CCO COVID19 Resources Downloadable Vaccines

Comprehensive COVID-19 Slideset:
Vaccines and Variants
Version 4 – August 4, 2022
This program is supported by educational grants from Gilead Sciences, Inc.; Janssen
Therapeutics, Division of Janssen Products, LP; and Merck Sharp & Dohme Corp.
About These Slides
 Please feel free to use, update, and share some or all of these slides in
your noncommercial presentations to colleagues or patients
 When using our slides, please retain the source attribution:
Slide credit: clinicaloptions.com
 These slides may not be published, posted online, or used in

commercial presentations without permission. Please contact
permissions@clinicaloptions.com for details
Faculty
Arthur Kim, MD Sharon Lewin, AO, FRACP, PhD,
Associate Professor FAHMS
Department of Medicine Director, The Peter Doherty Institute
Harvard Medical School for Infection and Immunity
Director, Viral Hepatitis Clinic Professor of Infectious Diseases,
Division of Infectious Diseases University of Melbourne
Massachusetts General Hospital Consultant Infectious Disease
Boston, Massachusetts Physician, Alfred Hospital and Royal
Melbourne Hospital
Melbourne, Australia
Faculty
Kristen Marks, MD Renslow Sherer, MD
Associate Professor of Medicine Director
Division of Infectious Diseases International HIV Training Center
Weill Cornell Medicine Professor of Medicine
New York, New York University of Chicago
Chicago, Illinois
Faculty Disclosures
Arthur Kim, MD, has disclosed that he is on the drug and safety monitoring board of
Kintor Pharmaceuticals.
Sharon Lewin, AO, FRACP, PhD, FAHMS, has disclosed that she has received consulting
fees from AbbVie, Gilead Sciences, and ViiV Healthcare; funds for research support
from Leidos; and other financial or material support from Gilead Sciences, Merck, and
ViiV Healthcare.
Kristen Marks, MD, has disclosed that she has received funds for research support
paid to Weill Cornell Medicine from Gilead Sciences.
Renslow Sherer, MD, has disclosed an unrestricted research grant from Gilead
Sciences, Inc.
Overview
 SARS-CoV-2 Mutations and Variants  Vaccine Third Doses and Boosters
‒ Omicron, Alpha, Beta, Delta, and  COVID-19 Vaccination in PWH
Gamma Variants
 Additional Investigational Vaccines
 Implications of SARS-CoV-2 Variants
 Vaccine Safety: Management of
 Vaccine Development Anaphylaxis
‒ mRNA and Ad26.COV2.S Vaccines  Vaccine Hesitancy
‒ ChAdOx1 nCoV-19 (AZD1222) Vaccine
‒ CoV2 preS dTM-AS03 Vaccine
‒ NVX-CoV2372 Vaccine
SARS-CoV-2 Mutations and Variants
What Are Variants?
 Mutations occur during viral RNA transcription that cause new variants of a virus
 Viral mutations and variants in the United States are routinely monitored through
sequence-based surveillance, laboratory studies, and epidemiological investigations
 The US government developed a classification scheme that defines
3 classes of SARS-CoV-2 variants:
‒ Variant Being Monitored (VBM)
‒ Variants of interest (VOI)
‒ Variants of concern (VOC)
‒ Variants of high consequence (VOHC)
CDC: SARS-CoV-2 Variant Classifications and Definitions. https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html.

Last updated April 26, 2022. Slide credit: clinicaloptions.com
Variant Classification Scheme: Variant of Concern
 A variant of concern demonstrates:
‒ Evidence of increased transmissibility
‒ Evidence of increased disease severity
‒ Evidence of impact on diagnostics, treatments, or vaccines
(reduction in expected outcomes)
CDC: SARS-CoV-2 Variant Classifications and Definitions https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html.

Selected Variants of Concern Characteristics
Spike Protein
WHO Label PANGO Lineage Date of Designation
Substitutions?
Alpha B.1.1.7 ✅ December 2020
Beta B.1.351, B.1.351.2, B.1.351.3 ✅ December 2020
Delta B.1.617.2 and AY lineages ✅ May 2021
Gamma P.1, P.1.1, P.1.2 ✅ December 2020
Epsilon B.1.427, B.1.429 ✅ March 2021
B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4,
Omicron and BA.5 lineages ✅ November 2021
 The only current variant of concern is omicron; other variants have

been demoted to variants being monitored
CDC: SARS-CoV-2 Variant Classifications and Definitions. cdc.gov/coronavirus/2019-ncov/variants/variant-info.html.
Updated
Genomic Epidemiology of SARS-CoV-2: Geography
Phylogeny
Clade
20H (Beta, V2) 21L (Omicron)
20I (Alpha, V1) 21M (Omicron)
20J (Gamma, V3) 22A (Omicron)
21A (Delta) 22B (Omicron)
21I (Delta) 22C (Omicron)
21J (Delta) 19A
21B (Kappa) 19B
21C (Epsilon) 20A
21D (Eta) 20C
21F (lota) 20G
21G (lambda) 20E (EU1)
21H (Mu) 20D
21K (Omicron) 20F
GISAID. Updated April 18, 2022. gisaid.org/phylodynamics/global/nextstrain/. Slide credit: clinicaloptions.com

Updated
Genomic Epidemiology of SARS-CoV-2: Phylogeny
Depicting 2866 Genomes

Sampled Between
Dec 2019 and July 2022
Phylogeny
Clade
20H (Beta, V2) 21L (Omicron)
20I (Alpha, V1) 21M (Omicron)
20J (Gamma, V3) 22A (Omicron)
21A (Delta) 22B (Omicron)
21I (Delta) 22C (Omicron)
21J (Delta) 19A
21B (Kappa) 19B
21C (Epsilon) 20A
21D (Eta) 20C
21F (lota) 20G
21G (lambda) 20E (EU1)
21H (Mu) 20D
21K (Omicron) 20F
GISAID. Updated May 18, 2022. gisaid.org/phylodynamics/global/nextstrain/. Slide credit: clinicaloptions.com

SARS-CoV-2 Pseudotyped Virus: Spike Mutations
 Li and colleagues analyzed >13,000  Analyzed infectivity against human
spike sequences reported to GISAID and primate cell lines: 293-T-
 Filtered out incomplete, redundant, hACE2, Huh-7, Vero, LLC-MK2
ambiguous sequences to yield 80  Tested antigenicity against
natural variants
13 neutralizing mAbs and
 Generated 26 substitutional mutations convalescent sera from 10 patients
at all 22 putative glycosylation sites in recovered from COVID-19
RBD of spike protein
 Created 106 pseudotyped viruses to
characterize impact of SARS-CoV-2
spike mutations
Li. Cell. 2020;182:1284. Slide credit: clinicaloptions.com

SARS-CoV-2 Pseudotyped Virus: In Vitro Responses
Characteristic Group A: Excluding RBD Group B: Within RBD Group C: Glycosylation Sites
Number of variants or mutants 29 51 26
D614G, D614G+L5F, D614G+D936Y, D614G+V341I, D614G+K458R,
↑infectivity D614G+S939F, D614G+S943T D614G+I472Va none
V341I, D364Y, 385-387del, D405V, N122Q, N343Q, N717Q,

Q239K, D839Y, P1263L,
↓infectivity D614G+Q675H Q414P, I434K, S438F, D467V, P491R, T719A, N801Q, N1074Q,
V503F, R509K, V510L, P521S N331Q+N343Q*
V367F, Q409E, Q414E, I468F,
↑sensitivity to neutralizing mAb None I468T, Y508H, A522V N165Q, N709Q
N439K, L452R, A475V, V483A,

↓ sensitivity to neutralizing mAb A831V F490L, Y508H, D614G+A435S, N234Q
D614G+I472Va
N149H, N149Q, N165Q,
↑ sensitivity to convalescent sera V615L F338L, V367F, I468F, I468T N331Q, N354D, N709Q,
N1173Q
Q414E, N439K, G446V, K458N,
↓ sensitivity to convalescent sera Y145del, A831V, D614G+A831V, I472V, A475V, T478I, V483I, F490L, none
D614G+A879S, D614G+M1237I H519P, D614G+Q321L,
D614G+I472Va
*Glycosylation deletion with either N331Q or N343Q resulted in 3- to 20- fold reductions in infectivity, respectively, whereas removal of both glycosylation sites
(N331Q + N343Q) resulted in 1200-fold reduction; suggests these sites may be involved in receptor binding or RBD conformation.
Li. Cell. 2020;182:1284. Slide credit: clinicaloptions.com
Omicron Variant (B.1.1.529)
Omicron Variant
Changes in Omicron Variant
Delta Omicron
 ≥30 amino acid changes in the spike
protein
 Antivirals target the replicase
‒ nsp5 protease: single coding
change nowhere near the active
site
‒ nsp12 polymerase: single coding
change, already dominant mutation
compared with the original Wuhan
strain
Kumar. J Med Virol. 2022;94(4).1641. cdc.gov/coronavirus/2019-ncov/science/science-briefs/scientific-brief-omicron-variant.html.
Shah. Front Immunol. 2022; [Epub online ahead of print]. Slide credit: clinicaloptions.com
Updated
Omicron: Transmissibility United States: April 24, 2022 – July 30, 20223
Delta B.1.617.2 Omicron BA.4.6 Omicron BA.1.1.529
Omicron BA.5 Omicron BA.2.12.1 Omicron BA.1.1
 Omicron spreads rapidly1,2 100
Omicron BA.4 Omicron BA.2 Other
Nowcast
Viral Lineages Among Infections (%)

‒ Increased transmissibility1
80
‒ Secondary attack rate in households
with omicron vs delta: 31% vs 21%
60
‒ Unvaccinated individuals have
higher transmissibility compared 40
with fully vaccinated individuals
‒ Omicron is 2.7-3.7 times more 20
transmissible than delta among
vaccinated individuals1
0
5/7
5/14
5/21
5/28
6/4
6/11
7/9
7/30
4/30
6/18
6/25
7/2
7/16
7/23
‒ Immune evasion
1. Lyngse. medRxiv. 2021;[Preprint]. Note: This study has not been peer reviewed. Collection Date (Wk Ending)
2. cdc.gov/coronavirus/2019-ncov/variants/omicron-variant.html.
3. covid.cdc.gov/covid-data-tracker/#variant-proportions. Slide credit: clinicaloptions.com
Omicron: Infectiousness
 Anterior nares and oropharyngeal COVID-19 testing samples from NBA players
Omicron Delta
Peak Viral Concentration Proliferation Time Clearance Time
Log10 RNA copies/mL

9 12.5 12.5
Clearance Time
20 10.0 10.0
8
7.5 7.5
Days
25 7 5.0 5.0
6 2.5 2.5
0 0
 Compared with delta, omicron had lower peak viral load and shorter clearance time
‒ Unclear whether these characteristics are inherent to the variant or other population
factors (eg, number of vaccine doses)
Hay. medRxiv. 2022;[Preprint]. Note: This study has not been peer reviewed. Slide credit: clinicaloptions.com
Omicron: Disease Severity
 Omicron replicates faster in the  To understand intrinsic severity
bronchi but less efficiently in the of omicron compared with
lung1,2 delta, need to adjust for:
‒ Less lung replication may be ‒ Vaccination status
associated with reduced disease
severity ‒ Prior infection
 Initial data from England, ‒ Age

Scotland, and South Africa ‒ Comorbidity
demonstrate 15% to 80%
fewer hospitalizations with
omicron compared with delta3
1. McMahan. Med (NY). 2022;3:262. 2. Diamond. Nature. 2022;603(7902):687. 3. Christie. BMJ. 2021;375:n3144. Slide credit: clinicaloptions.com
Omicron Severity Based on Reduced Pathogenicity
or Increased Immunity
Delta Omicron Delta Omicron
Omicron less Variants equally
pathogenic pathogenic
Similar levels of Increased

pre-existing pre-existing
immunity in immunity in
population population
Disease Disease
Mild Severe
Sigal. Nat Rev Immunol. 2022;22:69. Slide credit: clinicaloptions.com

Omicron Subvariants BA.1, BA.2, and BA.3
 BA.1: total of 60 mutations on nonstructural and BA.14
structural proteins compared with ancestral genome1
13 unique
‒ 32 mutations are on the spike protein; main antigenic mutations
target of antibodies generated through vaccination or
natural infection
‒ 15 mutations affect RBD1; predominant function is to

bind with host ACE2 to allow entry of the virus into the 5 mutations
host cell2
‒ BA.1 shares 32 mutations with BA.2 and BA.3 32 mutations
 BA.2 has estimated 30% to 50% higher infectivity 10 unique 1 unique

BA.2 BA.3
than BA.11 mutations mutation
7 mutations
‒ BA.2 becoming dominant in Denmark, India,
Philippines, UK, Switzerland, Sweden, Norway,
Belgium, Hong Kong, South Africa, and others3
1. Chen. J Phys Chem Lett. 2022;13(17):3840.

2. Walls. Cell. 2020;181:281. 3. covariants.org/per-variant. 4. forbes.com/sites/williamhaseltine/2022/01/26/
birth-of-the-omicron-family-ba1-ba2-ba3-each-as-different-as-alpha-is-from-delta/?sh=5fa11e743da9. Slide credit: clinicaloptions.com
Alpha Variant (B.1.1.7)
Alpha (B.1.1.7): Variant Being Monitored
 Circulating in the UK since at least September 20, 2020; first reported in December
2020 with 277,468 confirmed and probable cases in the UK as of December 10,
20211,2
 Variant belongs to lineage B.1.1.7 and is characterized by 12 key amino acid
changes (6 in the spike protein), the Q27stop in ORF8, and 3 deletions3
‒ N501Y in the spike RBD increases binding affinity to human ACE2 receptor4
 Temporal association between rapid increase in COVID-19 cases and emergence of
new B.1.1.7 variant in the Southeast UK, East UK, and London areas1
 Designated as VBM on September 21, 20215
1. ECDC. Risk related to the spread of new SARS-CoV-2 variants of concern in the EU/EEA – first update. January 21, 2021. 2. Public Health England.
SARS-CoV-2 variants of concern and variants under investigation in England, Technical briefing 7. March 11, 2021. 3. Public Health England.
Investigation of SARS-CoV-2 variants of concern in England. Technical briefing 6. February 13, 2021. 4. Public Health England. Investigation of novel
SARS-CoV-2 variant VOC 202012/01. Technical briefing 1. December 21, 2020. 5. CDC: SARS-CoV-2 variant classifications and definitions.
cdc.gov/coronavirus/2019-ncov/variants/variant-info.html. Last updated April 26, 2022. Slide credit: clinicaloptions.com
Transmission of B.1.1.7 Variant
Relative Abundance of Major SARS-CoV-2 Variants in the UK 1
South East London East of England  Suggestion of
1.00
0.75 increased viral load in
0.50 persons infected with
0.25
B.1.1.7 variant2
Relative Abundance
0
South West Midlands North East and Yorkshire
1.00
0.75  Public Health of
0.50
0.25 England reported an
0
Scotland North West Wales
estimated increase in
1.00
0.75
Rt of 0.74 (95% CI:
0.50 0.44-1.29) by random
0.25
0 effect Bayesian
semi-mechanistic
Jan
Jan
Mar
Mar
Mar
May
May
Sep
Nov
Sep
Nov
Mar
Jul
Jul
Jan
Mar
May
Nov
Sep
Mar
Jul
B B.40 B.1.1 B.1.1.315 B.1.1.7 transmission model

B.1.98 B.1 B.1.1.1 B.1.177 Minority variants in December 20203
Shaded area represents model extrapolation until March 1. Minority variants, n = 440.
1. Davies. Science. 2021;372(6538). 2. Challen. BMJ. 2021;372:n579. 3. Public Health England.
Investigation of novel SARS-CoV-2 variant: 202012/01. Technical briefing 1. December 21, 2020. Slide credit: clinicaloptions.com
Additional Evidence for Increased
Transmissibility of B.1.1.7 Variant
 Applied a 2-strain 2.5 Oct 26, 2020 Nov 9, 2020 Nov 23, 2020
mathematical model of 2.0
Mean Reproduction Number

SARS-CoV-2 transmission 1.5
to multiple epidemiologic 1.0
indicators*
0 0.25 0.50 0.75 1.00 0 0.25 0.50 0.75 1.00 0 0.25 0.50 0.75 1.00
‒ Assessed proportion of
2.5 Dec 7, 2020 Dec 21, 2020 NHS region Cases
tests with S gene target East of England 4000
failure (indicating Δ69-70 2.0 London 8000
deletion in spike protein 1.5 Midlands 12,000
North East and 16,000
sequence of B.1.1.7) 1.0 Yorkshire
North West
 Rt for B.1.1.7: 43% to 90% 0 0.25 0.50 0.75 1.00 0 0.25 0.50 0.75 1.00
South East
South West
higher vs preexisting Frequency of S Gene Target Failure
variants (95% CI: 38-130) *COVID-19 hospital admissions, hospital and ICU bed occupancy, and deaths; SARS-CoV-2 PCR prevalence and
seroprevalence; and the relative frequency of VOC-202012/01 in the 3 most heavily-affected NHS England regions
(South East, East of England, and London).
Davies. Science. 2021;372(6538). Slide credit: clinicaloptions.com

Impact of B.1.1.7 Variant on COVID-19 Disease
 Evidence for increased risk of hospitalization within 14 days of sampling for B.1.1.7
vs nonvariant cases (N = 63,609 sequences)1
‒ HR: 1.34 (95% CI: 1.07-1.66; P = .01) in Public Health England analysis of admissions
during Oct to Dec 2020 adjusted for sex, age, ethnicity, residence type, wk of diagnosis
 Case fatality rate for confirmed/probable B.1.1.7: 2.6%1
‒ 2858 deaths (within 28 days) among 109,093 cases as of March 10, 2021
 Based on preliminary UK data, RR of death is 1.65 (95% CI: 1.212.25) for B.1.1.7 vs
matched cohort of nonvariant cases2
 No evidence for higher rate of B.1.1.7 reinfection or substantially reduced vaccine
efficacy based on data from multiple vaccine manufacturers2
1. Public Health England. SARS-CoV-2 variants of concern and variants under investigation in England, Technical briefing 7. March 11, 2021.
2. ECDC. SARS-CoV-2 increased circulation of variants of concern and vaccine rollout in the EU/EEA, 14th update. February 15, 2021. Slide credit: clinicaloptions.com
Neutralization of B.1.1.7 SARS-CoV-2 Pseudovirus
by BNT162b2-Elicited Sera
 Assessed neutralization of B.1.1.7 Neutralization by BNT162b2-Elicited Sera
and Wuhan lineage SARS-CoV-2 GMTs and 95% CIs are indicated
spiked VSV pseudoviruses by sera 2560
P <.01
23-55 yr of age
from participants who received the 1280
57-73 yr of age
COVID-19 mRNA vaccine BNT162b2 640
in a phase I/II trial (N = 40) 320
pVNT50
‒ Assessed 7 or 21 days after second 160
dose via 50% neutralization assay 80
 Geometric mean of pVNT50 titer 40

against B.1.1.7 vs Wuhan: 0.80 20
Wuhan B.1.1.7
‒ No difference between age groups Virus
Muik. Science. 2021;371:1152. Slide credit: clinicaloptions.com

Beta Variant (B.1.351)
Beta (B.1.351): Variant Being Monitored
 Circulating in South Africa starting August Nucleotide Mutations
2020; preliminary analyses suggest that it is in Circulating South Africa Variants
50% more transmissible vs previously Whole Spike
Genome Region
circulating variants1,2 30 30
‒ Identified in 40 countries with
No. of Mutations
~1400 cases as of February 11, 2021 20 20
 Characterized by 8 defining mutations in the 10 10

spike protein3
‒ 3 residues in RBD including N501Y 0 0
B.1.1.54
B.1.1.56
C.1
B.1.1.54
C.1
S.501Y.V2
S.501Y.V2
B.1.1.56
 Designated a VBM on September 21, 20214
1. ECDC. Risk related to the spread of new SARS-CoV-2 variants of concern in the EU/EEA – first update. January 21, 2021. Variant
2. ECDC. SARS-CoV-2 increased circulation of variants of concern and vaccine rollout in the EU/EEA, 14th update. February 15, 2021.
3. Tegally. Nature. 2021;592:438. 4. CDC: SARS-CoV-2 variant classifications and definitions.
cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html. Last updated April 26, 2022. Slide credit: clinicaloptions.com
Spread of 501Y.V2 Variant (B.1.351)
 Assessment of 2882 SARS-CoV-2 Frequency of Circulating Variants in
South Africa Over Time1
genomes from samples in South 1.00
Africa collected between March
Proportion of Genomes
and December 20201 0.75
‒ 501Y.V2 displaced the other 0.50

3 main South Africa variants
0.25
starting in mid-November
0
 As of December 21, 2020, more
30-Nov
9-Mar
6-Apr
20-Apr
4-May
18-May
14-Dec
10-Aug
24-Aug
16-Nov
24-Feb
1-Jun
15-Jun
29-Jun
7-Sep
23-Mar
27-Jul
5-Oct
19-Oct
21-Sep
2-Nov
13-Jul
than 300 genomes of 501Y.V2
had been identified2 Date
Lineages B.1.1.54 B.1.1.56 C.1 501Y.V2 Others
1. Tegally. Nature. 2021;592:438-43. 2. Africa CDC. Alert notification: new SARS-
CoV-2 variant with multiple spike protein mutations. December 21, 2020. Slide credit: clinicaloptions.com
Escape of B.1.351 From Neutralization by
Convalescent Plasma
 Assessed neutralization of live
virus grown from July 2020 IC50
sample and two B.1.351 virus Plasma donor: 1st wave B.1.351 Ratio
200
samples by plasma from persons 1 0.004312 KO* ND
infected with non-B.1.351 2 0.001691 0.3454 204.3 150

variants (n = 6) 3 0.001158 0.06167 53.23
100
‒ Determined IC50 values by fitting 4 0.001567 0.05978 38.13
sigmoidal function to data from 5 0.00113 0.01083 9.589 50
microneutralization focus
forming assay 6 0.003114 0.01768 5.677
0
*Neutralization knockout.
Cele. Nature. 2021;593:142. Slide credit: clinicaloptions.com

Neutralization of B.1.351 by Convalescent
Serum and Impact of Disease Severity
 Assessed neutralization of WT lineage  Mean ID50 titer for individuals with
virus, chimeric virus containing only mild-to-moderate disease against WT
the RBD of B.1.351, and B.1.351 (n = 30): 488
lineage virus by plasma/serum
samples from individuals previously  Mean ID50 titer for individuals with
infected with SARS-CoV-2 (N = 44) severe disease against WT (n = 14):
4212
‒ Spike-pseudotyped lentivirus
neutralization assay  48% of individuals had no detectable
Original B.1.351 RBD Only B.1.351
ID50 Titer neutralization activity against B.1.351
<20
21-100
14% 101-400 ‒ 3 samples with ID50 titers >400 were
23% 27%
50%
23%
48%
≥401 individuals with severe disease who
36% 14% 45%
23%
had high neutralization titers to WT
36%
Wibmer. Nat Med. 2021;27:622. Slide credit: clinicaloptions.com

Delta Variant (B.1.617.2)
Delta (B.1.617.2): Variant Being Monitored
 First described in India (B.1.651.2) Evasive Maneuver
The spike protein’s N-terminal domain (left) includes a
“supersite” where powerful antibodies latch on to the
 Increased affinity for host cell virus (middle). Mutations there (right) can prevent
receptors (ACE2) them from binding.
 Develops high viral carriage

Spike protein Neutralizing
N-terminal
‒ 50% to 70% more transmissible N-terminal antibody domain with
domain mutations
 Higher levels of antibodies needed
for protection
Kupferschmidt, Wadman, Science 6/24/21. CDC: SARS-CoV-2 variant classifications and definitions.
cdc.gov/coronavirus/2019-ncov/variants/variant-info.html. Last updated April 26, 2022. Slide credit: clinicaloptions.com
Delta Variant: What We Know
More than twice as contagious as previous variants
Some evidence of increased illness severity vs previous strains

in unvaccinated people
Greatest risk of transmission still among unvaccinated people
Fully vaccinated people with delta breakthrough infections can

spread virus to others
However, vaccinated people appear to be infectious for a shorter
period of time than unvaccinated people
cdc.gov/coronavirus/2019-ncov/variants/delta-variant.html. Slide credit: clinicaloptions.com

Key Characteristics of
SARS-CoV-2 Alpha and Delta Variants
SARS-CoV-2 Variant Characteristics
vs WT Comparator B.1.1.7 (Alpha) B.1.617.2 (Delta)
Disease severity Increased1 Possibly increased5,6
Mortality Increased1 Possibly increased5,6
No impact to <5-fold
Immune evasion ~6-8–fold reduced sensitivity7,8
reduced sensitivity2,3
Transmissibility 50% to 100% higher >2-fold higher5,6
reproduction number4
1. Grint. Clin Infect Dis. 2021;[Epub]. 2. Collier. Nature. 2021;593:136. 3. Wu. NEJM. 2021;384:1468. 4. Nature. 2021;593:266.
5. cdc.gov/coronavirus/2019-ncov/variants/delta-variant.html. 6. cdc.gov/coronavirus/2019-ncov/variants/variant-info.html.
7. Grannis. MMWR Morb Mortal Wkly Rep. 2021;70:1291. 8. Mlcochova. Nature. 2021;599:114. Slide credit: clinicaloptions.com
Effectiveness of COVID-19 Vaccines Against Variants
 First data were available for BNT162b2 (Pfizer-BioNTech) mRNA vaccine
Against Hospitalization1: Against Symptomatic Disease2:

June 14, 2021 July 21, 2021
95% for alpha 94% for alpha
96% for delta 88% for delta
1. Stowe. khub.net/web/phe-national/public-library/-/document_library/v2WsRK3ZlEig/view/479607266.
2. Lopez Bernal. NEJM. 2021;385:585. Slide credit: clinicaloptions.com
US COVID-19 Vaccines in Delta Era:
Comparative Efficacy
 Vaccine effectiveness against COVID-19–associated hospitalization among adults without immunocompromising conditions
 Data represents 21 hospitals in 18 US states, March 2021 through August 2021
VE Against COVID-19 Hospitalization
Vaccinated Patients/Total Patients (%) (95% CI)
Vaccine/Period
Case Patients Control Patients
mRNA-1273 VE after full vaccination
Full surveillance period 54/1517 (3.6) 422/1321 (31.9) 93 (91-95)
14-120 days after full vaccination 36/1499 (2.4) 345/1244 (27.7) 93 (90-95)
>120 days after full vaccination 18/1481 (1.2) 77/976 (7.9) 92 (87-96)
BNT162b2 VE after full vaccination
14-120 days after full vaccination 65/1528 (4.3) 495/1394 (35.5) 91 (88-93)
Ad26.COV2.S VE after full vaccination
MMWR. September 24, 2021;70:1337. Slide credit: clinicaloptions.com

US COVID-19 Vaccines in Delta Era:
Antibody Responses
Serum antireceptor-binding domain and antisplice immunoglobulin G
levels 2-6 wk after full vaccination among healthy adult volunteers:
3 hospitals in 3 US states, April - June 2021
100,000
Antibody Concentration (BAU/mL)

10,000
1000
100
10
na
ch
h
J)
na
ec
J)
Te
er
&
er
NT
&
od
N
(J
od
(J
io
io
n
M
M
r-B
en
se
r-B
ns
s
ze
ze
ns
Ja
Vaccine
Pfi
Pfi
Ja
Anti-RBD IgG Anti-spike IgG
MMWR. 2021;70:1337. Slide credit: clinicaloptions.com

Vaccination Offers Strong Protection Against COVID-19
After delta became the most common variant, fully vaccinated people had reduced risk of…
Infection Hospitalization Death
5x >10x >10x
 Comparison is to people not fully vaccinated
 Based on data from June 20 - July 17, 2021
MMWR. 2021;70:1284. Slide credit: clinicaloptions.com

Gamma Variant (P.1)
Gamma (P.1): Variant Being Monitored
 Initially reported among Brazilian travelers in Japan, then in Brazil1
‒ Approximately 117,382 cases in 91 countries as of December 10, 20212
‒ Accounts for <0.1% of sequences3
‒ 17 unique mutations (11 spike mutations vs ancestral lineage, 3 in the RBD)1,4
 No microbiologic/epidemiologic evidence of increased transmissibility1
‒ However, P.1 contains N501Y—also present in B.1.1.7 and B.1.351—which suggests
potential for increased transmissibility
 Designated a variant being monitored on September 21, 20215
1. ECDC. SARS-CoV-2 increased circulation of variants of concern and vaccine rollout in the EU/EEA, 14th update. February 15, 2021.
2. GISAID. gisaid.org/hcov19-variants/. Accessed December 10, 2021. 3. who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---
7-december-2021 4. CDC. Science brief: emerging SARS-CoV-2 variants. Last updated January 28, 2021. 5. CDC: SARS-CoV-2 variant classifications and
definitions. cdc.gov/coronavirus/2019-ncov/variants/variant-info.html. Last updated April 26, 2022. Slide credit: clinicaloptions.com
Implications of SARS-CoV-2 Variants
Neutralization of SARS-CoV-2 Variant
Pseudoviruses by mRNA Vaccine-Elicited Plasma
 Assessed neutralization of Neutralization by mRNA Vaccine-Elicited Plasma
SARS-CoV-2 spiked HIV-1 mRNA-1273 BNT162b2
pseudoviruses by plasma from NS P = .0002 P = .0033 P <.0001
participants who received the 104
BNT162b2 (n = 6) or mRNA-1273
(n = 14) COVID-19 vaccines 103
NT50
‒ Average time from second 102
vaccine to sample collection:
8 wk (range: 3-14 wk) 101
WT K417N WT N501Y WT E484K WT K417N
E484K
N501Y
R683G Background
Virus
Wang. Nature. 2021;592:616-22. Slide credit: clinicaloptions.com
Neutralization of SARS-CoV-2 Variant
Pseudoviruses by mRNA-1273 Vaccine-Elicited Sera
 Assessed neutralization of SARS-CoV-2 Neutralization by mRNA-1273 Vaccine-Elicited Sera
spiked pseudoviruses by sera from 1.2X 6.4X
individuals who received the mRNA- NS P = .008
1273 COVID-19 vaccine in a phase I 4
trial (N = 8)
Reciprocal ID50 (log10)

‒ Samples collected 1 wk after 2nd dose 3
 Greatest reduction (6.4x) in ability of

sera to neutralize observed for B.1.351 2
‒ However, all sera fully neutralized this

variant, albeit at relatively low dilutions 1
(geometric mean neutralizing titer of D614G B.1.1.7 D614G B.1.351
Backbone* Backbone*
1:290)
Virus
Wu. NEJM. 2021;384:1468. *Dominant strain in 2020. Slide credit: clinicaloptions.com
Neutralization of N501Y SARS-CoV-2 Viruses by
BNT162b2 Vaccine-Elicited Sera
 Assessed neutralization of isogenic N501Y
Neutralization by BNT162b2-Elicited Sera
SARS-CoV-2 viruses on the genetic
background of the USA_WA1/2020 strain 2048
by sera from participants who received 2 wk post
the COVID-19 mRNA vaccine BNT162b2 1024 vaccination
(N = 20) 4 wk post
512
PRNT50
‒ Isogenic viruses do not include full set of vaccination
spike mutations in B.1.1.7 or 501Y.V2 256
‒ Assessed 2 or 4 wk after second dose via 128

50% plaque reduction assay
64
 Ratio of 50% neutralization of 501Y virus
501N 501Y
to 501N virus: 1.46 Mutation
Virus
Xie. Nat Med. 2021;27:620. Slide credit: clinicaloptions.com
Neutralization of SARS-CoV-2 Mutant Viruses by
BNT162b2 Vaccine-Elicited Sera
 Assessed neutralization of mutant Neutralization by BNT162b2 Vaccine-Elicited Sera*
SARS-CoV-2 viruses with key
mutations found in B.1.1.7 and
2048 2048
B.1.351 variants by sera from persons
1024 1024
PRNT50 (log2)
who received the BNT162b2 COVID-19
512 512
vaccine (N = 20)
256 256
‒ Samples collected 2 and 4 wk 128 128
following second dose 64 64
WT Δ69/70 + N501Y WT E484K + N501Y
 Ratio of 50% neutralization geometric + D614G + D614G
(B.1.1.7) (B.1.351)
mean titer of B.1.1.7 vs WT: 1.41
Virus
 Ratio of 50% neutralization geometric 2 wk post-vaccination
mean titer of B.1.351 vs WT: 0.81 4 wk post-vaccination
*Plaque reduction assay.
Xie. Nat Med. 2021;27:620. Slide credit: clinicaloptions.com
Monoclonal Antibody Activity Against
Emerging SARS-CoV-2 Variants
 Assessed ability of monoclonal Neutralization by Monoclonal Antibody
antibodies to neutralize SARS-CoV-2 Combinations in Clinical Use
VSV-based pseudoviruses containing 10-4 LY-CoV555
the B.1.1.7 or B.1.351 mutations REGN10933 + REGN10987
(REGEN-COV)
10-3 LY-CoV555 + CB6
 Individual mAbs in clinical use
lC50 (μg/mL)
S309
demonstrated reduced activity against Brii-196 + Brii-198
10-2
B.1.351 COV2-2196 + COV2-2130
‒ LY-CoV555 (bamlanivimab): complete 10-1

loss of activity mediated by E484K
100
‒ REGN10933 (casirivimab): reduced B.1.1.7 D614G B.1.351
activity mediated by K417N and E484K
Virus
Wang. Nature. 2021;593:130. Slide credit: clinicaloptions.com

Vaccine Development
Vaccine Candidates in Development for SARS-CoV-2
Vaccine Platforms Viral vector
Vaccine Candidates
DNA (nonreplicating) Other DNA
Coronavirus
spike gene
Viral vector RNA

Virus genes
(replicating) 10
(some inactive)
Viral vector 12
RNA (+ LNPs) Coronavirus (replicating) 14
spike gene
20
Virus genes Viral vector SARS-CoV-2
(some inactive) (nonreplicating) live
16 3
Virus attenuated
(inactivated) 8
Protein based
(eg, spike)
Virus 44 SARS-CoV-2
(attenuated) inactivated
Protein based
Funk. Front Pharmacol. 2020;11:937. Slide credit: clinicaloptions.com
Vaccine Development Pathway and Updated
Remaining Questions
 COVID-19 vaccine development milestones SARS-CoV-2 Vaccine Candidates in Development2
have been compressed from a time frame Limited/
Phase I Phase II Phase III Early Use Approved Abandoned
of 10-15 yr to 1-2 yr; enabled by1:
34 19 41 21 12 15
‒ Overlapping preclinical and clinical trials
‒ Scale-up manufacturing processes occurring in parallel
 As most individuals infected with SARS-CoV-2 are asymptomatic or develop only mild symptoms,
vaccine safety is critically important
‒ Theoretical risk/concern for vaccine-associated disease enhancement not supported by currently available
data; ultimately, phase III trials and postlicensure surveillance will reveal true risk 3
 Immune function declines with age, and this decline is likely partially responsible for greater risk of
severe COVID-19 in older adults  vaccine responses may be diminished and may require higher
doses in older adults4,5
1. Jeyanathan. Nat Review Immunol. 2020;20:615. 2. The New York Times. Coronavirus vaccine tracker.
nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html. Updated August 3, 2022.
3. Haynes. Sci Transl Med. 2020;12:eabe0948. 4. Heaton. NEJM. 2020;383:1986. 5. Zhu. Lancet. 2020;395:1845. Slide credit: clinicaloptions.com
NEW
COVID-19 Vaccine Adverse Events
Frequency Adverse Event Implicated Vaccine Comments
Mild fever, arthralgia,
Common All  Lasts 1-2 days
fatigue, sore arm
 Most common in patients with prior
Anaphylaxis All hypersensitivity reaction
 75% occur within first 15 min
Pfizer-BioNTech
Myocarditis  Self-limited in majority
Moderna
Rare
Thrombosis and Johnson & Johnson*
thrombocytopenia syndrome AstraZeneca  Highest risk in younger women aged 18-49 yr
Guillain-Barré syndrome Johnson & Johnson*  Risk of Guillain-Barré syndrome due to COVID-19
is 10x greater than risk due to vaccination
*FDA advises that Johnson & Johnson vaccine be used only when mRNA vaccine is unavailable.
 Risk of severe outcomes is far greater with COVID-19 infection than risk of
severe adverse reactions to any of the vaccines
secure.medicalletter.org/w1621g Slide credit: clinicaloptions.com
CDC: US COVID-19 Vaccine Schedules for Patients NEW
Without Immune Compromise

In 3-8 In at least
Pfizer-BioNTech Dose 1 weeks Dose 2 8 weeks Dose 3 2nd booster dose for
(ages 6 mo-4 yr) (primary) (primary) (primary) some groups
In 3-8 In at least In at least Dose 4
Pfizer-BioNTech Dose 1 weeks Dose 2 5 months Dose 3 4 months (2nd mRNA
(ages ≥5 yr) (primary) (primary) (booster*) booster)
In 4-8 People ages ≥50 yr should get
Dose 1 weeks Dose 2
Moderna a 2nd booster
(primary) (primary)
(ages 6 mo-17 yr)
In 4-8 In at least In at least Dose 4
Moderna Dose 1 weeks Dose 2 5 months Dose 3 4 months (2nd mRNA
(ages ≥18 yr) (primary) (primary) (booster*) booster)
In 3-8 People ages ≥50 yr should get
Novavax Dose 1 weeks Dose 2 a 2nd booster
(ages ≥18 yr) (primary) (primary)
Dose 3
In at least In at least
Janssen (J&J) Dose 1 2 months Dose 2 4 months (2nd mRNA
(ages ≥18 yr)* (primary) (booster*) booster)
People ages ≥50 yr should People ages ≥18 yr who received 2
get a 2nd booster Janssen doses may get a 2nd booster.
*Age-appropriate mRNA and Novavax COVID-19 vaccines are preferred over Janssen COVID-19 vaccine for primary and booster vaccination.
cdc.gov/vaccines/covid-19/downloads/COVID-19-vacc-schedule-at-a-glance-508.pdf Slide credit: clinicaloptions.com

CDC: US COVID-19 Vaccine Schedules for Patients With
NEW
Immune Compromise
In 3 In at least
Pfizer-BioNTech Dose 1 weeks Dose 2 8 weeks Dose 3
(primary) (primary) (primary)
(ages 6 mo-4 yr)
In 3 In at least In at least
Pfizer-BioNTech Dose 1 weeks Dose 2 4 weeks Dose 3 3 months Dose 4
(ages 5-11 yr) (primary) (primary) (primary) (booster)
In 3 In at least In at least In at least Dose 5

Pfizer-BioNTech Dose 1 weeks Dose 2 4 weeks Dose 3 3 months Dose 4 4 months
(primary) (primary) (primary) (booster*) (2nd mRNA
(ages ≥12 yr) booster)
Moderna Dose 1 In 4 In at least Dose 3

weeks Dose 2 4 weeks
(ages 6 mo-17 yr) (primary) (primary) (primary)
Moderna In 4 In at least In at least In at least

Dose 1 weeks Dose 2 4 weeks Dose 3 3 months Dose 4 4 months Dose 5
(ages ≥18 yr) (primary) (primary) (primary) (booster*) (2nd mRNA
booster)
In 3
Novavax Dose 1 weeks Dose 2
(primary) (primary)
(ages ≥18 yr)
In at least In at least Dose 4
Janssen (J&J) In 4 Dose 2 2 months 4 months *Age-appropriate mRNA and Novavax
Dose 1 weeks (additional Dose 3 (2nd mRNA COVID-19 vaccines are preferred over
(ages ≥18 yr)* (primary) mRNA dose) (booster*) Janssen COVID-19 vaccine for primary and
booster) booster vaccination.
cdc.gov/vaccines/covid-19/downloads/COVID-19-vacc-schedule-at-a-glance-508.pdf Slide credit: clinicaloptions.com

mRNA Vaccine Data
mRNA Vaccines Against SARS-CoV-2
Primary
Endpoint:
Phase Case Additional Analyses
Vaccine Description (Total N) Count, n Prevention of Reported
Symptomatic
COVID-19
Vaccinations on Day 1 and Day 22 in  94.7% efficacy in
persons ≥12 yr of age with nucleoside- 95.0% adults ≥65 yr of age
II/III 7 days after
BNT162b21,2 modified mRNA (modRNA) encoding (43,998)* 170 second dose  9/10 severe cases
the membrane-bound occurred in placebo
full-length spike protein (P <.0001) group
Vaccinations on Day 1 and Day 29 in 94.1%
persons ≥18 yr of age with mRNA 14 days after  30/30 severe cases
mRNA-12733 III (30,351) 196 occurred in placebo
encoding a prefusion stabilized second dose group
spike protein (P <.001)
*N = 36,523 without baseline infection included in efficacy analysis. Among N = 37,706 in the main safety population, 42% were >55 yr of age,
35% were obese, 28% were Hispanic/Latinx, and 9% were Black.
1. Polack. NEJM. 2020;383:2603. 2. NCT04368728. 3. Baden. NEJM. 2021;384:403. Slide credit: clinicaloptions.com
BNT162b2 Phase II/III Efficacy:
Results After Second Vaccine Dose
 N = 43,448; similar efficacy observed across subgroups, including age, sex, race,
ethnicity, baseline BMI, and presence of coexisting conditions
BNT162b2 Placebo
Symptomatic
COVID-19
Vaccine Efficacy, %
Occurrence (95% Credible Interval)
≥7 Days After No. of Surveillance Time,* No. of Surveillance Time,*
Second Dose Cases 1000 PY (n) Cases 1000 PY (n)
Without
evidence of prior 8 2.2 (17,411) 162 2.2 (17,511) 95.0 (90.3-97.6)
infection
With or without
evidence of prior 9 2.3 (18,559) 169 2.3 (18,708) 94.6 (89.9-97.3)
infection
*Accrual from 7 days after second dose to end of surveillance period.
.Polack. NEJM. 2020;383:2603. Slide credit: clinicaloptions.com

BNT162b2 Phase II/III Safety:
Solicited Local Events Within 7 Days of Vaccination
Solicited Local Events After Dose 1 Solicited Local Events After Dose 2
Pain at Pain at
Redness Swelling Redness Swelling
Injection Site Injection Site
100
100 78 Dose 1
83 Dose 1 80
80
60
60
40
16-55 yr of age 40
20 12
Percentage
20 14 6 6
Percentage
5 1 6 1 0
0 0 0
100 100
Dose 1 Dose 1
80
80 71 66
60 60
40 >55 yr of age 40
20 20 8 7 7
9 5 7 1 1 1
1 0
0 2 2
2
2b cebo 2 b2 ebo 2
2b cebo 62b cebo 6
2
2b cebo 62b cebo
6 6 c 6 T1 Pla T1 Pla T1 Pla
T1 Pla T1 Pla T1 Pla BN BN BN
BN BN BN
Mild Moderate Severe Grade 4
Polack. NEJM. 2020;383:2603. Slide credit: clinicaloptions.com
BNT162b2 Phase II/III Safety: Solicited Systemic Events
and Antipyretic Use Within 7 Days of First Dose
Solicited Systemic Events After Dose 1 Systemic Events/Fever, ⁰C
Use of
Fever Fatigue Headache Chills Vomiting Diarrhea Muscle Pain Joint Pain Antipyretic Mild/38.0-38.4
100 Medication Moderate/38.4-38.9
80 Dose 1 Severe/38.9-40.0
60 Grade 4/>40.0
47 42
Percentage
40 33 34 28
21
20 14 11 12 11 11 6 14
4 1 6 1 1 16-55 yr of age
0
100 Systemic Events / Fever ⁰C
80
60
40 34
23 25 20
20 18 14 8
1 6 3 8 7 9 6 12
0 0 1 >55 yr of age
0 2 o
2b ceb 2 b2 ebo 2 b2 ebo 2 b2 ebo 2b2 ebo 2 b2 ebo 2 b2 ebo 2 b2 ebo 2 b2 ebo
6 16 Plac 16 Plac 6
1 Plac
T1 Pla T16 Plac T T T16 Plac T 16 Plac T T 16 Plac T16 Plac
N BN N
B BN BN BN BN B BN BN
BNT162b2 Phase II/III Safety: Solicited Systemic Events
and Antipyretic Use Within 7 Days of Second Dose
Solicited Systemic Events After Dose 2 Systemic Events/Fever, ⁰C
Use of
Fever Fatigue Headache Chills Vomiting Diarrhea Muscle Pain Joint Pain Antipyretic Mild/38.0-38.4
100 Medication Moderate/38.4-38.9
80 Dose 1 Severe/38.9-40.0
59 Grade 4/>40.0
60 52 Dose 1 45
37
Percentage
40 35
23 24 22
20 16 10 8 13
8
0 4 2 1 5 16-55 yr of age
0
100 Systemic Events / Fever ⁰C
80
60 51
39 38
40 29
17 23 19
20 11 14 8 10
0 3 1 0 6 5 4 >55 yr of age
0
2 b2 ebo 2 b2 ebo 2b2 ebo 2b2 ebo 2b2 ebo 2 b2 ebo 2 b2 ebo 2 b2 ebo 2b2 ebo
T16 Plac T 16 Plac T 16 Plac T16 Plac T16 Plac T 16 Plac T16 Plac T 16 Plac T 16 Plac
BN BN BN BN BN BN BN BN BN
Efficacy and Safety of BNT162b2 Vaccine in Children 6NEW
Mo Up to 5 Yr: Topline Results
 1678 participants enrolled
‒ Vaccine consisted of three 3-μg doses
‒ Doses 1 and 2 were administered 21 days apart
‒ Dose 3 was administered ≥2 mo after dose 2
 Immunogenicity was similar to 30-μg 2-dose primary series in patients
aged 16-25 yr, meeting noninferiority criteria and coprimary endpoints
 3-dose vaccine efficacy at preventing SARS-CoV-2 infection
(during omicron): 80.3%
 FDA authorized vaccine for use in this age group in June 2022
Pfizer. Press release. May 23, 2022. Data not peer reviewed. FDA. Press release. June 17, 2022. Data not peer reviewed. Slide credit: clinicaloptions.com
FDA Approval and EUA of BNT162b2: Specific
Populations and Warnings
Use in specific populations Warnings
 Pregnancy: available data insufficient to  Appropriate medical treatment used to
inform vaccine-associated risks in manage immediate allergic reactions
pregnancy must be immediately available in the
event of acute anaphylactic reaction
 Lactation: no data to assess effects on following administration of the vaccine
infants, or milk production/excretion
 Immunocompromised persons or those
 Pediatrics: EUA includes use in individuals on immunosuppressant therapy may
as young as 6 mo of age have a diminished immune response to
‒ Different doses for different pediatric age the vaccine
ranges  Vaccine may not protect all recipients
Pfizer-BioNTech COVID-19 Vaccine. Fact sheet for HCPs administering vaccine. Last updated July 8, 2022.
fda.gov/media/151707/download. Last updated July 2022. Slide credit: clinicaloptions.com
mRNA-1273: Preliminary Safety Data Within
7 Days of First or Second Dose
Mild Moderate Severe
Symptom Dose Group Vaccination 1 Vaccination 2 Symptom Dose Group Vaccination 1 Vaccination 2
Any systemic 25 μg 25 μg
symptom 100 μg Myalgia 100 μg
250 μg 250 μg
25 μg 25 μg
Arthralgia 100 μg Nausea 100 μg
250 μg 250 μg
25 μg 25 μg
Any local
Fatigue 100 μg 100 μg
symptom
250 μg 250 μg
25 μg 25 μg
Fever 100 μg Size of erythema
100 μg
250 μg or redness
250 μg
25 μg 25 μg
Chills 100 μg Size of induration
100 μg
250 μg or swelling 250 μg
25 μg 25 μg
Headache 100 μg Pain 100 μg
250 μg 250 μg
0 20 40 60 80 100 20 40 60 80 100 0 20 40 60 80 100 20 40 60 80 100
Participants (%) Participants (%)
 No serious adverse events reported

Jackson. NEJM. 2020;383:1920. Slide credit: clinicaloptions.com
mRNA-1273: Safety Subgroup Analysis in Older Adults
Within 7 Days of First or Second Dose
 N = 40 participants, 10 in each  10 solicited local events, all
of 2 age groups and 2 dose classified as moderate
subgroups, between April 16
 41 solicited systemic events;
and May 12, 2020
2 classified as severe (grade 3):
‒ Age groups: 56-70 yr vs ≥71 yr
‒ Fever in a participant 56-70 yr
‒ Dose subgroups: two 25 µg
doses vs two 100 µg doses ‒ Fatigue in a participant ≥71 yr
 Most common solicited AEs:  71 unsolicited AEs, 17 vaccine

headache, fatigue, myalgia, related: 16 mild, 1 moderate
chills, and injection-site pain, (decreased appetite)
typically on day of vaccination
Anderson. NEJM. 2020;383:2427. Slide credit: clinicaloptions.com
Efficacy and Safety of mRNA-1273 Vaccine in NEW
Children 6 Mo Up to 6 Yr: KidCOVE Interim Analysis

 6 mo to <2 yr and 2 yr to <6 yr cohorts enrolled ~6700 participants
‒ Vaccine consisted of two 25-μg doses administered 28 days apart
 Immunogenicity similar to 100-μg 2-dose primary series in adults
aged 18-25 yr, meeting noninferiority criteria and “immunobridging”
 2-dose vaccine efficacy at preventing SARS-CoV-2 infection (during omicron)
‒ 6 mo to <2 yr cohort: 43.7%
‒ 2 yr to <6 yr cohort: 37.5%
 FDA authorized vaccine for use in this age group in June 2022
Moderna. Press release. March 23, 2022. Data not peer reviewed. Moderna. Press release.
April 28, 2022. Data not peer reviewed. Moderna. Press release. June 17, 2022. Data not peer reviewed. Slide credit: clinicaloptions.com
Prescribing Information for mRNA-1273:
Specific Populations and Warnings
Use in specific populations Use with other vaccines
 Pregnancy: available data insufficient to  No information on coadministration of this
inform vaccine-associated risks in pregnancy vaccine with other vaccines
‒ Pregnant women vaccinated with the Moderna Warnings
vaccine encouraged to enroll
in pregnancy exposure registry ‒ Appropriate medical treatment used to manage
1-866-663-3762 immediate allergic reactions must be
 Lactation: no data to assess effects on infants immediately available in the event of acute
anaphylactic reaction following administration
or milk production/excretion
of the vaccine
 Pediatrics: EUA includes use in individuals as
‒ Immunocompromised persons or those
young as 6 mo of age
receiving immunosuppressant therapy may
‒ Different doses for different pediatric age have a diminished response to the vaccine
ranges
‒ Vaccine may not protect all recipients
Moderna COVID-19 Vaccine. Fact sheet for HCPs administering vaccine. Last updated June 17, 2022.
fda.gov/media/155675/download. Last updated January 2022. Slide credit: clinicaloptions.com
Ad26.COV2.S Vaccine Data
Ad26.COV2.S: Study Design
 Multicenter, randomized, placebo-controlled phase I/IIa trial comparing low- and
high-dose administration of Ad26.COV2.S in single- and 2-dose schedules (N = 805)
‒ Ad26.COV2.S: recombinant, replication-incompetent adenovirus serotype 26 vector
encoding full-length, stabilized SARS-CoV-2 spike protein
Cohort 1: 18-55 Yr of Age Cohort 3: ≥65 Yr of Age
Low High Low High
Baseline Overall Placebo Baseline Overall Placebo
Dose Dose Dose Dose
Characteristic (N = 402) (n = 162) (n = 158) (n = 82) Characteristic (N = 403) (n = 161) (n = 161) (n = 81)
Male sex, n (%) 190 (47) 78 (48) 72 (46) 40 (49) Male sex, n (%) 201 (50) 84 (52) 79 (49) 38 (47)
Mean age, yr 35.4 36.1 34.8 35.4 Mean age, yr 69.8 69.6 70.0 69.9
(SD) (10.2) (10.1) (10.3) (10.0) (SD) (4.0) (4.0) (4.2) (3.7)
Race, n (%) Race, n (%)
 White 364 (91) 149 (92) 145 (92) 70 (85)  White 397 (99) 158 (98) 158 (98) 81 (100)
 Black 20 (5) 4 (2) 7 (4) 9 (11)  Black 3 (1) 1 (1) 2 (1) 0
Mean BMI (SD) 24.6 (3.2) 24.5 (3.3) 24.6 (3.1) 24.5 (3.0) Mean BMI (SD) 25.4 (2.8) 25.3 (2.8) 25.5 (2.7) 25.2 (3.1)
Dosing: 5 x 1010 (low) or 1 × 1011 (high) viral particles/mL. Overall SARS-CoV-2 seropositivity rate at baseline: 1% (n = 11).
Sadoff. NEJM. 2021;384:1824. Slide credit: clinicaloptions.com
Ad26.COV2.S: Solicited AEs After First Dose
Systemic AEs Local AEs
Any
18-55 Yr Any
≥65 Yr 18-55 Yr Any
≥65 Yr
Any
Low dose Low dose Low dose Low dose
High dose High dose High dose High dose
Placebo Placebo Placebo Placebo
Fatigue Fatigue Erythema Erythema
Headache Headache Pain Pain
Myalgia Myalgia Swelling Swelling
Nausea Nausea 0 20 40 60 80 100
Low dose Low dose 0 20 40 60 80 100
High dose High dose Participants With Reaction (%) Participants With Reaction (%)
Placebo Placebo
Pyrexia Pyrexia
Low dose Low dose
High dose High dose Grade 1
Placebo Placebo
Grade 2
0 20 40 60 80 100 0 20 40 60 80 100 Grade 3
Participants With Reaction (%) Participants With Reaction (%)
Sadoff. NEJM. 2021;384:1824. Slide credit: clinicaloptions.com
FDA EUA of Ad26.COV2.S:
Specific Populations and Warnings
 Use in specific populations  Use with other vaccines
‒ Pregnancy: available data insufficient to ‒ No information on coadministration of this
inform vaccine-associated risks in vaccine with other vaccines
pregnancy
 Warnings
‒ Pregnant women vaccinated with the
Janssen vaccine encouraged to enroll in ‒ Appropriate medical treatment used to
pregnancy exposure registry by visiting manage immediate allergic reactions must
https://c-viper.pregistry.com/ be immediately available in the event of
acute anaphylactic reaction following
‒ Lactation: no data to assess effects on
administration of the vaccine
infants, or milk production/excretion
‒ Immunocompromised persons or those on
‒ Pediatrics: EUA does not include use in
immunosuppressant therapy may have a
individuals <18 yr of age
diminished immune response to the vaccine
‒ Vaccine may not protect all recipients
Janssen COVID-19 Vaccine. Fact sheet for HCPs administering vaccine. Last updated January 31, 2022. Slide credit: clinicaloptions.com
mRNA and Ad26.COV2.S Efficacy
COVID-19 Vaccines: Where Are We Now?
% People Fully Vaccinated
 In <1 year: genome to vaccine 55 60 65 70 75 80 85 90 95
‒ mRNA vs adenovirus vaccine

 Booster required for being fully
vaccinated
‒ Only 34% of adults in US boosted
 Pros and cons of vaccine mandates
‒ Overcoming vaccine hesitancy
 Global vaccine access  1.1M deaths and 10.3M
hospitalizations prevented by
vaccination by November 2021
https://coronavirus.jhu.edu/vaccines/story. Accessed June 29, 2022.
commonwealthfund.org/publications/issue-briefs/2021/dec/us-covid-19-vaccination-program-one-year-how-many-deaths-and Slide credit: clinicaloptions.com
Vaccination Protects Against Infection and
Severe Disease
 Data from 18,231 adults with an ED or UC encounter for COVID-19–like
illness during June - August 2021:
‒ Laboratory confirmed SARS-CoV-2 infection in 28.9% of unvaccinated
patients and 7.0% of fully vaccinated patients
Of Fully Vaccinated* Adults
Vaccine Total (N) No. of SARS-CoV-2–Positive Tests (%) VE, % (95% CI)†
BNT162b2 3946 314 (8.0) 77 (74-80)
mRNA-1273 2656 98 (3.7) 92 (89-93)
Ad26.COV2.S 757 100 (13.2) 65 (56-72)
*Full vaccination was defined as index testing or admission date ≥14 days after second dose of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) or after a single dose of
Ad26.COV2 (Janssen) vaccine.
†
Estimated using a test-negative design, adjusted for age, geographic region, calendar time (cubic spline with quartile knots), and virus circulation (percentage of SARS-CoV-2–
positive results from testing within the counties surrounding the facility on the date of the event) and weighted for inverse propensity to be vaccinated or unvaccinated
(calculated separately for each of the 10 VE models) using facility characteristics, sociodemographics, and underlying medical conditions.
cdc.gov/mmwr/volumes/70/wr/mm7037e2.htm. Slide credit: clinicaloptions.com

Omicron: Vaccine Protection
 Immunity against omicron infection conferred by vaccination or
previous infection is less than with delta
‒ Omicron neutralization following 2 mRNA vaccine doses is low
compared with other variants
 People who received vaccine booster and/or have been previously
infected likely have stronger protection against infection with omicron;
however:
‒ Even boosted, vaccination efficacy against symptomatic infection is
4-fold to 6-fold less than against the wild-type virus
 Vaccines remain effective at preventing hospitalization and death
Garcia-Beltran. Cell. 2022;185:1. Rössler. NEJM. 2022;NEJMc2119236. Slide credit: clinicaloptions.com
2- vs 3-Dose Vaccine Effectiveness Against Omicron
UK Health Security Agency Data1
Vaccine Effectiveness, %*
2 Doses (Initial) 2 Doses (20-25 Wk) 3 Doses (Initial) 3 Doses (15+ Wk)
Symptomatic disease 25-70 0-10 50-75 40-50
Hospitalization 65-85 55-65 80-95 75-85
Death† -- 59 95 --
*Combined data from recipients of ChAdOx1-S, BNT162b2, and mRNA-1273 vaccines.
†
Estimates in patients ≥50 years of age.
CDC VISION Network Data2

Vaccine Effectiveness, %*
2 Doses (Initial) 2 Doses (≥25 Wk) 3 Doses (Initial)
Hospitalization 81 57 90
*Combined data from recipients of BNT162b2 and mRNA-1273 vaccines.
1. assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/
1050721/Vaccine-surveillance-report-week-4.pdf. 2. Thompson. MMWR. 2022;71:139. Slide credit: clinicaloptions.com
Omicron Neutralization Activity After Vaccination
 28 days after a third vaccine
Victoria Delta Omicron
dose, neutralization titers are
FRNT50 (Reciprocal Serum Dilution)

P <.0059 (1.9X) P <.0001 (2.7X) P <.0001 (2.7X)
lower for omicron compared 104
390 723
104
75 206
104
21 57
with victoria and delta 103 103 103
102 102 102
 Neutralization titers against 101 101 101
omicron are increased after 100

V2+28 V3+28
100
V2+28 V3+28
100
V2+28 V3+28
a third vaccine dose Victoria Delta Omicron

P <.0001 (4.6X) P <.0001 (8.3X) P <.0001 (34.2X)
‒ Booster vaccines should be
FRNT50 (Reciprocal Serum Dilution)

P <.0001 (22.3X) P <.0001 (63.2X) P <.0001 (49.9X)
P <.0001 (25.4X) P <.0001 (77.9X) P <.0001 (59X)
encouraged for protection 105

104
1993 413 363 9219 105
104
282 37 30 2337 105
104
19 13 11 649
against omicron infection 103 103

102
103
102
102
101 101 101
100 100 100
V2+28 V2+6M Pre-V3 V3+28 V2+28 V2+6M Pre-V3 V3+28 V2+28 V2+6M Pre-V3 V3+28
Dejnirattisai. Cell. 2022;185:467. Slide credit: clinicaloptions.com

T-Cell Response Following Vaccination
 COVID-19 vaccination may provide protection against hospitalization due to the omicron
variant despite decreased antibody neutralization
‒ COVID-19 vaccination elicits highly cross-reactive T-cells capable of recognizing multiple VOC
Ad26.COV2.S BNT162b2
10 1
101
%IFN+/CD8+ T-Cells
%IFN+/CD8+ T-Cells
100 100
10-1 10-1
10-2 10-2
10-3 10-3
A a n A a n A on
W Delt icro W Delt icro W ic r
Om Om Om
Mo 1 Mo 8 Mo 8
Time Following Immunization
Liu. medRxiv. 2022;[Preprint]. Note: This study has not been peer reviewed. Slide credit: clinicaloptions.com
ChAdOx1 nCoV-19 (AZD1222) Vaccine Data
ChAdOx1 nCoV-19 Vaccine Against SARS-CoV-2
(Oxford-AstraZeneca): Study Design
 Randomized, single-blind, controlled phase I/II trial
 ChAdOx1 nCoV-19: chimpanzee adenovirus-vectored vaccine expressing SARS-CoV-2 spike
protein
ChAdOx1 nCoV-19*
Healthy adults aged 18-55 yr Single IM dose†: 5 x 1010
with no history of laboratory
(n = 543)
confirmed SARS-CoV-2
infection or COVID-19–like MenACWY*
symptoms (N = 1077) Single IM standard dose
(n = 534)
*Protocol amendment allowed prophylactic paracetamol to be administered before vaccination to 56 participants in
ChAdOx1 nCoV-19 group and to 57 in MenACWY group. †10 additional participants assigned to a nonrandomized,
unblinded prime-boost group received a second vaccine dose 28 days after the first dose.
 Median age: 35 yr (IQR: 28-44 yr); 50.2% male; 90.9% White
 Primary endpoints: number of symptomatic virologically confirmed COVID-19 and safety
 Current preliminary analysis: safety, reactogenicity, cellular, and humoral responses
Folegatti. Lancet. 2020;396:467. NCT04324606. Slide credit: clinicaloptions.com
ChAdOx1 nCoV-19 Vaccine Against SARS-CoV-2:
Antibody Response
 62% of prime-only ChAdOx1 nCoV-19 recipients and 100% of prime-boost
recipients had neutralizing antibodies that completely inhibited the cytopathic
effects of SARS-CoV-2 by Day 56
‒ Strong correlation between neutralizing antibody responses and antibody levels
measured by ELISA (R2 = 0.67; P <.001)
Prime Prime Boost
MenACWY
256 256
Marburg VNIC100
ChAd0x1 nCoV-19
Marburg VNIC100
64 64
16 16
4 4
1 1
0 56 Patients Health-
14 28 35 42 0 14 28 35 42 56 Patients Health-
with PCR- care with PCR- care
Number assessed Days since vaccination confirmed workers Days since vaccination confirmed workers
ChAd0x1 nCoV-19 44 44 44 0 0 37 COVID-19 (n = 3) 10 10 10 10 9 10 COVID-19 (n = 3)
MenACWY 44 44 43 0 0 25 (n = 5) - - - - - - (n = 5)
Folegatti. Lancet. 2020;396:467. Slide credit: clinicaloptions.com
ChAdOx1 nCoV-19 (AZD1222) Safety: Solicited Local
Events Within 7 Days After Standard Prime Dose
Induration Itch Pain Redness Swelling Tenderness Warmth Mild
75 75 75 75 75 75 75 Moderate
50 50 50 50 50 50 50 Severe
18-55 yr
25 25 25 25 25 25 25 of age Requiring hospital
admission
0 0 0 0 0 0 0
1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7
75 75 75 75 75 75 75
Percentage
50 50 50 50 50 50 50 56-69 yr
of age
25 25 25 25 25 25 25
0 0 0 0 0 0 0
1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7
75 75 75 75 75 75 75
50 50 50 50 50 50 50 ≥70 yr
of age
25 25 25 25 25 25 25
Days After Prime
Vaccination → 0 0 0 0 0 0 0
1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7
Ramasamy. Lancet. 2021;396:1979. Slide credit: clinicaloptions.com
ChAdOx1 nCoV-19 (AZD1222) Safety: Solicited Systemic
Events Within 7 Days After Standard Prime Dose
Joint Muscle
Mild
Chills Fatigue Fever Feverish Headache Pain Malaise Aches Nausea
75 75 75 75 75 75 75 75 75 Moderate
50 50 50 50 50 50 50 50 50 Severe
18-55 yr
25 25 25 25 25 25 25 25 25 of age Requiring hospital
admission
0 0 0 0 0 0 0 0 0
1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7
75 75 75 75 75 75 75 75 75
Percentage
50 50 50 50 50 50 50 50 50 56-69 yr
25 25 25 25 25 25 25
of age
25 25
0 0 0 0 0 0 0 0 0
1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7
75 75 75 75 75 75 75 75 75
50 50 50 50 50 50 50 50 50 ≥70 yr
of age
25 25 25 25 25 25 25 25 25
Days After Prime 0 0 0 0 0 0 0 0 0

Vaccination → 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7
ChAdOx1 nCoV-19 (AZD1222) Safety: Solicited Systemic
Events Within 7 Days After Standard Boost Dose
Joint Muscle
Mild
Chills Fatigue Fever Feverish Headache Pain Malaise Aches Nausea
75 75 75 75 75 75 75 75 75 Moderate
50 50 50 50 50 50 50 50 50 Severe
18-55 yr
25 25 25 25 25 25 25 25 25 of age Requiring hospital
admission
0 0 0 0 0 0 0 0 0
1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7
75 75 75 75 75 75 75 75 75
Percentage
50 50 50 50 50 50 50 50 50 56-69 yr
25 25 25 25 25 25 25
of age
25 25
0 0 0 0 0 0 0 0 0
1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7
75 75 75 75 75 75 75 75 75
50 50 50 50 50 50 50 50 50 ≥70 yr
of age
25 25 25 25 25 25 25 25 25
Days After Boost 0 0 0 0 0 0 0 0 0

Vaccination → 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7 1 3 5 7
CoV2 preS dTM-AS03 Vaccine
VAT08: CoV2 preS dTM-AS03 Vaccine Primary Series
 Phase III trial of 2 doses of adjuvanted protein–based COVID-19 vaccine in
seronegative patients
Efficacy Outcome Efficacy of VAT00008 2-Dose Series (%)
Severe COVID-19 disease and hospitalization 100
Moderate or severe COVID-19 75
Any symptomatic COVID-19 disease 57.9
 Preliminary data indicate 77% efficacy against any delta variant–associated

symptomatic COVID-19 disease
 No safety concerns identified in phase II or III trials
 Protein-based vaccine is a well-established vaccine formulation and is refrigerator
temperature stable
Sanofi. Press release. February 23, 2022. Press release only, not peer reviewed. Slide credit: clinicaloptions.com
CoV2 preS dTM-AS03 Vaccine: Pre vs Post Booster
Neutralizing Antibody Titers by Age
Patients Aged 18-55 Yr Patients Aged ≥56 Yr
By Priming Vaccine By Priming Vaccine
ID50 Titer (Neutralizing Abs)
10,000 84x
9x 27x 153x
23x 34x 25x 11x 25x
23x
1000
28,545
20,409
7894
7204
6958
6188
7006
5294
5829
5392
100
808
473
339
315
249
259
222
230
224
146
n 189 202 66 67 50 63 58 50 27 30 89 99 32 34 25 28 43 42 27 28
10
Primary series BNT162b2 mRNA-1273 Ad26.COV2.S ChAdOx1 CoV2 preS BNT162b2 mRNA-1273 Ad26.COV2.S ChAdOx1 CoV2 preS
nCoV-19 dTM-AS03 nCoV-19 dTM-AS03
Booster vaccine CoV2 preS CoV2 preS CoV2 preS CoV2 preS CoV2 preS CoV2 preS CoV2 preS CoV2 preS CoV2 preS CoV2 preS
dTM-AS03 dTM-AS03 dTM-AS03 dTM-AS03 dTM-AS03 dTM-AS03 dTM-AS03 dTM-AS03 dTM-AS03 dTM-AS03
Day 1
Day 15
Sanofi. Press release. February 23, 2022. Press release only, not peer reviewed. Slide credit: clinicaloptions.com
NVX-CoV2372 Vaccine
NVX-CoV2373 Nanoparticle Vaccine
Against SARS-CoV-2: Study Design
 Randomized, placebo-controlled phase I/II trial of trimeric full-length SARS-CoV-2
spike glycoproteins ± Matrix-M1 adjuvant in adults aged 18-59 yr (N = 131)
Group A (n = 23) Placebo on Day 0 and Day 21
Group B (n = 25) rSARS-CoV-2 25 μg on Day 0 and Day 21
Group C (n = 29)* rSARS-CoV-2 5 μg + Adjuvant 50 μg on Day 0 and Day 21
Group D (n = 28)* rSARS-CoV-2 25 μg + Adjuvant 50 μg on Day 0 and Day 21
Group E (n = 26) rSARS-CoV-2 25 μg + Adjuvant 50 μg on Day 0, Placebo on Day 21

*Includes n = 3 sentinel participants who received open-label vaccination.
 Primary outcomes: reactogenicity, safety, and IgG anti–spike protein response
 Secondary outcomes: unsolicited AEs, WT virus neutralization, and T-cell responses
Keech. NEJM. 2020;383:2320. NCT04368988. Slide credit: clinicaloptions.com
NVX-CoV2373 Nanoparticle Vaccine
Against SARS-CoV-2: Baseline Characteristics
Group C Group D
Group A Group B Group C Group D Group E
Characteristic Sentinel Sentinel
(n = 23) (n = 25) (n = 26) (n = 25) (n = 26)
(n = 3) (n = 3)
25 μg +
rSARS-CoV-2 Dose -- 25 μg x 2 (5 μg + Adjuvant) x 2 (25 μg + Adjuvant) x 2 Adjuvant
Male sex, % 47.8 48.0 50.0 66.7 68.0 66.7 34.6
30.3 27.2 29.5 23.7 35.6 25.0 33.0
Mean age, yr (SD) (10.92) (9.38) (7.99) (7.37) (12.50) (4.58) (8.91)
Race or ethnicity, %
 White 82.6 96.0 69.2 66.7 80.0 66.7 69.2
 Hispanic/Latino 8.7 12.0 23.1 0 12.0 0 19.2
 Asian 8.7 0 23.1 33.3 12.0 33.3 15.4
24.94 25.59 24.10 21.43 26.18 25.67 25.52
Mean BMI (SD)
(3.418) (4.217) (3.872) (2.401) (3.454) (2.294) (3.342)
Matrix-M1 adjuvant dosed at 50 μg.

Keech. NEJM. 2020;383:2320. Slide credit: clinicaloptions.com
NVX-CoV2373 Nanoparticle Vaccine Against
SARS-CoV-2: Solicited Local and Systemic AEs
 No serious AEs noted; reactogenicity absent/mild in most participants
Mild Moderate Severe
Vaccination 1 Vaccination 2
Placebo Placebo
25 µg 25 µg
Any localized 5 µg + Matrix-M1 5 µg + Matrix-M1
adverse events 25 µg + Matrix-M1 25 µg + Matrix-M1
25 µg + Matrix-M1 Placebo
0 20 40 60 80 100 0 20 40 60 80 100
Placebo Placebo
Any systemic 25 µg 25 µg
5 µg + Matrix-M1 5 µg + Matrix-M1
adverse events
25 µg + Matrix-M1 25 µg + Matrix-M1
25 µg + Matrix-M1 Placebo
0 20 40 60 80 100 0 20 40 60 80 100
Keech. NEJM. 2020;383:2320. Percentage of Participants Slide credit: clinicaloptions.com
NVX-CoV2373 Nanoparticle Vaccine Against
SARS-CoV-2: Anti-Spike IgG Response
63,160 47,521
8344
Anti-Spike IgG (EU/ml)
105 10 5
575 2932 53,391

104 104 7420 Asymptomatic
1661 Outpatient
103 113 10 3
symptomatic
Hospitalized
102 102
Day 0 21 35 0 21 35 0 21 35 0 21 35 0 21 35 Human
Placebo 25 µg 5 µg 25 µg 25 µg Convalescent
(dose 1 and 2) rSARS-CoV-2 rSARS-CoV-2+Matrix-MI rSARS-CoV-2+ Serum
(dose 1 and 2) (dose 1 and 2) Matrix-MI (dose 1)
and Placebo (dose 2)
No. of Patients
23/21 23/21 23/21 23/21 26/26
(dose 1/dose 2)
Keech. NEJM. 2020;383:2320. Slide credit: clinicaloptions.com
PREVENT-19 Clinical Trial
 Phase III clinical trial in adults aged ≥18 yr (n = 25,000) in the US and Mexico
without known previous SARS-CoV-2 infection
Confirmed, Symptomatic COVID-19 Local and Systemic Adverse Events
(≥7 days after second dose)
Incidence per 1000 Person-Yr
Vaccine
100 100 Placebo
80 Incidence: 34.0 80 78.9
Participants (%)
69.5
95% CI: 20.7-55.9 58.0
60 (63 cases) 60
Incidence: 3.3 47.7
40.0 35.9
40 95% CI: 1.6-6.9 40
(14 cases) 21.1 21.7
20 20
0 0
Vaccine Placebo Dose 1 Dose 2 Dose 1 Dose 2
Local Systemic
Dunkle. NEJM. 2022;386:531-43. Slide credit: clinicaloptions.com

Novavax (NVX-CoV2373) Data Updated
Study Location N Predominant Variant Efficacy at Day 7 Post Vaccination

(Prevention of Symptomatic COVID-19)
Study 3011 Mexico and B.1.1.7
(Phase III) United States >29,000 (89% of cases) 90.4%
Study 3022 B.1.1.7
United Kingdom >15,000 89.7%
(Phase III) (>50% of cases)
Study 5013 B.1.351  49.4% in population including PWH
South Africa >4400
(Phase IIb) (92.7% of cases)  60% in population without HIV
 FDA authorized NVX-CoV2373 for adults ≥18 yr on July 13, 2022
1. Dunkle. NEJM. 2022;386:531. 2. Heath. NEJM. 2021;385:1172. 3. Shinde. NEJM. 2021;384:1899. Slide credit: clinicaloptions.com
PREVENT-19 Pediatric Expansion Updated
 Phase III clinical trial in US in adolescents aged 12-17 yr (n = 2247)

without known previous SARS-CoV-2 infection
‒ Study timeframe: May 24 - September 27, 2021
 Efficacy
‒ 79.5% against infection with any SARS-CoV-2 variant
‒ 82.0% against infection with SARS-CoV-2 delta variant
 No safety issues identified
 Received CMA for use in adolescents aged 12-17 yr in Europe and awaiting
approval for same age group in Canada and the US
Novavax. Press release. February 14, 2022. Data not peer reviewed. Novavax. Press release.
April 22, 2022. Data not peer reviewed. Novavax. Press releases. June 23, 2022. Data not peer reviewed. Slide credit: clinicaloptions.com
Vaccine: Additional Doses and Boosters
FDA Authorized or Approved COVID-19 Vaccine Boosters
Homologous or Heterologous Booster Dose* Authorization Date†
BNT162b2 (aged ≥12 yr) September 22, 2021, and January 3, 2022
BNT162b2 (aged 5-11 yr) May 17, 2022
mRNA-1273 (aged ≥18 yr) October 20, 2021, and January 7, 2022
Ad26.COV2.S (not preferred) October 20, 2021
Second Booster Dose‡ Authorization Date

BNT162b2 (aged >50 yr, immunocompromised aged ≥12 yr, or prior March 29, 2022
Ad26.COV2.S vaccine)
mRNA-1273 (aged >50 yr, immunocompromised aged ≥18 yr, or prior March 29, 2022
Ad26.COV2.S vaccine)
*>5 mo after primary mRNA series (or >3 mo if immunocompromised) or >2 mo after Janssen (J&J); †Date for homologous booster authorization;
‡
>4 mo after last booster
cdc.gov/coronavirus/2019-ncov/vaccines/booster-shot.html. FDA News Release. May 17, 2022. Slide credit: clinicaloptions.com
Immunocompromised Hosts Have Heterogeneous
Response Following mRNA Immunization
12
100,000
10
RBD-Binding IgG (s/co)
Log 50% Neutralization Titer

8 10,000
6
1000
4
100
2
0 0
P L V S s x x T x a l P L I V DS ies Tx x CT Tx a rol
IC NH HI MD ncie er T rt T SC ey T lom ntro IC NH H M nc er T m
rt HS ney elo ont
L/ a Liv a H n L/ a i v a
C L g n H e id ye Co C L
l ign L He Kid My C
i K M
al le m
a
p le
m tip ti
lid u l o lid ul
So M S M
Rahav. EClinicalMedicine. 2021;41:101158. Slide credit: clinicaloptions.com

Triple Dose of mRNA Vaccine in
Solid Organ Transplant Patients
 101 SOT recipients in France given Anti–SARS-CoV-2 Antibodies
third dose of Pfizer-BioNTech vaccine By Prevalence By Titer
100 104 P <.001
 First 2 doses were given 1 mo apart,
and the third dose was administered 80
61 ± 1 days after the second dose 103
Prevalence (%)
 68% developed anti–SARS-CoV-2 60
IgG Titer
antibodies after third dose 102
40
‒ 32% still with no detectable
antibodies 1 mo after third dose 20
101
 Third dose intends to complete initial

0 100
immune response in an Before Before Before 1 Mo Before Before Before 1 Mo
immunocompromised host; First Second Third After First Second Third After
incomplete responses are still seen Dose Dose Dose Third Dose Dose Dose Third
Dose Dose
Kamar. NEJM. 2021;385:661. Slide credit: clinicaloptions.com

SARS-CoV-2 Vaccine Booster Effectiveness by Age:
Data From Israel
 Comparison of people with vs without Incidence of any SARS-CoV-2 Infection By Age, Pre and Post Booster
booster (N = 1,456,642) 125

Age Group*
10,000
30-39 yr
‒ Median age: 52 yr, 51% female 40-49 yr
Daily Incidence Proportion per

100
Daily Number of New Cases

50-59 yr 7500
100,000 Population (%)

‒ Median follow-up: 13 days ≥60 yr
75
 Results at ≥7 days after receipt of third 5000
dose vs second dose given ≥5 mo ago: 50
‒ Severe disease: 92% VE (17 vs 157 events) 2500

25
‒ Death: 81% VE (7 vs 44 events)
‒ Severe disease ages 40-69 yr: 0 0
6
5 12 19 y 26 ug 2 ug 9 g 1 g 23 g 30 pt 6 t 13 t 20
3.5/100,000 persons vs 57.9/100,000 l y y y
Ju Jul Jul Jul A A Au Au Au Se Sep Sep
persons Date
*Vertical dashed lines represent the day that age group became third dose eligible
Barda. Lancet. 2021;398:2093. Slide credit: clinicaloptions.com

BNT162b2 Vaccine Effectiveness Wanes in Age >60 Yr
From Time of Second Dose: Data From Israel
BNT162b2 Vaccine Effectiveness 6 Mo Post Vaccine Series Completion
100 91 89 83 88 91 94 84 91 Date of Series

79 82 86 Completion
75
Vaccine Effectiveness (%)
67 69
80 Jan 21
44 44 Feb 21
39 41
60
16 16 Mar 21
40 Apr 21
20 All
0
SARS-CoV-2 Symptomatic COVID-19 Severe
Infections COVID-19 Hospitalizations COVID-19
Goldberg. NEJM. 2021;385;e85. Slide credit: clinicaloptions.com

100
BNT162b2 Booster: Effect on Severe Illness
Primary Outcomes of Confirmed Infection and Severe Illness*
Outcome Nonbooster Group Booster Group Adjusted Rate Ratio

(95% CI)†
Confirmed infection 11.3 (10.4-12.3)
No. of cases 4439 934
No. of person-days at risk 5,193,825 10,603,410
Severe illness 19.5 (12.9-29.5)
No. of cases 294 29
No. of person-days at risk 4,574,439 6,265,361
*Poisson regression analysis of 1,137,804 Israeli persons ≥60 yr old who did or did not receive a booster. Booster group includes data from at least 12 days post
booster dose. †Estimated factor reduction in rate in booster group vs nonbooster group
Bar-On. NEJM. 2021;385:1393. Slide credit: clinicaloptions.com

Concept: SARS-CoV-2 Vaccine Mixing and Matching
Predominant Immunity
Homologous Humoral immunity:
mRNA vaccines mRNA mRNA Anti-spike IgG, neutralizing titers
and spike-specific B cells
Heterologous
SARS-CoV-2
vector or mRNA Vector mRNA Humoral and cellular immunity
(and variants)
vaccines
Cellular immunity:
Homologous
Vector Vector Spike-specific CD4+ and
vector vaccines
CD8+ T-cells
Deming. Nat Med. 2021;27:1510. Schmidt. Nat Med. 2021;27:1530. Borobia. Lancet. 2021;398:121. Slide credit: clinicaloptions.com
NIAID: Booster “Mix & Match” Study
N = 458 (150+ per vaccine) Boost: Ad26.COV2.S Boost: Ad26.COV2.S
 12 wk post vaccine Ad26.COV2.S mRNA-1273 BNT 162b2
Ad26.COV2.S mRNA-1273 BNT 162b2
 Safety, antibody titers at 10 5 104
IgG Binding Ab (BAU/mL) to S-2P-WA1

29 days
NAb titers (IU50/mL) to D614G

104
103
Results: 103
 Boosters increased
neutralizing antibody 102 102
activity 4.2‐76x and binding
101
antibody titers 4.6‐56x 101
overall 100
 4x increases in antibodies
100
with Ad26.COV2.S boost of 10-1
1 15 29 1 15 29 1 15 29 1 15 29 1 15 29 1 15 29
Ad26.COV2.S
 33-56x increases in Study Day Study Day
antibodies with mRNA Study Day: Day 1 Day 15 Day 29

boost of Ad26.COV2.S
Atmar. medRxiv;[Preprint]. Note: this study has not been peer reviewed. Slide credit: clinicaloptions.com 103
Rationale for Second Vaccine Booster Dose
 Continued virus evolution  Evidence that first booster
improved immune response
 Waning of neutralizing antibody against earlier variants
levels
‒ During omicron surge in US, those
 Risk of severe disease in key with first booster vs those
populations unvaccinated were:
‒ Older patients ‒ 21 times less likely to die from
COVID-19
‒ Aged >50 yr with multiple
underlying conditions ‒ 7 times less likely to be
hospitalized
Painter. Immunity. 2022;54:2133. cdc.gov/media/releases/2022/s0328-covid-19-boosters.html. Slide credit: clinicaloptions.com

Fourth Dose of BNT162b2 Vaccine in Israeli
Individuals
 Population analysis of individuals with no history of SARS-CoV-2 infection who had
received 3 doses of BNT162b2 vaccine
‒ On January 2, 2022, people in Israel aged ≥60 yr, high-risk populations and healthcare
workers authorized to receive a fourth BNT162b2 dose if >4 mo out from last dose
February 18 March 2
Days 3-7 Post Dose Days 8 Post Dose
Individuals ≥60 yr of Received fourth BNT162b2 dose Received fourth BNT162b2 dose
age who were eligible (n = 623,355) (n = 623,355)
Internal Control 4-Dose Group Confirmed
for a fourth COVID-19 Severe
COVID-19
vaccine dose in illness
Did not receive fourth BNT162b2 dose infection
January 2022 (n = 628,976)
(N = 1,289,003) 3-Dose Group

Primary Outcomes With Fourth Vaccine Dose
Confirmed Infections, by Number Incidence of Severe COVID-19,
Unadjusted Rate of Severe COVID-19

of Vaccine Doses by Number of Vaccine Doses
450 4.5
388 4.2
(per 100,000 Person-Days)

400 4.0 3.9
(per 100,000 Person-Days)
366
350 3.5
Confirmed Infection
300 3.0
250 2.5
200 177 2.0
1.5
150 1.5
100 1.0
50 0.5
0 0
4-Dose 3-Dose Internal Control 4-Dose 3-Dose Internal Control
Group Group
 4-Dose Group: received fourth vaccine dose; evaluated 8 days post dose
 Internal Control Group: received fourth vaccine dose; evaluated 3-7 days post dose
Fourth Dose of BNT162b2 Vaccine:
Real-World Effectiveness
7.5
7.0 Severe illness
Confirmed infection
6.5
6.0
(3
5.5
5.0
Doses:4 Doses)
Adjusted Rate Ratio
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Internal Wk 2 Wk 3 Wk 4 Wk 5 Wk 6 Wk 7 Wk 8
control (Days 8-14) (Days 15-21) (Days 22-28) (Days 29-35) (Days 36-42) (Days 43-49) (Days 50-56)
(Days 3-7) Time Since Dose 4

Decreased Risk of Death With Fourth BNT162b2
Vaccine Dose
 Data from 182,122 patients who received a fourth BNT162b2 vaccine
dose compared with 182,122 matched controls
100 Primary Relative effectiveness against

Cumulative Incidence of analysis COVID-19 related death: 76%
0.06 begins
Mortality (%) Control group
4-dose group
0.04
0.02
0
0 7 14 21 28
Days Since Dose 4
Magen. NEJM. 2022;386:1603. Slide credit: clinicaloptions.com

Fourth Dose With Either BNT162b2 or mRNA-1273
Vaccine
 Prospective, open-label, clinical intervention trial of healthcare professionals with no
history of SARS-CoV-2 infection who had received 3 doses of Pfizer vaccine
Follow-up
Healthcare
professionals ≥18 yr Received fourth BNT162b2 dose Received fourth mRNA-1273 dose
of age who received (n = 154) (n = 120)
3 doses of mRNA Days 7, 14, 21,
vaccine (N = 274) and 30
compared with age- Age-matched controls
matched controls (N = 426)
(N = 426)
Regev-Yochay. medRxiv. 2022. Note: this study has not been peer reviewed. Slide credit: clinicaloptions.com
Primary Outcome: Virus Neutralization Efficiency With
Fourth Vaccine Doses
Fourth Dose of BNT162b2 Fourth Dose of mRNA-1273

1542 1162
1407 645.1 966.5
497.4 771
4096 638.3 4096
Neutralization (titer)/log2
136.3 102.7
1024 135.6 1024 101.6 98.7
57.02 107.6 49.3
256 256 14.2
64 12.7 64
16 16
4 4
1 1
WT Delta icron WT Delta icron WT Delta icron WT Delta icron WT Delta icron WT Delta icron
Om Om Om Om Om Om
5 mo after 1 wk after 2 wk after 5 mo after 1 wk after 2 wk after

third dose fourth dose fourth dose third dose fourth dose fourth dose
Secondary Outcome: Fourth Dose Safety of
BNT162b2 and mRNA-1273 Vaccines
100 mRNA-1273-Age >60
Proportion of the Study Population (%)
mRNA-1273-Age 25-60
80 BNT162b2-Age >60
BNT162b2-Age 25-60
60
40
20
0
Any Local Any Systemic Fatigue Myalgia Headache Fever Lymphadenopathy
Symptoms Symptoms
Effectiveness of Second mRNA Vaccine Booster in NEW
Patients Aged ≥60 Yrs

 1.1 million Israeli adults aged ≥60 yrs Cumulative Hazard Ratio of Death Due to COVID-19
eligible for a second booster (4th Vaccination Group
Cumulative Hazard
vaccine dose) 0.00075 First Booster
Second Booster
 Results in 4-dose vs 3-dose group: 0.00050
‒ 2-fold reduction in new infections 0.00025
‒ 4.3-fold reduction in severe disease 0

0 5 10 15 20 25 30 35 40
Follow-up Time (Days)
‒ 2.5-fold reduction in death due to
COVID-19  Expected duration of efficacy is 4-5 mos
 4th dose effective in Israeli long-term ‒ Unclear implications for regular or
care residents annual COVID-19 vaccine boosters
Abel. Research Square. 2022;[preprint]. Note: these data have not been peer reviewed. Bar-On. MedRxiv. 2022;[Preprint].
Note: these data have not been peer reviewed. Muhsen. JAMA Internal Med. 2022. Epub ahead of print. Slide credit: clinicaloptions.com
CDC Eligibility for Second Booster Dose
Primary eligibility Secondary considerations for those eligible but
unsure if want booster
 Adults ≥50 yr of age
 If you are or someone you live with is:
 People ≥12 yr of age with
moderate or severe ‒ Moderately or severely immunocompromised
immunocompromise
‒ At high risk of getting very ill from COVID-19
 People who received 2 doses of
the Janssen (J&J) vaccine ‒ More likely to be exposed to COVID-19 based on
occupation, residence, or other factors
‒ In an area with medium to high COVID-19
community levels
‒ Unvaccinated (someone you live with)
cdc.gov/coronavirus/2019-ncov/vaccines/booster-shot.html#second-booster. Slide credit: clinicaloptions.com

Second Booster Doses: Which Vaccine and When?
 Which vaccine?  When?
12 yr 17 yr 18+ yr
‒ Wait until at least 4 mo after
your first COVID-19 vaccine
BNT162b2 booster before receiving a
mRNA-1273
second booster
‒ If COVID-19 infection in the
past 3 mo, consider delaying
‒ Ad26.COV2.S may be considered
second booster dose
in some situations
cdc.gov/coronavirus/2019-ncov/vaccines/booster-shot.html#second-booster Slide credit: clinicaloptions.com

COVID-19 Vaccination Efficacy and
Pandemic Impact on Viral Suppression in PWH
Immunogenicity of mRNA Vaccination Against
SARS-CoV-2 in People With HIV: Methods
Design Outcomes
 Stratification of persons with HIV who  Proportion of antibody responders
received anti-SARS-CoV-2 mRNA-1273 or
BNT162b2 vaccination according to  Magnitude of anti-RBD IgG, neutralizing
degree of immunodeficiency antibodies, and cell-mediated immune
response after priming dose (T1) and 1
‒ Severe: current CD4+ cell count mo after the second dose (T2)
<200 cells/mm³
 Association between CD4+ count at
‒ Minor: current CD4+ cell count vaccination and the magnitude of the
≥200 and ≤500 cells/mm³ immune response
‒ No: current CD4+ cell count
 Comparison of the immunogenicity in
>500 cells/mm³
PWH with an unmatched control group
of healthcare workers without HIV
Antinori. EACS 2021. Abstr OS4/3. Slide credit: clinicaloptions.com

Immunogenicity of mRNA Vaccination Against
SARS-CoV-2 in People With HIV: Outcomes
Severe Minor No Healthcare
Measure
(n = 32) (n = 56) (n = 78) Workers
Detectable RBD-binding IgG, n/n (%) 26/30 (86.7) 53/53 (100) 76/77 (98.7) 168/168 (100)
 P vs no immunodeficiency .021 NS Ref --
 P vs healthcare workers <.001 NS NS Ref
Median BAU/mL of RBD-binding IgG (IQR) 507 (212-1143) 1477 (471-2056) 1782 (989-2769) 2353 (1378-3758)
 P vs no immunodeficiency <.001 NS Ref --
 P vs healthcare workers <.001 <.001 .031 Ref
Neutralizing antibodies ≥10, n/n (%) 21/30 (70) 45/51 (88.2) 67/72 (93.1) 72/73 (98.6)
 P vs no immunodeficiency .002 NS Ref --
 P vs healthcare workers <.001 .019 NS Ref
Median reciprocal dilution values at MNA (IQR) 30 (5-80) 40 (10-160) 80 (40-160) 80 (40-160)
 P vs no immunodeficiency <.001 <.001 Ref --
 P vs healthcare workers <.001 .05 NS Ref

CD4+ Cell Count Levels vs CD4/CD8 Ratio as
Predictor of Immune Response
Adjusted β (95% CI) CD4/CD8 Ratio
<200 200-500 >500
per 0.5 Increase
Humoral Immune Response
-0.64* -0.16* 0.16†
Ref
RBD-binding IgG (BAU/mL) (-0.94 to -0.34) (-0.39 to 0.07) (0.01 to 0.30)
P <.001 P = .182 P = .033
-0.41* -0.08* 0.06†
nAb titer
(reciprocal dilution at MNA) (-0.70 to -0.12) (-0.31 to 0.15) Ref (-0.09 to 0.20)
P = .006 P = .497 P = .426
Cell-Mediated Immune Response (IFN-γ release After S-peptide stimulation)
-0.74* -0.03* -0.05*
IFN-γ (pg/mL) (-1.13 to -0.34) (-0.28 to 0.34) Ref (-0.19 to 0.10)
P <.001 P = .850 P = .544
*Adjusted for age, yr of HIV infection, CD4+ cell count nadir, HIV-1 RNA <50 vs ≥50 copies/mL, BNT162n2 vs mRNA-1273 vaccine), previous or current malignancy.
†
Adjusted for age, yr of HIV infection, current CD4+ cell count; CD4+ cell count nadir, HIV-RNA <50 vs ≥50 copies/mL, BNT162n2 vs mRNA-1273 vaccine), previous
or current malignancy.
 Immunogenicity of vaccines strongly related to CD4+ cell count at the time of vaccination; lower CD4+ cell
count significantly and independently predicts a poorer immune response to SARS-CoV-2 vaccine
Reactogenicity of mRNA-1273 Anti–SARS-Cov-2 Vaccine
in People With HIV
Design Outcomes
 Follow-up of people with HIV who received ≥1 dose  Higher rate of moderate symptoms after first dose
of mRNA-1273 vaccine using in-person or online of vaccine in female, younger, and unsuppressed
questionnaire within 1 wk of each dose (N = 453) persons
‒ Queries: severity of symptoms related to the ‒ After second dose, younger patients with moderate
inoculation, previous COVID-19 (if applicable) symptoms
‒ Moderate symptoms: Interfered with ADL or required  Lower rate of moderate symptoms in those with
time off work
latest CD4+ cell count <200 cells/mm³ after both
‒ Severe: required hospitalization, access to ED, or resulted first and second dose (both NS)
in death
 Risk of moderate symptoms decreased with every
‒ HIV-related clinical data collected via medical records 10 yr of age, after adjustment
 BL characteristics: latest CD4+ <200 cells/mm³ in  Data comparable with those compiled from cohort
15 (3.3%); 11 patients (2.4%) unsuppressed; of healthcare workers vaccinated with mRNA-
31 (6.8%) reported previous COVID-19 infection, BNT162b2
mostly asymptomatic or mildly symptomatic
Tomasoni. EACS 2021. Abstr OS4/4. Slide credit: clinicaloptions.com
Outcomes With Infrequent HIV-1 RNA Monitoring
During the COVID-19 Pandemic
 Outcomes for PWH suppressed with HIV-1 RNA <200 copies/mL on ART
pre–COVID-19 (March 2019 to February 2020) were compared with outcomes
during the COVID-19 period (March 2020 to February 2021)
 N = 2571 had HIV-1 RNA <200 copies/mL pre–COVID-19
‒ n = 523 (20.3%) did not have an HIV-1 RNA test during COVID-19 period
‒ n = 45 (1.8%) had an HIV-1 RNA >200 copies/mL during COVID-19, n = 2 with emergent
resistance
Measure Pre–COVID-19 COVID-19
(N = 2661) (N = 2048)
Number of VL tests per patient per yr, mean (SD) 2.3 (1.08) 1.1 (0.83)
Longest time between VL tests, mean wk (SD) 29.5 (8.25) 43.7 (12.64)
Previously suppressed people without a VL test for
≥12 mo, n (%) 82 (3%) 581 (28%)
Alagaratnam. EACS 2021. Abstr BPD3/3. Slide credit: clinicaloptions.com

Additional Investigational Vaccines
Ad-5-Vectored Vaccine Against SARS-CoV-2
(CanSino): Study Design
 Randomized, double-blind, placebo-controlled phase II trial
Ad-5-Vectored Vaccine
Single dose: 5 x 1010 viral particles/mL
(n = 129)
Healthy adults aged ≥18 yr, HIV Ad-5-Vectored Vaccine
negative, with no previous SARS- Single dose: 1 x 1011 viral particles/mL
CoV-2 infection (N = 603) (n = 253)
Placebo
(n = 126)
 Primary immunogenicity endpoints: ELISA antibody responses to the receptor

binding domain and neutralizing antibody responses at day 28
 Primary safety endpoint: incidence of adverse reactions within 14 days
Zhu. Lancet. 2020;395:1845. NCT04341389. Slide credit: clinicaloptions.com
Ad-5-Vectored Vaccine Against SARS-CoV-2:
Baseline Characteristics
Ad-5-Vectored Ad-5-Vectored
Vaccine Vaccine Placebo
Baseline Characteristics
5 x 1010 vp/mL 1 x 1011 vp/mL (n = 126)
(n = 129) (n = 253)
Male sex, n (%) 64 (50) 126 (50) 64 (51)
Mean age, yr (SD) 39.7 (12.1) 40 (12.8) 39.2 (12.5)
Mean BMI (SD) 24.2 (2.7) 24.2 (2.8) 23.3 (2.6)
Underlying diseases, n (%)
 Yes 8 (6) 8 (3) 6 (5)
 No 121 (94) 245 (97) 120 (95)
Preexisting Ad5-neutralizing antibody, n (%)
 ≤ 1:200 titre 54 (42) 127 (50) 61 (48)
 >1:200 titre 75 (58) 126 (50) 65 (52)
Zhu. Lancet. 2020;395:1845. Slide credit: clinicaloptions.com

Safety Profile
Ad-5-Vectored Vaccine Ad-5-Vectored Vaccine
Adverse Reactions, n (%) 5 x 1010 vp/mL 1 x 1011 vp/mL Placebo P Value
(n = 126)
(n = 129) (n = 253)
Solicited
 Any 96 (74) 183 (72) 46 (37) <.0001
 Grade 3 1 (1) 24 (9) 0 <.0001
Unsolicited
 Any 7 (5) 19 (8) 7 (6) .65
 Grade 3 0 1 (<1) 0 1
Overall
 Any 98 (76) 196 (77) 61 (48) <.0001
 Grade 3 1 (1) 24 (9) 2 (2) .0002
 Most common solicited systemic reactions in vaccine groups were fatigue, fever, and
headache; most common ISR was pain
‒ Fever was the most reported grade 3 adverse reaction (1% of participants in the 5 x 10 10 group
and 8% in the 1 x 1011 vp/mL group)
Antibody Response
Binding Antibodies to RBD Neutralizing Antibodies at Day 28
800 GMT 100 75 100

700 Seroconversion
Geometric Mean Titer
Geometric Mean Titer

Seroconversion* (%)
Seroconversion* (%)
80 60 80
600
500 60 45 60
400
300 40 30 40
200
20 15 20
100
0 0 0 0
5x10 vp 1x10 vp Placebo 5x10 vp 1x10 vp Placebo
10 11 10 11
5x10 vp 1x10 vp Placebo 5x10 vp 1x10 vp Placebo
10 11 10 11
Day 14 Day 28 Live SARS-CoV-2 Pseudovirus

*Seroconversion was defined as increase in postvaccination titer of ≥4 x baseline.
 Participants with low preexisting Ad5 antibodies had approximately 2 x

higher binding antibody and neutralising antibody levels
Variables Associated With Seroconversion
 Participants aged ≥55 yr had lower antibody titers and seroconversion rates
in both vaccine dose groups, particularly for neutralizing antibodies to live
SARS-CoV-2
Seroconversion Rate of Seroconversion Rate of Neutralizing
RBD Binding Antibodies Antibodies to SARS-CoV-2
Logistic Regression Analysis Estimates P Value OR (95% CI) Estimates P Value OR (95% CI)
Parameter*
Intercept 8.49 <.0001 -- 2.51 <.0001
Dose group of 1 x 1011 vp/mL -0.13 0.83 0.88 (0.25-3.04) 0.43 .068 1.54 (0.97-2.44)
Placebo group† NR NR NR -5.14 <.0001 0.006 (0.001-0.04)
Age -0.08 .0018 0.92 (0.87-0.97) -0.04 <.0001 1.0 (0.94-0.98)
Male sex -0.26 .066 0.8 (0.24-2.46) -0.39 .085 0.7 (0.44-1.06)
Preexisting Ad5 antibodies (>200) -1.53 .052 0.2 (0.05-1.02) -1.24 <.0001 0.3 (0.19-0.45)
*Independent variables included in multivariable analysis. †Only included in neutralising antibody analysis.

Ad-26 and Ad-5-Vectored Prime/Boost
Vaccine Against SARS-CoV-2: Study Design
 2 open-label, prospective, nonrandomized phase I/II trials assessing frozen and
lyophilized vaccine formulations
Phase I Phase II*
Healthy adults aged rAd26-S on Day 0
18-60 yr; no current or prior Single dose: 1011 viral particles rAd26-S on Day 0
SARS-CoV-2, no infectious (n = 18) + rAd5-S on Day 21
disease within 14 days, no Each dose: 1011 viral particles
rAd5-S on Day 0
vaccination within 30 days (n = 40)
Single dose: 1011 viral particles
(N = 76)
(n = 18)
Gam-COVID-Vac (frozen, 0.5 mL) and Gam-COVID-Vac-Lyo (lyophilized, 1.0 mL when reconstituted) administered to equal number
of participants in each group. *Began ≥5 days after phase 1 vaccination.
 Primary outcomes: antigen-specific humoral immunity and safety

 Secondary outcomes: antigen-specific cellular immunity and change in NAbs
Logunov. Lancet. 2020;396:887. NCT04436471. NCT04437875. Slide credit: clinicaloptions.com
Vaccine Against SARS-CoV-2: Baseline Characteristics
Gam-COVID-Vac CAM-COVID-Vac-Lyo
Characteristic rAd26-S rAd26-S
rAd26-S rAd5-S rAd26-S rAd5-S
(n = 9) (n = 9) + rAd5-S (n = 9) (n = 9) + rAd5-S
(n = 20) (n = 20)
Male sex, % 100 100 70 56 22 70
Mean height, m (SD) 1.8 (0.1) 1.8 (0.1) 1.7 (0.1) 1.7 (0.1) 1.7 (0.1) 1.8 (0.1)
83.4 74.6 72.1 72.0
Mean body weight, kg (SD) 80.6 (6.0) 65.8 (9.4)
(13.8) (12.5) (13.1) (12.6)
Mean age, yr (SD) 27.8 (5.1) 25.3 (6.1) 26.4 (4.4) 31.4 (8.2) 27.0 (7.7) 26.7 (5.8)
Ethnicity, %
 White 100 100 100 89 100 95
 Asian 0 0 0 11 0 5
SARS-CoV-2 IgM/IgG negative, % 100 100 100 100 100 100
Logunov. Lancet. 2020;396:887. Slide credit: clinicaloptions.com

Vaccine Against SARS-CoV-2: Safety
 Most common systemic and local reactions across studies: pain at
injection site, 58%; hyperthermia, 50%; headache, 42%; asthenia, 28%;
muscle and joint pain, 24%
‒ Majority of mild severity
 Lab value changes were mild and transient
 No serious AEs reported, no AE led to study or treatment withdrawal
 In general, AEs mirrored known profiles from other vaccines containing
recombinant viral vectors
 Among phase II participants, most AEs arose after second vaccination
Ad-26 and Ad-5-Vectored Prime/Boost Vaccine
Against SARS-CoV-2: Phase II Humoral Responses
RBD-Specific Antibodies Neutralizing Antibodies
Gam-COVID-Vac Gam-COVID-Vac-Lyo Gam-COVID-Vac Gam-COVID-Vac-Lyo

102,400 320.0
51,200
25,600 160.0
IgG Reciprocal Titer
12,800 80.0
Reciprocal Titer
6,400
3,200 40.0
1,600
20.0
800
400 10.0
200
100 5.0
50 2.5
25
0 14 21 28 42 0 14 21 28 42Convalescent 0 14 28 42 0 14 28 42 Convalescent
plasma plasma
Days After rAd26-S Administration Days After rAd26-S Administration

Vaccine Rollout: Management of Anaphylaxis
Assessment of Anaphylaxis
Following COVID-19 Vaccination
On-Site Emergency Equipment Recommended Postvaccination Observation
Required If Feasible 30 Minutes 15 Minutes
 ≥3 doses of  Pulse oximeter  History of  All other persons
epinephrine  Oxygen immediate allergic
 H1 antihistamine  Bronchodilator reaction (any
 Blood pressure  H2 antihistamine severity) to other
monitor  Intravenous fluids vaccine/injectable
 Timing device to  Intubation kit  Contraindication to
assess pulse  CPR mask a type of COVID-19
vaccine other than
the one received
 Ensure available supplies and trained staff are  History of
commensurate with volume of vaccinations anaphylaxis (any
cause)
 Consider anaphylaxis when signs/symptoms
are generalized or serious/life-threatening,
even if only 1 body system involved
cdc.gov/vaccines/covid-19/clinical-considerations/managing-anaphylaxis.html. Last updated February 11, 2022. Slide credit: clinicaloptions.com
Early Signs/Symptoms of Anaphylaxis
Respiratory: sensation of throat closing or Skin/mucosal: generalized hives,
tightness, stridor, hoarseness, respiratory widespread redness, itching, conjunctivitis,
distress (eg, shortness of breath or or swelling of eyes, lips, tongue, mouth,
wheezing), coughing, trouble swallowing/ face, or extremities
drooling, nasal congestion, rhinorrhea,
sneezing Neurologic: agitation, convulsions, acute
change in mental status, sense of impending
Gastrointestinal: nausea, vomiting, diarrhea, doom
abdominal pain, or cramps
Other: sudden increase in secretions from
Cardiovascular: dizziness, fainting, eyes, nose, or mouth; urinary incontinence
tachycardia, hypotension, pulse difficult to
find or “weak,” cyanosis, pallor, flushing

Management of Anaphylaxis
 If anaphylaxis suspected:  Considerations in special populations:
‒ Assess airway, breathing, circulation, ‒ Older adults (eg, LTCF residents): to avoid
mental activity; call for EMS unnecessary epinephrine administration,
ensure staff able to recognize signs/
‒ If no vomiting/upper airway obstruction, symptoms of anaphylaxis; MI, acute
position patient face up with feet elevated coronary syndrome observed in some
epinephrine recipients, especially older
‒ Immediately administer 0.3 mg IM adults with HTN and/or atherosclerosis
epinephrine in mid-outer thigh; repeat
every 5-15 mins if symptoms return or do ‒ Pregnancy: manage anaphylaxis as in
not improve nonpregnant persons
‒ Monitor in a medical facility for ≥4 hrs ‒ Homebound persons: consider
after resolution of signs/symptoms vaccination in setting where medical care
is immediately available; if infeasible,
ensure provider prepared and trained

Vaccine Hesitancy
COVID-19 and Vaccine Hesitancy
 WHO Strategic Advisory Group of Experts on Immunization defines
vaccine hesitancy as: a delay in acceptance or refusal of vaccination
despite availability of vaccination services
 WHO identified vaccine hesitancy as a top 10 global health threat in
2019
 Anti-vaccination activists are campaigning in multiple countries, with
some denying the existence of COVID-19
‒ Misinformation could reduce acceptance of a COVID-19 vaccine, only
exacerbated by fears about speed of COVID-19 vaccine development
Lazarus. Nat Med. 2020;20:1. WHO. who.int/news-room/spotlight/ten-threats-to-global-health-in-2019. Slide credit: clinicaloptions.com

Factors That Affect COVID-19 Vaccine Hesitancy
Estimated Effect Size of Vaccine Attributes
 Vaccine characteristics: efficacy, Efficacy, %
duration, safety, side effects ‒ 50
‒ 70
‒ 90
 Concerns about the approval process: Protection duration, yr
too fast, political influence ‒ 1
‒ 5
Major side effects
 Sources of information: healthcare ‒ 1 in 10,000
‒ 1 in 1,000,000
providers, public health officials more Minor side effects
trusted than politicians ‒ 1 in 10
‒ 1 in 30
FDA approval
 Demographics: on average, older ‒ Full approval
people, black people, and women less ‒ Emergency use authorization
willing to be vaccinated -0.2 -0.1 0 0.1 0.2

Change in Probability of
Choosing Vaccine
Kreps. JAMA Netw Open. 2020;3:e2025594. Slide credit: clinicaloptions.com
Go Online for More CCO
Coverage of COVID-19!
Medical Minute presentations on timely topics related to care of patients with COVID-19
Frequently Asked Questions Module containing expert answers to questions on COVID-19

epidemiology, prevention, and clinical management
clinicaloptions.com/infectious-disease

CCO COVID19 Resources Downloadable Vaccines

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

CCO COVID19 Resources Downloadable Vaccines

Uploaded by

Copyright:

Available Formats

Comprehensive COVID-19 Slideset:

Vaccines and Variants

Version 4 – August 4, 2022

Slide credit: clinicaloptions.com

 These slides may not be published, posted online, or used in

CDC: SARS-CoV-2 Variant Classifications and Definitions. https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html.

CDC: SARS-CoV-2 Variant Classifications and Definitions https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html.

 The only current variant of concern is omicron; other variants have

GISAID. Updated April 18, 2022. gisaid.org/phylodynamics/global/nextstrain/. Slide credit: clinicaloptions.com

Depicting 2866 Genomes

GISAID. Updated May 18, 2022. gisaid.org/phylodynamics/global/nextstrain/. Slide credit: clinicaloptions.com

Li. Cell. 2020;182:1284. Slide credit: clinicaloptions.com

V341I, D364Y, 385-387del, D405V, N122Q, N343Q, N717Q,

N439K, L452R, A475V, V483A,

Viral Lineages Among Infections (%)

Log10 RNA copies/mL

 Initial data from England, ‒ Age

Similar levels of Increased

Sigal. Nat Rev Immunol. 2022;22:69. Slide credit: clinicaloptions.com

‒ 15 mutations affect RBD1; predominant function is to

‒ BA.1 shares 32 mutations with BA.2 and BA.3 32 mutations

 BA.2 has estimated 30% to 50% higher infectivity 10 unique 1 unique

1. Chen. J Phys Chem Lett. 2022;13(17):3840.

B B.40 B.1.1 B.1.1.315 B.1.1.7 transmission model

Mean Reproduction Number

Davies. Science. 2021;372(6538). Slide credit: clinicaloptions.com

 Geometric mean of pVNT50 titer 40

Muik. Science. 2021;371:1152. Slide credit: clinicaloptions.com

 Characterized by 8 defining mutations in the 10 10

‒ 501Y.V2 displaced the other 0.50

infected with non-B.1.351 2 0.001691 0.3454 204.3 150

Cele. Nature. 2021;593:142. Slide credit: clinicaloptions.com

Wibmer. Nat Med. 2021;27:622. Slide credit: clinicaloptions.com

 Develops high viral carriage

More than twice as contagious as previous variants

Some evidence of increased illness severity vs previous strains

Greatest risk of transmission still among unvaccinated people

Fully vaccinated people with delta breakthrough infections can

cdc.gov/coronavirus/2019-ncov/variants/delta-variant.html. Slide credit: clinicaloptions.com

Against Hospitalization1: Against Symptomatic Disease2:

95% for alpha 94% for alpha

96% for delta 88% for delta

MMWR. September 24, 2021;70:1337. Slide credit: clinicaloptions.com

Antibody Concentration (BAU/mL)

MMWR. 2021;70:1337. Slide credit: clinicaloptions.com

Infection Hospitalization Death

MMWR. 2021;70:1284. Slide credit: clinicaloptions.com

Reciprocal ID50 (log10)

 Greatest reduction (6.4x) in ability of

‒ However, all sera fully neutralized this

‒ Assessed 2 or 4 wk after second dose via 128

‒ LY-CoV555 (bamlanivimab): complete 10-1

Wang. Nature. 2021;593:130. Slide credit: clinicaloptions.com

Viral vector RNA

‒ Scale-up manufacturing processes occurring in parallel

Without Immune Compromise

cdc.gov/vaccines/covid-19/downloads/COVID-19-vacc-schedule-at-a-glance-508.pdf Slide credit: clinicaloptions.com

In 3 In at least In at least In at least Dose 5

Moderna Dose 1 In 4 In at least Dose 3

Moderna In 4 In at least In at least In at least

cdc.gov/vaccines/covid-19/downloads/COVID-19-vacc-schedule-at-a-glance-508.pdf Slide credit: clinicaloptions.com

.Polack. NEJM. 2020;383:2603. Slide credit: clinicaloptions.com

 No serious adverse events reported