Safety and Efficacy of the BNT162b2

mRNA Covid-19 Vaccine

By: Maggie Kline, PharmD

PGY-1 Pharmacy Resident
IU Health Bloomington Hospital

Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA
Covid-19 Vaccine [published online ahead of print, 2020 Dec 10]. N Engl J Med.
2020;10.1056/NEJMoa2034577. doi:10.1056/NEJMoa2034577
 Objectives

Describe safety and efficacy results of the phase 2/3

trial of the BNT162b2 mRNA Covid-19 vaccine

Identify limitations of the trial

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 Background: Author and Sponsor

 First author Fernando P. Polack is a professor and pediatric infectious

disease expert at Vanderbilt University.
 Author on 103 results listed in PubMed

 Trial sponsored by BioNTech and Pfizer.

Vanderbilt University Medical Center.

 Background: Timeline
December 31st 2019: WHO picked up media release about viral respiratory
illness in China
January 10th: Genome sequence of SARS-CoV-2 was released by Chinse
Center for Disease Control and Prevention
January 31st: Public Health Emergency Declared by U.S. Dept HHS
April: Phase 1 Pfizer trial begins in Germany
July 27th: Phase 3 trial begins
December 10th: Article published and FDA Emergency Use Authorization
(EUA) granted
December 14th: First vaccine administered
As of December 20th: >76 million cases and >1.6 million deaths globally
Anticipated March 2021: Pfizer will have supplied USA 100 million doses
of vaccine total

US Deparmtent of HHS. John Hopkins.

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World Health Organization. Guarino B.
Pfizer.
 Background: Novel Mechanism of Action

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Image from N Engl J Med. 2020;10.1056/NEJMoa2034577.
 Mechanism of Action

FDA Advisory Committee Meeting Dec 10.

 BNT162b2 Previous Studies
N Engl J Med. 2020;383(25):2439-2450.
• Placebo-controlled, observer-blinded, dose-
escalation, phase 1 trial conducted in the United
States,
• N=192 total
• Showed BNT162b2 had more favorable systemic
reactogenicity and similar immunogenicity to
candidate BNT162b1
• Tested 10, 20, and 30 microgram doses  higher
doses had better immunogenicity (IgG binding and
neutralizer titers)
• Noted no major safety concerns and that response
was decreased in age >55
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Trial Design

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 Trial Design

Objective: Assess the efficacy and safety of two

30-microgram doses of BNT162b2 administered
IM 21 days apart, as compared to placebo.

Phase 2/3 of global phase 1/2/3 trial

Multinational, placebo-controlled, observer

blinded

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 Methods
Inclusion Criteria
Adults >= 16 years of age
Healthy or stable chronic medical
conditions as determined by investigators
Stable HIV, hepatitis B, or C were eligible
for the phase 3 trial
Did include individuals at higher risk for
Covid-19 including use of mass transit,
frontline workers
Exclusion Criteria
History of Covid-19 diagnosis
Treatment with immunosuppressive
therapy (including systemic
corticosteroids within 28 days)
Immunocompromising condition
Other medical or psychiatric condition or
lab abnormality that might increase
risks of trial participation
Receipt of medications intended to
prevent Covid-19
Pregnant or breastfeeding; Bleeding
risk; History of ADR to vaccine
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component
 Methods
Subjects randomized 1:1 to receive two doses 21 days
apart of

30
Saline micrograms
placebo BNT162b2
Administered IM in deltoid by unblinded administrator
Subject observed for 30 minutes after each dose by
blinded observer
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 Efficacy Endpoints
Efficacy
Confirmed Covid-19 Definition:
Primary: Confirmed Covid-19
cases with onset at least 7 days At least one symptoms:
after second dose in ⎻Fever, chills, new or increased
participants who had been cough, shortness of breath, or
without serologic or virologic muscle pain, new loss of taste
evidence of SARS-CoV-2 or smell, sore throat, diarrhea,
infection up to 7 days after vomiting
second dose AND positive NAAT test of
Secondary: Efficacy in respiratory sample
participants with and without
evidence of prior infection;
Efficacy against severe Covid-
19 12
Safety Endpoints
 Local or systemic adverse events
 Use of antipyretics or pain medication
within 7 days after each dose

 Reactogenicity subset of patients was

prompted with an electronic diary
 Other partipcants were able to report
adverse events in an unsolicited manner

 Published data include adverse events

through approx. 14 weeks after second
dose

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 Statistical Analysis
Efficacy:
Efficacy was estimated by 100 x (1- IRR)
IRR = ratio of confirmed cases of Covid-19 per 1000
person years of follow-up in vaccine group compared
to placebo groups

Example: 10 in 1k person years vs 100 in 1 k person

years then:
efficacy = 100 x (1 – 10/100) = 90%

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 Statistical Analysis
Efficacy:
Efficacy was estimated by 100 x (1- IRR)

95% credible interval for efficacy and probability

efficacy greater than >30% was calculated with the
use of Bayesian beta-binomial model…overall type 1
error rate of 2.5%

Safety-descriptive

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Results

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 Results

Placebo IM
n=21,728 Placebo IM
assigned n=18,530 second
n=18,846 first dose
dose
Randomized
n=43,548 BNT162b2 IM
n=21,720 BNT162b2 IM
assigned n=18,556 second
n=18,860 first dose
dose

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 Baseline Characteristics

Overall, well balanced between groups (Table 1)

About 50/50 male/female
Overall 83% were white, 9.3% black, 4.3% Asian
About 28% identified as Hispanic/Lantinx
About 30% obese

Balanced for baseline comorbidies (Table S2)

Any Charlson Comorbidy (20.9% vaccine vs 20.6% placebo)
Malignancy (3.9% vs 3.5%)
Chronic Pulmonary Disease (7.8% vs 7.7%)
Diabetes without chronic complication (7.8% vs 7.8%)
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Efficacy

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 Protection Against Severe Covid-19

 Appendix

Table S5.
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*Severe Covid-19 defined as hospitalization, admission to ICU,
intubation or mechanical ventilation or death
 Efficacy Consistent Across Subgroups
Efficacy consistent across demographics (Table 3)
Gender, age group, race or ethnic group, country

Efficacy consistent across clinical subgroups (Table S4)

Similar rates of efficacy seen regardless of obesity,
age group, and at risk comorbidities

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Safety

n=8,183 subjects for reactogenicity subset

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A higher frequency of AE
was seen after 2nd dose
compared to first dose.

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For age >55, systemic AE
and medication use
were less frequent than
age <55.

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 Safety Summary
Overall more patients in the vaccine group (27%) reported adverse
events than in the placebo group (12%).
The rate of serious adverse events was low (n=4 for vaccine group).
Injection site pain, fatigue, headache, and muscle pain were
common side effects. Systemic side effects were more prevalent
after the second dose.
Deaths: 2 in vaccine group (arteriosclerosis, cardiac arrest); 4 in
placebo group (2 unknown, 1 hemorrhagic stroke, 1 MI)

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Discussion

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 Strengths
Data demonstrate robust reduction in number of new
Covid-19 cases in vaccine recipients compared to
placebo
Rigorous safety analysis
Multi-site, multinational controlled trial
Meets (and exceeds?) FDA requirements for emergency
use authorization approval.

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 Limitations
Limited data for older age groups, African Americans, or
severe infection
Unknown duration of efficacy
Limited detection of less common adverse effects
Unknown effect on asymptomatic infection
Ethical: Cannot follow placebo patients for 2 years for
full safety analysis; plan to unblind trial and to offer
vaccine if received placebo
Did not describe efficacy based on comorbidity
subgroups
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 Conclusions
Authors:
“A two-dose regimen BNT162b2 conferred 95% protection
against Covid-19 in persons 16 years of age or older. Safety over
a median of 2 months was similar to that of other viral vaccines.”

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 Generalizability
Not generalizable to patients who:
Had previous Covid-19 diagnosis
Pregnant or breastfeeding
Immunosuppressed
Less than 16 years old

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 Vaccine Comparisons
Vaccine Sponsor Pfizer & BioNTech ModernaTX USA
Product BNT162b2 mRNA-1273
Vaccine Type mRNA mRNA
Dosing Regimen 0 + 21 days 0 + 28 days
# of subjects 30,351 43,448
Overall Efficacy 95% (95% CI 90.3, 97.6) at 94.1% (CI 89.3, 96) at least 14
least 7 days after 2nd dose days after 2nd dose
Adverse events Common: injection site Common: injection site reaction,
reaction, fatigue, headache, fatigue, headache, muscle pain,
muscle pain, chills, joint pain, joint pain, chills
fever
Deaths 2 vaccine arm vs 4 control 6 vaccine arm vs 7 control

Other Notes Anaphylactic reactions post- 2 Anaphylactic reactions observed

study (1 placebo, 1 vaccine 63 days after
dose 2) 33

FDA Advisory Committee Meeting Dec 10 & 17

 Clinical Impact

Emergency Use Authorizations (EUAs) for Pfizer and Moderna’s

vaccines have been approved by the FDA and vaccination has
started in the United States.
Use in patient populations not included in the study should involve
a risk-benefit discussion.
Evidence of efficacy of an mRNA vaccine may lead to other
vaccines with this mechanism of action in future.
 Mask-wearing, frequent handwashing, and social distancing
should be continued to prevent transmission even after 2 doses of
vaccine.

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 Planned subsequent studies
Data for subjects age 12-15 and younger
Studies in patients with immunosuppression and HIV
Studies with serologic endpoints to address asymptomatic infection
Post-marketing monitoring for long-term and rare adverse events

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 Further monitoring: V-safe
Check-ins daily for the first week; weekly for 5 weeks; then 3, 6,
and 12 months after your final dose of vaccine.

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Centers for Disease Control and Prevention.

 Key Takeaways

We don’t know long-term

efficacy and safety.
We do know that Covid-19
has caused considerable
morbidity and mortality.
Available evidence
suggests that benefits of
BNT162b2 and mRNA-
1273 vaccines outweigh
the risks studied
populations.
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Image: xkcd.com/2400/
 References

 Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19
Vaccine [published online ahead of print, 2020 Dec 10]. N Engl J Med.
2020;10.1056/NEJMoa2034577. doi:10.1056/NEJMoa2034577
 Vanderbilt University Medical Center. Fundación Infant (Argentina) - An International
Clinical/Research Opportunity. Available at: https://www.vumc.org/vvc/fundacion-infant-
argentina-international-clinicalresearch-opportunity. Accessed December 20, 2020.
 U.S. Department of Health and Human Services. Determination that a Public Health Emergency
Exists. Available at: https://www.phe.gov/emergency/news/healthactions/phe/Pages/2019-
nCoV.aspx. Accessed December 20, 2020.
World Health Organization. Listings of WHO’s response to COVID-19. Available at:
https://www.who.int/news/item/29-06-2020-covidtimeline. Accessed December 20, 2020.
 John Hopkins University & Medicine. COVID-19 Dashboard. Available at:
https://coronavirus.jhu.edu/map.html. Accessed December 20, 2020.
 Guarino B, et al. ‘The weapon that will end the war’: First coronavirus vaccine shots given
outside trials in U.S. Available at: https://www.washingtonpost.com/nation/2020/12/14/first-
covid-vaccines-new-york/. Accessed December 20, 2020.

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 References

 Pfizer. PFIZER AND BIONTECH CELEBRATE HISTORIC FIRST AUTHORIZATION IN THE U.S. OF
VACCINE TO PREVENT COVID-19. Available at: https://www.pfizer.com/news/press-
release/press-release-detail/pfizer-and-biontech-celebrate-historic-first-authorization. Accessed
December 20, 2020.
 U.S. Food and Drug Administration. Vaccines and Related Biological Products Advisory
Committee December 10, 2020 Meeting Announcement. Available at: www.fda.gov. Accessed
December 20, 2020.
 Walsh EE, Frenck RW Jr, Falsey AR, et al. Safety and Immunogenicity of Two RNA-Based Covid-19
Vaccine Candidates. N Engl J Med. 2020;383(25):2439-2450. doi:10.1056/NEJMoa2027906
 U.S. Food and Drug Administration. Vaccines and Related Biological Products Advisory
Committee December 17, 2020 Meeting Announcement. Available at: www.fda.gov. Accessed
December 20, 2020.
 Centers for Disease Control and Prevention. Frequently Asked Questions about v-safe. Available
at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/faq.html. Accessed December
20, 2020.

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Safety and Efficacy of the BNT163b2
mRNA Covid-19 Vaccine
By: Maggie Kline, PharmD
PGY-1 Pharmacy Resident
IU Health Bloomington Hospital
mkline4@iuhealth.org