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BNT162b2 [COMIRNATY® (COVID-19 Vaccine, 

mRNA)] Booster (Third) Dose

William C. Gruber, MD, FAAP, FIDSA, FPIDS September 22, 2021

Senior Vice President

Vaccine Clinical Research and Development 

Pfizer Inc
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Data to Support Public Health Need for Booster

Data from Israel and the United States suggest vaccine protection against COVID-19 

infection wanes approximately 6 to 8 months following the second dose

1 2

3 weeks 6-8 months after D2

VACCINE EFFICACY WANES

3

Data Source Type Result

Kaiser Permanente Southern 

California (KPSC)

Retrospective 

Cohort Study

• Reduction in VE is likely due to waning effectiveness rather 

than to Delta escaping vaccine protection

FDA requested analysis Post-hoc • Waning effectiveness over time

C4591001 substudy RCT • A booster dose of BNT162b2 has an acceptable safety profile 

and elicits robust immune responses 

Israeli booster vaccination 

program

RWE

• Reactogenicity profile similar or better to that seen 

after the second primary series dose 

• Restores high levels of protection against COVID-19 

outcomes
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Overview of Clinical Program 
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BNT162b2-elicited Sera Effectively Neutralize a Broad 

Range of SARS-CoV-2 Spike Variants After 2 Doses

LLOD

Viruses are isogenic, recombinant SARS-CoV-2 strains, with variant spike coding sequences 

on a common, USA-WA1/2020 genetic background

Circles: 2 weeks PD2

Triangles: 4 weeks PD2

Data from Liu et al., 2021, Nature DOI: ; L10.1038/s41586-021-03693-y; Liu et al., 2021 NEJM, DOI: 10.1056/NEJMc2102017; 

Delta-AY.1, Lambda data submitted for publication

194
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3

rd Dose Evaluated in Both Phase 1 and Phase 3 

Participants from Original Pivotal Trial

Follow-up period

Active Surveillance

for Potential COVID-19 symptoms TRIGGER 

telehealth or in-person visit and nasal swab

Vaccination

period

21 days

apart

UP TO 2-YEARS through study DEATHS: all participants

Vaccination 

1 and 2

DAYS PD3

MONTH PD3

Reactogenicity

AE

PHASE 1 BOOSTER

~8 months PD2

(N=23)

7 1 6 18

SAE

DAYS PD3

MONTH PD3

Reactogenicity

AE

PHASE 3 BOOSTER

~7 months PD2

(N=312)

7 1 6 18

SAE
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Summary of Data for BNT162b2 Booster (3rd Dose) 

Administered in C4591001: Phase 1
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LLOD

10

497

387

83

1754

2119

10

538

261

41

1318

2032

10

150

103

40

1202

1546

10

147

76

20

879

1567

10

100

1,000

10,000

Before

Dose 1

7 Days 

after 

Dose 2

1 Month 

after 

Dose 2

Before 

Dose 3

7 Days 

after 

Dose 3

1 Month 

after 

Dose 3

Before

Dose 1

7 Days 

after 

Dose 2

1 Month 

after 

Dose 2

Before 

Dose 3

7 Days 

after 

Dose 3

1 Month 

after 

Dose 3

18-55 Years Old

n=11/group

65-85 Years Old

n=12/group

Post-dose 3 BNT162b2 GMTs Indicate a Substantial Boost and 

Reduced Gap Between WT and Beta Neutralization

1.0

(1.00, 1.00)

0.30

(0.20, 0.45)

0.27

(0.18, 0.39)

0.48

(0.36, 0.66)

0.69

(0.52, 0.91)

0.73

(0.52, 1.02)

1.0

(1.00, 1.00)

0.27

(0.16, 0.45)

0.29

(0.17, 0.49)

0.49

(0.34, 0.69)

0.67

(0.53, 0.84)

0.77

(0.51, 1.16)

GMRBeta/WT

(95% CI)

50% Serum Neutralizing Titer

PRNTWT PRNTBeta

SARS-CoV-2 Neutralization with BNT162b2 Vaccine Dose 3 | NEJM (openathens.net), DOI: 10.1056/NEJMc2113468 
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LLOD

Post-dose 3 BNT162b2 GMTs Indicate a Substantial Boost 

to the Delta Variant Similar to Wild Type

PRNTWT PRNTDelta

10

100

1,000

10,000

1 Month After Dose 2 1 Month After Dose 3 1 Month After Dose 2 1 Month After Dose 3

1613 1479

310 241

1546 1321

196

123

50% Serum Neutralizing Titer

0.78

(0.63, 0.96)

0.85

(0.71, 1.03)

0.63

(0.46, 0.86)

0.92

(0.71, 1.18)

18-55 Years Old

n=11/group

65-85 Years Old

n=12/group

GMRDelta/WT

(95% CI)

SARS-CoV-2 Neutralization with BNT162b2 Vaccine Dose 3 | NEJM (openathens.net), DOI: 10.1056/NEJMc2113468. 
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Summary of Data for BNT162b2 Booster (3rd Dose) 

Administered in C4591001: Phase 3
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Subjects Receiving 3rd Dose were Representative of US 

18-55 Year Olds in Parent Study

SAFETY POPULATION

BNT162b2

N=306

Sex, n (%)

Male 140 (45.8)

Female 166 (54.2)

Race, n (%)

White 249 (81.4)

Black or African American 28 (9.2)

American Indian or Alaska Native 2 (0.7)

Asian 16 (5.2)

Native Hawaiian or other Pacific Islander 1 (0.3)

Multiracial 4 (1.3)

Not reported 6 (2.0)

Ethnicity, n (%)

Hispanic/Latino 85 (27.8)

Non-Hispanic/non-Latino 219 (71.6)

Not reported 2 (0.7)

Comorbiditya Present 174 (56.9)

Age at booster vaccination (years)

Mean (SD) 41.3 (9.44)

Min, Max (19,55)

Time from Dose 2 to booster dose (months)

Mean (SD) 6.8 (0.56)

Min, Max (4.8. 8.0)

a. One or more Charlson comorbidity index, hypertension or obese
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Immunogenicity
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Geometric Mean Ratio of Neutralization Titers Non-inferiority Criterion 

(Post-dose 3 vs. Post-dose 2) was Met, with Titers ~3-fold Higher

a. Noninferiority is declared if the lower bound of the 97.5% confidence interval is > 0.67 and the point estimate of the GMR is ≥0.8

NT50 = 50% neutralizing titers (Booster Evaluable Immunogenicity Population)

Booster Evaluable Immunogenicity Population

1 Month Post Booster 

(Dose 3)

1 Month After 

Dose 2

1M Post Booster/1M 

PD2a

Assay N

GMT 

(95% CI)

GMT 

(95% CI)

GMR 

(97.5% CI)

Met NI 

(Y/N)

SARS-CoV-2 neutralization 

assay - NT50 (titer) 210 2476.4 (2210.1, 2774.9) 753.7 (658.2, 863.1) 3.29 (2.76, 3.91) Yes
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Noninferiority of Booster Dose Demonstrated Based 

on Proportion of Subjects with a Seroresponse 

a. Noninferiority is declared if the lower bound of the 2-sided 97.5% confidence interval for the percentage difference is greater than -10

If the baseline measurement is below the LLOQ, a postvaccination assay result ≥4 × LLOQ is considered a seroresponse

Seroresponse is defined as achieving a ≥4-fold rise from baseline (before Dose 1)

Booster Evaluable Immunogenicity Population

1 Month Post Booster 

(Dose 3)

1 Month After 

Dose 2

1M Post Booster 

- 1M PD2a

Assay N

n (%)

(95% CI)

n (%)

(95% CI)

%

(97.5% CI)

SARS-CoV-2 neutralization 

assay - NT50 (titer) 198 197 (99.5)(97.2, 100.0)

194 (98.0)

(94.9, 99.4)

1.5

(-0.7, 3.7)
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Safety
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Follow-up Time for Booster Dose

BNT162b2 (30μg)

Booster (3rd) Dose

N=306

Total exposure from booster 

vaccination to cutoff date (months)

Mean (SD) 2.7 (0.15)

Median 2.6

Min, Max (1.1, 2.8)

Total exposure from Dose 2 

to cutoff date (months)

Mean (SD) 9.4 (0.57)

Median 9.5

Min, Max (7.5, 10.8)

Data cutoff date 17Jun2021
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8.7%

63.7%

48.4%

29.1%

1.7%

8.7%

39.1%

25.3%

0%

20%

40%

60%

80%

100%

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

Fatigue, headache, chills, muscle pain, joint pain severity definition: Mild=no interference; Moderate=some interference; Severe=prevents daily activity; Grade 4=ER visit or hospitalization

Vomiting severity definition: Mild=1-2 time in 24h; Moderate=>2 times in 24h; Severe=Requires IV hydration; Grade 4=ER visit or hospitalization

Diarrhea severity definition: Mild=2-3 times in 24h; Moderate=4-5 times in 24h; Severe=6 or more times in 24h; Grade 4=ER visit or hospitalization

Fever: 38.0 °C-38.4 °C 38.4 °C-38.9 °C 38.9 °C-40.0 °C >40.0 °C

Systematic Events: Mild Moderate Severe Grade 4

Systemic Events by Maximum Severity within 7 Days 

of 3rd Dose Similar to Post-dose 2 in Parent Study

16.4%

61.5%

54.0%

37.8%

2.2%

10.0%

39.3%

23.8%

0%

20%

40%

60%

80%

100%

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

BNT162b2 

(30 μg)

Fever Fatigue Headache Chills Vomiting Diarrhea Muscle Pain Joint Pain

Dose 2

(N=2682)

16-55 yrs

(full reacto subset)

Dose 3

(N=289)

18-55 yrs
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Percent of Subjects Reporting ≥1 AE

Blood and lymphatic disordersb

General disorders and administration 

site conditionsc

Musculoskeletal and connective tissue disorders

Nervous system disordersd

Gastrointestinal disorderse

Skin and subcutaneous tissue disorders

Investigations

Adverse Events by System Organ Class ≥1% 1 Month Post

3

rd Dose Overall Less than Those Post-dose 2 in Parent Studya

Safety Population

a. In participants 16-55 years

b. Predominantly reflect lymphadenopathy (5.2%)

c. Predominantly reflects injection site pain/pain

d. Predominantly reflects headache

e. Predominantly reflects nausea

Injury, poisoning and procedural complications

Infections and infestations

5.2

2.6

2.3

1.6

1.3

1.3

0.3

1.0

1.0

0.6

24.3

9.2

8.2

0.9

3.4

1.5

1.0

0.8

0.0 20.0 40.0 60.0 80.0 100.0

BNT162b2 Post Dose 3 (N=306) BNT162b2 Post Dose 2 (N=12995)
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BNT162b2 (30 μg)

N=306

n (%)

Any event 1 (0.3)

Acute myocardial infarction 1 (0.3)

One Serious Adverse Event Through Median 2.6 Months 

Follow-up, Assessed as Unrelated to Vaccination
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Ongoing and Active Pharmacovigilance 

and Pharmacoepidemiology

Collaborate with Vaccine Safety 

Stakeholders

• Interface with CDC (VAERS, V-SAFE, 

VSD, CISA) to optimize 

pharmacovigilance activities

• Collaborate with international groups 

to ensure consistent approach to PV 

Pharmacovigilance

• Expanded intake capability with webbased AE portal

• Active follow-up of safety reports

• Frequent signal detection and evaluation

• Post-approval safety monitoring

• Continued pharmacovigilance for adverse 

events of special interest including 

anaphylaxis and myocarditis

Pharmacoepidemiology Studies

• Extended follow up (for high-severity lowincidence events in large populations)

• Safety surveillance studies (including 

analysis of booster dose and myocarditis)

• Vaccine effectiveness 

• Event background rate (contextualization)

Proactive Risk minimization

• Labeling & Educational Materials

• Real-time product quality monitoring 

(cold-chain)
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Summary of Safety and Immunogenicity 

Safety and Immunogenicity Data Meet FDA Criteria 

for Booster Dose ≥16 Years of Age

Phase 1

• Resulted in acceptable safety profile 

• Elicited robust immune responses against the 

wild-type (reference strain), Beta and Delta 

variants of concern support effectiveness to be 

inferred against Delta variant

BNT162b2 demonstrated high efficacy (>90%) against COVID-19 and safety in 

the pivotal clinical trial after a 2-dose primary series

While VE against severe disease and hospitalization remains high in most 

populations in the US, data from Israel predicts this may not be sustained 

Phase 3

• Safety profile similar or better than dose 2

• Elicited immune responses against wild-type 

non-inferior to responses observed post dose 2

• Met protocol pre-specified immunobridging

success criteria for GMTs and seroresponse

rates