have – who have a
5 naturally acquired immunity, should not be at risk of
6 developing severe disease, even if variants arise that
7 can effectively bypass the narrower immunity conferred
8 by COVID-19 vaccines that are focused on a single

9 component of SARS-CoV-2, such as the spike protein.”
10 Do you see that?
11 A. Yes.
12 344 Q. Excellent. And you cite to citation 40 for that,
13 which is a preprint from March 2021, entitled,
14 “Negligible Impact of SARS-CoV-2 Variants on CD4 + and
15 CD8 + T Cell Reactivity in COVID-19 Exposed Donors and
16 Vaccinees.” Do you recall that? Is that the citation
17 there at 40?
18 A. Yes.
19 345 Q. Okay. And you cited to the Biorxiv Org, Version 1 of
20 that document, correct?
21 A. Yes.
22 346 Q. Okay.
23 A. Yeah. Just – and just to point out why that was –
24 this was from my original report that I put out after
25 reporting on the bio distribution study. That
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1 Japanese bio distribution study.
2 347 Q. Okay. Well, thank you for that context. This study
3 didn’t include consideration of Delta or Omicron
4 variants of concern, correct?
5 A. This particular study, no. But the – my – my
6 statement still stands and it’s due to the – again,
7 the concept of – well, it’s not even cross-reactive
8 immunity, because again, so, when the virus changes,

9 the – it changes the spike protein quite substantially
10 because of the pressures we’ve put on the virus using
11 very poor performing vaccines, right, that are very
12 leaky. And so it’s changed the spike protein quite a
13 bit, but the other components not nearly as much. And
14 again, a naturally induced immune response will induce
15 responses against multiple components of the virus.
16 So, again, we’ve pushed the virus to mutate much more
17 rapidly than we would anticipate from a coronavirus

18 and to a much greater degree, at this point in time,
19 but not to the point where people that have naturally
20 acquired immunity would be unable to have some level –
21 some degree of protection, which is what I’ve stated
22 there. So, we expected every time a virus mutates to
23 a certain degree, everybody, whether it’s vaccine-
24 induced immunity or naturally acquired immunity, is
25 again, going to be susceptible to infection. But if
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1 we keep up-to-date with that immunity and don’t
2 isolate ourselves from these viruses, as they change,
3 that to say, what most people will get a mild
4 infection and their immunity will be up-to-date for
5 that new version of – of the virus.
6 348 Q. Okay. Did you look at the updated version of this,
7 once it was published?
8 A. Ah, no, I haven’t seen that updated version.

9 349 Q. Okay. And you didn’t update this section then, when
10 you prepared it for this Expert Report?
11 A. Ah, no. I would have – just let me look at my report,
12 again, can you remind me what para – what paragraph
13 number it was?
14 350 Q. Well, sir, we were looking at paragraph 32.
15 A. Okay.
16 351 Q. And reference for you.
17 A. Ah, yeah. Yeah. For this particular portion, no,

18 this was dealing with my concerns about the childhood
19 vaccines and the context of the earlier – what was
20 considered a more dangerous versions of the – of the
21 virus.
22 352 Q. Okay.
23 A. So, again, to put in – perspective. This was a
24 document that I wrote that was at – this is an excerpt
25 taken from a document that I wrote, which was entitled
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1 – which was a – a guide to COVID-19 vaccines for
2 parents. So, that they could make fully informed
3 decisions, as we were starting to consider rolling
4 these out to children.
5 353 Q. Part of your public outreach that you described in
6 your CV?
7 A. Yes.
8 354 Q. Okay. So, do you agree with me then that a copy was
9 published in Cell Reports Medicine in July of 2021?
10 A. Um, I – I haven’t seen that.
11 355 Q. Okay. Well, not a problem. Sir, I’m going to share a
12 screen with you, if that’s okay.
13 A. Sure.
14 356 Q. Thank you. I mean I’m gonna – gonna do it, but I like
15 to be polite about it, of course. It’s a little joke.
16 So, I’m going to share this with you and what you
17 should be able to see here is “Negligible Impact of

18 SARS-CoV-2 Variants on CD4+ and CD8+ T Cell Reactivity
19 in COVID-19 Exposed Donors and Vaccinees.” Do you see
20 that?
21 A. Yes.
22 357 Q. And is that the document you were referring to at
23 citation 40?
24 A. Yes.
25 358 Q. Okay. And you see now here, now, published in Cell
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1 Reports Medicine and it gives a DOI. Do you see that?
2 A. Yes.
3 359 Q. Okay. And if you could open up a document that was
4 shared with you called, “Impact of SARS-CoV-2 Variants
5 on the Total CD4 and CD8 T Cell Reactivity in Infected
6 or Vaccinated Individuals.PDF,” please.
7 A. Okay.
8 360 Q. And I’m just gonna click on this and we’ll – we’ll go
9 to wherever it takes us. I don’t have the fastest
10 internet, I’m afraid. Okay. And so, as you see, it’s
11 got the – well, there we go. It’s got the name, the
12 impact of SARS-CoV-2 variants on the total CD4 and CD8
13 and both with pluses, T Cell reactivity in infected or
14 vaccinated individuals. So, would you agree that
15 that’s a published copy of the study that you referred
16 to?
17 A. Ah....
18 361 Q. Take your time to read it and look at it and consider
19 it, sir, if you haven’t had an opportunity yet.
20 A. Yeah. Yeah. It appears to be the same one. I’m just
21 looking at the version that I received, it visually
22 looks different than the one online. Okay. Yeah.
23 So, I – ’cause I’ve got the PDF version. Yes. Yeah.
24 It appears to be the same one.
25 362 Q. Okay. Great. And I’d like to go down, and I’ll tell
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1 you which page it’s on in a moment here. Actually,
2 Ma’am - Madam Court Reporter, we can stop sharing now,
3 I think. Great. Thank you very much. So, we can go
4 down to discussion and I have it as page 9 of the PDF.
5 Do you have the discussion on that page, sir?
6 A. Let me go to page 9. Yes. I’m there.
7 363 Q. Okay. And so, if we can go to the second paragraph.
8 A. Okay.
9 364 Q. And in the second paragraph, it’s about one, two,
10 three sentences in. I’d like you to – and you can
11 read the whole paragraph. Read the context, please.
12 A. Ah, you – do you want me to read it out loud?
13 365 Q. Well, I’ll read it to you and you can confirm that it
14 says that.
15 A. Okay.
16 366 Q. And then I’ll ask you about it. But I’m just saying
17 to you, you don’t have to answer the question without

18 reading the context, you know.
19 A. Okay.
20 367 Q. “While it is not anticipated that circulating memory T
21 cells would be effective in preventing SARS-CoV-2
22 infection, it is plausible that they can contribute in
23 reducing CoV – COVID-19 severity.” Do you see that?
24 A. Yes.
25 368 Q. Okay. So you didn’t have a consideration of that
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1 conclusion by the authors of this study in front of
2 you when you wrote at paragraph 32, “Indeed, most
3 people who have acquired – who have naturally acquired
4 immunity, should not be at risk of developing severe
5 disease, even if variants arise that can effectively
6 bypass the narrower immunity conferred by COVID-19
7 vaccines that are focused on a single component of
8 SARS-CoV-2, such as spike protein.”

9 A. Okay. And sorry. What – what was the question?
10 369 Q. You didn’t have that before you?
11 A. Um, I’d have to go back to confirm what was in the
12 preprint version.
13 370 Q. Okay. No. That’s – that’s – that’s fair, sir. But
14 you agree – I mean you cited to the – the authors, so,
15 I assume you – you agree with their methodology, but
16 would you agree with their statement, it is not
17 anticipated that certain memory T cells would be

18 effective in preventing SARS-CoV-2 infection?
19 A. Ah, not necessarily. Again, it probably is dependent
20 on the – well, okay. So – so, I agree, but again,
21 there’s a nuance here to what’s meant by infection.
22 Some people view infection as being like infiltration
23 of the body with the virus. Here, ah, no, t cells are
24 not going to prevent infection of cells. So, actual
25 infection that occurs, it’s not just infiltrate –
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1 having – so, having the virus, for example, present in
2 the lungs, does not, in of itself, constitute
3 infection. That’s an invasion of the lung space with
4 a virus. Infection is when it actually, for the SARS-
5 CoV-2, when it grabs onto its receptor on a cell, and
6 then fuses with the cell, and enters the cell, where
7 it can then potentially start replicating. So, that
8 would constitute infection. So, no. T cells are

9 designed to kill virus – virus-infected cells. There
10 has to be an infection that takes place before a T
11 cell can kill that cell. That’s because T cells are
12 designed to see pieces of the virus, that are
13 expressed on the surface of the cell, shown to the T
14 cell and that means that for a cell to do that, it has
15 to have the virus inside, and so, it has to be able to
16 chop up pieces of the viral protein, so, it can show
17 them on the surface to the T cells. So, by

18 definition, a T cell requires infection to occur and
19 then the T cell can eliminate the infected cell, such
20 that it cannot serve any longer as a virus replication
21 factory. And therefore, protecting the surrounding
22 non – uninfected cells. So, this is exactly – this
23 biology is exactly why people also want what we call
24 neutralizing antibodies, because neutralizing
25 antibodies can prevent that initial binding of the
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1 virus to – it’s a receptor that it uses to infect the
2 cell. But the most effective mechanism is generally –
3 are generally cytotoxic T cells that get generated.
4 So, these memory cells are talking about would be in
5 circulation. Once cells start to get infected and
6 display the pieces of the virus on their surface,
7 these T cells would quickly recognize those cells,
8 kill them, and eliminate the – the viral infection.

9 So, no, T cell – T cells, by definition, have to
10 function their – they – they function post infection,
11 after a cell’s infected. That’s what they’re
12 referring to here.
13 371 Q. I’d like to move onto paragraph 43.
14 A. Okay. Okay. I’m there.
15 372 Q. Great. So, at paragraph 43, you indicate that the
16 three other vaccines in use in Canada contain a
17 manufacturing blueprint from a modified version of the

18 spike protein, referred to as a prefusion stabilized
19 spike. Is that correct?
21 373 Q. And the one you’re not talking about there is the
22 AstraZeneca, which contains as you state, “The
23 manufacturing blueprint for the exact same spike
24 protein as is found in SARS-CoV-2.”
25 A. Yes. That’s correct. The other ones contain what’s
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1 called a “Prefusion stabilized version.”
2 374 Q. Okay. And of course, you’re talking about Pfizer,
3 Moderna, and the Janssen & Janssen vaccine?
5 375 Q. But of course now there’s some other vaccines that
6 have been approved as well?
7 A. Yes. That is correct.
8 376 Q. And you’re not talking about them here?

9 A. No. They weren’t available at this time. They
10 weren’t approved.
11 377 Q. When you wrote this?
12 A. Yes.
13 378 Q. Okay. And so, you agree that prefusion stabilize
14 spike in the spike protein is what can be called in a
15 – a closed shape.
16 A. No. No. So, yeah. This – this needs – the Court
17 definitely needs clarification on this. So, I – I

18 know what you’re referring to in Dawn Bowdish’s report
19 and I honestly, I don’t know where she got that
20 information. She is patently incorrect about these
21 being in the closed state. Um, I can’t be more
22 emphatic about that. She is completely wrong in that
23 entire section and she uses it quite extensively to
24 try and critique my report. It’s patently incorrect.
25 And I’ll explain.
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2 The – this is based on – so, the vaccine
3 manufacturers, themselves, had the hypothesis that the
4 ability for the spike protein that they reason is an
5 antigen. So, first, let me back up just for a moment,
6 because it’s important to understand. The spike
7 protein was selected as an antigen for the vaccine for
8 the very reason that I just mentioned in answering

9 your previous question. Because it’s the protein the
10 virus uses to grab onto the – the – a protein on cells
11 that line a respiratory track and that allows it to
12 infect our cells. And so, the idea was if you use the
13 spike protein to trigger an immune response, the hope
14 was we would get neutralize in antibodies, antibodies
15 that would bind to that spike protein, and antibodies
16 are very large molecules. So, the idea of being what
17 was thought was that we were giving the antibodies

18 that would bind specifically to the receptor-binding
19 domain. So, this – the spike protein has these
20 multiple projections, sort of three – you can view
21 them as like three arms, and at the – at the end of
22 each of them is the receptor-binding domain, that can
23 grab onto this – this protein on our cells. So, the
24 idea being you want to target that receptor-binding
25 domain and if you have an antibody, this huge protein
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1 bound to it, it’s going to physically impede the
2 ability of that spike protein to grab onto our cells,
3 and therefore, facilitate infection. And – and the
4 way this works biologically is this – this stabilized
5 spike protein – or sorry – the spike protein, again,
6 has these three arms, and typically it will alternate
7 with one in the open position and two in the closed
8 position, and it will alternate between that and the

9 one that has two in the open position and one that’s
10 not accessible. Uh, but they’re - but – so, in a
11 natural form, there’s always at least one receptor-
12 binding domain that can – that can bind. And so, the
13 vaccine manufacturers actually hypothesized that they
14 wanted their spike protein that was in the vaccine to
15 be able to have at least one receptor-binding domain
16 exposed, so that they could generate antibodies
17 against that receptor-binding domain. In fact, in

18 parallel, with this – with this prefusion stabilized
19 spike, they tested a vaccine version, where they just
20 took the receptor-binding domain, and actually
21 stitched three of the receptor-binding domains
22 together, so that – ‘cause that’s what they knew they
23 – so, that’s what they wanted to target, were the
24 receptor-binding domains. So, that was actually – so,
25 their philosophy was they actually wanted their
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1 prefusion stabilized spike to bind. And so, I think
2 where the – the misconception comes in here, is
3 there’s a third-generation spike protein that has been
4 manufactured, where all three receptor-binding
5 domains, all three of the arms, so, think kind of like
6 tentacles on an octopus, except there’s just three,
7 well, all three are forced together into what we call
8 the “closed confirmation.” And what that does is it

9 largely obscures the receptor-binding domain. So,
10 just a portion of the – each of the receptor-binding
11 domains is available. And the reason why that third-
12 generation spike protein is now and the – and the next
13 generation vaccines, why it’s so popular is because of
14 this understanding that the original spike protein
15 combined to the ACE2 protein, that’s the – the
16 receptor it uses on our cells and cause signalling
17 through that receptor. Whereas this version, it

18 actually generates more potently neutralizing
19 antibodies. So, it turns out that antibodies that
20 bind to the area around the receptor-binding domain,
21 are better at neutralizing than those that bind
22 directly to the receptor-binding domain. So, that –
23 so, (a), it’s more immunogenic, it generates better at
24 neutralizing antibodies; and on the safety side, it
25 shouldn’t be able to – it’s not that it can’t bind the
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1 receptor on the cells, it binds with lower affinity.
2 But that’s the – that’s the third-generation spike
3 protein, where all three are in the closed formation.
4 And these vaccines – no. It’s the prefusion
5 stabilized spike.
7 All this – so, what this means is – and the man – the
8 vaccine manufacturers have stated this very clearly

9 themselves, they’ve shown the crystal structures of -
10 of these, they’ve shown very clearly, and a matter of
11 fact, what they were very proud of in their
12 publications where they were demonstrating this, was
13 they were able to show generation neutralizing
14 antibodies, but one of the things that they were
15 particularly excited about and highlighted was that
16 some – some of the spike proteins defintiely had the
17 receptor-binding domain obscured with all three, on

18 all three of the arms, but – so, those ones could bind
19 to the ACE2 receptor with lower affinity. But what
20 they highlighted was more importantly 20 per cent of
21 them had one of the arms in the up position.
22
23 So, a fully exposed receptor-binding domain. But what
24 this does is the pre – see, the – the – this prefusion
25 stabilized, what that means is, once you have one of
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1 those arms that binds, the other arms normally would
2 swing freely, and then there’s a fusion, we call
3 “fusion domain,” that allows the virus to actually
4 fuse with the cell and enter, ’cause all the spike
5 protein on its own can do, is allow it to grab onto
6 the cell. So, it needs those arms to move, in order
7 to – for the virus to be able to fuse and literally
8 spew its internal contents into the cell, so that it’s

9 genome can start being replicated, and can make new
10 viral particles. But no, these prefusion – so, like I
11 said, the one in AstraZeneca has the wild type, so,
12 all three – three arms have the receptor-binding
13 domain open. But this prefusion stabilized spike can
14 bind very efficiently to the ACE2. So, no, I – I – I
15 – that unfortunately, I – I – again, I don’t know
16 where Dr. Bowdish got that from, but she has
17 completely misunderstood the – the literature, like I

18 said, I think she’s probably – she probably read the
19 paper for the third-generation spike protein, which
20 was made well after these vaccines were developed.
21 So, no. These – the – all versions of the spike
22 protein that are in these vaccines, can bind to the
23 ACE2 protein on the surface of – of our cells quite
24 efficiently and therefore triggers signalling.
25 379 Q. Okay. So, you don’t agree then that the mRNA
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1 instructions used in the mRNA vaccines and code, in
2 the closed formation of the spike protein, and
3 consequently the spike protein that is produced by the
4 mRA [sic] - mRNA vaccines can’t bind to the ACE2
5 receptors? That’s....
6 A. No. I – I – yeah. That again, I can’t emphasize,
7 that is patently false. That is true of one of the
8 third-generation. So, for example, I – I have been

9 involved in – in vaccine research myself, with the
10 Public Health Agency of Canada to work on some SARS-
11 CoV-2 vaccines. The spike protein we put in there is
12 that version, where all three arms are in the closed –
13 or locked in the closed confirmation and the primary
14 reason why we – so, we also didn’t do it for safety at
15 the time, because we didn’t know about the safety
16 concerns, but we did do it because it actually is
17 found that the best – what happens actually, is if you

18 allow antibodies to be induced against the receptor
19 binding domain, they are neutralizing, but they’re not
20 as effectively neutralizing, it turns out, as if the
21 antibodies bind to the peripheral region. And – and
22 so that’s why we did, because it was found to induce
23 more potently neutralizing antibodies. But yes,
24 that’s a third-generation and by third-generation, I
25 mean there’s the wild-type spike, like what’s in the
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1 AstraZeneca, then there’s the prefusion stabilized,
2 which is the second-generation and so what Dr. Dawn
3 Bowdish is talking about, is the third-generation – a
4 third-generation spike protein, which is not in any of
5 the currently authorized vaccines. The version that’s
6 in all the vaccines right now, can very efficiently
7 bind to ACE2.
8 380 Q. Okay. None of that is in your report?

9 A. Ah, no. Well – well – well, it – those details, no.
10 I’m responding specifically to Dawn Bowdish’s, but
11 yes, I have – I mean there was no need, because I have
12 in my report, that the spike protein can bind to the
13 ACE2 receptor.
14 381 Q. Yeah.
15 A. There was – there was – that – that’s fact, so,
16 there’s no need for me to have the additional – I
17 didn’t know that anybody would question it based on –

18 and in fact, when you look at her section, you’ll note
19 she doesn’t have a single citation. I don’t even –
20 so, I’m – I’m guessing, even that third-generation
21 spike protein that I was telling you about, I’m
22 guessing that that’s where she got the idea from, but
23 I really don’t know, because she doesn’t have a single
24 citation.
25 382 Q. And you’re saying that the damage caused – that – that
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1 SARS causes is because of this spike protein binding
2 to these....
3 A. No, no, no. In part. They’re – they’re multiple
4 mechanisms, multiple mechanisms of – of harm, both
5 from the virus and from the spike expressed from
6 vaccines, of which free spike protein would rank among
7 one of my minor concerns.
8 383 Q. Well, sir, I didn’t ask about the vaccines. I asked

9 about the SARS-CoV-2 spike protein.
10 A. Oh, well, I’m sorry. Because the vaccines are...
11 384 Q. In your report....
12 A. ...in code, the SARS-CoV-2 spike protein. So, I’m
13 sorry. I misinterpreted.
14 385 Q. Okay. Well, I’m just going off of your report here,
15 where paragraph 63 and 64, you talk about the spike
16 protein from SARS-CoV-2 has the potential to damage
17 cells in the body.

18 A. Yes. That’s true.
19 386 Q. And you cite to a few studiers here, to demonstrate
20 that, but you’d agree with me that all the studies you
21 rely on, involve either the SARS-CoV-2 infection or an
22 invitro lab study using spike protein related to the
23 SARS-CoV-2 infection and not ones induced by
24 vaccination.
25 A. Exactly. That’s why I used the term potential for
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1 harm. Yes.
2 387 Q. Okay. So, you agree then it’s just potential?
3 A. Yes. At this point, yes. Then no – no studies have
4 been done to – to address that – that important
5 serious question.
6 388 Q. Okay.
7 A. Despite – despite numerous, you know, repeated
8 requests for that – that safety testing to be done.

9 389 Q. Right. You did mention your own vaccine and that
10 obviously hasn’t come out?
11 A. No. And – and won’t actually. So, the people that
12 I’m collaborating with, one has decided to go in a
13 different direction with their COVID-19 research and
14 they’re doing work with gene therapy, and the – we
15 were collaborating with the public health agency of
16 Canada. And I believe that they decided to go in
17 different directions, so, in fact, the research – or

18 funding for that research, in fact, I have to have the
19 final report into the funding agency this – later this
20 week, and that will officially shut down our – our
21 vaccine research with COVID-19, at least at this point
22 in time. I still – as I – I – I think I’ve mentioned,
23 for example, I have on my webpage indicated clearly,
24 that what we – you know, we – we – ’cause I recognize
25 that in order to get a properly functioning – like a
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1 true vaccine, one that can confer sterilizing and near
2 sterilizing immunity, we need to follow a more – a
3 much more typical timeline for vaccine development. I
4 recognize that, you know, not long after we started a
5 research, so, that’s why my focus has changed to doing
6 the proper longer term research and trying to develop
7 a platform for future, highly-pathogenic
8 Coronaviruses. So, yeah. That’s the direction that

9 my research has taken. We’re nowhere close – nowhere
10 close to being able to even consider human clinical
11 trials, nor do we have the funding for that, which
12 requires millions of dollars.
13 390 Q. Okay. So, ’cause you agree that initially, you had
14 made comments suggesting that it would be ready for
15 approval by as early as 2021.
16 A. Yeah. And the grants – so, that’s called
17 “Grantsmanship.” That’s my – I – I - I know that they

18 wouldn’t be ready, but that’s what my co – there were
19 three of us, three co-principal investigators. What
20 they want – wanted to put in there, they were involved
21 in writing it as well, three of us. And yeah. I mean
22 anybody – any – any of the researchers, who wanted to
23 get any of the COVID-19 funding had to, by definition,
24 hope that they could have something within a year.
25 Everybody expressed that hope and that goal. Nobody,
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1 not one single person in Canada, who received COVID-19
2 funding to start development of a vaccine from scratch
3 has been able to get their vaccine to market, because
4 again, it highlights – it’s just completely
5 unrealistic.
6 391 Q. Okay. And you’re....
7 A. But again, as I want to emphasize, it’s about
8 researchers following the money. And so, when the

9 government dictates an unrealistic expectation in
10 order to achieve the funding, everybody raises their,
11 you know, scientists raise their hopes and think,
12 “Well, we’ll try and do what nobody’s done before,”
13 but clearly nobody in Canada was successful in meeting
14 that goal.
15 392 Q. Okay. And so, you’re saying that anyone predicting
16 successful vaccines within that timeframe, was doing
17 it just to get access to government funds and....

18 A. Well, I – I’m – sorry. Okay. Can I answer?
19 393 Q. Yes. You can answer.
20 A. Sure. So, I – I’m – I’m not going – that is – I –
21 that certainly going to have played a role with a lot
22 of the applications. I mean I knew looking at the –
23 looking at a lot of the applications, I mean I saw
24 what funds were awarded for. And I, over and over
25 again, these are – these are not going to be into
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1 market in the timeframe that’s indicated. Again, I
2 can’t – I’m not going to on an individual basis, say
3 that anybody – you know, what anybody was intending.
4 I’m sure there were lots of people who really did hope
5 that for the first time in their careers, they could
6 break all records for bringing something from
7 preclinical development to the market.
8 394 Q. But you agree, you made public statements to that

9 effect, that you were expecting to have something
10 prepared for approval by 2021?
11 A. We were hopeful. And I had to keep resetting the
12 goal, as we progressed with the research. So, for
13 example, since the first funding, the first bit of
14 funding that I got, I got a second grant, the same –
15 the same three co-principal investigators, and then in
16 there, we had to refine expectations. And in fact,
17 midway through, we had to modify timelines. And not

18 once, for that second grant, which was from the
19 National Research Council of Canada, not once did we
20 promise a vaccine. It was recognized at that time,
21 they were much more realistic with the funding, that
22 there’s no way at the end – it was supposed to be one
23 year of funding, and we were hoping to have some
24 preclinical testing done. We weren’t even close to
25 starting – well, I shouldn’t say – we started some
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1 translational testing, but nowhere close to being
2 ready for clinical testing. It was agreed that that
3 would be, at some point, in the future. And – and
4 then even there, we had to revise timelines for the
5 research and expectations in terms of milestones. So,
6 yes. People – so, we started with high hopes and I’ve
7 had to revise our – our predictions to be more
8 realistic, because we’ve progressed through the

9 research.
10 395 Q. So, paragraph 44, you state that Canada does not have
11 an Act of surveillance for monitoring vaccine safety,
12 is that correct? Take your time in getting to
13 paragraph 44 and review.
14 A. Yeah. That’s correct. Ours is called the Canadian –
15 CAEFIS, C-A-E-F-I-S. Canadian Adverse Effect
16 Following Immunization System.
17 396 Q. Okay. So, you...

18 A. Yes.
19 397 Q. ...weren’t considering then, CANVAS-COVID, which has a
20 website at https://CANVAS-COVID.ca then?
21 A. I – I’m not sure what that website is.
22 398 Q. Okay. You’re not familiar with CANVAS-COVID then?
23 A. No.
24 399 Q. Okay. And how about IMPACT, which can be found at
25 https://CPS.ca/impact. You’re not familiar with
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1 IMPACT either then?
2 A. No.
3 400 Q. Okay. Now, I’d like to turn to paragraph 73. Just
4 let me know when you’re there.
5 A. I’m there.
6 401 Q. Great. So, at paragraph 73, you rely on Ogata. A.F.,
7 et al., and the title is, “Circulating SARS-CoV-2
8 Vaccine Antigen Detected in the Plasma of mRNA [excuse

9 me] 1273, Vaccine Recipients,” and that’s in Clinical
10 Infectious Diseases, 2021, and I’m not going to bother
11 reading the DOI, but is that correct? That’s your
12 citation there?
13 A. Yes.
14 402 Q. And that’s cite 60?
15 A. Yes.
16 403 Q. And that was cited for the suggestion that a spike
17 protein or – or of the protein, excuse me – strike

18 that. And that’s for the suggestion that the spike
19 protein or the portion that binds the two receptors
20 could be detected in the blood for up two weeks, post-
21 vaccination in most individuals?
22 A. Yes. So, we were told this would stay at the
23 injection site and there would be no spike proteins
24 circulation. So, yes, this was proof of principal
25 that that – that there could be spike protein or the
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1 S1 subunit found in circulat – found circulating in
2 the blood. Yes.
3 404 Q. Okay.
4 A. Of – of – of people receiving the COVID inoculations.
5 Yes.
6 405 Q. And you say that it said – that it showed that the
7 spike protein could be detected in the blood, up to
8 two weeks post-vaccination in most individuals?

9 A. Yes. Yes. It was – ah, if I recall correctly, um,
10 uh, I think it was three of – they looked at 13 – only
11 13 healthcare workers, I believe it was three where
12 they found the intact spike protein and I believe it
13 was 11, almost – yeah, I believe it was 11 of 13,
14 well, I’ve got it here. Look at the paragraph. Yes.
15 And 11 out of 13, where they found the S1 portion of
16 the protein, and – and then this matches – ah, of - of
17 greater concern since then, there’s been reports

18 showing that the spike protein can also be found in
19 circulation via the release of exosomes, which is
20 quite concerning because the spike protein, again,
21 it’s a lesser concern of mine. The – the circ – the
22 circulating – free-circulating spike protein, it’s
23 designed to actually be embedded in the membrane of
24 cells, but our cells, in order to mediate cell-to-cell
25 communication released on a regular basis, what are
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1 called, “Exosomes.” These are little – these can be
2 like little fat bubbles that blub off from the surface
3 of a cell, and they carry proteins, the proteins that
4 are on the surface of the cell, with them. So, now in
5 addition to this, we now know that the spike protein
6 can also be found circulating through these exosomes
7 that carry the membrane-embedded spike protein around
8 the body.
9 406 Q. Okay. I’d like you to open up the document entitled,
10 “Circulating SARS-CoV-2 Vaccine Antigen Detected in
11 the Plasma of mRNA 1273 Vaccine Recipients.PDF,”
12 please.
13 A. Okay. Okay. I have it in front of me.
14 407 Q. Okay. And as we’ve discussed, it’s a study of 13
15 individuals?
16 A. Yes.
17 408 Q. And this is the – this is the document though that you
18 were citing at, it’s cite 60, correct?
20 409 Q. Okay. Could I get you to turn to – if I can find the
21 page here. The “Result Section,” I’m just trying to
22 figure out what page it is. I think it’s 204. So,
23 the second page.
24 A. Sorry. This is of the PDF?
25 410 Q. Yeah of the PDF, please. Thank you, sir.
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1 A. It – okay. Sorry. And what do you want? Okay.
2 Result Section and which paragraph?
3 411 Q. It is going to be the third paragraph. So, it’s on
4 that page 2. It’s the first full paragraph on page 2.
5 A. Okay. I’ve got it.
6 412 Q. Okay. Thank you. And, sir, you’ll agree with me that
7 the authors write, “The mean S1 peak levels was 68
8 pg/mL + -21 pg/mL. [Excuse me] S1 in all participants

9 declined and became undetectable by day 14. No
10 antigen was detected at day zero for 12 of 13
11 participants, as expected. However, one individual
12 presented detectable S1 on day zero, possibly due to
13 assay cross reactivity with other human coronaviruses
14 or asymptomatic infection at the time of vaccination.
15 Spike protein was detectable in three of 13
16 participants on an average of 15 days after the first
17 injection. This means that spike peak level was 62

18 pg/mL + -13 pg/mL. After the second vaccine dose, no
19 S1 or spike was detectable, and both antigens remained
20 undetectable through day 56. For one individual
21 (Participant 8), spike was detected at day 29, one day
22 after the second injection and was undetectable two
23 days later.” Do you – do you agree that’s what they
24 wrote?
25 A. Ah, yes. I agree.
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1 413 Q. Okay. And you’d agree that they specifically said,
2 “S1 and all participants decline and became
3 undetectable by day 14?”
4 A. Yes. That’s exactly why I mentioned the 14 days.
5 That one where they’re referring to day 29, I – I
6 don’t consider that to have been in circulation for 29
7 days. I believe that that was due to the second dose.
8 So, therefore, yes, I agree that the maximum duration

9 was 14 days.
10 414 Q. Okay. So, when you wrote....
11 A. Oh-oh. Sorry. Just to correct. Did you say 14?
12 Because actually, I remember it said, “...spike
13 protein was detectable in 13 of – 3 of 13, an average
14 of 15 days after.” So, an average of 15 days.
15 415 Q. Yeah. Okay.
16 A. Yeah. Approximately – approximately two weeks.
17 416 Q. All right. Thank you, sir. So, 3 of 13, you said,
18 right?
19 A. Yes.
20 417 Q. So, is that slightly different than the spike protein
21 could be detected in the blood up to two weeks, post-
22 vaccination in most individuals?
23 A. Ah, no. There was – it’s the spike protein or the S1
24 subunit of the spike protein.
25 418 Q. Oh, but you just wrote spike protein here, “...or the
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1 portion that binds,” and so you’re saying that
2 [inaudible]....
3 A. Or – or – or the portion that binds these two
4 receptors, which is the S1 subunit. Yes.
5 419 Q. And so S1....
6 A. And it can be found in 3 out of 13.
7 420 Q. I’m sorry. I’m talking over you. Please continue.
8 A. Yeah. So, noticeably, the spike protein or the

9 portion that binds to the ACE2 receptor, which is that
10 S1 subunit, can be found in circulation 3 out of 13
11 people, and 11 out of the 13 respectively.
12 421 Q. Okay.
13 A. And the spike protein detects in the blood up to two
14 weeks post-vaccination in most individuals and at –
15 and actually, I – I see now that was – I’m going to
16 say 28, but 29 days...
17 422 Q. Right.
18 A. ...in the one individual. But again, I don’t believe
19 that was circulating for 28 days. It was probably in
20 circulation for approximately two weeks and then the
21 circulation renewed after the second dose.
22 423 Q. Okay, but it doesn’t say, “most individuals.”
23 A. Ah, well, yeah, again, as I – as I – I clarify it up
24 above. The spike protein or the portion that binds
25 these two. The S1 subunit.
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1 424 Q. Okay.
2 A. Yes. In other words, uh, the spike protein or portion
3 thereof, that would have the potential to induce
4 signalling through the ACE2 receptor. Yes.
5 425 Q. Right. I – I’m – I guess I’m just confused by their
6 reference to 3 of 13, 15 days after the first
7 injection and then also their comments about the S1...
8 A. Yes.
9 426 Q. ...being undetectable by day 14. Do we have different
10 understandings of what two weeks are, sir? Or....
11 A. No. They’re both – yup. Fourteen – fourteen days for
12 the S1 and 15 for those in which they found the full
13 spike protein.
14 427 Q. Okay. Maybe – maybe we just misund – maybe we’re just
15 disagreeing on what “most” means, in the context.
16 Because I....
17 A. Ah, yeah. “The spike protein can be detected in the

18 blood up to two weeks post-vaccination in most
19 individuals.” So, that’s 11 out of 13, that’s where I
20 get the most.
21 428 Q. Okay.
22 A. Most individuals, 11 out of 13.
23 429 Q. I didn’t see that in the paragraph, but maybe I’m
24 missing it, but that’s fine.
25 A. Yeah. I guess I can clarify if I were to clarify a
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1 sentence, I would reword it to say, “The spike
2 protein...” like – like previously, but I didn’t want
3 to be repetitive. “The spike protein and/or S1
4 subunit could be detected in the blood up to two weeks
5 post-vaccination in most individuals.”
6 430 Q. Okay. Thank you, sir. I’d like to mark this as an
7 exhibit. Madam Court Reporter, do you have it?
8 COURT REPORTER: Yes, I do. It would be Exhibit 5.

9 MR. ELFORD: Yes.
12
13 EXHIBIT NUMBER 5: “Circulating Severe Acute Respiratory
14 Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine Antigen
15 Detected in the Plasma of mRNA – 1273 Vaccine
16 Recipients”, in NIH, 2021, by Ogata, et al.
17
18 431 Q. And so, you’ll agree with me, sir, as well, that one
19 of the authors of this paper, David R. Walt, has been
20 quoted as saying, “Bridle is taking our results and
21 completely misinterpreting them.”
22 A. Ah, yeah. I – I – I am aware of him making that
23 statement and I completely disagree. And I’ll tell
24 you why. The – what – what they’re – so, first of
25 all, as I’ve said, many – to put this into some
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1 context for the Court. Criticisms about this came
2 out, none of these individuals, by the way, including
3 the author that you’re referring to, I mean, I – I –
4 there’s been zero individuals in the entire world that
5 have talked to me, personally, about any of my
6 scientific perspectives. The only place I’ve been
7 able to do this is in Court. So, thank you for
8 allowing me to speak with you about it. But

9 otherwise, outside of Court, not one single person.
10 And so, the messaging from this came after – it’s
11 almost exactly one year to the day, I gave an
12 interview, which I do as a public servant, that’s part
13 of what I do, every university has a media relations
14 department, our expertise is listed, and we’re
15 expected to answer questions to the – that the public
16 has, if it’s within our area of expertise. So, on a
17 radio interview, somebody asked me about whether or

18 not the mRNA might be potentially related to cases of
19 Myocarditis that have been detected in young males. I
20 said, “Yes,” and then I started to explain potential
21 mechanisms, whereby that could occur. And, of course,
22 now it’s widely accepted that Myocarditis is part of –
23 it's on the vaccine labels. We all accept that
24 Myocarditis is a – a side effect of these vaccines,
25 especially young males. But I started to talk about
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1 potential mechanisms of action, of which this was one.
2 This is one of my minor concerns, in terms of
3 potential mechanisms of action, I never got to finish
4 my discussion. It was a radio interview. They’re
5 dealing with a tight timeline. And so, I was cut-off
6 and – and then people ran with that. And that’s the
7 information nobody consulted with me, or – or talked
8 to me about it. But so, I’m happy to provide this

9 feedback now.
10
11 So, first of all, the issue here is this is a minor
12 concern, because the proteins actually supposed to –
13 it has an anchor portion of which we call
14 transmembrane component. So, when – when cells –
15 remember these mRNA vaccines carry just the blueprint.
16 When these – when that blueprint gets delivered into a
17 cell, it’s designed to use the cell’s own protein

18 manufacturing capacity to read that genetic blueprint
19 and make the spike protein. And the spike protein is
20 designed to have a transmembrane component, which
21 means that the spike protein ends up being embedded in
22 the cell membrane. And it’s supposed to stay anchored
23 there like a flag on the surface of the cell. So,
24 like I said, my greater concern is now we know these
25 exosomes that can bud off, have mul – can have
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1 multiple copies of the spike protein, that can then
2 bind to ACE2 receptors and cause signalling.
4 So, even more so than that, a greater concern is the
5 fact that we’re actually getting their own cells to
6 express the spike protein. So, we’re actually, when
7 we induce an immune response, we’re causing an
8 autoimmune response, because then our cells – and with

9 the biodistribution study, you see, it could be cells
10 anywhere in the body are now expressing that spike
11 protein. So, that’s actually my major concern, along
12 with the toxicity of lipid nanoparticles themselves,
13 when they get distributed. But with it’s lessor,
14 lessor concern, about this potential mechanism, it was
15 if this were a potential mechanism of action, it’s the
16 fact that – like we just talked about, the spike
17 protein in these vaccines can bind to the ACE2. So,

18 if it does get into circulation, it can potentially
19 bind to the ACE2 receptors and po – potentially cause
20 cardiovascular damage.
21
22 And so, what he was criticizing me about is that –
23 yeah, yeah, they didn’t look directly at
24 cardiovascular damage, that came, again, from studies
25 of looking at the natural pathogenesis of the virus,
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1 itself. And when the virus got deep into the lungs
2 and started to spread throughout the body through the
3 – through the blood, a condition we call, “Viremia,”
4 there were a lot of – it was found that the spike
5 protein, itself, either on the virus particles, or in
6 experiments, when administered on its own, and that’s
7 how we then got to learn a lot of the pathology caused
8 by the virus is mediated by the spike protein, binding

9 ACE2 on cells in the circulatory system. And that can
10 cause clotting problems, bleeding problems, and so on.
11
12 So, that’s what I recognize, is this protein has the
13 potential, on its own, if it can bind to the ACE2
14 receptor, of potentially causing harm in the
15 cardiovascular system. This paper showed the
16 potential for it to be circulating in the
17 cardiovascular system. So, yes, the authors of this

18 study, didn’t show it directly here that it – it could
19 cause damage, and in fact, arguably in – in the 13
20 people they did, 11 people where they found the spike
21 protein, or a portion thereof, there’s no way at the –
22 these are tiny concentrations, very tiny
23 concentrations. There’s no way if these tiny
24 concentrations, I would expect there to be any
25 substantial obvious harm to somebody’s cardiovascular
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1 system. Again, and so, that’s what they criticized me
2 about. And so, told me that I misinterpreted. I
3 didn’t misinterpret it at all. I - I would – I would
4 – if these were high concentrations of the spike
5 protein, I would say there’s no way this could
6 possibly be a mechanism of harm for the vaccines. Why
7 do I say that? Because we don’t have a vast majority
8 of people receiving these vaccines, having serious

9 cardiovascular issues, at least not in the acute
10 periods we’ve been able to evaluate.
11
12 And so, the example that I like to use is in Canada,
13 we ended the AstraZeneca vaccine program when it was
14 found that blood clots were occurring in – and again,
15 because of the way we do the reporting, I – I would
16 actually argue, it’s almost certainly a higher
17 frequency, but the publicized frequency was that 1 in

18 55,000 people were developing potentially dangerous,
19 potentially fatal, and several Canadians did die,
20 because of the AstraZeneca vaccine rollout due to
21 fatal blood clots. So, 1 in 55,000, that’s what I
22 keep emphasizing.
23
24 More recently with the Moderna vaccine, we’ve
25 recommended that young males don’t receive the Moderna
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1 vaccine because of, again, reported incidents of 1 in
2 5,000 cases of Myocarditis and/or Pericarditis. Um,
3 with the Pfizer vaccine, you know, in Canada, we’re
4 claiming a 1 in 28,000 incidents, but Pfizer
5 themselves, claim that 1 in 10,000 incidents. But the
6 whole purpose of bringing out those numbers is, it
7 shows what we have defined as being too unsafe for the
8 vaccines. The point at which we say, “These vaccines

9 carry too much risk, relative to the risk associated
10 with COVID-19.”
11
12 So, again, let’s go back. So, pick one of those
13 numbers. Let’s pick the 1 in 55,000 for AstraZeneca.
14 For adults, once we saw that 1 in 55,000 Canadians
15 receiving the AstraZeneca vaccine were at risk of
16 developing these dangerous blood clots, we shut the
17 program down. We said, “The AstraZeneca vaccine is

18 too dangerous for Canadian adults, relative to the
19 dangers that they face from COVID-19.” So, again, I
20 come back to this paper. If, and I say, if this is a
21 mechanism of action and it’s one of the minor
22 mechanism of action, potential mechanisms of harm that
23 I would consider, a minor one, but if it were, then if
24 – if this were, for example, causing something that
25 occurred 1 in 55,000 people, which would be – which
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1 would cause the program to be shut down, we would have
2 to – I would only expect to see substantial
3 concentrations of this protein in about 1 in 55,000
4 people. So, if they were to find this in a bunch of
5 people and they’ve only looked at 13, that would be
6 crazy. There’s no way this could – I wouldn’t
7 actually have any concern that this could possibly be
8 related to vaccine-related harm.

9
10 So, you see, that’s where – so they claim that I
11 interpreted this incorrectly. No. I’m corr – I’m
12 interpreting this based on the sum total of the data
13 that I see. And I see that that we are shutting down
14 programs, when severe problems, cardiovascular
15 problems in occur in 1 in 28,000, 1 in 55,000, you
16 know, 1 in 5,000 people. And so, if this is a
17 mechanism of action, again, you’d have to sample – and

18 – and if you only sampled 5,000 people, chances of
19 finding that 1 in 5,000 actually is very rare. You’d
20 probably have to sample, I’d say 15 to 20, maybe
21 25,000 people to be sure that you’re finding those 3,
22 4, or 5 that – that might have substantial
23 concentrations.
24
25 So, you know, it’s not that I didn’t understand this
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1 paper. I understand this paper full well. But, of
2 course, the author didn’t want to talk to me about
3 that, they just went on with their fact check and –
4 and that’s fine. As you can see, I – I – I can
5 interpret the data. I – I know the data, I know what
6 it means, I know these are very low concentrations in
7 these people. And that’s actually the reason why I
8 got concerned, it’s the proof of principal. And now

9 we’ve added to this proof of principal, the clear cut
10 knowledge that these – these are primarily expressed
11 on the surface, like a – like a flag. And so, the
12 whole purpose of these vaccines are to induce
13 antibodies and T cells that are spike protein
14 specific.
15
16 Now, this is my primary concern, when those antibodies
17 and T cells start appearing, based on the

18 biodistribution study, we have cells throughout our
19 body that are expressing a spike protein, they now
20 become targets of their own antibodies and T cells and
21 get killed, and that risks induction of autoimmune
22 diseases potentially. That’s a bigger primary
23 concern, as well as the toxicity of repeated
24 administration of lipid nanoparticles that can be
25 distributed stomachly [sic] throughout the body. So,
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1 that’s just to put that in perspective. It’s a minor
2 potential mechanism of harm, that I highlighted from
3 this paper.
4 432 Q. And your concerned that these adverse events could
5 happen years down the road?
6 A. Oh, absolutely. So, yeah. There’s – there’s this – I
7 don’t know where – actually where it comes from, this
8 – this misunderstanding that somehow vaccine-related

9 harm would be – could only be found within two – you
10 know, about two months after administration of a
11 vaccine. That’s ridiculous. So, for an example, I
12 published a paper, there’s – in this – in the spike
13 protein, there’s a portion that is – that has – shares
14 a lot of identity with, um, ah, a prions – prion-like
15 protein and there’s the potential, if this were to get
16 into the central nervous system, of being able to
17 induce things like Prion Disease.

18
19 So, I published a paper on this within the last year,
20 and if that were – and we stated right in there, if
21 that were to occur, that might not become apparent for
22 decades, because Prion – Prion diseases are very, very
23 slow progressing. So, signs and symptoms could take
24 10, 20, even 30 years before there’s onset. Another
25 example, I’d like to use is with the biodistribution
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1 study that I brought up. We see high concentrations
2 of the lipid nanoparticles going to the ovaries. And,
3 again, the lipid nanoparticles on their own are pro-
4 inflammatory and can be toxic to cells, especially if
5 – if dosed multiple times. The – the – the CEO of
6 Moderna and many of the biotech companies have openly
7 acknowledged this. In fact, interesting thing is
8 that’s exactly why they have – they applied the lipid

9 nanoparticle technology to vaccines, because they knew
10 that traditional vaccines, you know, things that
11 actually function, like true immunizations, were
12 usually a one and done, or a two and done process.
13 Meaning one dose, or two doses and you’re done for
14 life. Because they recognize that multiple, repeated
15 dosing with lipid nanoparticles is very toxic to
16 cells, and can cause a lot of damage. So, that’s
17 exactly why they – they applied the technology instead

18 of things like gene therapies and drug delivery
19 systems, which require multiple dosing over short –
20 short periods of time. But here we are, doing
21 multiple dosing, over short periods of time, because
22 they’re not functioning like true immunizations. And
23 so, the whole consequence of this is that if – if
24 these go to the ovaries, there’s multiple mechanisms
25 of action. There’s the lipid nanoparticles, that
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1 cause inflammation and damage to – to ovarian cells,
2 or I would argue when you think about it, in order to
3 get to the ovaries, it would be gong through the blood
4 vessels, so, what they’re going to be seeing is the –
5 what we call the endothelial lining of the blood
6 vessels, in places like the ovaries. That’s the first
7 thing they’re going to encounter. And so, it’s going
8 to be infecting the cells that line the blood vessels

9 and causing inflammation to blood vessels. And so,
10 the lipid nanoparticles can cause damage, and – and
11 then, when we get them, those cells expressing the
12 spike protein, which is sitting there on the surface,
13 like it’s supposed to, designed to do, and then we
14 have antibodies and T cells come in and killing them,
15 we can – we can potentially causing harm in whatever
16 tissues these are accumulating in. And so, one can
17 envision, if the ovaries were to become damaged, so,

18 let’s use the example of – I mean we’re vaccinating
19 down to five-years-old, so, let’s say it’s a five-
20 year-old girl, and let’s say for example, that a five-
21 year-old girl has damage done to the ovaries, damage
22 that would cause her to become infertile. Now I know
23 that Dr. Dawn Bowdish mentioned, “Well, if there’s
24 harm to the ovaries, you would see signs, like maybe
25 some vaginal bleeding, or something like that.” She
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1 should mention the, you know, the medical terms
2 related to that, but it’s evidence of bleeding from
3 the ovaries, which could be revealed potentially
4 through blood, you know, spotting, and you wouldn’t
5 expect that, in – in – for example, a five-year-old.
6 Well, those signs and symptoms from that are – are
7 actually quite rare. It’s rare for there to be
8 obvious signs and symptoms of that kind of harm to the

9 ovaries, and plus, we don’t have – nobody’s looked, we
10 haven’t more experience with this technology when it
11 comes to the ovaries. I’ve been saying, we need to do
12 these studies, and nobody’s doing them. But let’s
13 say, for as an example, so, there’s harm, and then
14 that person is like most of the people where there’s
15 harm to the ovaries, where they’re – there is no
16 obvious signs of potential damage, there is no
17 bleeding that appears, vaginal bleeding in that five-

18 year-old, then the only way that we are going to know
19 that – that five-year-old is infertile is when she
20 tries to have children, right? Maybe after she goes
21 to university, she gets married, and wants to have
22 children, you know, at age 30. So, there’s an example
23 there, where it could 25 years, right. You can’t have
24 a child and then it gets investigated. Now, the
25 problem is 25 years later, chances of linking that to
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1 the vaccination at five-years-old is – is a long
2 stretch. But yeah, nobody – nobody can really –
3 there’s absolutely, we can – the only way we can be
4 sure, is if we document all these things properly, and
5 which really requires active monitoring, and we need
6 some long-term safety assessments. And with this
7 biodistribution, we need to be looking at the ovaries,
8 and we need to be actually addressing that issue, is

9 it accumulating? Is it causing the spike protein to
10 be expressed? Because the biodistribution study just
11 looked at the lipid nanoparticles and they didn’t look
12 at the messenger RNA, they didn’t look at the spike
13 protein, and of course they should have. So, in
14 short, yes, there could be long-term consequences.
15 There’s also, I want to point out one final thing,
16 it’s not just that there could be – there could be
17 harm that isn’t – that could take a long time to

18 reveal itself, in terms of signs and/or symptoms, but
19 there’s also delays in detection. So, if we aren’t
20 doing active monitoring, like is – what is done in a
21 clinical trial, and we don’t do it properly, or for a
22 long enough period of time, there can be delays in the
23 detection of safety signals. So, we’ve already seen
24 that many times with this rollout. There’s all kinds
25 of safety signals that have a – arisen that were not
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1 detected in the clinical trials, because they were not
2 of large enough scale, they were not tracked for long
3 enough. So, for example, we saw anaphylactic shock,
4 which – which was revealed in the very first day of
5 the rollout, which was not disclosed from the clinical
6 trials. We’ve seen myocarditis. We’ve seen
7 pericarditis, right. We’ve seen all kinds of these
8 other things appearing. And that was after the fact.

9 And I like to use the example of the 2009 Swine Flu
10 Pandemic, where then there – there was a – a version
11 of – of a vaccine that was used, and it used a special
12 antigen, the – the vaccine was called Pandemrix. And
13 that was used in Europe. And again, the harm
14 occurred, and – and like I say, it occurred within
15 eight weeks, but it certainly occurred in less than
16 two years. But it took two years to detect the safety
17 signal, right, of narcolepsy. Narcolepsy was being

18 caused in people, where they can suddenly lose muscle
19 tone, um, for – for no apparent reason. Right. That
20 took – that took two years to be recognized. And now,
21 the United States CDC, makes sure that everybody knows
22 that when it comes to, you know, the flu vaccines,
23 they have listed very clearly that, you know,
24 Pandemrix is not used in North America for that
25 reason. It’s an issue of concern. So – so, yes.
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1 Definitively, there’s absolutely no way that anybody
2 can – can monitor vaccine safety for a matter of a few
3 months and then be confident that there could be no
4 long-term harm. That – that is just ludicrous and to
5 put it in perspective, for example, Pfizer’s clinical
6 trial, a lot of people don’t realize that they removed
7 the placebo group, which is designed to look for
8 safety signals. They removed the placebo group four

9 months into their clinical trial, and then, so when
10 you look at the median time, because of course,
11 they’re rolling people in the trial at different time
12 points. So, when you look at the median time for when
13 people were enrolled in the trial to the removal of
14 that group, it is two months. So, that’s literally
15 what we have in terms of active formal proper, you
16 know, active safety monitoring. So, we have two
17 months worth of data. So, no, that’s not sufficient

18 to be confident that there are not going to be any
19 long-term consequences for these COVID-19
20 inoculations.
21 433 Q. Okay. So, you mentioned fact check. I assume that’s
22 because you had read the article at Fact Check.org,
23 where David Walt makes that comment, is that correct?
24 A. I can’t confirm which one it was. I – I’ve been –
25 I’ll be honest, I’ve been fact checked to the whazoo
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1 and I – I have addressed every single fact check that
2 has been raised, that I’m aware of in various media
3 interviews at time-to-time. So, I’m not sure exactly
4 what the cite was, but I’m happy to address any fact
5 checker question, at any time.
6 434 Q. Okay. If you could just open up the document 72,
7 “COVID-19 Vaccine Generated Spike Protein is Safe
8 Contrary to Viral Claims.PDF.” It should have been

9 provided to you, sir.
10 A. Okay. And does it start with the number 72, did you
11 say?
12 435 Q. Yes, it does, sir.
13 A. Um, was that one sent this morning, do you know? I
14 don’t see one that starts with 7-2.
15 436 Q. It should have been. But you know what, do you agree
16 with me that he made this statement? There’s – well,
17 I guess there’s another one that may have been sent

18 without that number, but....
19 A. Okay. I – okay. I think I do have it here.
20 437 Q. Okay.
21 A. Is it, “Side Checks, COVID-19 Vaccination Project?”
22 438 Q. Yeah.
23 A. COVID-19 Vaccine Generated Spike Protein is Safe
24 Contrary to Viral Claims. Okay. Yes. I received
25 that this morning.
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1 439 Q. Yeah. And is that the article that you may have read
2 to – or that you did read, excuse me, where you first
3 learned about Dr. Walt’s comment?
4 A. No. This wasn’t the article.
5 440 Q. Oh, okay. Why don’t you take a quick read of it for a
6 second here.
7 A. Okay.
8 441 Q. When you’re done let me know. And then I’m going to
9 ask you a very simple question for you, which is, is
10 this consistent with the criticism that you were
11 describing?
12 A. This deals with additional things. So, I’d like to
13 make two comm – or yeah. At least two comments....
14 442 Q. Sure. Sure. How about you do that after I ask you
15 just – is this consistent with what you recall David
16 Walt’s saying in respect to what you said about his
17 study?
18 A. Okay. Just give me one sec here again, ’cause I see
19 there’s mul – multiple different people quoted here.
20 443 Q. Yeah. It’s underneath the words that are large, “No
21 evidence vaccine generated spike protein lingers in
22 blood stream.” And it’s about two paragraphs down.
23 It’s the third paragraph. And then he talks from
24 there and there’s more comments.
25 A. I – I don’t think that’s the section for...
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1 444 Q. Okay.
2 A. ...Walt. I do see under “Protein,” oh, wait, did you
3 say, “Protein lingers in bloodstream?” That
4 [inaudible].
5 445 Q. Yeah. It says – there’s – there’s a large text that
6 says, “No evidence vaccine generated spike protein
7 lingers in bloodstream.”
8 A. Ah. No. I see – I see up above that, protein lingers

9 in bloodstream. And I see, one, two, three, four,
10 five, six paragraphs below that, Walt – Walt told us –
11 told us in an e-mail, you’re talking about the Walt
12 Study?
13 446 Q. Okay.
14 A. Is that correct?
15 447 Q. Yeah. He actually – there’s a quote from him about
16 three paragraphs up from that, but that Walt told us
17 in an e-mail is also part of the commentary. Yes.

18 From – from the author Walt.
19 A. Okay. So, what I can see is for this portion, Walt
20 talked about the extremely low concentrations, which I
21 did as well. Yeah.
22 448 Q. So, is that consistent with the criticism that you’ve
23 heard from him?
24 A. Ah, just let me finish what he has to say here. Well,
25 there – there’s a sec – a second one. Ah, which I
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1 wasn’t addressing. So, the second one raised is that
2 these vaccines induce antibodies.
3 449 Q. Sure.
4 A. Right.
5 450 Q. But that – I – I – we can talk about that in a moment.
6 I just want to know if this commentary from Walt is
7 consistent....
8 A. Well, he talks about the – well, he talks about the

9 antibodies. So, what we’ve talked about was the
10 portion about the low concentrations of the protein...
11 451 Q. Uh-hmm.
12 A. ...in circulation. Yes. That’s – that’s what I...
13 452 Q. Okay. Right. Okay.
14 A. ...that’s the portion that I’ve addressed.
15 453 Q. Sir, and then what I’m going to ask you to do is –
16 hold on for a second. I’m gonna ask to have this
17 entered as an exhibit because we’ve talked about it

18 for a while and you’re going to want to respond, I
19 understand, to other comments here, and – and fair
20 enough. But I’d like to mark this document as an
21 exhibit, but what I’d like you to do, sir, is just
22 read the name of the PDF document you’ve got.
23 A. Ah, like - like the file name?
24 454 Q. The file name, please. Yes. So, Madam Court Reporter
25 knows what it is.
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1 A. Okay. It’s “Factcheck.org_COVID-19 Vaccine-Generated
2 Spike Protein is Safe, Contrary to Viral Claims,” and
3 then in brackets, it says, “Screen Capture, May 20,
4 2022.”
5 MR. ELFORD: Okay. And do you have that Madam Court
6 Reporter?
7 COURT REPORTER: Yes, I do. That’s Exhibit 6.
8 MR. ELFORD: Okay. Sir....

9
10 EXHIBIT 6: “Fact Check.Org COVID-19 Vaccine-Generated
11 Spike Protein is Safe, Contrary to Viral Claims,” (May
12 20, 2022)
13
14 MR. WILSON: Counsel, before – before you go further, I
15 have not been able to bring up these 80 documents in
16 the speed that you obviously both have them on your
17 screens. So, you’ve been exchanging questions and

18 answers referring to this. And, “Is this it?” And
19 “Yes, that is,” “This is that.” I have no idea what
20 this is. Is this PDF document one-page or a thousand
21 pages? Were you referring to paragraph 2 on page 2,
22 or Section 7 on page 50? Could you just help us with
23 – you guys used the word “this,” probably 10 or 12
24 times and I have no idea what “this,” is, so, I would
25 be grateful if you could do that.
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1 MR. ELFORD: Sorry. That’s fine by me, if you give me a
2 moment, here.
4 MR. ELFORD: So, just so I know, Counsel, do you have the
5 document open now?
6 MR. WILSON: No. I’m not even – there’s 80 documents.
7 I’m trying not to slow this down.
8 MR. ELFORD: No, I appreciate that.

9 MR. WILSON: I keep up with the – the stuff that I had
10 notice of and so on, but if you could just simply –
11 you’re going to need it for the record anyway. The
12 transcript’s not gonna mean anything because you guys
13 will say you’re this meant that, and I’ll say, “Oh,
14 no. This meant something else.”
15 MR. ELFORD: Oh, wow.
16 MR. WILSON: So, I’m sort of doing you a favour here, to
17 give it some precision, as to what “this” means.

18 MR. ELFORD: Well, I appreciate the favour, sir. So,
19 I’m looking at page 2.
21 MR. ELFORD: And about the third paragraph down, it says
22 [quote], “Bridle is taking our results and completely
23 misinterpreting them,” [end quote], said David Walt, a
24 Member of the Faculty of Harvard Medical School and
25 Harvard Wyss Institute for Biologically Inspired
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1 Engineering, who co-authored a study that found
2 circulating SARS-CoV-2 vaccine antigen in the plasma
3 vaccine recipients.
4 MR. WILSON: That’s very helpful. Thank you.
5 MR. ELFORD: You’re very welcome.
8 455 Q. Dr. Bridle, I – I take it, you agree with how I

9 described that document?
10 A. Ah, yes. But – but again, it would good if we’re in
11 agreement on what – what portion we’re talking about.
12 Because again, this document is five pages and
13 includes multiple, multiple comments.
14 456 Q. Sure. The comments I’m talking about are from where I
15 just read. Down that same page to the following and
16 this is about Walt, [quote] “COVID-19 on the other
17 hand is known to have significant effects on many

18 tissues and organs,” [end quote] he said. [Quote]
19 “The most important message is that over 400 million
20 doses of the mRNA vaccine that have been administered
21 with negligible, serious consequences. It is
22 incredibly safe,” [end quote]. So, that’s the
23 section, I asked you if that’s consistent with what
24 you understood his criticisms to be, that area,
25 between those two parts.
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1 A. Ah, yes, but there’s two criticisms that he has that
2 he said I didn’t understand. I’ve only addressed one
3 of them.
4 457 Q. Okay. And I am not going to stop you from addressing
5 the second one. So, I just want to mark this as an
6 exhibit and then if you want to address the second
7 one, I – I understand.

9 A. Okay. And may I address the second one?
10 458 Q. Yes. What is your concerns with respect to his second
11 criticism?
12 A. Okay. So, he said, first of all, I understand it’s a
13 small concentration. And – and I already said that I
14 – I understand that fully. And explained that if – if
15 this was – and this is a minor concern of mine, as a
16 potential mechanism of harm, again, I emphasize that,
17 but if this were a mechanism of harm, again, I would

18 expect therefore to only see reasonable concentrations
19 of the spike protein are portions thereof, in one in
20 tens of thousands of people. Not – and it wouldn’t be
21 detectable in only 13. So, that’s – that’s the first
22 part, where he’s claimed that I didn’t understand the
23 paper. But the second one with respect to antibodies,
24 and the idea being that this is the result of a
25 vaccine and the vaccine is – is designed to induce
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1 antibodies that – that should neutralize the spike
2 protein. So, he’s telling me as a vaccinologist, that
3 I somehow don’t understand that antibodies, which is
4 the purpose of administering a vaccine, one of the
5 effects or mechanisms that you want to induce, that
6 they can neutralize the spike protein. But see, he is
7 not an immunologist. So, he’s the one who has
8 actually not understood the scope of his study and –

9 and the limited scope. Just because – just because he
10 drew limited conclusions, doesn’t mean that those are
11 the only conclusions that can be drawn from the
12 science. So, he – he’s made a critical error here,
13 because what he says is, “But the vaccine is designed
14 to induce antibodies, and people have shown the
15 antibodies’ neutralize the spike protein and actually
16 protect the blood vessels from – from – from a spike
17 protein mediated harm. And therefore, you know, Dr.

18 Bridle, who’s a vaccinologist should know this and
19 should know the very – the vaccine is going to
20 neutralize the spike, and it can’t do any harm to the
21 immune system, even if there were any in circulation
22 in any substantial quantities. Well, he’s absolutely
23 100 per cent wrong and he’s not an immunologist and
24 this is the problem. So, I’m sorry. You don’t judge
25 a vaccinologist, when you haven’t talked to the
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1 vaccinologist. That’s not how science works. It’s
2 not how it’s suppose to work, but that’s how it works
3 for the last two years. So, let me correct this, and
4 – and ’cause I haven’t had the opportunity to speak
5 with Dr. Walt. This is an opportunity to put it on
6 public record.
8 One has to think, okay, when the vaccine is

9 administered, so, in this case, the Pfizer vaccine,
10 all it is, is a bunch of lipid nanoparticles that have
11 mRNA inside. The – the blueprint for the spike
12 protein. There are no antibodies in or on the
13 vaccine. There are no antibodies in the vial of the
14 vaccine. One administers the vaccine with the intent
15 to induce an immune response, T cell responses, and B
16 cell responses. Those B cells, hopefully will produce
17 antibodies that can neutralize that spike protein.

18
19 Is he correct that these vaccines induce spike
20 neutralize and antibodies? He’s 100 per cent correct.
21 Is Dr. Walt correct that these antibodies, if they’re
22 present, at the time that the spike protein enters the
23 circulation, that they would neutralize that spike
24 protein and prevent it from ACE2 receptors, on the
25 cells lining the blood vessels and therefore protect
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1 an individual from potential cardiac harm, harm to the
2 cardiovascular system. He is 100 per cent correct on
3 that. One hundred per cent. I couldn’t – I couldn’t
4 agree more. This is the thing. This is the mistake
5 he's made. He was studying this from the perspective
6 of vaccinating and then looking at what happens if
7 there’s a viral infection, and should that virus cause
8 viremia, where there is the – the intact virus with

9 the - with the spike protein on the surface, in
10 circulation now, or there were pieces of the spike
11 protein, or free spike protein, or people have shown
12 that there are virus-like particles, not – improperly
13 formed virus – virus-like particles, that only contain
14 two or three of the proteins from the virus. One of
15 which is the spike protein, which causes
16 cardiovascular harm. And these are the ways, thereby,
17 the virus, itself, can cause damage to the

18 cardiovascular system.
19
20 So, if one were to be vaccinated and induce these
21 antibodies, and then get exposed to the infection, and
22 the spike protein, in any of these forms, were to get
23 into circulation, would you expect those neutralizing
24 antibodies would prevent harm to the cardiovascular
25 system. Yes. We’re – he and I are 100 per cent in
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1 agreement. But this is where he has made a critical
2 error in his judgment of my knowledge and where he’s
3 showing a complete and utter lack of knowledge. When
4 that is – when the vaccine is injected into the
5 shoulder, how many – so, again, this is – this is
6 assuming somebody is naïve. They haven’t been
7 vaccinated before and they haven’t been naturally
8 infected. And again, nobody’s screening for evidence

9 of – of natural acquisition of immunity. We’ve
10 already established that. So, a person gets the
11 vaccine dose. Where are the antibodies? Right. The
12 Viral Distribution Study, his own study, showed that
13 within 24 hours, there’s detectable spike protein.
14 Albeit, low concentrations. But that’s not the point,
15 the proof of principal is, there is spike protein
16 getting in there. Other papers have shown that you
17 can get the spike protein appropriately, what it’s

18 suppose to do, the vast majority of the time, is
19 express it on the surface and then you can get these
20 exosomes that get released and carry multiple copies
21 of the spike protein and they can get into
22 circulation. That’s clearly been documented in the
23 scientific literature. And worse, these exosomes have
24 – can have multiple copies, multiple spike proteins,
25 which means not only can they bind with high affinity,
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1 as we’ve already discussed, because these versions of
2 spike protein can bind, but you can have multiple
3 spike proteins binding the multiple receptors on the
4 cell. We call that increasing the avidity, which
5 really causes a lot of signalling in those endothelial
6 cells.
8 So, there’s these various mechanisms, whereby the

9 spike protein can get into circulation and – but this
10 is the whole thing, where are the antibodies at the
11 moment? There are no antibodies. There are no
12 antibodies to neutralize the spike protein, whether
13 it's an intact spike protein, whether it’s a spike
14 protein embedded in the cell membrane, like it’s
15 supposed to, but having been released by exosomes, it
16 takes up to two weeks before they are readily
17 detectable antibodies present. Um, and I’ll

18 acknowledge, you can get low concentrations, maybe you
19 start detecting low concentrations by five days post-
20 vaccination. You might even, if you – you’re – like
21 ultra-sensitive enough. I don’t know what you want to
22 argue? Two or three days later? That’s fine. But
23 there is a period of time, that’s the whole point.
24 That’s why we have the innate immune response, which
25 is rapid, because adaptive immunity, like antibody
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1 responses are delayed. So, we have the innate
2 response to fill in the gap, and – and start fighting
3 the pathogens, to buy time until we can get these more
4 effective T cell and antibody responses. And these
5 antibodies that – like I said, usually they are
6 readily detectable by 14 days later, but the whole
7 point is, there is a window, after these vaccines are
8 delivered, what we’re seeing is the spike protein can

9 get into circulation in various forms, and there are
10 no antibodies present. It takes several days. So,
11 there’s a window, where this is in circulation and
12 there are no antibodies present.
13
14 So, when he says here that, “Dr. Bridle doesn’t
15 understand what he’s talking about as a vaccinologist,
16 therefore he should be – ah, you know, his claim to be
17 a vaccinologist seems invalid,” you see, he’s showing

18 his complete and utter lack of knowledge when it comes
19 to vaccinology. So, yeah. They were studying this in
20 the context of natural infection. Vaccinating and
21 then what’s the impact of the neutralizing antibodies
22 on spike protein that can get into circulation. I’m
23 talking about in the context of the vaccine. Forget
24 about infection. The vaccine causing stomach
25 distribution of lipid nanoparticles and the mRNA
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1 throughout the body, such that we can get expression
2 of the spike protein, like it should on the cells,
3 release through exosomes, and some, tiny
4 concentrations in the vast majority of people likely,
5 a free-spike protein. But it’s going to be several
6 days before there is a single antibody present to
7 start neutralizing that. And worse, what he doesn’t
8 recognize, what he does not recognize, which is –

9 which I’m aghast about, because everybody is saying,
10 “Dr. Bridle, you – you’re worried about these tiny
11 concentrations. You know that the spike protein is
12 suppose to be expressed in the surface of the cell.”
13 Yes. And hello, once you have that expressed on cells
14 throughout the body, you’re absolutely correct, Dr.
15 Walt, you are going to have antibodies, that are going
16 to bind to and get rid of that spike protein. And
17 when it’s on the surface of our cells, it’s going to

18 get rid of that cell. It’s going to kill that cell.
19 That is what we call an autoimmune response, and that
20 risks induction of autoimmune disease. So, I’m sorry.
21 I get kind of passionate about this, but I have not
22 had an opportunity to deal, face-to-face with any of
23 these fact checkers, and so, the Court understands as
24 well, because this is about – ah, ’cause I noticed you
25 emphasize they’re from Harvard, right? So, this is
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1 about, you know, who is the real expert in the area?
3 So, let me point out something. They even state this
4 here in the document, right. So, they tried to
5 contact me. I couldn’t be contacted, because I was
6 overwhelmed. I was overwhelmed. My e-mail is
7 completely overwhelmed and still is, it chronically
8 has been.
9
10 And you know what these fact checkers do? Typically
11 they give you a few hours, they send you an e-mail and
12 say, you know, maybe it’s like – they send you an e-
13 mail early in the afternoon, late morning, and they’ll
14 say, “We’ve got to have our story filed by five
15 o’clock. You respond to this.” I don’t see it till
16 several days later and guess what? They’re – there
17 was one time, where I was sitting at my computer and

18 the e-mail came in from a fact checker. And I
19 responded just like this to everything, everything,
20 because I understand the science. I follow the
21 science. I have been for the full two years. I make
22 it my job to keep up-to-date with all of the
23 literature. And I responded to everything and then
24 they didn’t publish anything. I refuted every part of
25 the fact check. They never show that. So, it’s a
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1 complete – it’s just a time and energy drain. So, as
2 you can see, that’s why I said, I’m happy to deal with
3 any fact check that anybody has. I’ve always offered
4 that. That’s why I’ve dealt with it in any interview.
5 Anybody’s welcomed to ask me any fact check,
6 whatsoever, because I do know what I’m talking about
7 and I think I’ve done a good job of demonstrating it
8 here with Dr. Walt.

9 459 Q. Okay. Thank you, sir. Now on paragraph 8(11) of the
10 Affidavit and I believe the Affidavit, it might be the
11 Expert Report. Give me one second. But it’s also at
12 paragraphs 69 to 70 of your Expert Report. So, you
13 can definitely look at that. You talk about a report,
14 a Japanese Report, do you recall that? You’ve
15 attached it as Appendix “E,” I believe. Let me know
16 when you’ve found it.
17 A. Oh, okay. Yes. So, would you like me to look at

18 Exhibit E?
19 460 Q. Oh, well, just I – I want to draw your attention to
20 it, so, you know, where we’re looking generally. You
21 don’t need to look at Exhibit E right now, unless you
22 need to for part of your answer. Okay.
23 A. Sure.
24 461 Q. All right. But just so you know, I am talking about
25 that in Exhibit E. So, you agree then that this was a
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1 study with respect to rats?
2 A. Yes.
3 462 Q. Do you agree?
4 A. Yeah. Ah, yes. Absolutely. Unfortunately, it has
5 not been done in humans, which is absolutely needs to
6 be done.
7 463 Q. Okay. And this is the Biodistribution Study that we
8 were talking about previously in respect of lipid

9 nanoparticles, correct?
10 A. Ah, yes. But I would point out that I have also
11 included, because it’s very important, Exhibit F,
12 which is the full version of the Biodistribution
13 Study, and that is very important, because one needs
14 to put the two side-by-side, which then allows us to
15 see how much incredibly important and very concerning
16 data Pfizer left out of the Japanese version of the
17 Biodistribution Study. There are some very concerning

18 portions, and I would like to remind the Court, the
19 only reason why we have Exhibit F, the English full –
20 full version of the Lipid Nanoparticles Distribution
21 Study is because of court - a court order to make the
22 FDA, to disallow them from taking 75 years to release
23 this information, but to accelerate that. So, it’s by
24 court order only and what we’ve found is a lot of
25 additional information, rele – so, I was already very
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1 concerned, when I saw the Japanese study, that’s why
2 when I was asked publicly, I’m a public servant, and I
3 disclosed what I knew, but I’m even more concerned
4 when I see the English version. So, that’s my – I
5 have as exhibits, both. And so, it’s very important
6 that if we’re going to discuss it, I think it’s
7 important that we discuss them side-by-side.
8 464 Q. Well, I was – I was going to ask you to confirm what

9 Exhibit F was, but we’ve done that now. Um, so, you
10 agree that this study was a study where a large amount
11 of the lipid nanoparticle was administered to the
12 rats?
13 A. The – ah, yeah. A relatively large amount. Yes.
14 465 Q. Okay.
15 A. It – so, again, so, it depends on the study. The
16 Japanese version disclosed one dose. The English
17 version disclosed two doses, that were given. And

18 even that is – this is – it’s highly suggested that
19 this study was, ah, a real shortcut, because a proper
20 study this way, should have had multiple doses tested,
21 when one’s trying to find, ah, you know, identify a
22 safe dose. And look at the impacts of
23 biodistribution. But yes. So – so, two doses and so,
24 to put that in perspective, ’cause you say a high dose
25 – a dose in itself is kind of irrelevant, it’s all
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1 relative. So, the way to put this into perspective
2 is, if you’re going to run a study, where you’re
3 trying to demonstrate, when you’re trying to put your
4 product in the best light, and if you’re running – and
5 if you’re going to pick one dose, like they did for
6 the Biodistribution Study, obviously you’re not going
7 to pick a dose, where you think it’s going to blow up
8 in your face, and – and provide results that are going

9 to shock the regulatory agency. So, that’s why it’s –
10 if you – so, that’s what this story – that’s what this
11 document tells us, that the fact that they picked one
12 dose, and the English version shows the – the – the
13 first dose that they selected, you’re going to pick a
14 dose, where you believe it’s going to satisfy the
15 safety requirements, but also not trash your medical
16 product. So, what people don’t realize is that the
17 dose that they gave in the first iteration of this

18 study, killed the rats, and the authors concluded,
19 it’s right there in – in the report, the – the study
20 director, clearly concluded that they found evidence
21 of lipid nanoparticles everywhere, tissues, all
22 throughout the – throughout the rats. To the point
23 where they had to contact the study sponsor, which is
24 Acuist (ph), which is a British Columbia company that
25 made the lipid nanoparticles that are used by Pfizer
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1 and Bioantac (ph) for the vaccine, to say, “Look this
2 is killing the mice and it’s going everywhere in the
3 body. What do you want us to do?” You know, “We’ve
4 had to euthanize...” Sorry, I think I said, “mice,” I
5 mean rats. “We had to euthanize...” I can’t
6 remember, “...one or two of the rats already.” Their
7 response was, “Oh. Cut the dose in half and run it
8 again.” So, the version that we saw in the Japanese

9 Study was the second lower dose, um, but the whole
10 point then being, high or low concentration, what I
11 can tell you is, having run these kinds of studies,
12 multiple times, is if you’re only going to pick one
13 dose, you’re going to pick a dose that you think puts
14 your medical product in the best light, obviously they
15 did not understand their medical product all that
16 well, because they were way off, way off, in their
17 choice of the one dose.

18 DR. ELFORD: Okay. Thank you, sir. Now, um, I only have
19 what I hope to be maybe another half hour worth of
20 questions. But I also know we’ve been going for about
21 an hour and a half, and I could use just a quick five
22 minutes. Is that enough for everyone else for a
23 little break? Madam Court Reporter? Mr. Wilson? Dr.
24 Bridle?
25 DR. BRIDLE: Yes.
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1 COURT REPORTER: That’s fine.
2 MR. WILSON: Yes.
3 MR. ELFORD: All right. Then let’s go off the record for
4 five minutes. Thank you.
6 OFF RECORD

9
11
12 466 Q. Okay. So, Dr. Bridle, at paragraphs 74 and 75 of your
13 Affidavit, or your Expert Report, excuse me, you talk
14 a little bit about breastfeeding. And specifically at
15 74, you talk about a preprint article on Med – or XIB
16 and cite to that to say that there are data that
17 indicate mRNA can be detected in breastmilk post-

18 vaccination. Do you recall that?
19 A. Yes.
20 467 Q. Okay. And you’d agree that the article entitled – the
21 article you’re referring to there is entitled, “BNT
22 162b2 Vaccination Induces SARS-CoV-2 Specific Antibody
23 Secretion into Human Milk with Minimal Transfer of
24 Vaccine mRNA.” Excuse me.
25 A. Yes.
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1 468 Q. Okay. And so, do you recall this article and the
2 contents?
3 A. Yes.
4 469 Q. Okay. So, you recall that the authors found in their
5 view, that there was minimal transfer of that mRNA
6 into human milk across all evidence?
7 A. Ah, I acknowledge they used the term, “minimal.” The
8 whole purpose of – of me reporting this study is to

9 point out that there isn’t suppose to be any – any
10 mRNA in breastmilk. So, it’s very concerning that
11 they found any. Again, it’s proof of principal. And
12 the call for follow-up studies have not been adhered
13 to. It’s just been ignored, that potential safety
14 concern. And again, my concern with them using the
15 term, “minimal,” is we haven’t established a safe dose
16 for a spike encoding mRNA to be present in breastmilk.
17 470 Q. Okay. But you – you agree that their determination

18 was that their result, lend immunological and clinical
19 evidence to the current recommendation of
20 organizations like WHO, that lactating individuals
21 should continue breastfeeding in an uninterrupted
22 manner, after receiving COVID-19 mRNA vaccines. That
23 was – you’d agree that is what they concluded?
24 A. Sorry. That they concluded that it contributed to
25 policies?
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1 471 Q. Well, what I’ll do is I’ll take you to it.
2 A. Okay.
3 472 Q. If you could open up the document, “BNT 162b2
4 Vaccination Induces SARS-CoV-2 Specific Antibody
5 Secretion into Human Milk with Minimal Transfer of
6 mRNA – or with a - Vaccine mRNA.PDF,” please?
7 A. Okay. Okay. I have it printed and in front of me.
8 473 Q. And is that the preprint you were referring to at

9 paragraph 74, sir?
10 A. Yes, it is.
11 474 Q. Okay. Great. And so, if we go to the last paragraph
12 under the discussion section, and that’s on page 17 of
13 38.
14 A. Yes. Okay.
15 475 Q. You’ll agree that they concluded, these results lend
16 immunological and clinical evidence to the current
17 recommendation of the ACOG, RCOG, and WHO, that

18 lactating individuals should continue breastfeeding in
19 an uninterrupted manner, after receiving COVID-19 mRNA
20 vaccines.
21 A. I – I acknowledge that that was their conclusion.
22 Yes. The presence of mRNA should have been sufficient
23 concern to investigate that further prior to
24 supporting and administering the vaccines to
25 breastfeeding women, but that is their conclusion that
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1 I disagree with.
2 MR. ELFORD: Yeah. I appreciate you clarifying that,
3 sir. I’m going to mark that as an exhibit then, Madam
4 Court Reporter. Do you have it?
5 COURT REPORTER: Ah, yes, I do. That’ll be Exhibit 7.
8 MR. ELFORD: Thank you, sir. I was just going to create

9 some space for you there, but you – you let us know.
10 And I appreciate that.
11
12 EXHIBIT NUMBER 7: “BNT162b2 vaccination induces SARS-CoV-
13 2 specific antibody secretion into human milk with
14 minimal transfer of vaccine mRNA,” published in
15 Semantic Scholar, by Low, et al.
16
17 476 Q. Now, going a little bit further into your comments

18 here at 74, 75 about breastfeeding. I note that at
19 75, you’ve made some references to VAERS, that’s the
20 US Reporting System, correct?
22 477 Q. And this is a passive reporting system?
23 A. That is correct. So, it underestimates the true
24 number of problems to a substantial, but difficult to
25 assess degree. Yes.
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1 478 Q. But you’d agree that there isn’t – there isn’t a
2 restriction on VAERS reporting. They – they don’t go
3 in and prevent reports from being submitted?
4 A. Ah, not – not initial submissions, but yes, they will
5 – there are – there’s a certain amount of overview of
6 reports, and reports are moved - are removed on a
7 regular basis, not a lot, but some, because they don’t
8 meet the quality standards.

9 479 Q. Right. Quality standards. But it’s pretty broad the
10 – the – the information that gets in there, and as a
11 result, they don’t suggest that there’s a cause
12 relationship just because there’s reporting in VAERS
13 between whatever’s being reported in the vaccine?
14 A. Well, there’s – there’s rarely a cause and effect
15 relationship that can be definitively proven, even
16 with active monitoring and clinical trials, because as
17 I always like to say, um, when you’re dealing with

18 studies and people, life goes on, right. You
19 vaccinate and then you look for things happening, but
20 at the same time, everybody’s lives have different
21 kind of activities, they have different environmental
22 exposures, different interactions, et cetera, et
23 cetera. So, there isn’t any – any system that – that
24 – in which you’d expect to get a definitive cause and
25 effect relationship, where that cause and effect is
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1 implied is when you have strong correlations. And
2 that’s why it’s so important to have active
3 monitoring, so that one can acquire all of the
4 information. One should not be making any assumptions
5 about – so, this is very important, because unlike our
6 system, the CAEFIS System, which I already mentioned
7 in Canada, where there are multiple stages, at which
8 people can make their own decision as to whether or

9 not they think a medical event, following vaccination,
10 was or was not related, and if they determine it was
11 not related, it doesn’t even get advanced to the
12 Public Health Agency of Canada. And that’s the reason
13 why we need active monitoring, so, that all potential
14 medical – all unusual medical events following a
15 vaccine get recorded, so, that we can see if there is
16 or is not a – a strong correlation with vaccination.
17 So, it’s always based on correlation, no matter what

18 the type of system is.
19
20 And – and the really important thing is to remember,
21 for Pfizer, for example, they – they have – they’ve
22 listed 1,290 adverse events of special interest, which
23 are things – that means things that are – we’re
24 supposed to be paying particular attention for, post-
25 vaccination, but were not, in Canada. So, I just want
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1 to clarify that. So, yes, it's a system that allows
2 people to report, it’s voluntary reporting, but any
3 system is going to rely on a strong correlation to
4 imply a cause and effect relationship.
5 480 Q. Okay. And you’ve provided these VAERS IDs (ph) to
6 show a possibility of correlation?
7 A. Ah, that there were these events that occurred. Yes.
8 I – yeah. There’s no way that one can, with a limited

9 number like this, be able to make a direct assessment
10 that there’s a cause and effect relationship here.
11 It’s again, showing proof of principal and that that
12 this is something that should be investigated very
13 carefully. Because this is the whole thing. What one
14 looks for is when one sees a potential mechanism of
15 action that could cause harm.
16
17 And so, we’ve already talked about this fact that

18 there was mRNA, which was surprisingly found in
19 breastmilk. So, again, something we were told –
20 again, remember, we were told - the public was told
21 that these injections act like traditional vaccine
22 technologies, and they would stay at the injection
23 site, and/or migrate to the draining lymph node. Um,
24 so the fact that there was any mRNA found in the
25 breastmilk is concerning. And so, when one sees that,
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1 you know, one can allay concerns, safety concerns, if
2 they go to the safety database, ideally you want an
3 active monitoring system to be able to look at,
4 because that’s going to be much more informative and
5 comprehensive, but since we, the public, aren’t –
6 aren’t privy to that, you know, we’ve been looking at
7 things like the VAERS database, and you ask yourself,
8 okay, I’ve seen this mechanism that – that is

9 concerning, are there any reports that would be – that
10 would fit with this potential mechanism of harm? And
11 that’s exactly what these reports show. And, of
12 course, the additional thing is, if mRNA, remember
13 mRNA is very – it’s a very fragile molecule. And
14 would actually be expected to – to degrade. So, it
15 wasn’t indicated, but presumably these – these were in
16 lipid nanoparticles, otherwise, mRNA, that’s free
17 outside of lipid nanoparticles would be degraded very

18 rapidly. So, if it’s lipid nanoparticles, then you’re
19 also talking about the potential delivery of lipid
20 nanoparticles, which can be resistant to things, like
21 the acid in the stomach, and again, I’ve – those lipid
22 nanoparticles can cause harm to cells as well. And if
23 that were to get into any cells, ah, upon injection,
24 the mRNA, then you could get an unknown quantity of
25 the spike protein being manufactured by cells in the –
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1 in the baby’s GI tract, and if anything were to get
2 through the stomach and the stomach acid, in that
3 harsh environment, there is the potential in a baby
4 then for a direct uptake in the circulation. So, that
5 – that’s the whole point of this. It’s – it’s one
6 sees the potential mechanism, where it raises a safety
7 question, a safety question that – that the
8 manufacturers and health regulatory agencies are

9 saying, “We’re not going to make the manufacturers
10 investigate this directly,” even though it would be
11 very, very easy to evaluate breastmilk specifically
12 for this and look at mRNA, spike protein, lipid
13 nanoparticles, in a much larger study. But so, you
14 see a concerning mechanism of action, nobody’s acting
15 upon that. So, then you look for if that is a
16 mechanism of action, is there potential for harm? Is
17 there – do you see harm? And that’s what we see here.

18 Potential mechanism, we’re seeing cases that – that
19 would fit that potential mechanism, and therefore,
20 this is something that I think is important to
21 highlight as a potential safety signal that needs to
22 be very carefully investigated in a properly designed,
23 controlled study, looking specifically at all the
24 components of the vaccine, and whether or not they’re
25 getting into the breastmilk. Because if the mRNA is,
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1 and there’s something, anything like – they didn’t
2 look for exosomes, they didn’t look at the spike
3 protein, and proteins that are in circulation, always
4 – always tend to get concentrated in breastmilk, so,
5 that you can pass on high concentrations, specifically
6 antibodies to the newborn.
7 481 Q. Thank you. Now, you – what was the term you used just
8 now to describe these? These are – these demonstrate

9 what again? The mechanism or the pathway, which was
10 it?
11 A. Yeah. Potential mechanism of harm.
12 482 Q. Potential mechanism of – and that’s what these do?
13 These – these very reports that you’re referring to
14 here?
15 A. Ah, no. The potential mechanism of harm was the
16 observation, the unexpected observation of messenger
17 RNA in the breastmilk. The reason why I went to the

18 VAERS database was you – you could alleviate those
19 concerns, if you go to a safety monitoring system and
20 see that there are no adverse events that would fit
21 with that mechanism of harm, right. So, in other
22 words, if you don’t see any harm occurring in suckling
23 infants of mothers who had been vaccinated, then that
24 lessens the concern. But in fact, as you can see
25 there, there – and – and that’s outdated now, there’s
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1 a lot more cases, but the point is, there were cases
2 documented of harm to neonates who are suckling from
3 mothers who had been vaccinated, right. So, there’s -
4 the paper was the potential mechanism of harm, and
5 then the VAERS is – is providing evidence of potential
6 harm.
7 483 Q. Okay. So, these provide evidence of the potential
8 harm, by showing harm?

10 484 Q. Okay. Thank you. Can I get you to open up a document
11 that was sent this morning and I note there that you
12 have one report, number 1168901. And there should be
13 one document sent to you called, “VAERS, Event Details
14 1168901-1, Screen Capture May 24th, 2022.PDF.”
15 A. Okay. I – I – so, I see there’s two. There’s event
16 details. Could you just read me that number again,
17 so, I can make sure I have the right one.

18 485 Q. No. Not a problem, 1168901-1.
19 A. Okay. Yes, I have that up.
20 486 Q. Great. Could you open this up, please, and take a
21 look at it and confirm for me if this is the VAERS
22 Report for that report that you reference in your
23 Expert Report?
24 A. Okay. Just give me a moment to cross-reference.
25 487 Q. Yes. Please, read the – read it.
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1 A. Um, yeah. I don’t – I don’t think this is the same.
2 This looks like an example of one that was modified
3 after the initial report.
4 488 Q. Oh, okay.
5 A. Let me just read this again. “This – the medical
6 history of the patients...” Yeah. Ah, it’s kind of
7 an unusual report because I see here that they
8 mentioned the baby experienced exposure during

9 breastfeeding. Um, but it doesn’t indicate how, on
10 what basis they claim there was exposure, and they
11 just state it as the report was non-serious, but yeah.
12 I – I know now when I look at the detail, if you go up
13 to the top left report form version, it’s version 2.
14 489 Q. Uh-hmm.
15 A. So, I would have been looking at version 1.
16 490 Q. Okay.
17 A. So, this is – this is a good example of how they do

18 modify reports, and/or remove reports.
19 491 Q. Uh-hmm. But you don’t cite what was in the original
20 version?
21 A. No. No. Ah, I – yeah. The only way to confirm would
22 perhaps be to use the way back machine (ph), and see
23 if they’ve got a screenshot of this, but I don’t think
24 that applies to the VAERS System, in fact, I’m quite –
25 I’m pretty sure it doesn’t.
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1 492 Q. Well, what was the original report then that you were
2 citing to, what was the content of?
3 A. Ah, well, I mean this one does state that they were
4 exposed, and that’s the concern, right? It does state
5 here the baby experience – so, um, it said the
6 patient’s parent received the ad – the Janssen &
7 Janssen vaccine, right. And uh, the baby experienced
8 exposure during breastfeeding.

9 493 Q. Okay.
10 A. Ah, that’s all. So, again, it’s suggesting that there
11 was exposure of the suckling baby to the vaccine,
12 which is a concern because the vaccine being - a
13 vaccine being administered to a woman, should not be
14 getting administered via breastfeeding to an infant.
15 That was something that was not in – in the publicly
16 disclosed biology of these – of how these mechanism of
17 action for these injections.

18 MR. ELFORD: Okay. Well, I would like to mark this as
19 the next exhibit, please.
20 COURT REPORTER: Counsel, I don’t have a copy of this
21 one.
22 MR. ELFORD: Okay. Well, we can get that to you shortly.
23 MR. WILSON: I have no concerns with that, that would be
24 MR. ELFORD: That should have been in the e-mail sent
25 this morning, Madam Court Reporter.
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1 COURT REPORTER: Yeah. I looked at it, but I don’t see
2 – I don’t see it.
3 DR. BRIDLE: Just to clarify, I think you had started
4 with a number in the file name. The file name I have
5 starts with VAERS, V-A-E-R-S.
6 MR. ELFORD: Yes.
7 COURT ELFORD: Yeah. I don’t have anything that has VAERS
8 in it.
9 MR. ELFORD: Okay. V-A-E-R-S. Gotcha. Well, we will
10 have to resend that after this, if we’re all
11 comfortable as marking it as an exhibit. Dr. Bridle,
12 you have a copy though, right?
13 DR. BRIDLE: I do.
14 MR. ELFORD: Great. So, we’ll mark that as Exhibit 8 for
15 now and we’ll provide a copy shortly afterwards. It
16 would have been in the – in that e-mail though, if
17 maybe it didn’t get forwarded to you. But....

18 COURT REPORTER: It – it’s possible just maybe that one
19 didn’t get forwarded to me.
20 MR. ELFORD: Okay.
21
22 EXHIBIT 8: “VAERS, Event Details 1168901-1, (Screen
23 Capture) May 24th, 2022.PDF,” from the Vaccine Adverse
24 Even Reporting System
25
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1 494 Q. Well, I’d like to move onto the next one, which is a
2 document “VAERS, Event Details 0913971-1 (Screen
3 Capture) May 24th, 2022.PDF.” Do you have that
4 document, Dr. Bridle?
5 A. Yes, I do. I’m opening it now.
6 495 Q. Okay. If you wouldn’t mind, just taking a look at it,
7 please.
8 A. Okay. I’ve got it open. Okay. Ah, let me have a

9 look here. Ah, yup, yup. This is – yeah, an example
10 of one listed that I don’t have particularly, you
11 know, any major concerns about this particular event
12 here, unlike the other ones, the ones that I – yeah.
13 496 Q. So – so, this one – and let’s just make sure it’s
14 clear. We agree that it says, “Since receiving the
15 vaccine, he has been much fussier than he normally
16 is.”
17 A. Yes.
18 497 Q. And this came from a nurse.
19 A. Yes.
20 498 Q. Okay. Well, I don’t....
21 A. Yes. So, again....
22 499 Q. I’d like to....
23 A. Or sorry.
24 500 Q. No. Just let me finish. I’d like to confirm that
25 this is the same number here that you’re referring to
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1 in your report, 913971?
2 A. Nine, one, three – ah, yes. Yup.
3 501 Q. Okay.
4 A. That’s the list of secondary reports, one that I
5 wasn’t particularly concerned about, that’s why I
6 listed above the “Serious Adverse Events” and gave
7 three examples there.
8 502 Q. Okay. So, you do recall seeing this?

9 A. Yeah. Yeah. Absolutely. Yeah. This was the cluster
10 of ones that I didn’t have – like where there were no
11 major concerns identified.
12 MR. ELFORD: Thank you. I’d like to mark this as an
13 exhibit as well, please.
14 COURT REPORTER: I don’t have this one either.
15 MR. ELFORD: Yeah. Exhibit 9, if there’s no objection
16 from Mr. Wilson.

18 MR. ELFORD: Thank you, sir. All right. And I’ll get
19 those to you later, Madam Court Reporter. I’m gonna
20 keep on moving on, again. I’m – I’m hoping to get
21 done here today.
22
23 EXHIBIT 9: “VAERS, Event Details 0913971-1 (Screen
24 Capture) May 24th, 2022.PDF,” document from the Vaccine
25 Adverse Event Reporting System
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2 503 Q. So, I want to talk about now, very briefly hopefully,
3 Ivermectin. And I’d like to refer you to a couple of
4 things. In one of which is you cite to the report at
5 paragraph 101, Elgazzar, et al. “Efficacy and Safety
6 of Ivermectin for Treatment and Prophylaxis of COVID-
7 19 Pandemic.” Do you recall that article, sir?
8 A. Ah, what – what’s the reference number? Citation

9 number?
10 504 Q. The citation would be – well, actually, I don’t think
11 you give a citation to it. I think it’s just
12 referenced, cause paragraph 101 is really long
13 frankly, sir. And – and that’s not meant as a
14 criticism. It’s long. And you talk about a – a
15 clinical trial in Egypt. And then somewhere else you
16 reference Elgazzar and I believe you’re talking about
17 – oh, here we go. Extracted from Elgazzar, et al.,

18 Efficacy and Safety of Ivermectin for Treatment and
19 Prophylaxis of COVID-19 Pandemic, and that is on page
20 – upper right-hand corner 161 of your Expert Report,
21 and ah, there’s no other numbers on it. But it’s all
22 within paragraph 101. And for further clarity, um....
23 A. Okay. Yeah. I see that. Yup.
24 505 Q. Okay. So, you know what I’m talking about?
25 A. Yeah. Yeah. And it’s come to my attention, since I
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1 wrote this, that that has been withdrawn as a
2 preprint.
3 506 Q. Okay.
4 A. I – I believe that’s the one...
5 507 Q. Yes.
6 A. ...if I recall correctly.
7 508 Q. Yes. So, you agree that it’s been withdrawn as a
8 preprint and that there’s been criticisms that there

9 was potential data fabrication, plagiarism, and
10 ethical breaches?
11 A. Well, there’s been criticisms. Yeah. The authors
12 have the opportunity now to respond to those.
13 509 Q. Okay.
14 A. Yes.
15 510 Q. But you agree that....
16 A. I – I....
17 511 Q. Sorry.
18 A. Yeah. I – I agree that it’s been withdrawn as a
19 preprint until such time as the authors can address
20 those questions and if they don’t address those
21 questions, it won’t be posted again.
22 512 Q. Okay. Yeah.
23 A. Yeah.
24 513 Q. And....
25 A. So, with that – could – could I just make one – one
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1 comment on that?
2 514 Q. Well....
3 A. Let me just think about this, because I think this is
4 something that you did send.
5 515 Q. I – I did send it, sir.
6 A. Something on this.
7 516 Q. I mean, you agreed that it’s been withdrawn, so, I
8 don’t intend to enter it as an exhibit, because it was

9 pulled for a variety of criticisms.
10 A. Oh, yeah, yeah, yeah. Okay. But I did just want to
11 mention though that’s there been a new study published
12 in Cureus, a peer-reviewed article that a very large
13 scale showing a 42 per cent reduction in COVID-19 with
14 Ivermectin used as prophylactic strategy. So, I think
15 that’s important and that’s – that’s been – that was
16 published, ah, since I wrote this report.
17 517 Q. Uh-hmm. So, this is all – yeah. Give me a second

18 here, sir.
19 A. Okay.
20 518 Q. I’m just looking for one thing. Ah, here we go. Um,
21 so, sir, and again this is in paragraph 101, and I’ll
22 try and find that the – the document – or sorry, the
23 citation here and what page it’s on, but there’s a
24 point where you say, “On January 14th, 2021, the NIH
25 Treatment Guidelines Panel, upgraded their
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1 recommendation on the use of Ivermectin for COVID-19.
2 The NIH is making it an option for use in the
3 treatment of patients with COVID-19.” Do you recall
4 writing that?
5 A. Yes.
6 519 Q. I’m going to try and find the page for you here.
7 Okay. Here we go. It’s on page 163, it’s about the
8 third paragraph up from the bottom.

9 A. Yes. I see that.
10 520 Q. Okay. And can you please turn to a document that I
11 provided you, and I hope you have it and I hope Madam
12 Court Reporter has it, called, “Statement – on –
13 Ivermectin – 01 – 14 – 2021.”
14 A. Okay. Yup. I got that, received this, this morning.
15 521 Q. Okay. Great. Just take a look at it, please, sir.
16 A. Okay. Yes. Okay. I’ve had a chance to take a look.
17 522 Q. Okay. And is this the document that you were

18 referring to when you got the – or when you were
19 writing your statement about the NA – the NIH
20 treatment guidelines panel?
21 A. Ah, yes. Exactly. That they have sufficient data to
22 recommended either for or against it, but support the
23 conducting additional studies...
24 523 Q. Okay.
25 A. ...on Ivermectin. Yeah.
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1 524 Q. So, you agree then that the – have said that there’s
2 insufficient data to recommend for or against the
3 treatment.
4 A. Yeah. That’s the important thing. Exactly. They
5 didn’t recommend against it.
6 525 Q. Right.
7 A. Unlike in Canada, where it was – we recommended
8 against it, and they asked for adequately powered,

9 well-designed, and well-conducted clinical trials, and
10 again, it emphasized the most recent one that was
11 published in the Journal Cureus, a peer-reviewed
12 publication. On a – it was a study done on 223,128
13 subjects in Brazil. It shows a clear-cut benefit.
14 So...
15 526 Q. Okay.
16 A. ...that’s what they were asking for and that’s what’s
17 been conducted or done by scientists. I mean there’s

18 been many other studies, since this as well.
19 527 Q. Okay. And....
20 A. But – but yes, they – that’s the whole point. They
21 did not recommend against it, had allowed physicians
22 to be able to access and use it, and plus this is
23 fairly outdated, right, in January 2021. It’s
24 important to note that in many of the states, they
25 have – now, they have actively instructed pharmacies
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1 to allow physicians to be able to prescribe Ivermectin
2 for the treatment of COVID-19.
3 528 Q. Well – well, sir, I mean it is the study or the
4 document you referred to, so, I....
5 A. Yeah.
6 529 Q. But anyways, that’s neither here or there. Under
7 clinical data, you’ll note that they do state the
8 following at the bottom of page 6. “However, most of

9 the studies reported in date, had incomplete
10 information and significant methodological
11 limitations, which makes it difficult to exclude
12 common causes of bias.” And then onto the next page,
13 they list what they think are some of the limitations
14 and then they state, “Because of these limitations,
15 the panel cannot draw definitive conclusions about the
16 clinical efficacy or safety of Ivermectin for the
17 treatment of COVID-19.” Do you agree it says that?

18 A. Yup. But they provide no – no details, no list of the
19 studies. Many of these studies have been actively
20 debated and but I mean, they – they’re allowed to have
21 their interpretation of the studies. Again, I – I
22 believe I – I have to doublecheck with my report here,
23 um, if you give me just one second, I want to see what
24 it was that I filed. Um. Okay. Yeah. Yeah. I’ll
25 leave it at that.
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1 530 Q. Okay. But you – you would agree with me then that
2 they didn’t say it’s an option, they just couldn’t
3 make a recommendation one way or the other?
4 A. Ah, yes. So – so, it is – so, it remained an option.
5 531 Q. Okay. That’s your – gotcha. And so, I’d like to take
6 you to – well, first of all, I want to actually enter
7 that as an exhibit. Madam Court Reporter, do you have
8 it?
9 COURT REPORTER: Statement – on – Ivermectin – 01, 14,
10 2021?
11 MR. ELFORD: Yes.
12 COURT REPORTER: Yes, I have that.
13 MR. ELFORD: Great.
14 MR. WILSON: Exhibit 10, no objection.
15 MR. ELFORD: Thank you. And I’ve got one more, then I’m
16 going to take a pause and see if there’s anything
17 else, and I may be done, if there isn’t. Okay. So,

18 last question here.
19
20 EXHIBIT 10: Statement – on – Ivermectin – 01 – 14 – 2021
21
22 532 Q. I’d like to take you to a document that you should
23 have. It’s “70 – Coronavirus Disease 2019 (COVID-19)
24 Treatment Guidelines.PDF.”
25 A. Ah, I don’t have one that begins with 70. Can – can
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1 you state the...
2 533 Q. Sure. Let me...
3 A. ...first word?
4 534 Q. ...see if I can find another name for it. There’s
5 probably – there should be one. So, it might just be
6 called, “COVID Treatment Guidelines,” all one word,
7 PDF.
8 A. Okay. Yeah. I recall – yeah, this is one that I was

9 granted permission to look at on Friday night, but I
10 haven’t actually looked at it yet.
11 535 Q. Okay.
12 A. But I have it open.
13 536 Q. Yeah. And you can take the time you need to look at
14 it to answer the question, okay.
15 A. Okay.
16 537 Q. So, you’d agree that this is the NIH COVID-19
17 Treatment Guidelines, entitled, “Coronavirus Disease

18 2019 (COVID-19) Treatment Guidelines?”
19 A. Yes.
20 538 Q. And if we go down on that first – I think it’s on the
21 first page here, it says, “Downloaded from
22 https://www.COVID19treatmentguidelines.nih.gov.on.5820
23 22.”
25 539 Q. That’s a little more updated than the last NIH
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1 document we saw?
2 A. Yes.
3 540 Q. Okay. And if you can go to PDF page 168.
4 A. Okay.
5 541 Q. Okay. And you’re there?
6 A. Yes.
7 542 Q. And you’ll see that it says, “Last updated April 29th,
8 2022.”
9 A. Yes.
10 543 Q. Okay. And so, if we go down that page, there’s a term
11 there that says, “Recommendation.” Do you see that,
12 sir?
13 A. Yes.
14 544 Q. And underneath it, it says, “The panel recommends
15 against the use of Ivermectin for the treatment of
16 COVID-19, except in clinical trials.” And then gives
17 a number, I don’t frankly understand. It looks like

18 A, two I’s and a small A in parenthesis.
19 A. Yes. I see that.
20 545 Q. Okay.
21 A. Yeah. I – I disagree with their comments. This is
22 largely based on – flaw – quite a few flawed trials,
23 that did not demonstrate efficacy of Ivermectin.
24 546 Q. Okay.
25 A. But there were fundamental flaws in those trials,
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1 right. One looks at the overall weight of the
2 evidence, and just as there were criticisms about some
3 of the study design, and – and they applied less
4 weight to some of the stuff, so, they didn’t want to
5 go with a positive direct recommendation, but weren’t
6 also weren’t recommending against it earlier. This
7 has largely been influenced by large studies that did
8 not show evidence, and therefore one would argue that

9 the – the sum total scientific evidence might lean
10 against recommending it, but again, those key major
11 trials that were done in the interim between these two
12 reports we’ve just looked at, had some very
13 fundamental flaws.
14 547 Q. Okay. But you haven’t looked at the reports that it
15 relies on yet?
16 A. Ah, I – I – again, I don’t see – I’d have to see the
17 studies that I have listed, yeah. So, I can’t be 100

18 per cent certain, but – but I would be surprised if
19 they haven’t cited a couple of the – well, yeah.
20 Actually I can see right here. I can confer. Yeah.
21 So, right there, a major one is this TOGETHER Trial.
22 Ah, that TOGETHER Trial, I can tell you is, again, as
23 an expert scientific reviewer, it is – I’ll be honest,
24 complete garbage. It should never have been published
25 and should be retracted. If – if you’d like, I can go
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1 – yeah, well actually, I think it’s very important,
2 very germane to this.
4 If you give me just one second, I – I think you sent
5 me a document on the TOGETHER Trial, is that – um, so,
6 because – because this is so germane to this, I think
7 it’s very important that I have the opportunity,
8 because they – they cite right here. Again, so, yes.

9 The TOGETHER Trial is one of the major trials, right,
10 which I didn’t show benefit, but I want to point out,
11 because this is a classic example of – of the types of
12 trials that they used to argue that the weight of
13 scientific evidence does not support recommending it.
14 And – and therefore, they’re recommending against it.
15 I remember they said they want to see additional
16 clinical trials, and then they’ll make a decision.
17 Because again, they go with the weight of the

18 evidence. Well, this is one of the key additional
19 trials, that they used to actually recommend against
20 the use of Ivermectin.
21
22 Now, one thing I want to point out is in this TOGETHER
23 Trial, there were major conflicts of interest. So,
24 with the two most senior authors. One is an employee
25 of Platform Life Sciences, actually another author is
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1 an employee of Platform Life Sciences. Um, so,
2 competing interests there. The most senior author is
3 an employee of Cital (ph), which got funding from the
4 Bill and Melinda Gates Foundation for COVID-19 work.
5 And they’re very much against the use of Ivermectin in
6 favour of the vaccine and heavily invested in the
7 vaccines, and have no money to be made from
8 Ivermectin, which of course is an un-patent drug.

9
10 The second most senior one, works for a company called
11 Citerra (ph), which also receives funding from the
12 Bill and Melinda Gates Foundation. Um, also, what –
13 what this fails to account for is that there’s 37
14 countries internationally using Ivermectin, as a first
15 line of defence.
16
17 Other – other funding – funders for this research

18 include – are funding that was received by authors of
19 this research, includes Rainwater Charitable
20 Foundation, and Fast Grant, um, and these have been
21 associated on their websites. They’ve had statements
22 that are – where they’re trying to combat, so-called
23 vaccine hesitancy and promote the use of the vaccines,
24 and – and not cheap, readily available drugs, like
25 Ivermectin.
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2 The – so, it’s important to note that one of the
3 authors, as well, is actually president of Citerra
4 (ph) and I think I’ve already mentioned, they’re
5 funded by the Bill and Melinda Gates Foundation, and
6 but even more importantly, they’re – they’re actually
7 competing directly by developing their own novel, un-
8 patent COVID-19 drugs. So, that’s very important.

9
10 The other thing that I would say, so, again, just so
11 you know, I mentioned the Fast Grants and the
12 Rainwater funding. So, Fast Grants is funded by Peter
13 Thiel who is co-founder of PayPal and a large investor
14 in Facebook. Both of which have been censoring
15 dissenting viewpoints when it comes to the COVID-19
16 narrative.
17
18 The Rainwater, which has provided – the Rainwater
19 Charitable Foundation actively supports, and I quote
20 from their website, “The use of mRNA technology to
21 create effective COVID-19 vaccines,” and they’re
22 directly targeting [quote] “Vaccine hesitancy.” Also,
23 I – I – I would point out that when anybody is
24 performing a clinical trial, you have to ensure that
25 the patient is not already on the drug that’s being
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1 investigated. And I’d like to point out, this
2 TOGETHER Trial was conducted in Brazil. In Brazil,
3 Ivermectin is available over-the-counter. So, it’s
4 very well likely that the test and control groups were
5 treatment with a known dose of Ivermectin versus
6 treatment with an undefined Ivermectin regiment. So,
7 they may have been comparing Ivermectin to Ivermectin
8 in some form. They did not rule that out in this

9 study, which is preposterous.
10
11 Um, you – you also have to make sure they aren’t
12 taking any other medication, or have any medical
13 conditions that can compromise results of the trial,
14 and this was not reported. Importantly, you have to
15 confirm the – the quality, meaning the identity and
16 purity of the drug that’s under investigation, the
17 Ivermectin. None of this data was provided. It has

18 to be demonstrated it was sourced from a reputable
19 manufacturer and it hasn’t been adulterated, and is
20 counterfeit in any way. You have to be able to
21 provide evidence in a trial like this that the patient
22 has taken the correct drug. And this is very simple
23 to do. You can take – simply take a blood sample and
24 look at the blood concentrations of the drugs, to make
25 sure that they’ve actually taken the – the prescribed
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1 medication, like the Ivermectin, if there hasn’t been
2 a mix-up at the pharmacy, when the – when the drug was
3 issued.
5 And then the other thing is, so, again, I would say –
6 so, these wouldn’t be what I would call the – the –
7 the fatal flaws. We often refer to fatal flaws in
8 papers, if – and fatal flaws would be reasons the

9 paper should not have got through the peer-review
10 process, or they should not have been published, and
11 they therefore should be retracted. First of all,
12 again, Ivermectin is freely available in – in Brazil,
13 and yet they did not screen to make sure that the
14 patients in the either arm were not taking Ivermectin
15 already.
16
17 Secondly, they – they provide no evidence of the

18 identity or purity of the drugs being investigated,
19 which means that you can’t be sure that they - they –
20 that the people have been receiving the correct
21 medication. And – and like I said, the – you have to
22 make sure that they’ve taken the correct medication
23 when they’re on this study, and they didn’t take blood
24 samples to do this. Um, so, there’s no way to be
25 certain that the patient has taken the relevant drug.
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1 Another thing is they – they did this with
2 outpatients, and the majority of outpatients, that
3 means it’s not particularly a serious disease. The
4 vast majority recover from treatment anyways. So, in
5 order to look at the benefit of Ivermectin, it would
6 have been much better to have looked at inpatients,
7 that are dealing with more serious disease. Also,
8 treatment was delayed for seven days, and as I

9 mentioned, the paper actually shows a 42 per cent
10 reduction in cases of COVID-19 was used
11 prophylactically. And – and the people that – the
12 physicians that are really – that have been very
13 effective using this, emphasize, it has to be early
14 treatment intervention. I don’t know why they delayed
15 seven days before treating. But any drug that you’re
16 administering is going to be put at a disadvantage, if
17 you’re allowing the disease to manifest itself for so

18 long.
19
20 And then you look here, clinicians provided
21 consultation on the management of symptoms and
22 provided anti-piratic agents, but this is the
23 important thing. Clinicians recommended antibiotic
24 agents, only if they suspected bacterial pneumonia,
25 then that’s the only mention.
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2 And it’s very important because the CDC, the United
3 States Centre for Disease Control has indicated that
4 up to 50 per cent of COVID-19 associated deaths have
5 had bacterial pneumonia as a comorbidity.
7 So, this could have a huge impact on the outcome of
8 this study, but yet, they don’t – they don’t disclose

9 any information about what this antibiotic treatment
10 looked like. What was the treatment? Who received
11 the treatments?
12
13 Um, and so, that’s a major confounding variable that
14 hey have in this study. And so, you know, on that
15 basis, um, you know, I – this TOGETHER Trial, in my
16 expert opinion, should not have been published. And
17 again, so that’s why – that’s why it’s important.

18
19 So, yes, I see that they make this recommendation, but
20 it’s based on – off of very flawed trials, like that
21 together trial. And not on trials that are properly
22 designed, where it’s either a prophylactic treatment,
23 or early intervention with all the proper controls in
24 place and disclosure of all of the information. So,
25 no, it’s – this is – they’re officially recommend
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1 against it, but I completely disagree. That decision
2 is based on fundamentally flawed studies.
3 MR. ELFORD: Okay. Now, I’d like to enter that document
4 as an exhibit, please.
6 MR. ELFORD: Do you have a copy of it, Madam Court
7 Reporter?
8 COURT REPORTER: Yes. This is the COVID Treatment Guide

9 – Guidelines PDF?
10 MR. ELFORD: All one word.
11 COURT REPORTER: Yup. I have that one.
12 MR. ELFORD: Excellent.
13 COURT REPORTER: That will be Exhibit 11.
14 MR. ELFORD: Great.
15
16 EXHIBIT 11: Page 168 from PDF, entitled, “Coronavirus
17 Disease 2019 (COVID-19) Treatment Guidelines.PDF” from

18 NIH
19
20 A. Just to clarify, I - we only discussed some of the
21 text on page 168, right?
22 548 Q. Um, I’ll have to go....
23 A. I’m just wondering if that whole document, am I to
24 comment on all 398 pages?
25 549 Q. No, sir. I just asked you about the one
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1 recommendation on page 168.
2 A. Okay.
3 550 Q. And so, when you – and this is just something I want
4 to follow-up on, is – is you contrasted the TOGETHER
5 Trial with what you consider to be well run and
6 organized trials, correct?
7 A. Yes.
8 551 Q. And you gave an example earlier, I think it was

9 Cureus?
10 A. Yes.
11 552 Q. Is that spelled C-U-R-E-U-S?
13 553 Q. Okay. I’d like to – I’d like to share my screen with
14 you. So, sir, can you – can you see this? Does this
15 appear to be the article you’re talking about?
16 A. Yes, that’s it.
17 554 Q. Okay. And so, this is what you considered a well-

18 designed study?
19 A. Yes.
20 555 Q. Okay. And, um, I note here it says, “This article’s
21 been corrected.” And I’m just going to click on that,
22 okay.
23 A. Ah, yes. They had the authors report potential
24 conflicts of interest. Yeah.
25 556 Q. Yeah. And so, the correct – the correction was to add
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1 those conflicts of interest in there, and as we look
2 through it, there’s a reference here to Jennifer A.
3 Hibberd is a cofounder of the Canadian COVID-19 Care
4 Alliance. And some other people with a Front Line
5 COVID-19 Critical Care Alliance. You see there’s a
6 paid consultant here, um, for VitaMedic, an Ivermectin
7 manufacturer, that’s Flavio A. Cadegiani, and – and
8 the people who were part of the Front Line COVID-19

9 Critical Alliance are the Pierre Kory and Juan J.
10 Chamie-Quintero, am I accurately describing these
11 conflicts that they’ve cited?
12 A. Yup. Potential perceived conflicts of interest. Yes.
13 557 Q. Yeah.
14 A. That’s required for – for any publication.
15 558 Q. Of course. Of course. And they – but they had to
16 correct to add these?
17 A. Ah, it would appear so. Yes.

18 559 Q. Okay. Oh, and Lucy Kerr is a paid consultant with
19 both VitaMedic, an Ivermectin manufacturer, and
20 Médicos Pela Vida, an organization that promotes
21 Ivermectin as a treatment.
22 A. I’m sorry. Am I – is that a question?
23 560 Q. Ah, yeah. I’m just making sure I’m accurately
24 describing the apparent conflict of Lucy Kerr, one of
25 the authors.
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1 A. Ah, yes. That’s what it says.
2 561 Q. And above that, above where they list all those
3 conflicts, it says the words, “Correction,” in large
4 letters. And then underneath that it says, “It has
5 come to the attention of the journal, that several –
6 several authors failed to disclose all relevant
7 conflicts of interest, when submitting this article.
8 As a result, Cureus is issuing the following erratum

9 and updating the relevant conflict of interest
10 disclosures to ensure these conflicts of interest are
11 properly described as recommended by the ICMJ.”
12 A. Yes.
13 562 Q. And you agree that it’s very important that these
14 conflicts are – are very clear, because of course,
15 it’s difficult to – to – to evaluate these things,
16 without knowing about these conflicts?
17 A. Yeah. Well, to a certain degree.

18 563 Q. Okay.
19 A. I mean the scien – the science is the science, right.
20 564 Q. The science is the science, but you – you certainly
21 expressed a great deal of concern earlier, you know,
22 sir?
23 A. Yeah. Yeah. I – I – yeah. I absolutely agree.
24 565 Q. I think – I think I’m good. So...
25 A. Yeah.
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1 566 Q. ...you’d agree with me? Thank you very much.
2 A. Yeah. Yeah. I express concern about the potential
3 conflicts of interest, but my major concerns with that
4 paper, were the scientific flaws that I pointed out.
5 MR. ELFORD: Well, what I’d like to do now is I’d like to
6 – we’ll get this a screenshot of this and mark this
7 particular page I’m looking at right now, called,
8 “Correction: Ivermectin Prophylaxis Used for COVID-19:

9 A Citywide, Prospective, Observational Study of
10 223,128 Subjects Using Propensity Score Matching.”
11 Excuse me. Whew. I’d like to mark that as an exhibit
12 and we’ll get a version of that we can share, if
13 that’s all right. Mr. Wilson, you’re, uh, muted.
14 MR. WILSON: No concerns.
15 MR. ELFORD: Okay. Thank you. So, we’ll mark that as
16 what – what exhibit are we at now, ten?
17 COURT REPORTER: 12.

18
19 EXHIBIT 12: “Correction: Ivermectin Prophylaxis Used for
20 COVID-19: A Citywide, Prospective, Observational
21 Study of 223,128 Subjects Using Propensity Score
22 Matching,” article from Cureus, Lucy Kerr, et al.
23
24 MR. ELFORD: Twelve? My goodness. Well, the time has
25 flied – flown, excuse me. Ah, folks, I’m gonna need
JML TRANSCRIPTION
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1 just five minutes and I might be done. We can stop
2 sharing the screen, please.
3 COURT REPORTER: Okay. And then would you like me to go
4 off the record?
5 MR. ELFORD: Um, yeah. So, I’m gonna take five minutes
6 and then I’ll go on the record.
8 OFF RECORD
9
10 MR. ELFORD: Okay. We’re back on the record and I am
11 happy to announce that those are my questions. Dr.
12 Bridle, thank you very much for your time and your
13 explanations. And Mr. Wilson, I – I see the floor to
14 you.
15 MR. WILSON: Thank you. We have....
16 MS. CHIPIUK: [inaudible].
17 MR. WILSON: Eva, your mic’s on. We have no questions by

18 way of re-direct.
19 MR. ELFORD: Okay. Then I guess we’re done.
20
21 OFF RECORD
22
23
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Certificate of Court Transcriber
I, Shannon Albert, Court Transcriber, hereby certify that I
have transcribed the foregoing and that it is a true and
accurate transcript of the evidence given in the matter, taken
by way of electronic tape recording.
June 6, 2022
Date Signature of Authorized Person
JML TRANSCRIPTION
AR08634
JCI ins1G~T RESEARCH ARTICLE
A majority of uninfected adults show

preexisting antibody reactivity against
SARS-CoV-2 I •<
1'
Abdelitah Majdoubi,\ l Christina Michalski? Sarah E. O'Connell,3 Sarah Dada,\ l Sandeep Narpala,3
Jean Cielinas,4-5 Disha Mehta,4-i Claire Cheung,\ l Dirk F.H. Winkler,' Manjula Basappa,3
Aaron C. Liu,1,2.a Matthias Citirges,\G Vilte E! Barakauskas,' Mike Irvine,1 Jennifer Mehalko,10
Dominic Esposito,10 lnna Sekirov,"n Agatha N. Jassem,"n David M. Cioldfarb,\l,'IZ Steven Pelech,1-13
Daniel C. Douek,3 Adrian B. McDermott,3 and Pascal M. Lavoie\2
'BC Children's Hospital Research Institute, Vancouver. British Columbia, Canada. 'Department of Pedlatrics, University
of British Columbia, Vancouver. British Columbia, Canada. 3\facclne Research Center, National Institute of Allergy and
Infectious Diseases. NIH, Bethesda, Maryland, USA. "Department of Anesthesiology, Surrey Memorial Hospital (SMH).
Surrey, British Columbia, Canada. 50epartment of Anesthesiology & Pain Medicine, University of Alberta, Edmonton,
Alberta. Canada. "Department of Anestheslology, Pharmacology and Therapeutics, University of British Columbia,
Vancouver, British Columbia, Canada. 'Kinexus Blolnformatlcs Corporation, Vancouver, British Columbia, Canada. "Vaccine
Evaluation Centre, BC Children's Hospital Research Institute, Vancouver, British Columbia. "Department of Pathology and
Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. "National Cancer Institute RAS
Initiative. Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical
Research Inc., Frederick. Maryland, USA TIBrltish Columbia Centre for Disease Control (CDC) Public Health Laboratory,
Vancouver, British Columbia, Canada. "Division of Medical Microbiology, Department of Pathology and Laboratory
Medicine, and "Department of Medicine, University of British Columbia, Vancouver, Canada.
Preexisting cross-reactivity to SARS-CoV-2 occurs in the absence of prior viral exposure. However,
this has been difficult to quantifyat the population level due to a lack of reliably defined
seroreactivitythresholds. Using an orthopal antibody testing approach, we estimated that about
0.6% of nontriaged adults from the greater Vancouver, canada, area between May 17 and June 19,
2020., showed dear evidence of a prior SARS-CoV-2 infection, after adjustingfor false-positive
and false-negative test results. Using a highly sensitive multiplex assay and positive/negative
thresholds established in infants in whom maternal antibodies have waned, we determined that
more than 90% of uninfected adults showed antibody reactivity against the spike protein, receptor-
binding domain (RBD), N-tenninal domain (NTD), or the nudeocapsid (N) protein from SARS-
CoV-2. This seroreactivity was evenly distributed across age and ~ correlated with drculating
coronaviruses' reactivity, and was partially outcompeted by soluble circulating coronaviruses'
spike. Using a custom SARS-CoV-2 peptide mapping array, we found that this antibody reactivity
Aallaslllp._,AM, CM. and SEO broadly mapped to spike and to conserved nonstructural viral proteins. We conclude that most
are ro-mt aulflOrs.
adults display preexisting antibody cross-reactivity against SARS-CoV-2, which further supports
£8llllld l/llllllnsl: SP is the majority investigation of how this may impact the dinical severity of COVID-19 or SARS-CoV-2 vaccine
- of Ki1exus Bioinfonnatics responses.
(orporatioo.
r.,,itpt: © 2021, Majdowiet

al. This is illl ape, act!SS article
poolist1ed under the tarns of the
Creative Commons Atbnition 4.0
International ~ Introduction
~ November B. 2020
Coronavirus disease 2019 (COVID-19) was declared a global pandemic on March 11, 2020, and has result-
~ Marth12,2021 ed in almost 100 million confirmed cases and 2.1 million deaths worldwide as of January 24, 2021. Almost
Ml1iied:Mard11S,2021 all individuals infected with SARS-CoV-2 seroconvert within 2- 3 weeks, with the spike and nucleocapsid
(N) proteins eliciting the strongest responses (1, 2). While much attention has focused on defining immune
llehreia lahnaalllll:JO Insight
2021;6(8):e146316. reactivity in individuals after infection, other data indicate that many individuals show preexisti:ng SARS-
https://~/10.1172/jd CoV-2 cross-reactive T and B cells without prior exposure to the virus (3-5). However, the extent of preex-
insight146316. isting SARS-CoV-2 antibody reactivity at the population level has been difficult to estimate, due to a lack
1
of assay sensitivity (6) and clearly definable background thresholds to identify meaningful seroreactivity
among individuals who have been unexposed to the virus (7).
There are 4 circulating coronaviruses predating COVID-19 that cause up to 30% of seasonal upper
respiratory tract infections (8). The spike proteins of β-coronaviruses HKU1 and OC43 exhibit approxi-
mately 40% sequence similarity, whereas the α-coronaviruses NL63 and 229E exhibit approximately 30%
structural similarity with SARS-CoV-2 (9). The common occurrence of circulating coronaviruses year after
year and their structural similarity with SARS-CoV-2 raises the possibility that the former may stimulate
cross-reactive responses toward SARS-CoV-2 and that this heterotopic immunity may impact clinical sus-
ceptibility to COVID-19 and/or modulate responses to the SARS-CoV-2 vaccine (10, 11).
The main objective of this study was to estimate the extent of the preexisting seroreactivity against
SARS-CoV-2 in the general adult population and its relationship to circulating coronaviruses. To confirm
that SARS-CoV-2 antibody reactivity in uninfected adults was genuinely cross-reactive and not due to wide-
spread unreported, asymptomatic SARS-CoV-2 circulation, we similarly assayed sera collected prior to the
emergence of SARS-CoV-2 and from infants before and after maternal antibodies have waned. In addition,
we used a SPOT peptide array to map this antibody reactivity on the SARS-CoV-2 proteome.
Results
Study population. In total, 276 healthy adults were recruited for this cohort between May 17 and June 19,
2020. The demographic characteristics and geographical area of residence of participants are shown in
Supplemental Table 1 (supplemental material available online with this article; https://doi.org/10.1172/
jci.insight.146316DS1) and Supplemental Figure 1, respectively. The majority (n = 196; 71%) were health
care workers. Less than half had traveled outside of British Columbia (BC) since January 1,2020, to
the USA, Europe, Iran, the Caribbean, Australia, Mexico and Japan. Two individuals had a history of
PCR-confirmed COVID-19.
Prevalence of prior SARS-CoV-2 infection in the study population. To estimate the proportion of individuals
who had been previously infected with SARS-CoV-2, we used a multiplex assay to profile antibody reac-
tivity against 4 viral antigens: the whole SARS-CoV-2 spike protein, its N-terminal domain (NTD) and
receptor-binding domain (RBD), and the N protein. Clustering analysis based on antibody reactivity for
these 4 antigens identified that 3 individuals (CW087, CW0150, FH0037) and 5 control sera from conva-
lescent COVID-19 patients (controls A, B, C, D and E) clustered together, separately from the rest of the
cohort (Figure 1). The antibody reactivity profile of these 8 distinct sera showed high reactivity against all
4 SARS-CoV-2 antigens, whereas all other individuals showed variable antibody reactivity against either
spike, RBD, or the N protein (Supplemental Figure 2).
The 3 individuals (CW087, CW0150, FH0037) who clustered with the 5 control sera included the 2
individuals who had a history of PCR-confirmed COVID-19, plus an asymptomatic woman who was not
aware she had COVID-19 initially but later identified that she had been in contact with a COVID-19 case
about 90 days prior to serology testing for this study (Supplemental Table 2).
All sera from the cohort who displayed above-the-mean antibody reactivity for at least 1 of the 4 SARS-
CoV-2 antigens (i.e., for a total of 222 out of 276 individuals) were further tested with a commercial diag-
nostic commercial chemiluminescent (CLIA) assay, which recognizes the spike protein S1 antigen (Supple-
mental Figure 3). With this assay, the same 3 individuals (CW087, CW0150, FH0037), plus the 5 control
sera mentioned above, tested positive. Therefore, based upon these data, it appeared that 3 of 276 partici-
pants (1.1%) showed clear evidence of a previous infection with SARS-CoV-2. After adjusting for bias by
using point estimates of specificity and sensitivity of the CLIA assay, we estimated that the prevalence of a
previous SARS-CoV-2 infection was 0.60% (95%CI, 0%–2.71%) in this cohort.
Antibody reactivity to circulating coronaviruses. The multiplex assay also included quantification of anti-
body reactivity against the spike proteins of circulating coronaviruses (OC43, HKU1, NL63, 229E). All
individuals showed high antibody reactivity against the spike proteins from these circulating coronaviruses
(Supplemental Figure 2). We used correlation analyses to understand the relationship between the antibody
reactivity against SARS-CoV-2 and circulating coronaviruses. Among the 273 seronegative individuals, we
detected significant correlations between antibody reactivity to SARS-CoV-2 spike, as well as spike proteins
from HKU1, NL63, and 229E, but not OC43 (Supplemental Table 3 and Supplemental Figure 4).
Specificity of SARS-CoV-2 antibody reactivity in uninfected individuals. Next, we conducted competition
experiments to exclude the possibility that the antibody reactivity against SARS-CoV-2 in uninfected

Figure 1. Hierarchical clustering of individual based on serum SARS-CoV-2 antibody reactivity profiles. COVID-19 diagnosis identifies convalescing
individuals who had a positive viral test by PCR. This figure combines data from 276 study participants plus the 5 COVID-19 convalescent control sera.
Color scale represents antibody reactivity as a Z score.
individuals was due to nonspecific binding in the multiplex assay and to assess whether this antibody
reactivity may represent cross-reactive antibody responses to circulating coronaviruses. To these ends, we
determined whether the antibody reactivity against antigens in the multiplex assay could be outcompeted
using either a cocktail of free SARS-CoV-2 RBD and full-length spike proteins — or the spike proteins
from all 4 other circulating coronavirus spike proteins (OC43, HKU1, NL63, and 229E) pooled (Figure
2). Antibody reactivity was measured on serial dilutions from selected COVID-19 convalescent and unin-
fected sera selected on the basis of a high reactivity to full-length SARS-CoV-2 spike protein, its RBD, or
its low reactivity to both of these antigens. As expected, the high SARS-CoV-2 spike and RBD antibody
reactivity in COVID-19 convalescent sera was efficiently outcompeted by free SARS-CoV-2 spike and
RBD proteins, but not by other free circulating coronavirus spike proteins (Figure 2, A and B).
Moreover, antibody reactivity to SARS-CoV-2 spike and RBD was partially outcompeted by cir-
culating coronavirus spikes in uninfected individuals — this latter finding supports the argument that
at least some of this SARS-CoV-2 antibody reactivity represented cross-reactivity toward circulating
coronaviruses. Conversely, reactivity to circulating coronavirus spike proteins was efficiently outcom-
peted by spike protein from circulating coronaviruses but not by SARS-CoV-2 spike and RBD proteins
(Figure 2, C and D). Therefore, this experiment confirms that SARS-CoV-2 spike and RBD antibody
reactivity in uninfected individuals is saturatable, essentially excluding nonspecific binding in the mul-
tiplex assay. Interestingly, competition of SARS-CoV-2 spike antibody reactivity was higher in unin-
fected individuals with higher detectable SARS-CoV-2 spike or RBD antibody reactivity compared
with individuals who showed low reactivity against these 2 antigens (Figure 2E). Unexpectedly, anti-
body reactivity against SARS-CoV-2 RBD in uninfected individuals was not efficiently competed by a
fixed amount of SARS-CoV-2 RBD.
Seroreactivity thresholds defined in sera from immunologically naive infants. To unequivocally distinguish unin-
fected individuals who could have SARS-CoV-2 antibody reactivity, we defined the background of antibody
reactivity of sera in the multiplex assay. We reasoned that infants would be immunologically naive, with the
exception of maternal antibodies that are expected to wane gradually after birth; thus, their sera can be used
to define antibody reactivity thresholds in uninfected adults in the multiplex assay. Using this assay, we mea-
sured antibody reactivity of sera from 45 infants less than 6 months of age and repeated this measurement in
the same infants approximately 8 months later, after BC’s lockdown period (Figure 3); the study included 21
infants in whom the first sera were obtained before the pandemic (i.e., before January 2020). In infant sera,
reactivity to circulating coronaviruses was uniformly detected in the first set of blood samples, albeit at much
lower levels than adults. In the second infant sample sets taken after July 1, 2020, antibody recognition of
circulating coronaviruses had decreased to approximately 1000-fold lower levels compared with adults, con-
sistent with a waning of maternal antibodies (Supplemental Figure 5). When comparing antibody reactivity
of SARS-CoV-2 in the second postnatal infant sera, levels were up to 100-fold higher in uninfected adults
compared with infants, regarding the different SARS-CoV-2 antigens (Figure 3).

Figure 2. Specificity of SARS-CoV-2 antibody reactivity. (A and B) Competition of SARS-CoV-2 spike and RBD antibody reactivity by SARS-CoV-2 spike
and RBD proteins (A) or by circulating coronaviruses (cCoVs) spike proteins (B). (C and D) Competition of cCoVs spike antibody reactivity by SARS-CoV-2
spike and RBD proteins (C) or cCoVs spike proteins (D). (E) Competition of SARS-CoV-2 spike antibody reactivity by SARS-CoV-2 spike and RBD proteins
or cCoVs spike proteins, in COVID-19 convalescent sera (seropositive, n = 5), or sera from uninfected individuals who showed highest SARS-CoV-2 spike (n
= 10) and high RBD (n = 9), or lowest SARS-CoV-2 spike and RBD antibody reactivity (all low; n = 10). All values represent the ratios of antibody reactivity
in competed samples over the antibody reactivity measured in absence of competing proteins (dash line). One sample in the RBD-high group failed, and
these data are not shown. In E, data are represented as boxes (25th to 75th percentile, line at median) and whiskers (minimum to maximum); comparisons
were made using 2-tailed paired t tests.

Thus, these second infant samples allowed us to define effective thresholds for SARS-CoV-2 antibody
reactivity in uninfected adults (Figure 3). Based on infants’ sera, we estimate that between 90% and 99% of
adults show positive antibody reactivity for SARS-CoV-2 spike, RBD, or the N antigen. Prepandemic sera
showed similar antibody reactivity, therefore excluding the possibility that the reactivity in adults after the
first pandemic wave is due to undiagnosed exposures to the virus in the study population. This baseline,
preexisting SARS-CoV-2 cross-reactivity in uninfected adults was evenly distributed according to age, sex,
travel history, or whether participants were healthcare workers (HCW), and the data were independent of
participants’ reporting “COVID-19-like” symptoms (Supplemental Figure 6).
Further characterization of SARS-CoV-2 antibody reactivity in uninfected adults. To map this antibody reac-
tivity on the viral proteome, we used a SPOT array assay where peptides broadly covering the SARS-
CoV-2 proteome were directly synthesized on a cellulose membrane (Supplemental Figure 7). To enrich
for high-affinity antibodies, sera from individuals who showed high spike or RBD antibody reactivity
were compared with infant samples. As shown in Figure 4, we detected high antibody reactivity against
nonstructural proteins, particularly the nonstructural protein 2 (nsp2) and nsp15 encoded in the replicase
polypeptides ORF1a and ORF1b. RBD-high samples showed the strongest antibody reactivity encom-
passing RBD, as well as the S1 and the S2 peptides, indicating a diverse anti–SARS-CoV-2 antibody
reactivity linked to a high RBD antibody cross-reactivity. This cross-reactivity was also detected in ran-
domly selected prepandemic sera, which demonstrated preexisting recognition prior to the SARS-CoV-2
pandemic. Importantly, we detected no antibody reactivity against any viral peptides in infants’ sera.
Discussion
In this study, we estimated that 0.60% (95%CI, 0%–2.71%) of the study population showed clear evidence
of a prior infection with SARS-CoV-2. The combination of a highly specific commercial CLIA assay and
a highly sensitive multiplex assay allowed us to distinguish individuals who have been infected with SARS-
CoV-2 from those who have not. This prevalence of SARS-CoV-2 infections was identical to the 0.55%
prevalence reported by the BC CDC on 885 residual sera obtained from an outpatient laboratory network
in the Lower Mainland of BC between May 15 and May 27, 2020. Data from the BC CDC represent a
wider geographical catchment and do not specifically target HCW (12). The current study confirms that
COVID-19 transmission in BC after the first wave was low, even among HCW, contrasting with a high sero-
prevalence reported among HCW in other studies (13–15), which may be attributed to the very low number
of total tested cases in BC during the first wave.
The main finding in this study is that, at a population level, the vast majority of adults show anti-
body reactivity against SARS-CoV-2 antigens. BC reported its first COVID-19 case on January 29,
2020, with the first documented case of community transmission on March 5, 2020. The first pandemic
wave peaked between the third week of March and late April 2020 (11). As of May 17, only 2445 diag-
nosed COVID-19 cases (approximately 49 of 100,000 population) had been reported in BC after the
first wave, which was the lowest rate in Canada and one of the lowest rates in North America. Because
of a relatively low number of COVID-19 cases in BC after the first wave, it is extremely unlikely that
this antibody reactivity results from a direct exposure to SARS-CoV-2. Moreover, findings of similar
antibody reactivity in prepandemic adult sera and from sera obtained from infants younger than 1 year
of age confirms that we are detecting genuine cross-reactivity rather than reactivity to SARS-CoV-2
from asymptomatic COVID-19 cases.
Our findings are consistent with another study in which prepandemic sera exhibited cross-reactive IgG
antibody reactivity with conserved epitopes in SARS-CoV-2 proteins (S2 and N) (5). The higher prevalence
of preexisting antibody reactivity in uninfected adults in our cohort compared with this previous study may
be explained by the high sensitivity of our assay and evidence of positive seroreactivity in those individuals
informed by the infant sera. However, whereas these previous studies have quantified cross-reactivity in
selected sera, to the best of our knowledge, the current study is the first to determine SARS-CoV-2 antibody
reactivity at the population level. The fact that we measured antibody reactivity between infected and unin-
fected individuals in the same population and time period in the current study also eliminates recruitment
or sampling biases and is another major strength of this study.
The presence of preexisting SARS-CoV-2 antibody reactivity in uninfected individuals in the current
study is consistent with the detection of T cell reactivity against SARS-CoV-2 in about 40% of uninfected
individuals (3, 4). This raises an important question: what is the antigenic source of this antibody reactivity?

Figure 3. Thresholds of antibody reactivity based on infants’ sera. Comparison of antibody reactivity (AU/mL) in
infants sampled before 6 months of age (darker blue) and again about 8 months later (lighter blue; n = 45), in SARS-
CoV-2–uninfected (orange; n = 273), in SARS-CoV-2–infected (convalescent) adults (red; n = 8), and in prepandemic
sera (yellow; n = 99). Infants sampled before the pandemic (January 1, 2020) are represented by the larger circle
symbols, whereas infants sampled after January 1, 2020, are shown using the small circle symbols. Boxes represent
median with 25th and 75th percentiles with positive/negative antibody reactivity thresholds for SARS-CoV-2 spike
calculated at the 99th percentile for value distribution (10.00 AU/mL), RBD (10.00 AU/mL), and N protein (10.00 AU/
mL) as 10(mean log[antibody reactivity] + SD log [antibody reactivity] × 2.33) in infants’ sera. Antibody detection for NTD was low and inconsis-
tent between experiments; therefore, the data are not presented and reactivity thresholds were not calculated.
Competition experiments and correlatives analyses indicate that it may, in part, be attributable to cross-re-
activity against circulating coronaviruses. Most humans become infected with circulating coronavirus-
es by their second year of age (16). On the one hand, correlations between SARS-CoV-2 and antibody
reactivity against either HKU1, N63L, or 229E, but not OC43, could reflect seasonal variations in recent
exposure to common coronaviruses (10, 17). On the other hand, the high antibody reactivity to SARS-
CoV in individuals in this study likely represents cross-reactivity due to the higher (>75%) sequence sim-
ilarity between SARS-CoV and SARS-CoV-2 (18, 19), rather than a previous exposure to SARS-CoV.
The data presented in this study shed light on another important question: what region of the virus
does this preexisting antibody reactivity bind to? We found in our peptide mapping experiments that it is
broadly distributed across the viral proteome, including whole spike, and proteins encoding the viral repli-
cation complex. The binding to ORF polypeptides could be a sign of infection by circulating coronaviruses
that share conserved sequences with SARS-CoV-2. High antibody reactivity against nonstructural ORF
proteins was reported in another study using a VirScan peptide mapping approach on prepandemic sera
(6). However, due to a lower sensitivity of the assay, antibody reactivity against spike was not detected in
the latter study. Here, we confirm that this preexisting antibody reactivity involves structural external ele-
ments of the virus in both epitope mapping and competition experiments.
It is unclear whether this antibody reactivity may confer clinical benefits — for instance, modulating
the severity of a SARS-CoV-2 infection. Data indicate that a past circulating coronavirus infection may
decrease the severity of a subsequent SARS-CoV-2 infection (20). Others have linked preexisting seroreac-
tivity against circulating coronaviruses to increased SARS-CoV-2 pseudovirus neutralization in vitro (5),
although this remains debated. Individuals with high RBD reactivity showed the most structurally diverse
antibody reactivity against spike epitopes, which may enhance viral clearance in addition to the improved
neutralizing activity specific to RBD-specific antibodies. Indeed, strong antibody response to RBD have
been linked to improved clinical outcomes from COVID-19 (21). However, reactivity against RBD in the
multiplex assay was not competed by soluble RBD in uninfected individuals, despite that this reactivity
was almost completely abrogated in COVID-19 convalescent sera. The latter finding is consistent with
another study that showed that preexisting antibody reactivity against SARS-CoV-2 in prepandemic sera
could be efficiently competed by a soluble S1 (that contains the RBD domain) but not a soluble S2 subunit
of the spike protein (5). Notably, we were also unable to detect ACE2 receptor binding inhibition from

Figure 4. Mapping of SARS-CoV-2 antibody reactivity in sera from uninfected individuals. Serum antibody binding to 15-mer peptides distributed across
the SARS-CoV-2 proteome or an IgG-binding peptide (positive control), from 5 randomly selected prepandemic samples, adults showing high level of
spike or RBD reactivity (n = 20 each), or infants (n = 5). Values represent signals on a scale from 0 to 10, after subtracting background. The column labeled
C shows the immunoreactivity signal in the absence of sera, but with the addition of anti–human IgA, IgM, and IgG horse-radish peroxidase–coupled
secondary antibody. In the spike protein, labels indicate the N-terminal (NTD), C-terminal (CTD), or receptor-binding (RBD) domains, receptor-binding motif
(RBM), heptad repeat sequence (HR1), central helix (CH), or connector domain (CD); N, nucleocapsid protein; M, membrane protein; ORF, open-reading
frame polypeptide proteins; nsp, nonstructural proteins.
sera of uninfected individuals (not shown), which could indicate that the preexisting antibody reactivity
against SARS-CoV-2 in uninfected adults represents an excess of low-affinity antibodies that have poor
overall viral neutralizing potential. This may not be surprising given that viral neutralization improves
generally with affinity maturation, an antigen-driven process that requires cognate interaction by B cells,
in collaboration with follicular T cells. Similarly, preexisting, highly variable low-avidivity SARS-CoV-2
CD4 memory T cells cross-reactive to circulating coronaviruses appeared less protective in uninfected
adults (22). More studies are needed to understand the origin of preexisting SARS-CoV-2 antibodies and
their impact on COVID-19 severity.
In conclusion, this study reveals common preexisting, broadly reactive SARS-CoV-2 antibodies in
uninfected adults. These findings warrant larger studies to understand how these antibodies affect the sever-
ity of COVID-19, as well as the quality and longevity of responses to SARS-CoV-2 vaccines.
Methods
Study design. Prospective cross-sectional study after the first pandemic wave in BC.
Participants. Adults over 18 years of age from the greater Vancouver metropolitan area were included if they
did not have active COVID-19, did not require self-isolation as per BC provincial public measures, or had recov-
ered from COVID-19 at least 14 days prior to the study visit and blood collection. Blood was drawn in gold-top
serum separator tubes with polymer gel (BD Biosciences, catalog 367989); after at least 30 minutes of clotting at
room temperature, the blood sample was then centrifuged at 1400g for 10 minutes at room temperature to obtain
serum aliquots that were frozen at –80°C within 4 hours of collection. Adult prepandemic sera were all obtained
before January 1, 2020. Infants’ sera were collected before discharge from hospital at birth (first sample) and after
June 11, 2020 (second sample), as part of a study examining antibody responses to respiratory viruses.

Recruitment. Greater Vancouver is the main urban center in BC and the third largest metropolitan
area in Canada, with a population of 2.5 million. Study participants were invited by an email sent to clin-
ical departments of the BC Children’s & Women’s (C&W) Hospitals (the largest pediatric referral center
in BC, located in Vancouver, and where no cases of COVID-19 were admitted during the pandemic’s
first wave) and its affiliated BC Children’s Research Institute (BCCHR). The study was also advertised to
hospitalists, anesthesiologists, and critical care physicians at SMH (located approximately 27 km from
Vancouver). To minimize recruitment bias, all adults who responded to the invitation email and returned
their signed consent form were enrolled sequentially and invited to give a blood sample, without triaging.
Blood samples were collected between May 17 and June 19, 2020.
Study size. Since there were little population seroprevalence data available at the time and none in BC or
Canada, no a priori sample size calculation was performed. The recruitment period was, therefore, defined
by convenience over a 3-week period of enrollment, in order to obtain baseline data.
Multiplex antibody assay. A highly sensitive multiplex (10-plex) assay (Meso Scale Diagnostics, catalog
K15369U) where each antigen is “spotted” into a single well of a 96-well plate (23) was used to measure
antibody profiles against 4 SARS-CoV-2 antigens: the trimeric (whole) S-2P native spike protein, its RBD,
its NTD (24), and N protein; the trimeric SARS-CoV spike protein; and spike proteins from circulating
β-coronaviruses (HKU1, OC43) and α-coronaviruses (229E, NL63) , plus BSA, a negative control. Briefly,
after blocking wells with 5% BSA, sera were added at 4 dilutions (1:100, 1:800, 1:3200, and 1:10,000)
and incubated with shaking for 2 hours. Sulfo-tag–labeled anti-IgG detection antibodies were added, and
the electrochemiluminescence signal was read using the MSD Sector 600 instrument (Meso Scale Diag-
nostics). Initial AUC of the electrochemiluminescence values for antibody detection were well above the
BSA background for all sera for SARS-CoV-2 antigens, except for 1 sera for the RBD and N antigens and
10 sera for the NTD antigen. Samples were rescreened again in a second set of experiments after Meso
Scale Diagnostics provided standards. Results are presented as dilution-corrected interpolated values from
a standard curve with assigned AU/mL. Assignment of AU/mL of serum was performed by Meso Scale
Diagnostics and is designed such that values are comparable with an International Standard Serum (ISS),
so that bridging to a WHO International Standard will be possible in the future.
Competition experiments. Eight 2-fold dilutions of sera prediluted in a ratio of 1:50 assay diluent were add-
ed to an equal volume of assay diluent (control) or to assay diluent mixes containing 5 μg/mL SARS-CoV-2
spike and 5 μg/mL RBD proteins (SARS-CoV-2 RBD-spike cocktail), or 5 μg/mL spike proteins from all 4
circulating coronaviruses (HKU1, OC43, 229E, NL63; circulating coronaviruses [cCoVs] cocktail) (25), for
an on-plate assay dilution of 1:100 through 1:12,800. The dilution series was incubated for 30 minutes at
room temperature and then analyzed using the multiplex antibody assay protocol, as mentioned previously.
CLIA antibody assay. Total antibody (IgA, IgG, and IgM) against recombinant spike (S1) protein was
determined using the VITROS 5600 analyzer (Ortho-Clinical Diagnostics) according to manufacturer
instructions. This is a Health Canada and FDA-licensed qualitative assay with reported performance and
in-house validation indicating sensitivities > 7 days after onset range between 96% and 100%, and specific-
ities from 99% to 100% (26, 27).
SPOT peptide array. Forty-one 15-mer peptides selected based on their reactivity on convalescent samples
and immunogenicity, and that were distributed over the entire SARS-CoV-2 proteome, were synthesized on
a cellulose trioxatridecanediamine membrane using a MultiPep synthesizer (CEM) (28). Additionally, each
membrane contained a human-IgG binding peptide as positive control (29). These in-house–made mem-
branes were incubated with a 1:400 dilution of sera and incubated for 2 hours at room temperature. A copy
of the array was also incubated with Tris buffered saline with Tween 20 only, as a negative control. After
washing, membranes were incubated with secondary antibody (HRP-conjugated goat anti–human IgA +
IgG + IgM polyclonal antibody, Jackson ImmunoResearch Inc., catalog 109-035-064) at a 1:30,000 dilution
for another 2 hours, and detection was carried out using enhanced chemiluminescence detection, with 8
images captured over an exposure time of 50 seconds. The grayscale of images represented as numeric
values between 0 and 10 were used before applying a uniform background correction of 1.
Variables. The following information was collected from participants by questionnaire: age; sex; the first
3 digits of their postal code; HCW status (and whether they worked at C&W or SMH); history of travel
outside BC since January 1, 2020; and history of COVID-19 symptoms and testing. SARS-CoV-2–exposed
cases were defined by a positive result on the commercial CLIA assay, validated for sensitivity by antibody
profiling on the multiplex assay.

Statistics. The seroprevalence from a SARS-CoV-2 exposure was adjusted for bias due to false-positive
and false-negative tests using the Greenland method (30). Differences in proportions were calculated using
a Fisher’s exact test, with significance threshold at P < 0.05. Hierarchical clustering of antibody levels
(based on the multiplex assay) was performed on log-transformed, Z score–normalized serology data, using
the complete linkage agglomeration method and Euclidean distance measures. Spearman correlations
between antibody levels and metavariables were adjusted for multiple testing using the Benjamini-Hoch-
berg FDR = 0.05. There were no missing data. For competition experiments, same-sample groups were
compared using 2-tailed paired t tests. Analyses were conducted in R version 4.0.2, R Studio version 3.6.2,
and GraphPad Prism version 8.4.
Study approval. Written informed consent was obtained from all participants. The study procedures were
approved by the University of British Columbia (UBC) C&W Research Ethic Board (H20-01205; H18-01724).
Author contributions
AM, CM, and SD coordinated the study sample accrual and blood processing in Vancouver. JG and DM
coordinated recruitment at SMH. CC collated the data and helped with data analysis. SEO performed
the multiplex assay, with help from SN and MB. MG provided important input into the study design.
JM and DE expressed and provided the soluble proteins for the multiplex assays and competition experi-
ments. ACL, IS, and ANJ revised the manuscript. MI supervised the statistical analyses. VEB and DMG
supervised the commercial CLIA testing of samples. DFHW and SP performed the SPOT peptide array
analysis. PML and ABM supervised the study in Vancouver and at the NAID/NIH, respectively. AM, CM,
SD, DCD, and PML wrote the manuscript’s first draft. All authors contributed to the study design, data
analysis, and reviewing the manuscript, and they accept the article submission in its final form. The order
of co–first authors was determined based on their earlier involvement at the study design stage.
Acknowledgments
We thank Lauren Muttucomaroe, Esther Alonso-Prieto, and Lisa-Marie Candeias for help with recruitment;
Linda Warner and Stuart Turvey for lending essential staff resources; Kim Schmidt and Kiara Gibbons for
advertising the study; and study participants who have generously donated their time and blood samples. AM is
supported by a Mining for Miracles postdoctoral award from the British Columbia Children’s Hospital (BCCH)
Foundation. CC is supported by BCCHRI Research Institute and UBC Faculty of Medicine Summer Student
Research Program Studentships. AL is supported by a UBC Four Year Fellowship. PML holds a salary award
from the BCCH Foundation through the Investigator Grant Award Program. ANJ and MG acknowledge
funding from the Michael Smith Foundation for Health Research. This study was funded by the BC Children’s
Hospital Foundation (to PML), the Intramural Research Program of the Vaccine Research Centre (VRC) at
the National Institute of Allergy and Infectious Diseases (NIAID), NIH (to ABM and DCD). These funders
did not play a role in the design, planning, execution, analysis, or publication of the study. The study was also
funded in part by the Government of Canada via its COVID-19 Immunity Task Force.
Address correspondence to: Pascal M. Lavoie, BC Children’s Hospital Research Institute, 4th Floor,
Translational Research Building, 950 West 28th Avenue, Vancouver, British Columbia V5Z 4H4, Canada.
Phone: 604.875.2135; Email: plavoie@bcchr.ca.
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AR08644 RESEAR
I@ ©<tJ OPEN ACCESS Public health impact of covid-19 vaccines in the United States:
I111) Check for updates ] observational study
Amitabh Bipin Suthar, Jing Wang, Victorii Seffren, Ryan EWiegand, Sea~ Griffing, Elizabeth Zell
Coronavirus Disease (COVID-19) ABSTRACT f lnboduction

Response, Centers for Disease OBJECTIVE As of 11 April 2022, 497960492 cases covid-19 and
Control and Prevention, Atlanta, To evaluate the impact of vaccine scale-up on t
GA, USA 6181850 covid-19 related deaths had been reported
population level covid-19 mortality and inciden~e in globally, and 80260092 covid-19 cases and 983237
Correspondence to: A B Suthar
icf4@cdc.gov the United States. covid-19 related deaths had been reported in the
(or@AmitabhSuthar on Twitter; DESIGN United States.12 The US death toll recently surpassed
OROD 0000-0001-9756-q593)
Observational study. the 1918 Spanish ftu as the deadliest pandemic in
ate this as: BMJ2022;3n:e06'.13t7
http://dx.doi.org/10.1136/ SETTING recent history.3 In addition to covid-19 related deaths
bmj-2021-06'.1317 US county level case surveillance and vaccine the pandemic has also had indirect effects on othe;
Accepted: 11 March 2022 administration data reported from 14 December 2020 health conditions. These effects are captured in excess
to 18 December 2021. mortality and reduced life expectancy estimates.
PARTICIPANTS Domestically, life expectancy decreased by 1.5 years
Residents of 2558 counties from 48 US states. from 2019 to 2020, representing the largest reduction
since the second world war.4
MAIN OUTCOME MEASURES Messenger RNA (mRNA) covid-19 vaccines
The primary outcome was county covid-19 mortality
developed by Plizer-BioNTech and Modema and an
rates (deaths/100000 population/county week).
adenovirus covid-19 vaccine developed by Johnson
The secondary outcome was incidence of covid-19
& Johnson have become valuable tools to combat this
(cases/100000 population/county week). Incidence
pandemic. Clinical trials evaluating efficacy against
rate ratios were used to compare rates across
symptomatic infection found that the Plizer-BioNTech
vaccination coverage levels. The impact of a 10%
improvement in county vaccination coverage (defined vaccine was 95 .0% effective, the Modema vaccine was
as at least one dose of a covid-19 vaccine among 94.1% effective, and the Janssen vaccine Oohnson &
adults 2:18 years of age) was estimated During the eras Johnson) was 66.3% effecttve.5•7 The US Food and
of alpha and delta variant predominance, the impact
ofvery low (0-9%), low (10-39%), medium (40-69%),
Drug Administration (FDA) granted emergency use
authori7.ationformRNA vaccinesin December 2020and -a
3
and high (2:70%) vaccination coverage levels was the Janssen vaccine in February 2021. FDA approval for -:::;
compared. the Plizer and Moderna vaccines was granted in August

RESULTS
In total, 30 643 878 cases of covid-19 and 439 682
deaths associated with covid-19 occurred over
2021 and January 2022, respectively.8 Emergency use
authorization was further granted to additional doses
of the mRNA vaccines for certain populations.8 As of
11 April 2022, nearly 570 million vaccine doses have
J
CT
~-
132 791 county weeks. A 10% improvement in
vaccination coverage was associated with an 8% (95%
been administered in the US and more than 11 billion 83
confidence interval 8% to 9%) reduction in mortality
rates and a 7% (6% to 8%) reduction in incidence.
vaccine doses have been administered globally.1 2 The
World Health Organization's target is to vaccinate 700/4
--
g
00
Higher vaccination coverage levels were associated of the world's population bymid-2022.9
with reduc;:ed mortality and incidence rates during the
eras of alpha and delta variant predominance.
Across countries, the real world effectiveness of the
covid-19 vaccines has largely been consistent with
l
I\)
0
estimates of efficacy observed in clinical triats.10-12 In
CONCLUSIONS ~
addition to the individual level effect on disease risk
Higher vaccination coverage was associated with ~
and progression, vaccines may also have secondary (C
lower rates of population level covid-19 mortality and C
benefits of slowing spread and reducing onward
incidence in the US.
transmission and its associated morbidity and ~
-0
mortality.13 Population level data and analyses have a
b een limi.teel.14 15 We anned
•
to estimate how increasing Ii
WHAT IS ALREADY KNOWN ON THIS TOPIC county coverage of vaccines affected population level ia.
mortality and incidence of covid-19. CT
The public health impact of scaling up covid-19 vaccination remains largely '<
0
uncharacterized 0
Methods
WHAT THIS STUDY ADDS Study design ~
cc·
Higher vaccination coverage was associated with lower rates of population level Our observational study of the US population used ~
incidence of covid-19 and mortality related to covid-19 national, county level surveillance data. In the US,
counties are a geographic administrative unit below
:hi~ ~ommunity level benefit complements the large body of evidence indicating
states and territories and include the nation's capital,
md1v1dual level benefits of covid-19 vaccination
Washington DC. The US Centers for Disease Control
the...., I BMJ2022-37/:e069317 I doi: 10.1136/bmj-2021-069317 I

AR08645
RESEARCH
and Prevention (CDC) receives surveillance data was an inclusion criterion for analysis. We used a 70%
from 3224 US counties (or county equivalents). We threshold for data completeness of reporting county
BMJ: first published as 10.1136/bmj-2021-069317 on 27 April 2022. Downloaded from http://www.bmj.com/ on 8 May 2022 by guest. Protected by copyright.
included and analyzed county covid-19 cases, deaths, of residence across all data sources. Specifically, we
and vaccinations reported to the CDC. We tracked excluded a jurisdiction if more than 30% of the case,
mortality as our primary outcome and incidence death, and/or vaccination data for the jurisdiction
(using reported probable and confirmed covid-19 were contributed by unspecified or unknown counties
cases) as our secondary outcome. We calculated of residence. We excluded Texas and Hawaii because
county level incidence by standardizing reported vaccination data were unavailable at county level.
county cases and deaths per 100 000 population over We excluded county equivalents in territories except
a week.2 for Puerto Rico and Guam, either because the county
level population data of adults ≥18 years old were
Study definitions unavailable (US Virgin Islands) or because the county
We defined a case as one that met the Council of equivalent vaccination data were unavailable (all other
State and Territorial Epidemiologists’ surveillance territories). In addition, we excluded eight counties
case definitions as confirmed or probable covid-19 in California with a population of fewer than 20 000
and a death as those that were related to covid-19, people, as California does not report the vaccination
as determined or reported by jurisdictions.16 17 Each data of counties with under 20 000 people. We
vaccine dose administered was attributed to the county excluded the Kusilvak Census Area in Alaska owing to
in which the person resided.18 We defined the county unavailable vaccination data and the Valdez-Cordova
vaccination coverage as the number of people aged Census Area in Alaska because the case and mortality
≥18 years who received at least one dose of covid-19 data were unavailable. We excluded the District of
vaccine among the total number of people aged ≥18 Columbia, villages in Guam, and municipalities in
years old residing in that county.2 Puerto Rico because of a lack of mobility data. Finally,
we excluded Rio Arriba County in New Mexico because
Data sources the social vulnerability index was missing. In addition,
For case and death counts disaggregated by county and we excluded any county week missing covariate
week, we used the CDC’s managed case surveillance information used in regression models.
dataset, which includes the most recent numbers
reported by states, territories, and other jurisdictions. Data analysis
This dataset is populated by routine reporting from County of residence case and first dose covid-19
jurisdictions to the CDC.16 To document new cases, vaccination data were aggregated by Morbidity and
jurisdictions may use the date that a case was reported Mortality Weekly Report (MMWR) week beginning
to the health department, a person took a covid-19 test, with MMWR week 2020-51 (13-19 December 2020)
a laboratory confirmed a covid-19 test as positive, or a and ending with MMWR week 2021-50 (12-18
person was diagnosed as having covid-19 by a clinician. December 2021).21 The CDC and Agency for Toxic
For death reporting, jurisdictions may use the date Substances and Disease Registry’s social vulnerability
when the death was reported to the health department index encompasses socioeconomic status (that is,
or the date of covid-19 associated death.2 We retrieved poverty rates, unemployment rates, income levels,
counts of covid-19 vaccine doses administered by and education levels), household composition and
week and county from the CDC’s managed vaccine disability (that is, ages, disability, and single parent
dataset. This dataset includes covid-19 vaccination households), minority status, language capability,
data (including the date of vaccine administration, and housing type and transportation (that is, multi-
the number of doses administered, and county of unit structures, mobile homes, crowding levels,
residence, among other variables) reported to the vehicle ownership, and group housing) into a single
CDC by jurisdictions, pharmacies, and federal entities measure.22 Google’s community mobility reports help
through Immunization Information Systems, the to measure changes in community mobility related
Vaccine Administration Management System, or direct to covid-19.23 To prevent confounding related to the
submission of vaccination records.19 The population social vulnerability and mobility of communities, we
data, used for denominators to measure vaccination included these variables in the model.24 25
coverage, came from the vintage 2019 US population We used generalized linear mixed models assuming
estimates.20 a negative binomial outcome distribution to assess
associations between vaccination coverage and rates
Inclusion criteria of deaths and cases by using continuous estimates.26
We included case surveillance and vaccine We used a first order autoregressive correlation
administration data from 14 December 2020 to 18 structure to account for multiple observations per
December 2021. We included people at least 18 years county and for potential autocorrelation. We included
of age with a valid county of residence in one of the county level population as an offset and included
states or territories who received at least one covid-19 social vulnerability index categorized into quarters
vaccination. Given that population benefits may extend and retail and work mobility data as covariates. To
beyond the primary vaccine recipient, we included case account for cases occurring during the period of
and mortality data across all ages. Data completeness developing immunity, a county remained in the lower
2 doi: 10.1136/bmj-2021-069317 | BMJ 2022;377:e069317 | the bmj

AR08646 RESEARCH
vaccination category for two weeks before moving to ratio 0.40, 95% confidence interval 0.39 to 0.42),
the next vaccination category. medium (0.25, 0.23 to 0.26), and high (0.19, 0.16 to
We calculated estimates during the period of alpha 0.22) vaccination coverage categories had lower rates of
variant predominance and the period of delta variant mortality (fig 3). Compared with very low coverage, low
predominance (starting when the national prevalence (incidence rate ratio 0.43, 0.41 to 0.44), medium (0.30,
of delta was estimated to be at least 50%—that is, 0.29 to 0.32), and high (0.20, 0.18 to 0.22) vaccination
the week of 20 June 2021 onward) categorically.27 28 coverage categories had lower incidence rates (fig 3).
We compared four different categories for county
vaccination coverage: very low (0-9% of the county Era of delta variant predominance
had been vaccinated), low (10-39% of the county had In total, we observed 15 150 579 cases of covid-19 and
been vaccinated), medium (40-69% of the county 175 809 covid-19 related deaths over 62 602 county
had been vaccinated), and high (≥70% of the county weeks during the era of delta variant predominance.
had been vaccinated) during the era of alpha variant When comparing high and medium coverage, we
predominance. As with the continuous analyses, observed similar mortality effects during the era of
to account for cases occurring during the period of alpha variant predominance (incidence rate ratio
developing immunity, a county remained in the lower 0.77, 0.66 to 0.90) and the era of delta variant
vaccination category for two weeks before moving to predominance (0.75, 0.71 to 0.79). When comparing
the next vaccination category. Moreover, we included high and medium coverage, we observed smaller
county level population as an offset and included incidence effect sizes during the era of delta variant
social vulnerability index categorized by quarter and predominance (incidence rate ratio 0.90, 0.87 to 0.94)
retail and work mobility data as covariates. Given the compared with the era of alpha variant predominance
inadequate number of county weeks accrued with very (0.66, 0.60 to 0.73).
low and low vaccination coverage, we compared the
mortality and incidence rates for medium and high Sensitivity analyses
coverage during the era of delta variant predominance. We observed sustained reductions in county mortality
and incidence rates when we included only fully
Sensitivity analyses vaccinated people in the vaccination coverage
We did three sensitivity analyses with the continuous categories, when we increased our data stringency
analyses. The first sensitivity analysis was to compare level, and when we removed the two week immunity
definitions of vaccination being at least one dose with lag period (fig 4).
including only fully vaccinated people (that is, at least
two mRNA doses or a single adenovirus dose). The Discussion
second was to compare use of a stringency level for Using data from 2558 counties—representing nearly
data completeness of 70% and 90%. The third was to 300 million people and 80% of the US population—
compare estimates with and without the two week lag we found that increasing the vaccination coverage
period. in counties was associated with a reduced incidence
of covid-19 related mortality and cases. We observed
Patient and public involvement decreasing trends in mortality and case incidence
We used routinely generated covid-19 vaccine and associated with higher levels of vaccination coverage
case surveillance data. No patients were involved in across the eras of both alpha and delta variant
setting the research question or the outcome measures, predominance. This effect was robust to various
nor were they involved in developing plans for design sensitivity analyses, which improves prediction and
or implementation of the study. No patients were asked confidence in these findings.
to advise on interpretation or writing up of results. Covid-19 associated mortality remains one of the
most important clinical outcomes to guide public
Results health decision making, measure pandemic severity,
First year of vaccine roll-out and evaluate mitigation efforts. It was our primary
We included data from 2558 counties in 48 US states (fig outcome. In the US, death registration rates, and cause
1). In total, we observed 30 643 878 cases of covid-19 of death ascertainment, remain high. This suggests
and 439 682 covid-19 related deaths over 132 791 that US mortality surveillance systems have been,
county weeks (table 1). Every 10% improvement in and will continue to be, useful for covid-19 mortality
vaccination coverage was associated with an 8% (95% surveillance. Previous vaccine studies have shown
confidence interval 8% to 9%) reduction in mortality survival benefits at the individual level.29 We observed
rates (fig 2) and with a 7% (6% to 8% reduction in case that these benefits may extend to the population level;
incidence (fig 2). counties with high coverage had a greater than 80%
reduction in mortality rates compared with largely
Era of alpha variant predominance unvaccinated counties. Given that infection fatality
In total, we observed 15 493 299 cases of covid-19 and rates for covid-19 increase with age, counties with
263 873 covid-19 related deaths over 70 189 county a higher proportion of older people may have more
weeks during the era of alpha variant predominance. covid-19 related mortality and stand to benefit from
Compared with very low coverage, low (incidence rate high coverage of covid-19 vaccines.30
the bmj | BMJ 2022;377:e069317 | doi: 10.1136/bmj-2021-069317 3

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100 workplaces, restaurants, entertainment venues,

Vaccine coverage (%)
schools, and outgoing international air travel, more
80 people without symptoms may be seeking out testing.32
These requirements, and their uptake, may vary across
60 states and counties. Nevertheless, the reduction
in incidence observed with increasing vaccination
40 coverage is consistent with surveillance data from
other countries that have achieved high vaccination
20
coverage and emerging evidence on transmission from
0 contact tracing programs.1 33
Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
2020 2021 Comparison with other studies
Increasing vaccination coverage may play a role in
Fig 1 | County scale-up of vaccinations from 13 December 2020 to 18 December 2021. mitigating the effects of the delta and omicron variants
Light purple lines represent individual counties; dark purple line is aggregated estimate
and reduce the emergence of future variants.34 35 By
27 June 2021 the delta variant made up more than
50% of circulating variants in the US, increasing to
We used reported cases as a proxy for incidence for almost 100% by 21 September 2021.2 More recently,
our secondary outcome. Although reliable, available the omicron variant was first reported on 1 December
across jurisdictions, and reported continuously, 2021 and comprised 95% of circulating variants by
reported cases may not reflect true transmission rates 2 January 2022.2 The delta variant had increased
because of variation in when people seek out testing.31 transmissibility and possible increased virulence
For example, people without symptoms may not compared with earlier SARS-CoV-2 strains.36 37 In our
actively seek out testing of their own accord but may study, by the time the delta variant predominated,
be important to test for gauging disease transmission. counties with lower levels of vaccination coverage
Owing to more recent reopening requirements for (that is, 0-39%) were rare. Nevertheless, our findings
Table 1 | Characteristics of included counties. Values are median (range) unless stated otherwise
Alpha variant (13 Dec 2020 to 27 Delta variant (28 June 2021 to 18
Characteristic 13 Dec 2020 to 18 Dec 2021 Jun 2021) Dec 2021)
Sample size (counties; weeks) 2558; 132 791 2557; 70 189 2543; 62 602
Vaccination coverage 46.4 (0.0-100.0) 24.9 (0.0-100.0) 58.8 (2.1-100.0)
Vaccination coverage, No (%):
0-9.9% 21 312 (16.0) 21 238 (30.3) 74 (0.1)
10-39.9% 31 838 (24.0) 28 138 (40.1) 3700 (5.9)
40-69.9% 65 473 (49.3) 19 513 (27.8) 45 960 (73.4)
≥70% 14 168 (10.7) 1300 (1.9) 12 868 (20.6)
Population size 24 538 (1074-7 894 557) 24 541 (1074-7 894 557) 24 696 (1404-7 894 557)
Social vulnerability index, No (%):
Quarter 1 620 (24.2) 620 (24.2) 614 (24.1)
Quarter 2 666 (26.0) 666 (26.0) 662 (26.0)
Quarter 3 655 (25.6) 654 (25.6) 652 (25.6)
Quarter 4 617 (24.1) 617 (24.1) 615 (24.2)
Adults aged ≥25 without high school diploma, % 11.8 (1.6-42.4) 11.8 (1.6-42.4) 11.8 (1.7-42.4)
Below federal poverty level, % 14.8 (2.3-55.1) 14.8 (2.3-55.1) 14.8 (2.3-55.1)
Per capita income, $ 26 256 (10 148-72 832) 26 256 (10 148-72 832) 26 262 (10 148-72 832)
Unemployment rate 5.6 (0.7-25.8) 5.6 (0.7-25.8) 5.6 (0.7-25.8)
Age ≤17, % 22.3 (7.3-40.3) 22.3 (7.3-40.3) 22.3 (7.3-40.3)
Age ≥65, % 17.9 (3.8-55.6) 17.9 (3.8-55.6) 17.8 (3.8-55.6)
Age >5 with disability, % 15.5 (3.8-33.7) 15.5 (3.8-33.7) 15.5 (3.8-33.7)
Racial or ethnic minority, % 15.1 (0.3-95.7) 15.1 (0.3-95.7) 15.1 (0.3-95.7)
Single parent households, % 8.2 (1.9-25.6) 8.2 (1.9-25.6) 8.2 (1.9-25.6)
Limited English proficiency, % 0.7 (0.0-21.7) 0.7 (0.0-21.7) 0.7 (0.0-21.7)
Households without vehicle, % 5.8 (0.5-77.0) 5.8 (0.5-77.0) 5.8 (0.5-77.0)
Housing in structures with ≥10 units, % 3.2 (0.0-89.4) 3.2 (0.0-89.4) 3.2 (0.0-89.4)
In mobile homes, % 10.7 (0.0-54.8) 10.7 (0.0-54.8) 10.7 (0.0-54.8)
Occupied housing units where people exceed rooms, % 1.8 (0.0-35.4) 1.8 (0.0-35.4) 1.8 (0.0-35.4)
People in institutionalized group residencies, % 2.0 (0.0-36.2) 2.0 (0.0-36.2) 2.0 (0.0-36.2)
Change in mobility, %:
Groceries 4.6 (−91.0-206.7) −0.7 (−91.0-140.0) 8.0 (−80.0-206.7)
Home 4.1 (−23.2-41.8) 6.0 (−4.0-41.8) 3.3 (−23.2-15.4)
Parks 33.0 (−84.6-490.0) 10.4 (−84.6-433.0) 58.7 (−81.3-490.0)
Retail −1.4 (−88.0-304.9) −7.1 (−88.0-163.4) 2.6 (−85.0-304.9)
Transit −6.6 (−85.4-280.1) −14.4 (−82.0-258.6) 3.1 (−85.4-280.1)
Offices −18.4 (−85.4-65.7) −18.4 (−79.8-32.4) −18.4 (−85.4-65.7)

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Mortality in population level vaccine impact that merit

8
exploration.41-43 Continuing to monitor the delta and
Estimated deaths
per 100 000 people
omicron variants, and the emergence of other variants
6 of interest, is critical and will require ongoing genomic
surveillance.
4
Clinical studies indicate that a single dose of an
mRNA vaccine provides a lower level of protection
than two doses.44 Furthermore, two mRNA doses seem
2 to be more effective than a single adenovirus dose
against symptomatic infection.5-7 We defined people
0 with at least one dose of vaccine as being vaccinated
for the purposes of vaccination coverage. Given that
Incidence our study design used population surveillance data,
500
Estimated cases
per 100 000 people
changing our coverage definition to include only fully

vaccinated people would place people with a single
400
dose of mRNA vaccine in our referent, the very low
coverage category. This may introduce bias in the
300
incidence and mortality estimates. When we changed
200 our definition of vaccination coverage to being fully
dosed during sensitivity analysis, we did not find
100 increased effect sizes, as would be expected from
clinical studies.44 Ongoing vaccine studies continue to
0 evaluate the comparative effectiveness of vaccines by
0 25 50 75 100
manufacturer.10
Vaccine coverage (%) Given that only people aged 18 and older were
Fig 2 | Effect of vaccination coverage on county covid-19 related mortality (top) and eligible for vaccination across vaccines during most
incidence (bottom) during first year of vaccine roll-out. Analyses are from 2558 counties of our study period, we used this age threshold to
in 48 US jurisdictions. Model controlled for county population size, social vulnerability define vaccination coverage. Pediatric studies will be
index, and mobility changes a welcome contribution to understanding the effects
of vaccines on younger age groups, when feasible. As
of September 2021 the FDA began recommending a
of continued population level protection against third dose for specific populations.8 Owing to waning
death and reductions in population level protection immunity and variant induced changes in vaccine
against infection during the period of delta variant effectiveness, additional doses may be needed in
predominance seem to be consistent with clinical specific populations and scenarios. Further studies
literature on vaccine effectiveness.29 38-40 Additional may benefit from evaluating the population impact of
studies aimed at assessing the population impact vaccination coverage by using different definitions and
of vaccines during the period of delta variant eligibility scenarios.
predominance merit consideration for validating
our observations. Although our study period did not Limitations of study
include the period of omicron variant predominance, Several limitations should be considered when
data suggesting reduced vaccine effectiveness and interpreting these data. We chose vaccination coverage
the importance of staying up to date on covid-19 thresholds based on programmatic experience;
vaccinations are emerging and may lead to changes exploring coverage thresholds above 70% may
be worth examining in future research once more
1.0 counties have achieved these levels for extended
Incidence rate ratio
Mortality periods of time. We excluded some jurisdictions

Incidence because they did not have county level information on
0.8
immunizations, cases, and deaths for at least 70% of
0.6 their counties. Additional markers of disease severity,
such as hospital admissions, were not explored in this
0.4 study owing to possible differences in ascertainment
and reporting coverage across jurisdictions. Given the
0.2 limited number of variables that were known to affect
mortality and incidence, collected at the county level,
0
0-9% 10-39% 40-69% ≥70% and available on a weekly basis, we did not control for
Very low Low Medium High masking, physical distancing, or other similar potential
confounding variables in this study. Furthermore,
Fig 3 | Effect of vaccination coverage on county covid-19 mortality and incidence
during era of alpha variant predominance. Analyses are from 2557 counties in 48 US given the limited number of county weeks, we lacked
jurisdictions. Model controlled for county population size, social vulnerability index, power to stratify by time periods and cannot rule out
and mobility changes the possibility of temporal confounding. Finally, given

AR08649
RESEARCH
necessarily represent the official position of the Centers for Disease

Incidence rate Incidence rate Control and Prevention. Use of trade names and commercial sources
ratio (95% CI) ratio (95% CI)
is for identification only and does not imply endorsement by the US
Death Department of Health and Human Services.
Contributors: ABS, JW, VS, REW, SG, and EZ conceived and designed
Baseline* 0.92 (0.91 to 0.92)
the study. JW, VS, REW, and EZ analyzed the data. ABS, JW, VS, REW,
Fully vaccinated† 0.93 (0.92 to 0.94) SG, and EZ wrote the manuscript. ABS, JW, VS, REW, SG, and EZ agree
90% completeness‡ 0.91 (0.91 to 0.92) with manuscript’s results and conclusions. The corresponding author
attests that all listed authors meet authorship criteria and that no
No immunity lag§ 0.91 (0.91 to 0.92) others meeting the criteria have been omitted. ABS is the guarantor.
Incidence Funding: None.
Baseline* 0.94 (0.94 to 0.95) Competing interests: All authors have completed the ICMJE uniform
Fully vaccinated† 0.95 (0.94 to 0.95) disclosure form at www.icmje.org/disclosure-of-interest/ and declare:
no support from any organization for the submitted work; no financial
90% completeness‡ 0.94 (0.94 to 0.95) relationships with any organizations that might have an interest in the
No immunity lag§ submitted work in the previous three years; no other relationships or
0.94 (0.93 to 0.94)
activities that could appear to have influenced the submitted work.
0.1 1 Ethical approval: Not applicable.
Data sharing: Centers for Disease Control and Prevention covid-19
Fig 4 | Sensitivity analyses of including only fully vaccinated people, increasing data vaccination, case, and death data are available at data.cdc.gov.
stringency requirements, and removing two week immunity lag period. *In baseline The lead author (the manuscript’s guarantor) affirms that the
group, vaccination coverage refers to coverage of at least one dose of vaccine, 2558 manuscript is an honest, accurate, and transparent account of the
counties and 48 US jurisdictions included had ≥70% completeness rates of reporting study being reported; that no important aspects of the study have
county of residence, and study period was 14 December 2020 to 18 December 2021. been omitted; and that any discrepancies from the study as planned
(and, if relevant, registered) have been explained
†Vaccination coverage refers to coverage of fully vaccinated people. ‡2164 counties
and 42 US jurisdictions included had ≥90% completeness rates of reporting county of Dissemination to participants and related patient and public
communities: This publication will be shared on appropriate websites
residence. §Two week immunity period was removed and social media platforms and at meetings.
Provenance and peer review: Not commissioned; externally peer
reviewed.
that we used aggregate case surveillance data to have This is an Open Access article distributed in accordance with the
the most complete case and death data available, other Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
characteristics of cases, such as demographics and which permits others to distribute, remix, adapt, build upon this work
non-commercially, and license their derivative works on different
comorbidities, were not available. States, territories, terms, provided the original work is properly cited and the use is non-
and jurisdictions adapt national guidance on which commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
date to use for case reporting.17 In this study we collated
1 World Health Organization. WHO Coronavirus (COVID-19) Dashboard.
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difference may be present depending on which date a 2 Centers for Disease Control and Prevention. COVID Data Tracker.
https://covid.cdc.gov/covid-data-tracker/#datatracker-home.
health department uses; however, this is unlikely to be
3 Centers for Disease Control and Prevention. 1918 Pandemic (H1N1
substantial enough to affect which week a case or death virus). 2019. https://www.cdc.gov/flu/pandemic-resources/1918-
occurs. Naturally acquired immunity resulting from pandemic-h1n1.html.
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disease-2019-covid-19/covid-19-vaccines.
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22 Centers for Disease Control and Prevention, Agency for Toxic HEROES-RECOVER Cohorts. Effectiveness of COVID-19 Vaccines in
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1/31/2020. https://www.atsdr.cdc.gov/placeandhealth/svi/ and During B.1.617.2 (Delta) Variant Predominance - Eight U.S.
documentation/SVI_documentation_2018.html. Locations, December 2020-August 2021. MMWR Morb Mortal Wkly
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AR07231

2 A. Yes, pardon, pardon me. Yes, yes, yes.

3 11 Q. Okay. And to clarify, I believe you referred to Dr.

4 Phillips, I think it’s just Mr. Owen Phillips.

7 A. Yes, I had a look at that as well, yes. That’s

12 14 Q. Okay. Are you in your residence?

14 15 Q. Okay. And do you have a copy of your affidavit and

15 exhibits before you?

16 A. I, I have - yes, I believe I do. I’ve got them - I’ve

17 got the affidavit, I can probably find the exhibits if

18 need be. I’m not - no, I don’t have the exhibits in

20 16 Q. The exhibits including your expert report?

21 A. No, I have my expert report. I have my, my expert

22 report and I have my CV, I think. Yes, I have, I have

23 those, yes. So I have those...

25 A. I don’t have all the footnotes for my, my affidavit.

2 18 Q. So when you say your footnotes you mean the

3 authorities on which you relied in your expert report?

4 A. That’s what I meant, yes.

5 19 Q. Okay. But you do - I wanted to clarify, you have your

6 exhibit - your, I’m sorry, your affidavit and the main

7 exhibits to it which include your CV and your expert

10 20 Q. Okay. Do you have anything else before you?

11 A. I have on, just looking at my computer screen, what I

12 have open, I have opened a copy of the Federal/

13 Provincial/ Territorial document that you circulated

14 to me a few hours ago. I think that’s all I have open

16 21 Q. Okay. Okay, thank you. Other than those documents we

17 just discussed, you can confirm you do not have any

18 notes or any other materials before you?

19 A. I do not, no. No.

21 else unless it is shared with you?

22 A. If that’s - I mean I don’t know the rules here, but

23 I’m quite happy not to access anything else unless

24 it’s okay with you. No problem.

2 aspect of this cross examination in any matter -

3 manner with any other person until it is concluded

4 including during any breaks we may take with the

5 exception of discussion with counsel on questions to

6 which he has raised an objection.

8 24 Q. Okay. And just a few other small housekeeping

10 but you can expect we’ll likely take a break at about

11 90 minutes in if we are not then concluded or close to

14 25 Q. However, if you consider you otherwise need a break,

15 please let me know and we will try to accommodate you.

16 A. Okay, thank you.

17 26 Q. And my - and of course also, almost all my questions

18 will be in respect of your expert report which you’ve

19 attached as an exhibit to your affidavit. I will

20 always try to be accurate and identify the document on

21 which I’m asking questions. However, if I’m silent on

22 this point, you should expect my questions to be in

23 respect of your report.

25 27 Q. Is that a fair approach and will you understand if I

2 A. Seems fine to me, yeah.

3 28 Q. Thank you. All right, one last question before we

4 proceed, are there any corrections you need to make to

5 your affidavit and attachments since it was sworn,

6 served, and filed?

7 A. I’m not aware of any. There are a couple of

8 grammatical errors, but I think you’ll probably

11 29 Q. Okay. Small typographical errors of and of things of

12 that nature is what you’re referring to.