VRBPAC-06.14.22-06.15.22-Meeting-Briefing-Document - FDA-Pfizer-COVID19-Vaccine-for-Pediatrics

Vaccines and Related Biological Products Advisory Committee Meeting
June 15, 2022
FDA Briefing Document
EUA amendment request for Pfizer-BioNTech COVID-19 Vaccine

for use in children 6 months through 4 years of age
VRBPAC Briefing Document: Pfizer-BioNTech COVID-19 Vaccine EUA Amendment for Use in Children 6 Months
Through 4 Years of Age
Table of Contents
List of Tables................................................................................................................................. 3
List of Figures ............................................................................................................................... 4
1. Executive summary ................................................................................................................... 5
2. Background ............................................................................................................................... 7
2.1. SARS-COV-2 virus and COVID-19 disease ...................................................................... 7
2.2. Authorized and approved vaccines and therapies for COVID-19 ...................................... 8
2.2.1. Comirnaty and Pfizer-BioNTech COVID-19 Vaccine ................................................. 8
2.2.2. Spikevax and Moderna COVID-19 Vaccine .............................................................. 9
2.2.3. Janssen COVID-19 Vaccine ...................................................................................... 9
2.2.4. Therapies for COVID-19 ............................................................................................ 9
2.3. Post-licensure/post-authorization experience with Comirnaty and Pfizer-
BioNTech COVID-19 Vaccine ......................................................................................... 10
2.3.1. Vaccine effectiveness against SARS-CoV-2 variants of concern ............................ 10
2.3.2. Post-EUA and post-licensure safety surveillance .................................................... 11
2.4. EUA amendment request for the Pfizer-BioNTech COVID-19 Vaccine for use in
children 6 months through 4 years of age ....................................................................... 13
3. EUA requirements, guidance and considerations pertaining to COVID-19 vaccines ............. 13
3.1. US requirements to support issuance of an EUA for a biological product ....................... 13
3.2. FDA guidance for industry related to COVID-19 vaccines .............................................. 14
3.3. Regulatory considerations for clinical development of COVID-19 vaccines in
children ............................................................................................................................ 14
4. FDA review of clinical safety and effectiveness data .............................................................. 15
4.1. Overview of study C4591007 .......................................................................................... 15
4.2. Phase 2/3 ........................................................................................................................ 16
4.2.1. Phase 2/3 study design ........................................................................................... 16
4.2.2. Phase 2/3 analysis populations ............................................................................... 17
4.2.3. Phase 2/3 disposition .............................................................................................. 18
4.2.4. Phase 2/3 comorbidities at baseline ........................................................................ 28
4.2.5. Phase 2/3 demographic and baseline characteristics ............................................. 28
4.2.6. Phase 2/3 vaccine effectiveness results .................................................................. 31
4.2.7. Phase 2/3 safety results .......................................................................................... 41
4.3. Summary of study C4591007 Phase 2/3 ......................................................................... 55
5. Pharmacovigilance activities ................................................................................................... 57
6. Benefit-risk in the context of the proposed EUA for Pfizer-BioNTech COVID-19
Vaccine in children 6 months through 4 years of age ............................................................ 58
6.1. Known and potential benefits .......................................................................................... 58
6.2. Uncertainties related to benefits ...................................................................................... 59
6.3. Known and potential risks................................................................................................ 59
6.4. Uncertainties related to risks ........................................................................................... 60
7. Topic for VRBPAC Discussion ................................................................................................ 61
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8. References.............................................................................................................................. 61
9. Appendix A: Study C4591007 Phase 1 information ................................................................ 64
9.1. Phase 1: Dose-finding and dose selection design........................................................... 64
9.2. Phase 1: Safety results.................................................................................................... 64
9.3. Phase 1: Immunogenicity results..................................................................................... 65
9.4. Phase 1: Dose selection decision.................................................................................... 65
10. Appendix B: COVID-19 case definitions ............................................................................... 66
List of Tables
Table 1. Study C4591007 in Participants 6 Months Through 4 Years of Age (3 µg BNT162b2) 16

Table 2. Disposition of Participants Ages 6-23 Months and 16-25 Years, Phase 2/3 Three-Dose
Primary Series Immunogenicity Populations, Studies C4591007 and C4591001 ...................... 19
Table 3. Disposition of Participants Ages 2-4 Years and 16-25 Years, Phase 2/3 Three-Dose
Primary Series Immunogenicity Populations, Studies C4591007 and C4591001 ...................... 20
Table 4. Disposition of Participants 6-23 Months, Phase 2/3 Efficacy Population, Study
C4591007 ................................................................................................................................... 21
Table 5. Disposition of Participants 2-4 Years, Phase 2/3 Efficacy Population, Study C4591007
.................................................................................................................................................... 22
Table 6. Disposition of Participants 6-23 Months of Age, Prior to Unblinding, Phase 2/3 Study
C4591007 ................................................................................................................................... 24
Table 7. Disposition of Participants 6-23 Months of Age, After Unblinding, Phase 2/3 Study
C4591007 ................................................................................................................................... 24
Table 8. Disposition of Participants 2-4 Years of Age, Prior to Unblinding, Phase 2/3 Study
C4591007 ................................................................................................................................... 26
Table 9. Disposition of Participants 2-4 Years of Age, After Unblinding, Phase 2/3 Study
C4591007 ................................................................................................................................... 27
Table 10. Demographic and Baseline Characteristics of Participants 6-23 Months, Phase 2/3
Safety Population, Study C4591007 ........................................................................................... 28
Table 11. Demographic and Baseline Characteristics of Participants 2-4 Years, Phase 2/3
Table 12. SARS-CoV-2 Neutralizing GMTs (NT50)a After Three Primary Series Doses in
BNT162b2 (3 µg) Recipients 6-23 Months of Age (1 Month After Dose 3) and BNT162b2 (30 µg)
Recipients 16-25 Years of Age (1 Month After Dose 2) Without Evidence of SARS-CoV-2
Infection, Phase 2/3 Evaluable Immunogenicity Populationsb, Studies C4591007 and C4591001
.................................................................................................................................................... 31
Table 13. Difference in Seroresponse Ratesa,b,c After Three Primary Series Doses in BNT162b2
(3 µg) Recipients 6-23 Months of Age (1 Month After Dose 3) and BNT162b2 (30 µg) Recipients
16-25 Years of Age (1 Month After Dose 2) Without Evidence of SARS-CoV-2 Infection, Phase
2/3 Evaluable Immunogenicity Populationsd, Studies C4591007 and C4591001 ....................... 32
Table 14. SARS-CoV-2 Neutralizing GMTs (NT50)a After Three Primary Series Doses in
BNT162b2 (3 µg) Recipients 2-4 Years of Age (1 Month After Dose 3) and BNT162b2 (30 µg)
Recipients 16-25 Years of Age (1 Month After Dose 2) Without Evidence of SARS-CoV-2
Infection, Phase 2/3 Evaluable Immunogenicity Populationb, Studies C4591007 and C4591001
.................................................................................................................................................... 33
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Table 15. Seroresponse Ratesa,b After Three Primary Series Doses in BNT162b2 (3 µg)
Recipients 2-4 Years of Age (1 Month After Dose 3) and BNT162b2 (30 µg) Recipients 16-25
Years of Ageb (1 Month After Dose 2) Without Evidence of SARS-CoV-2 Infection, Phase 2/3
Evaluable Immunogenicity Populationsc, Studies C4591007 and C4591001 ............................. 33
Table 16. Subgroup Analyses of Geometric Mean SARS-CoV-2 Neutralizing Titers, Phase 2/3
Participants 6-23 Months of Age (1 Month After Dose 3) and 16-25 Years of Age (1 Month After
Dose 2), All-Available Immunogenicity Population, Studies C4591007 and C4591001 ............. 34
Participants 2-4 Years of Age (1 Month After Dose 3) and 16-25 Years of Age (1 Month After
Dose 2), All-Available Immunogenicity Population, Studies C4591007 and C4591001 ............. 35
Table 18. Geometric Mean Fold Rises of SARS-CoV-2 Neutralizing GMTs Before Dose 3 and at
1 Month After Three Doses in Participants 6 Months Through 4 Years of Age, Phase 2/3
Evaluable Immunogenicity Populationb Subsets, Study C4591007 ............................................ 36
Table 19. First COVID-19 Occurrence Any Time After Dose 1, Blinded Follow-Up Period,
Participants 6-23 Months of Age, All-Available Efficacy Population, Study C4591007 ............... 39
Table 20. First COVID-19 Occurrence Any Time After Dose 1, Participants 2 to <5 Years of Age,
All-Available Efficacy Population, Study C4591007 .................................................................... 39
Table 21. Adverse Events in Participants 6-23 Months of Age, Blinded Follow-Up, Phase 2/3
Table 22. Adverse Events in Participants 2-4 Years of Age, Blinded Follow-Up, Phase 2/3
Table 23. Frequency of Solicited Local Reactions, by Severity, Within 7 Days After Each Dose
in Participants 6-23 Months of Age, Phase 2/3 Safety Populationa, Study C4591007 ................ 44
Table 24. Frequency of Solicited Systemic Reactions, by Severity, Within 7 Days After Each
Dose in Participants 6-23 Months of Age, Phase 2/3 Safety Populationa, Study C4591007 ...... 44
Table 25. Characteristics of Solicited Local and Systemic Reactions in Participants 6-23 Months
of Age, Phase 2/3 Safety Populationa, Study C4591007 ............................................................ 45
Table 26. Frequency of Solicited Local Reactions, Within 7 Days After Each Dose in
Participants 2-4 Years of Age, Phase 2/3 Safety Populationa, Study C4591007 ........................ 46
Table 27. Frequency of Solicited Systemic Reactions, Within 7 Days After Each Dose in
Participants 2-4 Years of Age, Phase 2/3 Safety Populationa, Study C4591007 ........................ 47
Table 28. Characteristics of Solicited Local and Systemic Reactions in Participants 2-4 Years of
Age, Phase 2/3 Safety Populationa, Study C4591007 ................................................................ 48
Table 29. Frequency of Solicited Local Reactions, Within 7 Days After Dose 2 and 3 in
Participants 2-4 Years of Age and Participants Who Turned 5 Years of Age and Received
BNT162b2 10 µg Dose 3, Phase 2/3 Safety Populationa, Study C4591007 ............................... 49
Table 30. Frequency of Solicited Systemic Reactions, Within 7 Days After Dose 3 in Participants
2-4 Years of Age and Participants Who Turned 5 Years of Age and Received BNT162b2 10 µg
Dose 3, Phase 2/3 Safety Populationa, Study C4591007............................................................ 49
List of Figures
Figure 1. Cumulative Incidence Curves for the First COVID-19 Occurrence After Dose 1,
Participants 6-23 Months, All-Available Efficacy Population ....................................................... 40
Participants 2-4 Years, All-Available Efficacy Population ........................................................... 41
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1. Executive summary
On May 27, 2022, Pfizer submitted a request to FDA to amend the Emergency Use
Authorization (EUA) for the Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) for prevention of
coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome
coronavirus-2 (SARS-CoV-2). The amendment would expand use of BNT162b2 to include a 3-
dose primary series (3 µg each dose) for use in infants and children 6 months through 4 years
of age. In its request, Pfizer submitted safety, immunogenicity, and preliminary descriptive
efficacy data from an ongoing randomized, double-blinded, placebo-controlled trial, C4591007.
Study participants 6 months through 4 years of age were randomized 2:1 to receive 2 doses of
either BNT162b2 at 3 µg mRNA per dose or saline placebo, administered 3 weeks apart.
Following analysis of the post-Dose 2 safety and effectiveness data, the protocol was amended
to administer a third primary series dose to participants 6 months through 4 years of age at least
8 weeks after Dose 2.
The EUA request included Phase 2/3 safety data from 1,178 BNT162b2 recipients and 598
placebo recipients 6 months through 23 months (hereafter 6-23 months) of age; and 1,835
BNT162b2 recipients and 915 placebo recipients 2 years through 4 years (hereafter 2-4 years)
of age who received at least one dose of the investigational product. Among participants 6
months through 4 years of age, the median follow up was 2.1 months after Dose 3 (inclusive of
both blinded and open-label follow up) at the time of the April 29, 2022, data cutoff.
In study C4591007, vaccine effectiveness was inferred by immunobridging based on SARS-

CoV-2 50% neutralizing antibody titers (NT50, SARS-CoV-2 mNG microneutralization assay). In
each of two further divided age groups (6-23 months and 2-4 years), neutralizing antibody titers
at 1 month post-Dose 3 were compared to titers at 1 month post-Dose 2 from a randomly
selected subset of 16-25-year-old participants who had received two doses of 30 μg BNT162b2
in the Phase 2/3 efficacy study, C4591001. A preliminary descriptive analysis of vaccine efficacy
(VE) among participants who received 3 study vaccinations (following accrual of 10 total
confirmed COVID-19 cases occurring at least 7 days post-Dose 3) was also provided.
The primary immunogenicity endpoints evaluated neutralizing antibody titers against the
USA_WA1/2020 reference strain, a Wuhan-like strain, as assessed by microneutralization
assay, among study participants with no evidence of prior SARS-CoV-2 infection up to 1 month
post-Dose 3. Immunobridging endpoints and statistical success criteria were tested sequentially
in the following order for each of the age groups 6-23 months and 2-4 years:
• SARS-CoV-2 neutralizing antibody geometric mean titers (GMTs) measured 1 month after
Dose 3 in study C4591007 Phase 2/3 participants 6-23 months of age versus GMTs 1
month after Dose 2 in a randomly selected subset of 16-25-year-old participants from study
C4591001, with immunobridging success criteria of >0.67 for the lower bound of the 95%
confidence interval (CI) around the GMT ratio (pediatric age group / 16-25 years of age),
and a point estimate of the GMT ratio ≥1.0.
• Seroresponse rates (percentage of participants with ≥4-fold rise in SARS-CoV-2 neutralizing
antibody titer from pre-Dose 1 baseline), with immunobridging success criterion of >−10%
for the lower bound of the 95% CI around the difference in seroresponse rates (pediatric age
group minus 16-25 years of age).
Immunobridging statistical success criteria, as described above, were met for both age groups.
Post-Dose 3 neutralizing antibody GMTs were numerically higher among participants in both
age groups with evidence of prior SARS-CoV-2 infection at baseline as compared to those
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without evidence of prior SARS-CoV-2 infection at baseline. Otherwise, subgroup analyses of

immunogenicity by age, gender, race and ethnicity showed no notable differences as compared
with the overall study population, although some subgroups were too small to draw meaningful
conclusions. Additional descriptive immunogenicity analyses, based on a non-validated SARS-
CoV-2 fluorescent focus reduction neutralization test (FFRNT), showed lower post-Dose 3
GMTs against the Omicron variant, as compared to the ancestral strain and Delta variant, in
both age groups.
Preliminary descriptive efficacy analyses of COVID-19 cases occurring at least 7 days post-
Dose 3 included 376 BNT162b2 recipients and 179 placebo recipients 6-23 months of age and
589 BNT162 recipients and 271 placebo recipients 2-4 years of age. In these analyses, three
COVID-19 cases occurred in participants 6-23 months of age, with 1 COVID-19 case in the
BNT162b2 group compared to 2 in the placebo group, corresponding to an estimated VE of
75.6% (95% CI: −369.1%, 99.6%), and 7 COVID-19 cases occurred in participants 2-4 years of
age, with 2 cases in the BNT162b2 group and 5 in the placebo group, corresponding to an
estimated VE of 82.4% (95% CI: −7.6%, 98.3%). In a combined analysis of both age groups, VE
was 80.4% (95% CI: 14.1%, 96.7%) with 3 cases in the BNT162b2 group and 7 cases in the
placebo group. Cases were accrued during February 2022 through April 2022, when the
Omicron variant was prevalent in the United States. Among all COVID-19 cases accrued from
Dose 1 through the data cutoff of April 29, 2022, 1 placebo recipient 6-23 months of age and 7
participants 2-4 years of age (6 BNT162b2 recipients and 1 placebo recipient) met the protocol-
specified criteria for severe COVID-19 during both blinded and open-label follow-up. Only one of
these severe COVID-19 cases (in a BNT162b2 recipient 99 days post-Dose 2) resulted in
hospitalization, and the remainder met criteria for severe COVID-19 based on vital sign findings
that were not clinically significant in the opinion of the investigator and FDA.
Solicited local adverse reactions (ARs) generally occurred at similar frequencies after any dose
and solicited systemic ARs occurred at slightly decreasing frequencies with each successive
dose. The most commonly reported solicited ARs after any dose for participants 6-23 months of
age were irritability (68.4%), drowsiness (41.3%), decreased appetite (38.6%), and tenderness
at the injection site (26.4%). The most commonly reported solicited ARs after any dose for
participants 2-4 years of age were pain at the injection site (47.0%), fatigue (44.8%), and
injection site redness (18.9%). Most local and systemic reactions were mild to moderate in
severity, with median onset 1-2 days post vaccination, and a median duration of 1-2 days after
onset. Subgroup safety analyses of reactogenicity by baseline SARS-CoV-2 status showed no
notable differences as compared with the overall study population.
The frequencies of unsolicited non-serious adverse events (AEs) reported were similar in the
BNT162b2 and placebo groups for participants 6-23 months of age (29.1% versus 26.3%) and
for participants 2-4 years of age (18.7% versus 18.7%). The most commonly observed
unsolicited AEs were consistent with those reported as solicited adverse events (local and
systemic reactogenicity) and/or were consistent with events frequently reported in this age
group, including infections and injuries. Lymphadenopathy was observed following vaccination
in two BNT162b2 recipients 6-23 months of age and one BNT162b2 recipient 2-4 years of age;
no cases were reported in the placebo groups. From the combined safety database of 3,013
BNT162b2 recipients 6 months through 4 years of age, 1% of participants (N=29) reported
serious adverse events (SAEs), as compared to 1.5% of participants (N=22) in the combined
safety database of 1,513 placebo recipients 6 months through 4 years of age. Two SAEs
(pyrexia [>40°C] and pain in extremity) which occurred in the same BNT162b2 recipient were
considered by the study investigator as possibly related to vaccination; FDA considered that
viral myositis could be an alternative etiology. Three participants in the BNT162b2 group
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withdrew from the study due to pyrexia (>40°C); these AEs were classified as non-serious.
There were no reports of myocarditis/pericarditis, no cases of anaphylaxis considered caused
by vaccination, and no deaths.
This June 15, 2022 meeting of Vaccines and Related Biological Products Advisory Committee
(VRBPAC) is being held to discuss whether, based on the totality of scientific evidence
available, the benefits of the Pfizer-BioNTech COVID-19 Vaccine, when administered as a
three-dose primary series, outweigh its risks for use in infants and children 6 months through 4
years of age.
2. Background
2.1. SARS-COV-2 virus and COVID-19 disease
SARS-CoV-2 is a zoonotic coronavirus that emerged in late 2019 and was identified in patients
with pneumonia of unknown cause. SARS-CoV-2 is the causative agent of COVID-19, an
infectious disease with respiratory and systemic manifestations. Disease symptoms vary, with
many persons presenting with asymptomatic or mild disease and some progressing to severe
respiratory tract disease including pneumonia and acute respiratory distress syndrome, leading
to multiorgan failure and death. Symptoms associated with SARS-CoV-2 infection in individuals
less than 18 years of age are similar to those in adults, but are generally milder, with fever and
cough most commonly reported. 1,2 Other symptoms in children include nausea and vomiting,
diarrhea, dyspnea, nasal symptoms, rashes, fatigue and abdominal pain. 3 Most children with
COVID-19 recover within 1 to 2 weeks. Estimates of asymptomatic infection in children vary
from 15% to 50% of infections. 4,5 However, COVID-19-associated hospitalizations and deaths
have occurred in children (see below), and for some children, COVID-19 symptoms may
continue for weeks to months after their initial illness. 6
The SARS-CoV-2 pandemic continues to present a challenge to global health and, as of June 8,
2022, has caused over 533 million cases of COVID-19, including 6.3 million deaths worldwide. 7
In the US, approximately 84 million cases and 1 million deaths have been reported to the
Centers for Disease Control and Prevention (CDC). 8,9 Following EUA of the first COVID-19
vaccines in December 2020, COVID-19 cases and deaths in the US declined sharply during the
first half of 2021. The emergence of the Delta variant, variable implementation of public health
measures designed to control spread, and continued transmission among unvaccinated
individuals were major factors in the resurgence of COVID-19 in the US, leading to the Delta
variant-associated peak in September of 2021 and the more recent surges in cases attributed to
the Omicron variant. As of the week ending March 26, 2022, the Omicron variant (B.1.1.529,
also called BA.1) comprised all of the tested strains in the US, and sublineages of the Omicron
variant (previously BA.2, which replaced BA.1 as the dominant strain, and currently BA.4, and
BA.5) are increasingly identified among tested strains. 10
Of the total COVID-19 cases reported in the US to date, 3.3% occurred among children 0-4
years of age. 11 According to death certificate data, 202 deaths have been attributed to
COVID-19 among children 6 months to 4 years of age through May 11, 2022. 12 During the week
ending May 21, 2022, there were 40 COVID-19-associated hospitalizations of children 0-4 years
of age. 13 During December 19, 2021 to May 7, 2022, when the Omicron variant was
predominant, children 6 months to 4 years accounted for 24% of COVID-19 associated
intensive care unit (ICU) admissions (n=535) among children 6 months to 17 years. 14 Of
children 6 months to 4 years of age with COVID-19 associated hospitalization, 49% had one or
more underlying health conditions. 15 The most common underlying medical conditions among
7
hospitalized children (≤18 years) were obesity (31.9%), neurologic disorders (14.8%), and
asthma (14.5%). Obesity was associated with increased risk of severe disease. Available
evidence suggests that highest risk groups include children with special healthcare needs,
including genetic, neurologic, metabolic conditions, or with congenital heart disease. 16 However,
a majority of children hospitalized for COVID-19 have no underlying medical conditions. As in
the adult population, COVID-19 in children disproportionally affects underrepresented racial and
ethnic groups, with hospitalizations and deaths more frequent among Native American/Alaskan,
Hispanic or Latin American, and non-Hispanic Black children than among White children. 17,18
Data on the prevalence of long COVID in children is sparse; however, a national survey in the
United Kingdom found that among children ages 2-11 years who tested positive for COVID-19,
7.2% reported continued symptoms at 12 weeks. 19
Following observation of an increased incidence of myocarditis in 2020 compared with 2019,

several studies have suggested an association between COVID-19 and myocarditis. 20,21 While
the overall incidence of myocarditis following COVID-19 is low, persons with COVID-19 have a
nearly 16-fold increase in risk for myocarditis, compared to individuals without COVID-19.
Myocarditis may also present as part of the multisystem inflammatory syndrome in children
(MIS-C), usually 3 to 5 weeks after a SARS-CoV-2 infection. MIS-C is a rare but serious
COVID-19-associated condition that occurs in less than 1% of children with confirmed SARS-
CoV-2 infection. 22 MIS-C presents with persistent fever, laboratory evidence of inflammation,
and at least two affected organs. In severe cases, hypotension and shock can occur.
Approximately 60-70% of patients are admitted to intensive care, and 1-2% die. 23,24,25 Between
May 2020 and May 2022, the CDC received reports of 8,210 cases and 68 deaths that met the
definition for MIS-C; the median age of participants was 9 years with 24% of cases occurring in
children 0-4 years. Males comprised 61% of cases, and 57% were reported in children who
were reported as Hispanic or Black. 26 Up to 66.7% of patients with MIS-C had cardiac
involvement, 27 including left ventricular dysfunction, mitral or tricuspid regurgitation, coronary
artery aneurysms, and/or arrhythmias. 28 One study of outcomes in children with MIS-C followed
up to 9 months found that while 76% children with MIS-C required ICU admission and therapy
with inotropes or pressors; most symptoms, including cardiovascular manifestations, resolved
within 1 to 4 weeks. 29 Limited data are available on long-term outcomes in MIS-C.
2.2. Authorized and approved vaccines and therapies for COVID-19
2.2.1. Comirnaty and Pfizer-BioNTech COVID-19 Vaccine
Comirnaty (COVID-19 Vaccine, mRNA) made by BioNTech Manufacturing GmbH (in

partnership with Pfizer, Inc.) is approved for active immunization to prevent COVID-19 in
individuals 16 years of age and older. Comirnaty contains a nucleoside-modified messenger
RNA (mRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2 that is formulated in lipid
particles. The primary immunization series consists of 2 intramuscular doses administered 21
days apart, with each 0.3 mL dose of the approved formulation containing 30 μg mRNA. During
clinical development it was called BNT162b2.
Under EUA, the vaccine is called the Pfizer-BioNTech COVID-19 Vaccine and is authorized for
use as: a two-dose primary series for individuals 12 years of age and older; a third primary
series dose for individuals 12 years of age and older with certain immunocompromising
conditions; a homologous first booster dose administered at least 5 months after completion of
primary vaccination to individuals 12 years of age and older; a heterologous first booster dose
administered after completion of primary vaccination to individuals 18 years of age and older
(the dosing interval is the same as that authorized for a booster dose of the vaccine used for
8
primary vaccination); and a second booster dose administered at least 4 months after a first
booster dose with any FDA authorized or approved COVID-19 vaccine to individuals 50 years of
age and older and individuals 12 years of age and older with certain immunocompromising
conditions. A different formulation of Pfizer-BioNTech COVID-19 Vaccine containing 10 μg
mRNA per 0.2 mL dose is authorized under EUA for use in children 5-11 years of age as: a two-
dose primary series; a third primary series dose in individuals with certain kinds of
immunocompromise; and a single homologous booster dose administered at least 5 months
after completion of a primary series. Safety and effectiveness data supporting approval of
Comirnaty and emergency use authorization of Pfizer-BioNTech COVID-19 Vaccine are detailed
in the decision memoranda available on the FDA website.
2.2.2. Spikevax and Moderna COVID-19 Vaccine
Spikevax (COVID-19 Vaccine, mRNA), manufactured by Moderna, is approved for active

immunization to prevent COVID-19 in individuals 18 years of age and older. Under EUA, the
vaccine is called the Moderna COVID-19 Vaccine. The vaccine is authorized for use under EUA
as: a two-dose primary series for individuals 18 years of age and older; a third primary series
dose for individuals 18 years of age and older with certain immunocompromising conditions; a
homologous or heterologous first booster dose administered after completion of primary
vaccination to individuals 18 years of age and older (the authorized dosing interval for a
homologous booster is at least 5 months after completion of a primary series, and the
authorized interval for a heterologous booster is the same as that authorized for a booster dose
of the vaccine used for primary vaccination); and a homologous or heterologous second booster
dose administered at least 4 months after the first booster dose to individuals 50 years of age
and older and individuals 18 years of age and older with certain immunocompromising
conditions.
Safety and effectiveness data supporting approval of Spikevax and authorization of Moderna
COVID-19 Vaccine are detailed in the decision memoranda available on the FDA website.
2.2.3. Janssen COVID-19 Vaccine
The Janssen COVID-19 Vaccine is authorized for use in individuals 18 years of age and older
for whom other FDA-authorized or approved COVID-19 vaccines are not accessible or clinically
appropriate, or who elect to receive the Janssen COVID-19 Vaccine because they would
otherwise not receive a COVID-19 vaccine. The vaccine is authorized for use in these
individuals as a single primary vaccination dose and as a single homologous or heterologous
booster dose (the dosing interval for a homologous booster is at least 2 months after the single
primary vaccination dose, and the dosing interval for a heterologous booster is the same as that
authorized for a booster dose of the vaccine used for primary vaccination). Safety and
effectiveness data supporting emergency use authorization of the Janssen COVID-19 Vaccine
are detailed in the decision memorandum on the FDA website.
2.2.4. Therapies for COVID-19
The antiviral remdesivir is currently approved by the FDA for the treatment of COVID-19 in
adults and pediatric patients (28 days of age and older and weighing at least 3 kg) with positive
results of direct SARS-CoV-2 testing who are hospitalized, or who are not hospitalized and have
mild-to-moderate COVID-19 and are at high risk for severe COVID-19. Additionally, the immune
modulator baricitinib is approved by the FDA for the treatment of COVID-19 in hospitalized
9
adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or

extracorporeal membrane oxygenation (ECMO).
Other pharmacological products for pre-exposure prophylaxis of COVID-19, post-exposure

prophylaxis and/or treatment of COVID-19 that have received emergency use authorization are
as follows:
Antivirals: Paxlovid (nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use) is
authorized under EUA for the treatment of mild-to-moderate COVID-19 in adults and pediatric
patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-
CoV-2 testing, and who are at high risk for progression to severe COVID-19, including
hospitalization or death. Molnupiravir is authorized under EUA for the treatment of mild-to-
moderate COVID-19 in adults with positive results of direct SARS-CoV-2 testing, and who are at
high risk for progression to severe COVID-19, including hospitalization or death, and for whom
alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically
appropriate.
SARS-CoV-2-targeting monoclonal antibodies: Bebtelovimab is authorized under EUA for the

treatment of mild-to-moderate COVID-19 in adults and pediatric patients 12 years of age and
older weighing at least 40 kg with positive results of direct SARS-CoV-2 testing, who are at high
risk for progression to severe COVID-19 and for whom alternative COVID-19 treatment options
approved or authorized by FDA are not accessible or clinically appropriate. Tixagevimab co-
packaged with cilgavimab is authorized under EUA as pre-exposure prophylaxis for prevention
of COVID-19 in certain adults and pediatric individuals (12 years of age and older weighing at
least 40 kg).
Immune modulators: Baricitinib is authorized for the treatment of COVID-19 in hospitalized

patients 2 to less than 18 years of age who require supplemental oxygen, non-invasive or
invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Tocilizumab
is authorized for the treatment of COVID-19 in hospitalized adults and pediatric patients (2 years
of age and older) who are receiving systemic corticosteroids and require supplemental oxygen,
non-invasive or invasive mechanical ventilation, or ECMO.
COVID-19 convalescent plasma with high antibody titer is authorized for emergency use as a
treatment for patients with COVID-19 in patients with immunosuppressive disease or receiving
immunosuppressive treatment, in inpatient or outpatient settings.
2.3. Post-licensure/post-authorization experience with Comirnaty and Pfizer-BioNTech

COVID-19 Vaccine
2.3.1. Vaccine effectiveness against SARS-CoV-2 variants of concern
The emergence of the highly transmissible Omicron variant of SARS-CoV-2 in December 2021
resulted in several waves of COVID-19 cases in many parts of the world and, in the US,
coincided with a rapid increase in COVID-19-associated hospitalizations among all age groups,
including children 6 months through 4 years of age. 30 Observational studies have indicated
waning effectiveness of mRNA COVID-19 vaccine primary series against symptomatic infection
over time for all age groups for which they are authorized, as well as reduced and more rapidly
waning effectiveness against symptomatic infection caused by the Omicron variant. Observed
estimates of vaccine effectiveness against symptomatic disease due to the Omicron variant
10
include the following: 8.8% (95% CI, 7.0 to 10.5) at 25 or more weeks since primary vaccination
in adults; 59.5% among adolescents 12 to 15 years of age 2 to 4 weeks after dose 2, 16.6%
during month 2 after the second dose, and 9.6% during month 3 after the second dose.; and
60.1% for children 5 to 11 years of age 2 to 4 weeks after dose 2, and 28.9% during month 2
after dose 2. 31,32,33,34
Recent estimates of primary series vaccine effectiveness against serious outcomes have been
lower for during the Omicron predominant period as compared to the Delta predominant period
across pediatric and adult age groups evaluated. Observed estimates of primary series mRNA
vaccine effectiveness against hospitalizations due to the Omicron variant in adults have been
reported at 41%-57% at 6-9 months or longer after the second dose. 35,36 In one observational
study among adolescents 12 to 18 years of age (median interval since vaccination, 162 days)
during the Omicron-predominant period, primary series vaccine effectiveness was 40% (95%
CI, 9 to 60) against hospitalization for COVID-19, 79% (95% CI, 51 to 91) against critical
COVID-19, and 20% (95% CI, −25 to 49) against noncritical COVID-19. Among children 5 to 11
years of age (median interval since vaccination, 34 days), vaccine effectiveness against
hospitalization was 68% (95% CI, 42 to 82). 37 Observed estimates of primary series mRNA
vaccine effectiveness against emergency department/urgent care visits due to the Omicron
variant in adults have been reported between 31%-38% at 6-9 months or longer after the
second dose. 38,39 Data from observational studies have also indicated higher estimates of
vaccine effectiveness against COVID-19 and serious outcomes in adults and adolescents
among those who have received a booster dose than among those who have received only a
primary series. 40 Additional updated data on vaccine effectiveness will be presented by CDC
during the VRBPAC meeting.
2.3.2. Post-EUA and post-licensure safety surveillance
As of May 18, 2022, more than 343 million doses of the Pfizer-BioNTech COVID-19 Vaccine
have been administered in the US. 41 The Vaccine Adverse Event Reporting System (VAERS)
was queried for AE reports following the Pfizer-BioNTech COVID-19 Vaccine, and the results
are summarized below. Spontaneous surveillance systems such as VAERS are subject to many
limitations, including underreporting, stimulated reporting, variable report quality and accuracy,
inadequate data regarding the numbers of doses administered, and lack of direct and unbiased
comparison groups. Reports in VAERS may not be medically confirmed and are not verified by
FDA. Also, there is no certainty that the reported event was actually due to the vaccine.
As of May 19, 2022, VAERS received 749,249 reports (including 385,218 US reports) following
vaccination with Pfizer-BioNTech COVID-19 Vaccine; 245 US reports were in children 6 months
through 4 years of age, 10,740 US reports were in children ages 5-11 years, 15,160 US reports
were in children ages 12-15 years, and 8,119 US reports were in children ages 16-17 years.
The top ten most frequently reported MedDRA Preferred Terms (PTs; US and foreign reports)
included:
• All ages: SARS-CoV-2 test, headache, fatigue, COVID-19, pyrexia, dizziness, pain,
nausea, pain in extremity, chills.
• Persons ≤17 years of age: dizziness, pyrexia, headache, syncope, product storage error,
nausea, product administered to patient of inappropriate age, fatigue, chest pain,
vomiting.
• Persons 6 months through 4 years of age: product administered to patient of
inappropriate age, exposure via breastmilk, pyrexia, SARS-CoV-2 test, body
temperature, off-label use, cough, headache, rash, diarrhea.
11
Note that a report may have one or more PTs. Among US VAERS reports for individuals aged 6
months through 4 years, which may reflect unauthorized use of the vaccine or may reflect a
reporting error, the majority (96.3%) were non-serious.
Safety concerns identified from post-authorization safety surveillance data in VAERS are
summarized below. Anaphylaxis, myocarditis, and pericarditis are existing safety concerns that
have been added to the product Fact Sheets. Review of passive surveillance adverse event
reports and the Sponsor’s periodic safety reports does not indicate new safety concerns. Most
adverse events are labeled events and consistent with the safety profile for this vaccine. No
unusual frequency, clusters, or other trends for adverse events were identified that would
suggest a new safety concern.
Anaphylaxis
Post-authorization surveillance has identified a risk of anaphylaxis, occurring at a rate similar to
reported rates of anaphylaxis following licensed preventive vaccines, primarily in individuals with
history of prior severe allergic reactions to other medications or foods. 42,43 Anaphylaxis is an
important identified risk in the pharmacovigilance plan and included in the Warnings sections of
the vaccine Fact Sheets and Prescribing Information. The estimated crude reporting rate for
anaphylaxis following Pfizer-BioNTech COVID-19 Vaccine for all ages in the US is 4.7 cases
per million doses administered based on VAERS data as of May 20, 2022, which is similar to
estimated rates for other vaccines. 44
Myocarditis and pericarditis

Post-EUA safety surveillance reports received by FDA and CDC identified increased risks of
myocarditis and pericarditis, particularly within 7-days following administration of the second
dose of the 2-dose primary series. Reporting rates for medical chart-confirmed myocarditis and
pericarditis in VAERS have been higher among males under 40 years of age than among
females and older males. The highest reporting rates have been in males 12 through 17 years
of age (rates of verified cases per million doses within 7-days following dose 2 administration
were 74.2 cases among males ages 16-17 years, 48.1 cases among males ages 12-15 years,
and 2.7 cases among males ages 5-11 years: data per CDC presentation to the Advisory
Committee on Immunization Practices [ACIP] on May 19, 2022). VAERS monitoring has also
shown that reporting rates of myocarditis among individuals ages 12-29 years following a first
booster dose exceeded background rates but were lower compared to post-Dose 2 rates for the
primary series (data per CDC presentation to the ACIP on April 20, 2022).
Although some cases of vaccine-associated myocarditis/pericarditis have required intensive

care support, available data from short-term follow-up suggest that most individuals have had
resolution of symptoms with conservative management. Information is not yet available about
potential long-term sequelae and outcomes in affected individuals, or whether the vaccine might
be associated initially with subclinical myocarditis (and if so, what are the long-term sequelae).
CDC is conducting enhanced surveillance for VAERS case reports using patient and healthcare
provider surveys to assess functional status and clinical outcomes among individuals reported
to have developed myocarditis after mRNA COVID-19 vaccination. A mechanism of action by
which the vaccine could cause myocarditis and pericarditis has not been established.
Myocarditis and pericarditis were added as important identified risks in the pharmacovigilance
plan and included in the Warnings sections of the vaccine Fact Sheets and Prescribing
Information. The Sponsor is conducting additional post-authorization/post-marketing studies to
assess known serious risks of myocarditis and pericarditis as well as to identify an unexpected
serious risk of subclinical myocarditis.
12
2.4. EUA amendment request for the Pfizer-BioNTech COVID-19 Vaccine for use in
children 6 months through 4 years of age
On May 27, 2022, Pfizer and BioNTech submitted a request to amend this EUA for use of the
Pfizer-BioNTech COVID-19 Vaccine in individuals 6 months through 4 years of age for active
immunization to prevent COVID-19 caused by SARS-CoV-2. The proposed regimen is a 3-dose
primary series (3 µg each dose), with a 3-week interval between the first two doses, followed by
a third dose at least 8 weeks after Dose 2.
The EUA amendment request contains data from participants in Phase 2/3 of ongoing study
C4591007, with a data cutoff date of April 29, 2022, by the following pre-specified age groups:
o Participants 6-23 months of age: Safety data from 1,178 BNT162b2 (3 μg) recipients and
598 placebo recipients, of whom 461 (60.8%) and 68 (37.0%), respectively, had at least 2
months (blinded and open-label) safety follow-up after completing a three-dose primary
series. Vaccine effectiveness was inferred by immunobridging based on a comparison of
immunogenicity endpoints (SARS-CoV-2 neutralizing antibody geometric mean
concentrations (GMTs) and seroresponse rates 1 month after Dose 3) between
participants 6-23 months of age from study C4591007 (n=146) and participants 16 through
25 years of age from study C4591001. Efficacy against COVID-19 was also assessed
descriptively.
o Participants 2-4 years of age: Safety data from 1,835 BNT162b2 (3 μg) recipients and 915
placebo recipients, of whom 596 (57.3%) and 104 (37.1%), respectively, had at least 2
months (blinded and open-label) safety follow-up after completing a three-dose primary
series. Vaccine effectiveness was inferred by immunobridging based on a comparison of
immunogenicity endpoints (SARS-CoV-2 neutralizing antibody GMTs and seroresponse
rates 1 month after Dose 3) between participants 2-4 years of age from study C4591007
(n=217) and participants 16 through 25 years of age from study C4591001. Efficacy
against COVID-19 was also assessed descriptively.
Vaccine Formulation for children 6 months through 4 years of age

Each 0.2 mL dose of the Pfizer‑BioNTech COVID-19 tris/sucrose formulation contains 3 μg of
mRNA encoding the S glycoprotein of SARS-CoV-2 that is formulated in lipid particles. The
vaccine is supplied as a concentrated multi-dose frozen suspension in a 2-mL vial (0.4 mL
volume). The frozen multiple dose vial needs to be thawed, then diluted with 2.2 mL of 0.9%
sodium chloride for injection prior to administration. After dilution, each vial contains 10 doses.
3. EUA requirements, guidance and considerations pertaining to COVID-19 vaccines
3.1. US requirements to support issuance of an EUA for a biological product
Based on the declaration by the Secretary of the United States Department of Health and
Human Services (HHS) that the COVID-19 pandemic constitutes a public health emergency
with a significant potential to affect national security or the health and security of United States
citizens living abroad, FDA may issue an EUA after determining that certain statutory
requirements are met (section 564 of the FD&C Act (21 U.S.C. 360bbb-3)).
13
• The chemical, biological, radiological, or nuclear agent referred to in the March 27, 2020,
EUA declaration by the Secretary of HHS (SARS-CoV-2) can cause a serious or life-
threatening disease or condition.
• Based on the totality of scientific evidence available, including data from adequate and well-
controlled trials, if available, it is reasonable to believe that the product may be effective to
prevent, diagnose, or treat such serious or life-threatening disease or condition that can be
caused by SARS-CoV-2, or to mitigate a serious or life-threatening disease or condition
caused by an FDA-regulated product used to diagnose, treat, or prevent a disease or
condition caused by SARS-CoV-2.
• The known and potential benefits of the product, when used to diagnose, prevent, or treat
the identified serious or life-threatening disease or condition, outweigh the known and
potential risks of the product.
• There is no adequate, approved, and available alternative to the product for diagnosing,
preventing, or treating the disease or condition.
If these criteria are met, under an EUA, FDA can allow unapproved medical products (or
unapproved uses of approved medical products) to be used in an emergency to diagnose, treat,
or prevent serious or life-threatening diseases or conditions caused by threat agents. FDA has
been providing regulatory advice to COVID-19 vaccine manufacturers regarding the data
needed to determine that a vaccine’s benefit outweigh its risks. This includes demonstrating that
manufacturing information ensures product quality and consistency.
3.2. FDA guidance for industry related to COVID-19 vaccines
An EUA allowing for rapid and widespread deployment of the vaccine to millions of individuals,
including healthy people, would need to be supported by clear and compelling evidence of
effectiveness and adequate safety follow-up to make a determination of favorable benefit/risk
(see guidance for industry “Emergency Use Authorization for Vaccines to Prevent COVID-19”
March 2022, originally issued October 2020). 45 These expectations would apply to age-group
specific data to support an EUA amendment for use of an unapproved COVID-19 vaccine in
children 6 months through 4 years of age. The timing, design, and appropriate endpoints for
pediatric studies are discussed in the context of specific vaccine development programs as
described in the guidance for industry "Development and Licensure of Vaccines to Prevent
COVID-19" from June 2020. 46
3.3. Regulatory considerations for clinical development of COVID-19 vaccines in

children
The VRBPAC convened on June 10, 2021, to discuss, in general, the data needed to support
authorization and/or licensure of COVID-19 vaccines for use in pediatric populations.
Effectiveness
Regulatory precedent with other preventive vaccines provides a basis for inference of vaccine
effectiveness in pediatric populations based on immunobridging to an adult population in which
clinical disease endpoint VE has been demonstrated for the same prototype vaccine. The
immune marker(s) used for immunobridging do not need to be scientifically established to
predict protection but should be clinically relevant to the disease. Based on available data in
humans and animal models, FDA considers neutralizing antibody titers (a functional measure of
the vaccine immune response against SARS-CoV-2) to be clinically relevant for immunobridging
to infer effectiveness of COVID-19 vaccines in pediatric age groups. Because no specific
14
neutralizing antibody titer has been established to predict protection against COVID-19, two
immunogenicity endpoints (GMT and seroresponse rate) are considered appropriate for
comparing the range of neutralizing antibody responses elicited by the vaccine in pediatric
versus young adult populations.
Safety
The size of the safety database sufficient to assess risks of COVID-19 vaccines for EUA in
pediatric age groups would generally be the same as for other preventive vaccines for infectious
diseases, provided that no specific safety concern is identified that could reasonably be
evaluated in pre-authorization clinical trials. These safety data would include characterization of
common ARs (reactogenicity, including injection site and systemic ARs), and less common but
medically important ARs. Depending on prior experience with the vaccine in adults, and prior
experience with licensed vaccines based on the same or similar platforms, FDA has accepted
an overall pediatric safety database in the range of ~500 to ~3,000 trial participants exposed to
the age-appropriate dose and regimen intended for licensure and have at least 6 months of
follow-up evaluations after completion of the vaccination regimen. Since COVID-19 vaccines
represent a new class of vaccines, with many of the lead candidates based on new platform
technologies, an appropriate overall pediatric safety database would approach the upper end of
this range, with adequate representation across all pediatric age groups, in particular younger
age groups (e.g., <12 years) that are less physiologically similar to adults. A control group
(ideally placebo control) would be important to inform interpretation of safety data and to comply
with the expectation for adequate and well- controlled studies to support licensure. If another
COVID-19 vaccine is licensed or authorized for use in the age group(s) enrolled in the trial,
recommended by public health authorities, and widely available such that it is unethical to use a
placebo control, the licensed or authorized COVID-19 vaccine could serve as a control.
Within the overall pre-licensure safety database, solicited reactogenicity could be adequately
characterized among several hundred trial participants in each relevant age group. Additionally,
safety evaluation in all trial participants would include collection of all AEs through at least 1
month after each study vaccination and collection of serious and other medically attended AEs
for the duration of the trial. Although longer-term follow-up (through 1 year or longer post-
vaccination) of trial participants would be important to ongoing assessment of both benefits and
risks, completion of such longer-term follow-up would not be a prerequisite to licensure unless
warranted by a specific safety concern. Post-licensure/post-authorization safety surveillance
and observational studies in pediatric populations would be needed to evaluate for ARs that
occur too rarely to be detected in clinical trials.
4. FDA review of clinical safety and effectiveness data
4.1. Overview of study C4591007
The EUA amendment request contains safety, immunogenicity, and efficacy data from
participants 6 months through 4 years of age enrolled in study C4591007, an ongoing Phase
1/2/3, randomized, placebo-controlled study (Table 1). Details of the study design and a
summary of data from the Phase 1 dose-ranging portion of the study that informed dose
selection for Phase 2/3 are provided in Appendix A.
The comparator groups for the Phase 2/3 immunobridging analyses to support vaccine
effectiveness in the pre-specified age groups (6-23 months, 2-4 years) were randomly selected
subsets of Phase 2/3 participants 16-25 years of age enrolled in study C4591001, the study in
which VE against COVID-19 was established in individuals 16 years of age or older.
15
Table 1. Study C4591007 in Participants 6 Months Through 4 Years of Age

Study Number/ BNT162b2 3 µg Placebo (Saline) Study
Countries Description N N Status
C4591007 Phase 1/2/3 randomized, Phase 1: 32 Phase 1:0 Ongoing
United States, placebo- controlled; to evaluate Phase 2/3*: 3013 Phase 2/3: 1513
Brazil, Finland, safety, immunogenicity and
Poland, and Spain efficacy of COVID- 19 vaccine
Abbreviation: N=number of randomized participants as of data cutoff dates July 16, 2021 (Phase 1 participants) and April 29, 2022
(Phase 2/3 participants). Phase 1 was conducted only in the United States.
* First participant was randomized on June 21, 2021.
4.2. Phase 2/3
4.2.1. Phase 2/3 study design
In Phase 2/3, a total of 4,526 participants 6 months through 4 years of age were randomized 2:1
to receive two doses of 3 µg BNT162b2 or placebo, 3 weeks apart. The Phase 2/3 portion of the
study did not exclude participants with a history of prior SARS-CoV-2 infection or clinical
symptoms/signs of COVID-19, participants with known HIV, hepatitis B or hepatitis C, or stable
pre-existing disease (defined as disease not requiring significant change in therapy or
hospitalization for worsening disease during the 6 weeks before enrollment). Based on analyses
of post-Dose 2 safety and effectiveness data, the protocol was amended to add a third primary
series dose at least 8 weeks after Dose 2 (C4591007 protocol amendment 6). Participants
enrolled prior to implementation of protocol amendment 6 (N=3,883; February 1, 2022), were
able to be unblinded at their 6-month post-Dose 2 visit, and those originally randomized to
placebo were offered BNT162b2 vaccination at the age-appropriate dose level. Participants
enrolled after implementation of protocol amendment 6 will be unblinded at their 6-month post-
Dose 3 visit, and those originally randomized to placebo will be offered BNT162b2 vaccination.
Parent/guardians of participants who turned 5 years of age during the study were offered the
option for their child to be unblinded to the treatment assignment and to receive the 10-µg dose
level of the Pfizer-BioNTech COVID-19 Vaccine under EUA if they originally received placebo.
Participants in the placebo crossover group who were unblinded and had not received any
BNT162b2 doses, but were age 5 years or older at the time of crossover vaccination, would
then receive two BNT162b2 doses 3 weeks apart and BNT162b2 Dose 3 at least 6 months after
Dose 2.
4.2.1.1. Phase 2/3 immunogenicity evaluation

Immunobridging was based on SARS-CoV-2 neutralizing antibody responses at 1 month post
Dose 2 or Dose 3 among participants in two separate age groups (6-23 months; 2-4 years)
compared to neutralizing antibody responses in a random subset of participants 16-25 years of
age at 1 month post Dose 2 (study C4591001, Phase 2/3), as measured by 50% neutralizing
antibody titers (NT50, SARS-CoV-2 mNG microneutralization assay) against the reference
strain (USA_WA1/2020).
Immunogenicity analyses of GMTs and seroresponse rates at 1 month after Dose 2 were
evaluated for both age groups, and the pre-specified immunobridging success criteria (below)
were not met for participants 2-4 years of age. Therefore, a third primary series dose was added
for both age groups with protocol amendment 6.
The primary analysis for the 3-dose primary series is based on the evaluable immunogenicity
population of participants without evidence of prior SARS-CoV-2 infection up to 1 month after
16
Dose 2 (comparator group 16-25 years of age) or Dose 3 (participants 6-23 months and 2-4
years of age).
Primary endpoints and statistical success criteria were evaluated sequentially in the following
order:
• Immunobridging success based on GMT was declared if the lower limit (LL) of the 95% CI
for the GMT ratio (pediatric age group / 16-25-year-olds) was >0.67, and the point estimate
of the GMT ratio was ≥1.0.
• Immunobridging success based on the seroresponse rate was declared if the LL of the 95%
CI for the difference in seroresponse rates (pediatric age group minus 16-25-year-olds) was
>−10%. Seroresponse was defined as a ≥4-fold rise in SARS-CoV-2 50% neutralizing titers
from before vaccination (pre-Dose 1) to 1 month after Dose 2 or Dose 3.
4.2.1.2. Phase 2/3 efficacy evaluation

A secondary objective is to evaluate efficacy of BNT162b2 against laboratory-confirmed
symptomatic COVID-19 occurring at least 7 days after Dose 3 in participants without evidence
of prior SARS-CoV-2 infection and in participants with or without evidence of prior SARS-CoV-2
infection. A secondary analysis to evaluate VE against a null hypothesis of H0: VE ≤30% was
planned once 21 confirmed cases had accrued across both each age groups, conditional on
successful immunobridging. See Appendix B for case definitions of COVID-19 and severe
COVID-19.
4.2.1.3. Phase 2/3 safety evaluation

Reactogenicity (solicited local and systemic ARs)
Parents/guardians of participants recorded local and systemic reactions and antipyretic/pain
medication use daily for 7 days (Day 1 through Day 7) after each vaccination in an e-diary.
Reactogenicity assessments included solicited injection site reactions (pain, redness, swelling),
which were the same for both age groups, and systemic AEs, which differed in each age group
(6-23 months of age: fever, irritability, drowsiness, decreased appetite and 2-4 years of age:
fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or
worsened joint pain).
Unsolicited adverse events

Other safety assessments included: AEs occurring within 30 minutes after each dose, non-
serious unsolicited AEs from Dose 1 through 1 month after Dose 3, and SAEs from Day 1 to 6
months after Dose 3 or the data cutoff date (April 29, 2021). AEs were categorized by frequency
and maximum severity according to MedDRA System Organ Class (SOC) and PT, and
relationship to the study intervention. Deaths will be recorded to the end of the study.
Adverse events of clinical interest

Specified events of interest including myocarditis/pericarditis were assessed as part of the
safety review, as well as additional AEs of clinical interest requested by FDA (including
angioedema, arthritis, convulsions, demyelination, hypersensitivity, peripheral neuropathy,
vasculitis, lymphadenopathy, and MIS-C cases).
4.2.2. Phase 2/3 analysis populations
• Safety: All participants who receive at least 1 dose of the study intervention.
17
• All-available immunogenicity: All randomized participants who receive at least 1 dose of the
study intervention with at least 1 valid and determinate immunogenicity result after
vaccination.
• Dose 3 evaluable immunogenicity: All eligible randomized participants who receive three
doses of the vaccine to which they are randomized, with Dose 2 received within the
predefined window (19-42 days after Dose 1), and Dose 3 received at least 60 days after
Dose 2, have at least 1 valid and determinate immunogenicity result from the blood sample
collected within an appropriate window (28-35 days after the specified dose), and have no
other important protocol deviations as determined by the clinician.
• All-available efficacy: All randomized participants who complete 1, 2 or 3 doses of the study
intervention.
• Evaluable efficacy: All randomized participants who receive all vaccinations as randomized,
with Doses 2 and 3 received within the predefined windows and have no other important
protocol deviations as determined by the clinician.
Data analysis cutoff dates:

• Phase 1: July 16, 2021
• Phase 2/3 Three-Dose Primary Series: April 29, 2022
4.2.3. Phase 2/3 disposition
Overall study disposition for each age group, prior to and following unblinding, are provided in
Table 2 through Table 9. More than 99% of participants received at least 2 doses of study
intervention, and approximately 33% received 3 doses as of the April 29, 2022 data cutoff date.
Immunogenicity population
Participants 6-23 months of age
The Dose 3 all-available immunogenicity population for Phase 2/3 participants 6-23 months of
age consisted of 146 BNT162b2 recipients and 73 placebo recipients. A total of 16 (10.8%)
subjects were excluded from the Dose 3 evaluable immunogenicity analysis population from the
BNT162b2 group, most commonly due to invalid or indeterminant immunogenicity results after
vaccination or because blood was drawn outside of the window. The analysis population for the
primary immunogenicity endpoint was the evaluable immunogenicity population, without
evidence of SARS CoV-2 infection up to 1 month after Dose 3 (n=82).
Comparator group for immunobridging analyses: The comparator group for both age groups (6-
23 months, 2-4 years) consisted of 200 randomly selected participants 16-25 years of age who
received both doses of BNT162b2 30 µg in study C4591001 Phase 2/3. A total of 17 (8.5%)
subjects were excluded from the evaluable immunogenicity analysis population, most commonly
due to invalid or indeterminant immunogenicity results after vaccination or because Dose 2 was
not administered within the prespecified window (Table 2). The analysis population for the
primary immunogenicity endpoint was the evaluable immunogenicity population, without
18
Table 2. Disposition of Participants Ages 6-23 Months and 16-25 Years, Phase 2/3 Three-Dose
Primary Series Immunogenicity Populations, Studies C4591007 and C4591001
C4591007 C4591001
6-23 Months 16-25 Years
BNT162b2 3μg BNT162b2 30μg
Disposition, n (%) N=148 N=200
All-available immunogenicity populations* 146 (98.6) 192 (96.0)
Participants excluded from all-available immunogenicity
2 (1.4) 8 (4.0)
population
Did not have at least 1 valid and determinate immunogenicity
2 (1.4) 8 (4.0)
result after vaccination
Evaluable immunogenicity populations* 132 (89.2) 183 (91.5)
Without evidence of infection up to 1 month after Dose 2 or 3a 82 (55.4) 170 (85.0)
Participants excluded from evaluable immunogenicity
16 (10.8) 17 (8.5)
populationb
Did not receive Dose 2 within 19-42 day window after Dose 1 4 (2.7) 1 (0.5)
Did not receive Dose 3 within window (at least 60 days after
0 N/A
Dose 2)
11 (7.4) 14 (7.0)
result within 28-42 days after Dose 2 or 3
Did not have blood draw at 1 month after Dose 2 visit N/A 2 (1.0)
1 Month after Dose 2 or 3 blood draw outside of window
10 (6.8) 7 (3.5)
(28-42 days after Dose 2 or 3)
Had blood draw within the window but no valid and
1 (0.7) 5 (2.5)
determinate immunogenicity result obtained in lab
Had important protocol deviation(s) as determined by the
4 (2.7) 2 (1.0)
clinician
Source: EUA 27034.556, C4591007-dose3-tables-ns-listings-6mo-4yr-immuno.pdf, Pages 51-53.
Abbreviations: NAAT=nucleic acid amplification test; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.
N=number of randomized participants in the specified group (the denominator for the percentage calculations); n=number of
participants with the specified characteristic.
* Dose 2 populations applicable to adults 16-25 years of age from Study C4591001 and Dose 3 populations applicable to
participants 6-23 months of age from Study C4591007.
a. Participants who had no serological or virological evidence (prior to the blood sample collection 1 month post-Dose 2 or 3) of past
SARS-CoV-2 infection (i.e., N-binding ant body [serum] negative at Dose 1 and 1 month post-Dose 2 or 3 visits, SARS-CoV-2 not
detected by NAAT [nasal swab] at Dose 1 and Dose 2 or 3 visits, and negative NAAT [nasal swab] result at any unscheduled visit
prior to the blood sample collection 1 month post-Dose 2 or 3) and had no medical history of COVID-19 were included in the
analysis.
b. Participants may have been excluded for more than one reason.
Vaccine administration timing: BNT162b2 recipients 6-23 months of age in the evaluable
immunogenicity population without evidence of prior SARS-CoV-2 infection up to 1 month post
Dose 3 received Dose 3 of BNT162b2 at least 8 weeks after Dose 2, most commonly between 8
and <13 weeks post-Dose 2. The median timing of Dose 3 administration was 11.0 weeks
(range: 8.6 to 20.0 weeks) after Dose 2 of BNT162b2.
Participants 2-4 years of age

The Dose 3 all-available immunogenicity population for Phase 2/3 participants 2-4 years of age
consisted of 217 BNT162b2 recipients and 98 placebo recipients. A total of 14 (6.4%) subjects
were excluded from the Dose 3 evaluable immunogenicity analysis population from the
BNT162b2 group, most commonly due to invalid or indeterminant immunogenicity results after
vaccination or because blood was drawn outside of the pre-specified window. The analysis
population for the primary endpoint was the evaluable immunogenicity population, without
19
Table 3. Disposition of Participants Ages 2-4 Years and 16-25 Years, Phase 2/3 Three-Dose
Primary Series Immunogenicity Populations, Studies C4591007 and C4591001
C4591007 C4591001
2-4 Years 16-25 Years
BNT162b2 3μg BNT162b2 30μg
All-available immunogenicity population* 217 (99.5) 192 (96.0)
Participants excluded from all-available immunogenicity
1 (0.5) 8 (4.0)
population
1 (0.5) 8 (4.0)
result after vaccination
Evaluable immunogenicity populations* 204 (93.6) 183 (91.5)
Without evidence of infection up to 1 month after Dose 2 or 3a 143 (65.6) 170 (85.0)
Participants excludedb from evaluable immunogenicity
14 (6.4) 17 (8.5)
populations*
Did not receive Dose 2 within 19-42 day window after Dose 1 0 1 (0.5)
Did not receive Dose 3 within window (at least 60 days after
3 (1.4) N/A
Dose 2)
10 (4.6) 14 (7.0)
result within 28-42 days after Dose 2 or 3
Did not have blood draw at 1 month after Dose 2 visit N/A 2 (1.0)
1 month after Dose 2 or 3 blood draw outside of window
10 (4.6) 7 (3.5)
(28-42 days after Dose 2)
Had blood draw within the window but no valid and
0 5 (2.5)
determinate immunogenicity result obtained in lab
Had important protocol deviation(s) as determined by the
1 (0.5) 2 (1.0)
clinician
Source: IND 19736.800, C4591007-dose3-tables-ns-listings-6mo-4yr-immuno.pdf, Pages 54-56.
Abbreviations: NAAT=nucleic acid amplification test; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.
* Dose 2 populations applicable to adults 16-25 years of age from Study C4591001 and Dose 3 populations applicable to
participants 2-4 years of age from Study C4591007.
N=number of randomized participants in the specified group (the denominator for the percentage calculations).
n=number of participants with the specified characteristic.
a. Participants who had no serological or virological evidence (prior to the blood sample collection 1 month post-Dose 2 or 3) of past
SARS-CoV-2 infection (i.e., N-binding ant body [serum] negative at Dose 1 and 1 month post-Dose 2 or 3 visits, SARS-CoV-2 not
detected by NAAT [nasal swab] at Dose 1 and Dose 2 or 3 visits, and negative NAAT [nasal swab] result at any unscheduled visit
prior to the blood sample collection 1 month post-Dose 2 or 3) and had no medical history of COVID-19 were included in the
analysis.
b. Participants may have been excluded for more than one reason.
Vaccine administration timing: BNT162b2 recipients 2-4 years of age in the evaluable
immunogenicity population without evidence of prior SARS-CoV-2 infection up to 1 month post
Dose 3 received Dose 3 of BNT162b2 at least 8 weeks after Dose 2, most commonly between 8
and <13 weeks post-Dose 2. The median timing of Dose 3 administration after Dose 2 of
BNT162b2 was 10.7 weeks (range: 8.6 to 15.6 weeks).
Efficacy population
The Phase 2/3 Dose 3 evaluable efficacy population for participants 6-23 months of age
included 376 BNT162b2 recipients and 179 placebo recipients. The treatment groups appear
imbalanced with respect to receipt of 3 vaccination and unblinding on or before 7 days post
Dose 3 because the Sponsor tabulated placebo recipients who did not receive 3 vaccinations
due to unblinding as “did not receive 3 vaccinations.” However, taking both reasons for
exclusion into account together, the treatment groups are balanced. As shown in Table 4, a total
of 802 (68.1%) and 419 (69.2%) participants were excluded from the BNT162b2 and placebo
20
groups, respectively, primarily due to not receiving Dose 3 or unblinding on or before 7 days
post-Dose 3. Approximately 32.7% of participants 6-23 months of age had ≥2 months of blinded
follow up time after Dose 3.
Table 4. Disposition of Participants 6-23 Months, Phase 2/3 Efficacy Population, Study C4591007
C4591007
BNT162b2 C4591007
3 μg Placebo Total
Disposition, n (%) N=1178 N=598 N=1776
1776
Dose 1 all-available efficacy population 1178 (100.0) 598 (100.0)
(100.0)
Dose 2 all-available efficacy population 1166 (99.0) 596 (99.7) 1762 (99.2)
Participants excludeda from Dose 2 all-available
12 (1.0) 2 (0.3) 14 (0.8)
efficacy population
Did not receive 2 vaccinations 11 (09) 2 (0.3) 13 (0.7)
Unblinded on or before 7 days post Dose 2 1 (0.1) 0 1 (0.1)
792 (67.2) 414 (69.2) 1206 (67.9)
efficacy population
Did not receive 3 vaccinations 420 (35.7) 414 (69.2) 843 (47.0)
Dose 2 Evaluable efficacy population 1132 (96.1) 588 (98.3) 1720 (96.8)
Participants without evidence of infection prior to 7
1012 (85.9) 514 (86.0) 1526 (85.9)
days after Dose 2
Participants excluded from Dose 2 evaluable efficacy
a
46 (3.9) 10 (1.7) 56 (3.2)
population
Did not receive all vaccinations as randomized or did
not receive Dose 2 within the predefined window (19- 31 (2.6) 9 (1.5) 40 (2.3)
42 days after Dose 1)
Had other important protocol deviations on or prior to
18 (1.5) 1 (0.2) 19 (1.1)
7 days after Dose 2
Unblinded on or before 7 days post Dose 2 1 (0.1) 0 1 (<0.1)
256 (21.7) 130 (21.7) 386 (21.7)
days after Dose 3
Participants excluded from Dose 3 evaluable
a
802 (68.1) 419 (69.2) 834 (47.0)
efficacy population
Did not receive all vaccinations as randomized 420 (35.7) 414 (69.2) 834 (47.0)
Did not receive Dose 2 within the predefined
31 (2.6) 9 (1.5) 40 (2.3)
window (19-42 days after Dose 1)
0 2 (0.3) 2 (0.1)
windowb
Had other important protocol deviations on or prior
11 (0.9) 2 (0.3) 13 (0.7)
to 7 days after Dose 3
Unblinded on or before 7 Days post Dose 3 372 (31.6) 0 372 (20.9)
Source: IND 19736.803, C4591007-dose-tables-figures-6mo-4yr-efficacy.pdf, Page 23 and 27034.567. Response to FDA 5 June IR,
Table 5, Page 17.
a. Participants may have been excluded for more than one reason.
b. At least 60 days after Dose 2 for participants enrolled before Protocol Amendment 6 and 54-70 days for participants enrolled after
Protocol Amendment 6.
Vaccine administration timing: In the Dose 3 evaluable efficacy population, the median interval
between Dose 2 and Dose 3 among participants 6-23 months of age was 16.0 weeks (range:
21
8.0 to 31.9 weeks) for BNT162b2 recipients and 15.9 weeks (range: 8.0 to 35.0 weeks) for
placebo recipients.

The Phase 2/3 Dose 3 evaluable efficacy population for participants 2-4 years of age included
589 BNT162b2 recipients and 271 placebo recipients. The treatment groups appear imbalanced
with respect to receipt of 3 vaccination and unblinding on or before 7 days post Dose 3 because
the Sponsor tabulated placebo recipients who did not receive 3 vaccinations due to unblinding
as “did not receive 3 vaccinations.” However, taking both reasons for exclusion into account
together, the treatment groups are balanced: As shown in Table 5, a total of 1,246 (67.9%) and
635 (69.4%) participants were excluded from the BNT162b2 and placebo groups, respectively,
primarily due to not receiving Dose 3 or unblinding on or before 7 days post Dose 3. 34.8% of
participants 2-4 years of age had ≥2 months of blinded follow up time after Dose 3.
Table 5. Disposition of Participants 2-4 Years, Phase 2/3 Efficacy Population, Study C4591007
C4591007
BNT162b2 C4591007
3 μg Placebo Total
16 (0.9) 8 (0.9) 24 (0.9)
efficacy population
1229 (67.0) 635 (69.4) 1864 (67.8)
efficacy population
1495 (81.5) 745 (81.4) 2240 (81.5)
days after Dose 2
Participants excludeda from Dose 2 evaluable efficacy
57 (3.1) 22 (2.4) 79 (2.9)
population
Did not receive all vaccinations as randomized or did
not receive Dose 2 within the predefined window (19- 38 (2.1) 20 (2.2) 58 (2.1)
42 days after Dose 1)
Had other important protocol deviations on or prior to
21 (1.1) 6 (0.7) 27 (101)
7 days after Dose 2
412 (22.5) 166 (18.1) 572 (21.0)
days after Dose 3
Participants excluded from Dose 3 evaluable
a
1246 (67.9) 644 (70.4) 1890 (68.7)
efficacy population
22
C4591007
BNT162b2 C4591007
3 μg Placebo Total
Did not receive all vaccinations as randomized 915 (49.9) 635 (69.4) 1550 (56.4)
37 (2.0) 20 (2.2) 57 (2.1)
window (19-42 days after Dose 1)
10 (0.5) 5 (0.5) 15 (0.5)
windowb
Had other important protocol deviations on or prior
6 (0.3) 2 (0.2) 8 (0.3)
to 7 days after Dose 2
Unblinded on or before 7 Days post Dose 3 435 (23.7) 0 435 (15.8)
Source: IND 19736.803, C4591007-dose-tables-figures-6mo-4yr-efficacy.pdf, Page 24 and 27034.567. Response to FDA 5 June IR,
Table 7, Page 21.
a. Participants may have been excluded for more than one reason.
b. At least 60 days after Dose 2 for participants enrolled before Protocol Amendment 6 and 54-70 days for participants enrolled after
Protocol Amendment 6.
Vaccine administration timing: In the Dose 3 evaluable efficacy population, the median interval
between Dose 2 and Dose 3 among participants 2-4 years of age was 11.0 weeks (range: 8.0 to
34.1 weeks) for BNT162b2 recipients and 11.0 weeks (range: 8.0 to 31.1 weeks) for placebo
recipients.
Safety population:
The overall Phase 2/3 safety population included 1,776 (1,178 BNT162b2, 598 placebo)
participants 6-23 months of age and 2,750 (1,835 BNT162b2, 915 placebo) participants 2-4
years of age. Of the 1,178 BNT162b2 recipients 6-23 months of age, 386 (32.8%) received 3
vaccine doses. Of the 1,835 BNT162b2 recipients 2-4 years of age, 606 (33.0%) received 3
vaccine doses.
Per protocol, the first participant unblinding occurred on September 28, 2021, the first placebo
crossover occurred on November 3, 2021, and the first Dose 3 was administered on January
31, 2022. Protocol amendment 6, which added the third primary series dose for participants 6
months through 4 years of age, was implemented on February 1, 2022.
The median duration of blinded follow-up for participants 6-23 months of age after Dose 3 was
1.3 months (range: 0-3.2 months). The median duration of blinded follow-up for participants 2-4
years of age after Dose 3 was 1.4 months (range: 1-3.2 months). The median duration of
combined blinded and unblinded follow-up after Dose 3 was 2.1 months for each age group.

The safety population for Phase 2/3 participants ages 6-23 months consisted of 1,178
BNT162b2 recipients and 598 placebo recipients. A total of 13 participants withdrew from the
study (9 BNT162b2 recipients and 4 placebo recipients).
23
Table 6. Disposition of Participants 6-23 Months of Age, Prior to Unblinding, Phase 2/3 Study
C4591007
C4591007
BNT162b2 C4591007
3 μg Placebo Total
Vaccinated: Dose 1 1178 (100.0) 598 (100.0) 1776 (100.0)
Vaccinated: Dose 2 1166 (99.0) 596 (99.7) 1762 (99.2)
Vaccinated: Dose 3 386 (32.8) 184 (30.8) 570 (32.1)
Completed 1 month post-Dose 2 visit (vaccination
1165 (98.9) 596 (99.7) 1761 (99.2)
period)
Completed 1 month post-Dose 3 visit (vaccination
262 (22.2) 179 (29.9) 441 (24.8)
period)
Discontinued from vaccination period but continued
1 (0.1) 0 1 (0.1)
in the study
Discontinued after Dose 1 and before Dose 2 1 (0.1) 0 1 (0.1)
Reason for discontinuation: Adverse event 1 (0.1) 0 1 (0.1)
Withdrawn from study 9 (0.8) 4 (0.7) 13 (0.7)
Withdrawn after Dose 1 and before Dose 2 5 (0.4) 0 5 (0.3)
Withdrawn on or after 1-month post-Dose 2 visit
3 (0.3) 3 (0.5) 6 (0.3)
and before Dose 3
Withdrawn on or after 1-month post-Dose 3 visit 1 (0.1) 1 (0.2) 2 (0.1)
Reason for withdrawal: Adverse event 1 (0.1) 0 1 (0.1)
Reason for withdrawal: Lost to follow-up 1 (0.1) 0 1 (0.1)
Reason for withdrawal: Withdrawal by participant 2 (0.2) 0 2 (0.1)
Reason for withdrawal: Withdrawal by
5 (0.4) 4 (0.7) 9 (0.5)
parent/guardian
Source: EUA 27034.556. eua-amendment-6m-4y-safety-immuno.pdf. Table 12.
A total of 715 (60.7%) original BNT162b2 and 377 (63.0%) original placebo recipients 6-23
months of age were unblinded. For participants 6-23 months of age originally randomized to the
BNT162b2 group prior to the implementation of protocol amendment 6, unblinding occurred for
1 (0.1%) participant who received Dose 2 open-label and 372 (52.0%) participants who received
Dose 3 open-label. For participants ages 6-23 months originally randomized to the placebo
group prior to the protocol revision which added the third primary series dose, unblinding
occurred for 344 participants (91.2%) who received BNT162b2 Dose 1 open-label, 296 (78.5%)
participants who received BNT162b2 Dose 2 open-label and 77 (20.4%) participants who
received Dose 3 open-label. Only 3 (4%) of original placebo recipients had follow-up through at
least 1 month post Dose 3 after unblinding and receiving BNT162b2.
Table 7. Disposition of Participants 6-23 Months of Age, After Unblinding, Phase 2/3 Study
C4591007
C4591007
BNT162b2 C4591007
3 μg Placebo
Disposition, n (%) Na=715 Na=377
Originally received BNT162b2 715 (100.0) --
Completed 3 doses before unblinding 174 (24.3) --
Vaccinated: Dose 2 1 (0.1) --
Awaiting next vaccination 158 (22.1) --
Completed 1-month post-Dose 2 visit (vaccination period) 2 (0.3) --
24
C4591007
BNT162b2 C4591007
3 μg Placebo
Disposition, n (%) Na=715 Na=377
Completed 1-month post-Dose 3 visit (vaccination period) 499 (69.8) --
Discontinued from vaccination period but continued in the study 4 (0.6) --
Discontinued after Dose 1 and before Dose 2 0 --
Discontinued after Dose 2 and before 1-month post-Dose 2 visit 1 (0.1) --
Discontinued after Dose 3 and before 1-month post-Dose 3 visit 3 (0.4) --
Reason for discontinuation: Adverse event 1 (0.1) --
Reason for discontinuation: Withdrawal by participant 1 (0.1) --
Reason for discontinuation: Other 2 (0.3) --
Withdrawn from study* 9 (1.3) --
Withdrawn after Dose 1 and before Dose 2 0 --
Withdrawn after Dose 2 and before 1-month post-Dose 2 visit 0 --
Withdrawn on or after 1-month post-dose 2 visit and before Dose 3 8 (1.1) --
Withdrawn after Dose 3 and before 1-month post-Dose 3 visit 1 (<0.1) --
Withdrawn on or after 1-month post-Dose 3 visit 3 (0.4) --
Reason for withdrawal: Lost to follow-up 1 (0.1) --
Reason for withdrawal: Withdrawal by parent/guardian 5 (0.7) --
Reason for withdrawal: Refused further study procedures 2 (0.3) --
Reason for withdrawal: Other 1 (0.1) --
Originally received Placebo -- 377 (100.0)
Did not receive BNT162b2 after unblinding -- 33 (8.8)
Received First dose of BNT162b2 -- 344 (91.2)
Received Second dose of BNT162b2 -- 296 (78.5)
Received Third dose of BNT162b2 -- 77 (20.4)
Awaiting next vaccination -- 23 (6.1)
Completed 1-month post-Dose 2 (BNT162b2) visit (vaccination period) -- 127 (33.7)
Completed 1-month post-Dose 3 (BNT162b2) visit (vaccination period) -- 15 (4.0)
Discontinued from vaccination period but continued in the study -- 0
Withdrawn from vaccination and/or study -- 10 (2.7)
Reason for withdrawal: Lost to follow-up -- 1 (0.3)
Reason for withdrawal: Withdrawal by parent/guardian -- 8 (2.1)
Reason for withdrawal: Refused further study procedures -- 1 (0.3)
Source: EUA 27034.556. c4591007-dose3-tables-ns-listings-6m-4y-safety-pdf. Pages 21-23. And EUA 27034.561 Response to
Information Request-31May22-safe-immuno-6m-4y.pdf. Table 1, Page 4.
a. N=number of participants unblinded.
*One participant was unblinded after withdrawal from the study and is not included.
Vaccine administration timing: In the safety population of participants 6-23 months of age, the
median timing of Dose 3 administration after Dose 2 was 25.3 weeks (range: 8.0 to 41.0 weeks)
for BNT162b2 recipients and 15.8 weeks (range: 8.0 to 35.0 weeks) for placebo recipients.

The safety population for Phase 2/3 participants 2-4 years of age included 1,835 BNT162b2
recipients and 915 placebo recipients. A total of 45 participants withdrew from the study (24
BNT162b2 recipients and 21 placebo recipients).
25
Table 8. Disposition of Participants 2-4 Years of Age, Prior to Unblinding, Phase 2/3 Study
C4591007
C4591007
BNT162b2 C4591007
3 μg Placebo Total
Vaccinated: Dose 1 1835 (100.0) 915 (100.0) 2750 (100.0)
Vaccinated: Dose 2 1819 (99.1) 907 (99.1) 2726 (99.1)
Vaccinated: Dose 3 606 (33.0) 280 (30.6) 886 (32.2)
Completed 1-month post-Dose 2 visit (vaccination
1814 (98.9) 907 (99.1) 2721 (98.9)
period)
Completed 1-month post-Dose 3 visit (vaccination
503 (27.4) 274 (29.9) 777 (28.3)
period)
Discontinued from vaccination period but continued
0 3 (0.3) 3 (0.1)
in the study
Discontinued after Dose 1 and before Dose 2 0 2 (0.2) 2 (0.1)
Discontinued after Dose 2 and before 1-month
0 1 (0.1) 1 (<0.1)
post-dose 2 visit
Reason for discontinuation: Adverse event 0 1 (0.1) 1 (<0.1)
Reason for discontinuation: Withdrawal by participant 0 1 (0.1) 1 (<0.1)
Reason for discontinuation: Other 0 1 (0.1) 1 (<0.1)
Withdrawn from study 24 (1.3) 21 (2.3) 45 (1.6)
Withdrawn after Dose 1 and before Dose 2 6 (0.3) 4 (0.4) 10 (0.4)
Withdrawn on or after 1-month post-dose 2 visit
14 (0.8) 16 (1.7) 30 (1.1)
and before Dose 3
Withdrawn after Dose 3 and before 1-month post-
2 (0.1) 1 (0.1) 3 (0.1)
dose 3 visit
Withdrawn on or after 1-month post-dose 3 visit 2 (0.1) 0 2 (0.1)
Reason for withdrawal: Adverse event 1 (0.1) 0 1 (0.0)
Reason for withdrawal: Lost to follow-up 4 (0.2) 3 (0.3) 7 (0.3)
Reason for withdrawal: Protocol deviation 2 (0.1) 3 (0.3) 5 (0.2)
Reason for withdrawal: Withdrawal by participant 4 (0.2) 2 (0.2) 6 (0.2)
Reason for withdrawal: Withdrawal by
13 (0.7) 13 (1.4) 26 (0.9)
parent/guardian
Source: EUA 27034.556. eua-amendment-6m-4y-safety-immuno.pdf. Table 3, Page 21.
A total of 842 (45.9%) original BNT162b2 and 424 (46.3%) original placebo recipients 2-4 years
of age were unblinded. For participants 2-4 years of age originally randomized to the BNT162b2
group prior to implementation of protocol amendment 6, unblinding occurred for 1 (0.1%)
participant who received Dose 2 open-label and 435 (51.7%) participants who received Dose 3
in an open-label manner.
For participants 2-4 years of age originally randomized to the placebo group prior to the protocol
revision which added the third primary series dose, unblinding occurred for 370 participants
(87.3%) who received BNT162b2 Dose 1 open-label, 350 (82.5%) participants who received
BNT162b2 Dose 2 open-label and 98 (23.1%) participants who received Dose 3 open-label.
Only 5% of original placebo recipients had follow-up through at least 1 month post Dose 3 after
unblinding and receiving BNT162b2.
Participants who turned 5 years of age during the study were voluntarily unblinded to receive
the age-appropriate dose (10 μg BNT162b2) authorized for emergency use; One participant
(0.1%) received the 10 μg dose level for Dose 2 and 121 participants (6.6%) received the 10 μg
dose level for Dose 3.
26
Table 9. Disposition of Participants 2-4 Years of Age, After Unblinding, Phase 2/3 Study C4591007
C4591007
BNT162b2 C4591007
3 μg Placebo
Originally received BNT162b2 842 (100.0) --
Completed 3 doses before unblinding 118 (14.0) --
Awaiting next vaccination 236 (28.0) --
Completed 1-month post-dose 2 visit (vaccination period) 9 (1.1) --
Completed 1-month post-dose 3 visit (vaccination period) 553 (65.7) --
Discontinued from vaccination period but continued in the study 2 (0.2) --
Discontinued after Dose 1 and before Dose 2 0 --
Discontinued after Dose 2 and before 1-month post-dose 2 visit 1 (0.1) --
Discontinued after 1-month post-dose 2 visit and before Dose 3 1 (0.1) --
Discontinued after Dose 3 and before 1-month post-dose 3 visit 0 --
Reason for discontinuation: Withdrawal by parent/guardian 2 (0.2) --
Withdrawn from vaccination or study study* 52 (6.2) --
Withdrawn after Dose 1 and before Dose 2 3 (0.4) --
Withdrawn after Dose 2 and before 1-month post-dose 2 visit 0 --
Withdrawn on or after 1-month post-dose 2 visit and before Dose 3 47 (5.6) --
Withdrawn after Dose 3 and before 1-month post-dose 3 visit 1 (0.1) --
Withdrawn on or after 1-month post-dose 3 visit 2 (0.2) --
Reason for withdrawal: Adverse event 1 (0.1) --
Reason for withdrawal: Protocol deviation 13 (1.5) --
Reason for withdrawal: Withdrawal by participant 5 (0.6) --
Reason for withdrawal: Withdrawal by parent/guardian 30 (3.6) --
Reason for withdrawal: Refused further procedures 3 (0.4) --
Originally received Placebo -- 424 (100.0)
Did not receive BNT162b2 after unblinding -- 54 (12.7)
Received Dose 1 of BNT162b2 -- 370 (87.3)
Awaiting next vaccination -- 21 (5.0)
Completed 1-month post-dose 2 (BNT162b2) visit (vaccination period) -- 212 (50.0)
Completed 1-month post-dose 3 (BNT162b2) visit (vaccination period) -- 21 (5.0)
Discontinued from vaccination period but continued in the study -- 0
Withdrawn from vaccination and/or study -- 33 (7.8)
Reason for withdrawal: Adverse event -- 1 (0.2)
Reason for withdrawal: Protocol deviation -- 3 (0.7)
Reason for withdrawal: Withdrawal by participant -- 2 (0.5)
Reason for withdrawal: Withdrawal by parent/guardian -- 27 (6.4)
Reason for withdrawal: Other -- 1 (0.2)
Source: EUA 27034.556. c4591007-dose3-tables-ns-listings-6m-4y-safety-pdf. Pages 24-25. and EUA 27034.561 Response to
Information Request-31May22-safe-immuno-6m-4y.pdf. Table 2, Page 5.
*One participant was unblinded after withdrawal from the study and is not included.
Vaccine administration timing: In the safety populations of participants 2-4 years of age, the
median timing of Dose 3 administration after Dose 2 was 21.4 weeks (range: 8.0 to 41.3 weeks)
for BNT162b2 recipients and was 11.0 weeks (range: 6.3 to 31.1 weeks) for placebo recipients.
27
4.2.4. Phase 2/3 comorbidities at baseline
Comorbidities were defined as one of the pre-specified comorbidities that increase the risk of
severe COVID-19 disease, as defined in Kim et al 2020, 47 and/or obesity (body mass index
[BMI] >95% percentile). Obesity was not evaluated in participants <2 years of age, since BMI-
for-age percentiles are based on CDC growth charts for children and teenagers 2 through 19
years of age. 48

Among participants 6-23 months of age, 4.2% of BNT162b2 recipients and 5.7% of placebo
recipients had a comorbidity at baseline (pre-Dose 1). In the BNT162b2 group, the most
common comorbidity (comorbidity category/PT) at baseline was prematurity (1.6%), followed by
asthma and congenital heart disease (each 0.8%), cardiovascular disease (0.4%), neurologic
disorder (0.3%), chronic lung disease (0.2%). Congenital heart disease was more frequent in
the placebo group (1.8%) than the BNT162b2 group (0.8%).

Among participants 2-4 years of age, 12.1% of BNT162b2 recipients and 14.2% of placebo
recipients had a comorbidity (including obesity) at baseline. Obesity was reported in 6.5% of
BNT162b2 and 4.9% of placebo recipients. Comorbidities at baseline that increase the risk of
severe COVID-19 disease were reported in 6.4% of the BNT162b2 group and 9.7% of the
placebo group. Other than obesity, the most common comorbidities at baseline in BNT162b2
group included asthma (2.8%), prematurity (1.1%), congenital heart disease (0.7%) and
neurologic disorders (0.6%). One BNT162b2 participant had a baseline comorbidity of
immunocompromised condition (neutropenia).
4.2.5. Phase 2/3 demographic and baseline characteristics
Safety populations
Demographic characteristics for the safety population of participants 6-23 months of age who
received 3 µg BNT162b2 are summarized in Table 10. Participants were predominately White,
with a mean age of 15.2 months. In the BNT162b2 group, 7.6% had evidence of prior SARS-
CoV-2 infection. Overall, 81.2% of participants in this age group were enrolled in the United
States. The percentage of participants 6-23 months of age who received other vaccines (e.g.,
influenza and other routine pediatric immunizations) after Dose 1 were similar between
treatment groups (27.2% BNT162b2, 28.8% in placebo).
Table 10. Demographic and Baseline Characteristics of Participants 6-23 Months, Phase 2/3 Safety
Population, Study C4591007
BNT162b2 Placebo
Characteristic N=1178 N=598
Sex, n (%) -- --
Female 589 (50.0) 307 (51.3)
Male 589 (50.0) 291 (48.7)
28
BNT162b2 Placebo
Race, n (%) -- --
White 922 (78.3) 480 (80.3)
Black or African American 42 (3.6) 24 (4.0)
American Indian or Alaska Native 3 (0.3) 1 (0.2)
Asian 91 (7.7) 40 (6.7)
Multiracial 117 (9.9) 49 (8.2)
Not reported 3 (0.3) 4 (0.7)
Ethnicity, n (%) -- --
Hispanic or Latino 161 (13.7) 64 (10.7)
Not Hispanic or Latino 1014 (86.1) 530 (88.6)
Not reported 3 (0.3) 4 (0.7)
Age -- --
Mean, months (SD) 15.2 (4.97) 15.4 (5.06)
Median, months 16.0 16.0
Comorbiditiesa, n (%) -- --
Yes 50 (4.2) 34 (5.7)
No 1128 (95.8) 564 (94.3)
Baseline evidence of prior SARS-CoV-2 infection, n (%) -- --
Negativeb 1078 (91.5) 541 (90.5)
Positivec 89 (7.6) 44 (7.4)
Missing 11 (0.9) 13 (2.2)
Country, n (%) -- --
Brazil 0 2 (0.3)
Finland 54 (4.6) 26 (4.3)
Poland 125 (10.6) 63 (10.5)
Spain 42 (3.6) 22 (3.7)
United States 9577 (81.2) 485 (81.1)
Source: IND 19736.800, C4591007-dose3-tables-ns-listings-6mo-4yr-safety.pdf, Pages 7-8.
Abbreviations: NAAT=nucleic acid amplification test; N-binding=SARS-CoV-2 nucleoprotein-binding; SARS-CoV-2=severe acute
respiratory syndrome coronavirus 2; SD=standard deviation
a. Number of participants who have 1 or more comorbidities that increase the risk of severe COVID-19 disease: defined as
participants who had at least one of the prespecified comorbidities based on MMWR 69(32);1081-1088.
b. Negative N-binding antibody result and negative NAAT result at Visit 1 and no medical history of COVID-19.
c. Positive N-binding antibody result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.

Demographic characteristics for the safety population of participants 2-4 years of age who
received 3 µg BNT162b2 are summarized in Table 11. Participants were predominately White,
with a mean age of 3 years of age. In the BNT162b2 group, 12.7% had evidence of prior SARS-
CoV-2 infection. Overall, 81.4% of participants in this age group were enrolled in the United
States. The percentage of 2-4-year-olds who received other vaccines (e.g., influenza and other
routine pediatric immunizations) after Dose 1 were similar between treatment groups (13.1%
BNT182b2, 11.6% in placebo).
29
Table 11. Demographic and Baseline Characteristics of Participants 2-4 Years, Phase 2/3 Safety
BNT162b2 Placebo
Sex, n (%) -- --
Female 934 (50.9) 444 (48.5)
Male 901 (49.1) 471 (51.5)
Race, n (%) -- --
White 1469 (80.1) 720 (78.7)
Black or African American 94 (5.1) 41 (4.5)
American Indian or Alaska Native 3 (0.2) 4 (0.4)
Asian 127 (6.9) 76 (8.3)
Native Hawaiian or other Pacific Islander 2 (0.1) 1 (0.1)
Multiracial 131 (7.1) 69 (7.5)
Not reported 9 (0.5) 4 (0.4)
Ethnicity, n (%) -- --
Hispanic or Latino 261 (14.4) 120 (13.1)
Not Hispanic or Latino 1568 (85.4) 795 (86.9)
Not reported 3 (0.2) 0
Age -- --
Mean, years (SD) 3.1 (0.79) 3.0 (0.79)
Median, years 3.0 3.0
Obesea, n (%) -- --
Yes 120 (6.5) 16 (3.9)
No 1712 (93.3) 870 (95.1)
Missing 3 (0.2) 0
Comorbiditiesb, n (%) -- --
Yes 222 (12.1) 130 (14.2)
No 1613 (87.9) 785 (85.8)
Baseline evidence of prior SARS-CoV-2 infection, n (%) -- --
Negativec 1597 (87.0) 783 (85.6)
Positived 233 (12.7) 125 (13.7)
Missing 5 (0.3) 7 (0.8)
Country, n (%) -- --
Finland 63 (3.4) 30 (3.3)
Poland 205 (11.2) 103 (11.3)
Spain 73 (4.0) 35 (3.8)
United States 1494 (81.4) 747 (81.6)
Source: IND 19736.800, C4591007-dose3-tables-ns-listings-6mo-4yr-safety.pdf, Pages 9-11.
Abbreviations BMI, body mass index; MMWR=Morbidity and Mortality Weekly Report; NAAT=nucleic acid amplification test; N-
binding=SARS-CoV-2 nucleoprotein-binding; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SD=standard
deviation.
a. Obese is defined as a BMI at or above the 95th percentile according to the Centers for Disease Control and Prevention growth
charts (https://www.cdc.gov/growthcharts/html_charts/bmiagerev.htm).
b. Number of participants who have one or more comorbidities that increase the risk of severe COVID-19: defined as participants
who had at least one of the prespecified comorbidities based on MMWR 69(32);1081-1088 and/or obesity (BMI ≥95th percentile).
c. Negative N-binding antibody result and negative NAAT result at Visit 1 and no medical history of COVID-19.
d. Positive N-binding ant body result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.
Immunogenicity and efficacy populations

Demographic and other baseline characteristics for the immunogenicity and efficacy populations
for each age group were generally similar to those described above for the safety populations,
with the exception that the immunogenicity subsets were derived only from participants in the
United States.
30
Comparator groups for immunogenicity

Phase 2/3 C4591001 participants, the study group for immunobridging comparisons, included
170 participants 16-25 years of age from sites in the United States (74.1%), Argentina (14.1%),
Brazil (7.6%), and South Africa/Turkey (4.1% combined total).
4.2.6. Phase 2/3 vaccine effectiveness results
4.2.6.1. Primary immunogenicity objectives

For each age group, SARS-CoV-2 neutralizing GMTs and seroresponse rates were assessed
against the reference strain (USA_WA1/2020) upon which the vaccine was based in the
evaluable immunogenicity population without evidence of prior SARS-CoV-2 infection.
GMTs of neutralizing antibodies to the reference strain: Among participants in the evaluable
immunogenicity population without prior evidence of SARS-CoV-2 infection up to 1 month after
Dose 2 (comparator group 16-25 years of age) or Dose 3 (participants 6-23 months of age), the
ratio of SARS-CoV-2 50% neutralizing GMTs was 1.19 (95% CI: 1.00, 1.42). The lower bound of
the 2-sided 95% CI for GMT ratio was >0.67, and the point estimate was ≥1, which met the
prespecified immunobridging success criteria (Table 12).
Table 12. SARS-CoV-2 Neutralizing GMTs (NT50)a After Three Primary Series Doses in BNT162b2
(3 µg) Recipients 6-23 Months of Age (1 Month After Dose 3) and BNT162b2 (30 µg) Recipients 16-
25 Years of Age (1 Month After Dose 2) Without Evidence of SARS-CoV-2 Infection, Phase 2/3
Evaluable Immunogenicity Populationsb, Studies C4591007 and C4591001
6-23 Months of Age 16-25 Years of Age
Study C4591007 Study C4591001 GMT Ratio
N=82 N=170 (6-23 Months of Age / 16-25 Years of
GMT GMT Age)c
(95% CI) (95% CI) (95% CI)
1406.5 1180.0 1.19
(1211.3, 1633.1) (1066.6, 1305.4) (1.00, 1.42)
Source: EUA 27034.556 eua-amendment-6m-4y-safety-immuno.pdf. Table 32, Page 139.
Abbreviations: CI=confidence interval; GMT=geometric mean titer; N=number of Phase 2/3 participants with valid and determinate
assay results for the specified assay at the given dose/sampling time point within specified window; NT50=50% neutralizing titer;
SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.
Note: Participants who had no serological or virological evidence [(up to 1 month after Dose 2 (Study 2) or 1 month after Dose 3
(Study 3) blood sample collection)] of past SARS-CoV-2 infection [(i.e., N-binding antibody [serum] negative at Dose 1, Dose 3
(Study 3) and 1 month after Dose 2 (Study 2) or 1 month after Dose 3 (Study 3), SARS-CoV-2 not detected by NAAT [nasal swab]
at Dose 1, Dose 2, and Dose 3 (Study 3) study visits, and negative NAAT (nasal swab) at any unscheduled visit up to 1 month after
Dose 2 (Study 2) or 1 month after Dose 3 (Study 3) blood collection)] and had no medical history of COVID-19 were included in the
analysis.
a. SARS-CoV-2 mNeonGreen virus microneutralization assay (SARS-CoV-2 mNG NT), reference strain: recombinant
USA_WA1/2020.
b. Evaluable immunogenicity population pertaining to Phase 2/3 BNT162b2 participants 6-23 months of age (study C4591007) and
Phase 2/3 BNT162b2 participants 16-25 years of age (study C4591001).
c. Immunobridging statistical success is declared if the lower limit of the 2-sided 95% CI for the GMT ratio is greater than 0.67 and
the point estimate of the GMT ratio is ≥1.0.
Rates of neutralizing antibody seroresponse to the reference strain: Seroresponse rates among
participants without evidence of prior SARS-CoV-2 infection up to 1 month after Dose 2
(comparator group 16-25 years of age) or Dose 3 (participants 6-23 months of age) are
presented in Table 13. Participants 6-23 months of age had a similar seroresponse rate (as
31
measured from pre-Dose 1 to 1 month after Dose 3) as in the comparator group 16-25 years of
age (as measured from pre-Dose 1 to 1 month after Dose 2). The difference in seroresponse
rates between the two age groups was 1.2% (95% CI: -3.4, 4.2). The immunobridging criterion
based on seroresponse rate was met, since the LL of the 95% CI for the difference in
seroresponse rate was −3.4%, which was greater than the prespecified margin of −10%.
Table 13. Seroresponse Ratesa,b,c After Three Primary Series Doses in BNT162b2 (3 µg) Recipients
6-23 Months of Age (1 Month After Dose 3) and BNT162b2 (30 µg) Recipients 16-25 Years of Age (1
Month After Dose 2) Without Evidence of SARS-CoV-2 Infection, Phase 2/3 Evaluable
Immunogenicity Populationsd, Studies C4591007 and C4591001
6-23 Months of Age 6-25 Years of Age
Study C4591007 Study C4591001 % Difference in Seroresponse Rate
N=80 N=170 (Age Group 6-23 Months Minus
Seroresponse Rate (%e) Seroresponse Rate (%e) Age Group 16-25 Years)f
(95% CI) (95% CI) (95% CI)
100 98.8 1.2
(95.5, 100.0) (95.8, 99.9) (-3.4, 4.2)
Abbreviations: CI=confidence interval; LLOQ=lower limit of quantitation; SARS-CoV-2=severe acute respiratory syndrome
coronavirus 2
N=number of subjects with valid and determinate assay results for the specified assay within the specified window for blood
samples collected at baseline (pre-Dose 1) and 1 month after primary series.
n=number of participants with seroresponse for the given assay at the given dose/sampling time point.
analysis.
USA_WA1/2020.
b. Seroresponse defined as at least 4-fold rise relative to pre-Dose 1; if the baseline measurement was below LLOQ
c. Postvaccination titer of ≥4 × LLOQ was considered a seroresponse.
d. Evaluable immunogenicity population pertaining to Phase 2/3 BNT162b2 participants 6-23 months of age (study C4591007) and
Phase 2/3 BNT162b2 participants 16-25 years of age (study C4591001).
f. Immunobridging statistical success is declared if the lower limit of the 2-sided 95% CI for the difference in percentages of
participants with seroresponse is >-10%.

GMTs of neutralizing antibody titers to the reference strain: Among participants in the evaluable
immunogenicity population without prior evidence of SARS- CoV-2 infection up to 1 month after
Dose 2 (comparator group 16-25 years of age) or Dose 3 (participants 2-4 years of age), the
ratio of SARS-CoV-2 50% neutralizing GMTs was 1.30 (95% CI: 1.13, 1.50). The lower bound of
the 2-sided 95% CI for GMT ratio was >0.67 and the point estimate was ≥1, which met the
prespecified immunobridging success criteria; see Table 14.
32
Table 14. SARS-CoV-2 Neutralizing GMTs (NT50)a After Three Primary Series Doses in BNT162b2
(3 µg) Recipients 2-4 Years of Age (1 Month After Dose 3) and BNT162b2 (30 µg) Recipients 16-25
Years of Age (1 Month After Dose 2) Without Evidence of SARS-CoV-2 Infection, Phase 2/3
Evaluable Immunogenicity Populationb, Studies C4591007 and C4591001
2-4 Years of Age 16-25 Years of Age
Study C4591007 Study C4591001
N=143 N=170 GMT Ratio
GMT GMT (2-4 Years / 16-25 Years)c
(95% CI) (95% CI) (95% CI)
1535.2 1180.0 1.30
(1388.2, 1697.8) (1066.6, 1305.4) (1.13, 1.50)
Abbreviations: CI=confidence interval; GMT=geometric mean titer; NT50=50% neutralizing titer; SARS-CoV-2=severe acute
respiratory syndrome coronavirus 2
N=number of Phase 2/3 participants with valid and determinate assay results for the specified assay at the given dose/sampling
time point within specified window.
analysis.
USA_WA1/2020
b. Evaluable immunogenicity population pertaining to Phase 2/3 BNT162b2 participants 2-4 years of age (study C4591007) and
Phase 2/3 BNT162b2 participants 16-25 years of age (study C4591001)
c. Immunobridging statistical success is declared if the lower limit of the 2-sided 95% CI for the GMT ratio is greater than 0.67 and
the point estimate of the GMT ratio is ≥1.0
Rates of neutralizing antibody seroresponse to the reference strain: Seroresponse rates among
participants without evidence of prior SARS-CoV-2 infection up to 1 month after Dose 2
(comparator group 16-25 years of age) or Dose 3 (2-4 years of age) are displayed in Table 15.
Participants 2-4 years of age had a similar seroresponse rate (as measured from before
vaccination to 1 month after Dose 3) as in the comparator group 16-25 years of age (as
measured from before vaccination to 1 month after Dose 2). The difference between the two
age groups was 1.2% (95% CI: −1.5, 4.2). The LL of the 95% CI for the difference in
seroresponse rate was −1.2%, which was greater than the prespecified margin of −10%, and
thus immunobridging based on seroresponse rate was met.
Table 15. Seroresponse Ratesa,b After Three Primary Series Doses in BNT162b2 (3 µg) Recipients
2-4 Years of Age (1 Month After Dose 3) and BNT162b2 (30 µg) Recipients 16-25 Years of Ageb (1
Month After Dose 2) Without Evidence of SARS-CoV-2 Infection, Phase 2/3 Evaluable
Immunogenicity Populationsc, Studies C4591007 and C4591001
2-4 Years of Age 16-25 Years of Age
% Difference in Seroresponse
Study C4591007 Study C4591001
Rate (Age Group 2-4 Years Minus
N=141 N=170
Age Group 16-25 Years)e
Seroresponse rate (%d) Seroresponse Rate (%d)
(95% CI)
(95% CI) (95% CI)
100.0 98.8 1.2
(97.4, 100.0) (95.8, 99.9) (−1.5, 4.2)
Abbreviations: CI=confidence interval; LLOQ=lower limit of quantitation; SARS-CoV-2=severe acute respiratory syndrome
coronavirus 2
N=Number of subjects with valid and determinate assay results for the specified assay within the specified window for blood
samples collected at baseline (pre-Dose 1) and 1 month after primary series.
n=number of participants with seroresponse for the given assay at the given dose/sampling time point.
33
analysis.
USA_WA1/2020
b. Seroresponse defined as at least 4-fold rise relative to pre-Dose 1; if the baseline measurement was below LLOQ, a
postvaccination titer of ≥4 × LLOQ was considered a seroresponse
c. Evaluable immunogenicity population pertaining to Phase 2/3 BNT162b2 participants 2-4 years of age (study C4591007) and
Phase 2/3 BNT162b2 participants 16-25 years of age (study C4591001)
e. Immunobridging statistical success is declared if the lower limit of the 2-sided 95% CI for the difference in percentages of
participants with seroresponse is >-10%.
Subgroup analyses of GMTs and seroresponse rates: GMTs of SARS-CoV-2 neutralizing titers
and seroresponse rates at 1 month after Dose 3 by age group were similar. No notable
differences in GMTs or seroresponse rates were observed by sex, race, or ethnicity.
Participants in both age groups with positive SARS-CoV-2 status at baseline had numerically
higher GMTs before vaccination and at 1 month after Dose 3 compared to those negative at
baseline, which is consistent with immunogenicity results observed in older age groups.
However, the numbers of participants with positive baseline SARS-CoV-2 status were limited to
6 participants in the 6-23 months age group and 13 participants in the 2-4 years age group.
Participants 6-23 Months of Age (1 Month After Dose 3) and 16-25 Years of Age (1 Month After
Dose 2), All-Available Immunogenicity Population, Studies C4591007 and C4591001
6-23 Months of 16-25 Years of
Age Age
BNT162b2 (3 µg) BNT162b2 (30 µg) GMRc
Subgroup n , GMT
a b
n , GMT
a b
(95% CIc)
Sex: Male 79, 1650.9 95, 1262.0 1.31 (1.07, 1.60)
Sex: Female 67, 1749.2 97, 1172.1 1.49 (1.18, 1.89)
Race: White 113, 1737.8 145, 1231.7 1.41 (1.18, 1.68)
Race: Black or African American 2, 777.0 19, 1210.8 0.64 (0.23, 1.77)
Race: American Indian or Alaska Native 1, 2715.0 3, 1716.0 1.58 (NE, NE)
Race: Asian 15, 1958.3 15, 914.8 2.14 (1.27, 3.62)
Race: Native Hawaiian/Pacific Islander 0, NE 2, 2012.3 NE (NE, NE)
Race: Multiracial 15, 1309.5 7, 1213.5 1.08 (0.63, 1.85)
Race: Not reported 0, NE 1, 1845.0 NE (NE, NE)
Ethnicity: Hispanic or Latino 18, 1719.0 59, 1108.9 1.55 (1.02, 2.36)
Ethnicity: Not Hispanic or Latino 127, 1681.4 133, 1266.4 1.33 (1.12, 1.57)
Ethnicity: Not reported 1, 3750.0 0, NE NE (NE, NE)
Baseline SARS-CoV-2: Positived 6, 3794.8 8, 2507.9 1.51 (0.76, 3.01)
Baseline SARS-CoV-2: Negativee 139, 1633.6 184, 1178.1 1.39 (1.19, 1.62)
Baseline SARS-CoV-2: Missing 1, 2325.0 0, NE NE (NE, NE)
Source: EUA 27024.554 Safety-Immunogenicity_508_Tables. Table H.1.1
Abbreviations: GMR=geometric mean ratio; GMT=geometric mean titer
Note: All-available population refers to Dose 3 all-available immunogenicity population for C4591007 and Dose 2 all-available
immunogenicity population for C4591001.
a. n=Number of participants with valid and determinate assay results for SARS-CoV-2 serum neutralizing titer 50 at the given
dose/sampling time point.
b. GMTs was calculated by exponentiating the mean logarithm of the titers. Assay results below the LLOQ were set to 0.5 × LLOQ.
c. GMRs and 2-Sided 95% CIs were calculated by exponentiating the mean difference of the logarithms of the titers (Vaccine Group
[6 months to <2 years] - Comparison Group [16-25 years]) and the corresponding CI (based on the Student t distribution).
d. Positive N-binding ant body result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.
e. Negative N-binding antibody result and negative NAAT result at Visit 1 and no medical history of COVID-19.
34
Participants 2-4 Years of Age (1 Month After Dose 3) and 16-25 Years of Age (1 Month After Dose
2), All-Available Immunogenicity Population, Studies C4591007 and C4591001
16-25 Years of
2-4 Years of Age Age
BNT162b2 (3 µg) BNT162b2 (30 µg)
Subgroup na, GMTb na, GMTb GMRc (95% CIc)
Sex: Male 97, 1531.4 95, 1262.0 1.21 (0.98, 1.50)
Sex: Female 120, 1756.6 97, 1172.1 1.50 (1.25, 1.80)
Race: White 158, 1684.5 145, 1231.7 1.37 (1.17, 1.59)
Race: Black or African American 10, 1893.0 19, 1210.8 1.56 (0.90, 2.72)
Race: American Indian or Alaska Native 0, NE 3, 1716.0 NE (NE, NE)
Race: Asian 24, 1384.8 15, 914.8 1.51 (0.76, 3.01)
Race: Native Hawaiian/Pacific Islander 0, NE 2, 2012.3 NE (NE, NE)
Race: Multiracial 22, 1778.9 7, 1213.5 1.47 (0.94, 2.29)
Race: Not reported 3, 900.1 1, 1845.0 0.49 (NE, NE)
Ethnicity: Hispanic or Latino 25, 1839.7 59, 1108.9 1.66 (1.17, 2.35)
Ethnicity: Not Hispanic or Latino 191, 1629.7 133, 1266.4 1.29 (1.10, 1.50)
Ethnicity: Not reported 1, 1533.0 0, NE NE (NE, NE)
Obesed: Yes 11, 1366.9 37, 1163.5 1.17 (0.71, 1.94)
Obesed: No 205, 1661.6 155, 1228.5 1.35 (1.17, 1.57)
Obesed: Missing 1, 4129.0 0, NE NE (NE, NE)
Baseline SARS-CoV-2: Positivee 13, 3574.5 8, 2507.9 1.43 (0.84, 2.41)
Baseline SARS-CoV-2: Negativef 204, 1572.8 184, 1178.1 1.34 (1.16, 1.53)
Source: EUA 27024.554 Safety-Immunogenicity_508_Tables. Table H.1.2
Abbreviations: GMR=geometric mean ratio; GMT=geometric mean titer
Note: All-available population refers to Dose 3 all-available immunogenicity population for C4591007 and Dose 2 all-available
immunogenicity population for C4591001.
a. n=Number of participants with valid and determinate assay results for SARS-CoV-2 serum neutralizing titer 50 at the given
dose/sampling time point.
b. GMTs was calculated by exponentiating the mean logarithm of the titers. Assay results below the LLOQ were set to 0.5 × LLOQ.
c. GMRs and 2-Sided 95% CIs were calculated by exponentiating the mean difference of the logarithms of the titers (Vaccine Group
[2 to <5 years] - Comparison Group [16-25 years]) and the corresponding CI (based on the Student t distribution).
d. Obese is defined as a body mass index (BMI) at or above the 95th percentile according to the growth chart for participants 2 to <5
years of age or BMI ≥30 kg/m2 for participants 16 to 25 years of age. Refer to the CDC growth charts at
https://www.cdc.gov/growthcharts/html charts/bmiagerev.htm.
e. Positive N-binding ant body result at Visit 1, positive NAAT result at Visit 1, or medical history of COVID-19.
f. Negative N-binding antibody result and negative NAAT result at Visit 1 and no medical history of COVID-19.
Exploratory analyses of immunogenicity against Delta and Omicron variants

In response to FDA’s request for additional immunogenicity data to support effectiveness of
three 3-μg primary series doses of BNT162b2 against the Delta and Omicron variants, Pfizer
submitted exploratory descriptive analyses of SARS-CoV-2 neutralizing GMTs from a randomly
selected subset of participants 6 months through 4 years of age (66 BNT162b2 recipients)
without evidence of SARS-CoV-2 infection up to 1 month post-Dose 3 (Table 18). These data
were generated using non-validated SARS-CoV-2 FFRNT assays with the reference strain
USA-WA1/2020 (reference), B.1.617.2 (Delta), and BA.1 (Omicron); the relative sensitivity of
the assays is not known.
The descriptive analyses indicate that post-Dose 3 in both age groups, neutralizing antibody
GMTs against the reference strain and against the Delta variant were similar, while neutralizing
antibody GMTs against the Omicron variant were notably lower. Post-dose 3 GMTs were lower
in the 2-4 years age group compared with the 6-23 months age group for the reference strain
and both variants. Geometric mean-fold rise (post-Dose 3 vs. pre-Dose 3) was similar for both
variants compared with the reference strain and similar between age groups.
35
Table 18. Geometric Mean Fold Rises of SARS-CoV-2 Neutralizing GMTs Before Dose 3 and at 1
Month After Three Doses in Participants 6 Months Through 4 Years of Age, Phase 2/3 Evaluable
Immunogenicity Populationb Subsets, Study C4591007
C4591007 C4591007
6-23 Months 2-4 Years
BNT162b2 3 μg BNT162b2 3 μg
Assay Target N=32 N=34
USA WA1/2020 (Reference strain) -- --
Post-Dose 3 GMT (95% CI) 640.0 (502.6, 815.0) 471.4 (344.6, 644.8)
GMFR (95% CI) 6.2 (4.7, 8.2) 6.7 (5.1, 8.9)
B.1.617.2 (Delta variant) -- --
Post-Dose 3 GMT (95% CI) 606.3 (455.5, 806.9) 471.4 (341.2, 651.1)
GMFR (95% CI) 6.4 (4.6, 9.1) 6.9 (4.9, 9.8)
B.1.1.529 (Omicron variant) -- --
Post-Dose 3 GMT (95% CI) 127.5 (90.2, 180.1) 82.5 (55.4, 122.9)
GMFR (95% CI) 7.8 (6.0, 10.2) 5.9 (3.9, 9.0)
Source: EUA 27034.556 eua-amendment-6m-4y-safety-immuno.pdf. Tables 27, 28, 37 and 38, Pages 125, 127, 152 and 154.
Abbreviations: CI=confidence interval; GMFR=geometric mean fold rises; GMT=geometric mean titer; NAAT=nucleic acid
amplification test; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.
N=number of participants with valid and determinate assay results for the specified assays at the given dose/sampling time point.
a. SARS-CoV-2 fluorescent focus reduction neutralization test assay, SARS-CoV-2 strains: recombinant USA_WA1/2020
(reference), B.1.617.2 (Delta), and BA.1 (Omicron).
b. Participants with no serological or virological evidence of SARS-CoV-2 infection: defined as N-binding antibody [serum] negative
from pre-Dose 1 to 1 month post-Dose 2 or 3, SARS-CoV-2 not detected by NAAT [nasal swab] prior to Dose 1, 2 and 3, and
negative NAAT [nasal swab] result at any unscheduled visit prior to 1 month post-Dose 2 or 3, and no medical history of COVID-19
c. Geometric Mean Fold Rise: GMFRs and 2-sided 95% CIs were calculated by exponentiating the mean logarithm of the fold rises
and the corresponding CIs (based on the Student t distribution). Assay results below the LLOQ were set to 0.5 × LLOQ in the
analysis.
Results in the evaluable immunogenicity population (regardless of evidence of prior infection)

and the all-available immunogenicity population were generally similar, noting that inclusion of
individuals with prior SARS-CoV-2 infection typically results in elevated baseline (before
vaccination) and post-vaccination neutralizing titers compared with individuals without evidence
of prior infection.
4.2.6.2. Descriptive efficacy analyses

A preliminary descriptive efficacy analysis of COVID-19 cases occurring at least 7 days post-
Dose 3 among participants 6-23 months of age in the Dose 3 evaluable efficacy population
included a total of 3 confirmed cases accrued in participants with and without evidence of prior
SARS-CoV-2 infection up to the data cutoff of April 29, 2022. The Dose 3 evaluable efficacy
population included 376 participants randomized to BNT162b2 and 179 participants randomized
to placebo. The VE estimate in this preliminary analysis was 75.6% (95% CI: -369.1%, 99.6%),
with 1 COVID-19 case in the BNT162b2 group compared to 2 in the placebo group (2:1
randomization BNT162b2 to placebo).
All post Dose 3 cases occurred from February-April 2022, during circulation of the Omicron
variant in the US. None of the participants with confirmed COVID-19 had a comorbidity that
increases the risk of severe disease.

A preliminary descriptive efficacy analysis of COVID-19 cases occurring at least 7 days post-
Dose 3 among participants 2-4 years of age in the Dose 3 evaluable efficacy population
included a total of 7 confirmed cases accrued in participants with or without evidence of prior
36
SARS-CoV-2 infection up to the data cutoff of April 29, 2022. The Dose 3 evaluable efficacy
population with and without evidence of prior SARS CoV-2 infection included 589 participants
randomized to BNT162b2 and 271 participants randomized to placebo. The VE estimate in this
preliminary analysis was 82.4% (95% CI: -7.6%, 98.3%), with 2 COVID-19 cases in the
BNT162b2 group compared to 5 in the placebo group (2:1 randomization BNT162b2 to
placebo). One confirmed case in the placebo group occurred in a participant with evidence of
SARS-CoV-2 infection prior to 7 days post-Dose 3.
All post-Dose 3 cases occurred from February-April 2022, during circulation of the Omicron
variant in the US. Comorbidities at baseline were present in only 1 confirmed COVID-19 case
(asthma in one placebo recipient).
Subgroup analyses of VE were not conducted because of the limited number of confirmed
COVID-19 cases that occurred 7 days after Dose 3. Nine of the 10 cases were in participants
who were seronegative at baseline, and one (a placebo recipient) had missing serostatus.
In a combined analysis of both age groups, VE was 80.4% (95% CI: 14.1%, 96.7%) with 3
cases in the BNT162b2 group and 7 cases in the placebo group. Interpretation of post-Dose 3
efficacy data for both age groups, and for the age group of 6 months through 4 years overall, is
limited for the following reasons:
• Vaccine efficacy post Dose 3 cannot be precisely estimated due to the limited
number of cases accrued during blinded follow-up, as reflected in the wide
confidence intervals associated with the estimates.
• These descriptive efficacy data are preliminary, as the protocol specified 21 cases
have not yet been achieved.
• There were highly variable dosing intervals between doses 2 and 3, with median
intervals of 112 (range 56 to 245) days among participants 6-23 months of age and
77 (range 42 to 239) days among participants 2-4 years of age in the Dose 3
evaluable efficacy population.
• The median blinded follow-up time post Dose 3 in the analyses was only 35 days for
participants 6-23 months of age and 40 days for participants 2-4 years of age.
Severe COVID-19
One COVID-19 case in a participant 6-23 months of age met the criteria for severe COVID-19
because of an increased heart rate (HR) of 172 beats per minute (bpm), with normal cutoff for
this age at 156 bpm) in a 14-month-old placebo recipient without evidence of prior SARS-CoV-2
infection. The participant reported symptoms of fever, rhinorrhea, sneezing and new or
increased cough. Initial central lab COVID-19 testing was negative within 5 days of symptom
onset; however, because of increased cough, repeat central lab testing was repeated 9 days
after the first test and was positive. BioFire testing identified coinfection with human
rhinovirus/enterovirus. Nine days later, the participant went to the emergency department (ED)
after a generalized tonic-clonic seizure lasting approximately 5-10 minutes. Vital signs in the ED
included a temperature of 38.4°C, HR 172 bpm, with the following symptoms noted: cough,
runny nose and congestion; no diagnostic tests were performed, and the participant was
discharged home the same day, after observation. All symptoms were reported as resolved 8
days after the ED visit. Because the participant had not returned back to baseline prior to the
ED visit for febrile seizure, the investigator thought the fever could be attributable to COVID-19
illness.
37
Seven cases in participants 2-4 years of age met the criteria for severe COVID-19: 6 in the
BNT162b2 group, of which 2 cases occurred post unblinding, and 1 in the placebo group. All
cases occurred post Dose 2 (range 32-208 days post Dose 2), and none occurred post-Dose 3.
In the BNT162b2 group, 5 of the 6 cases met criteria for a severe case based on 1 criterion:
increased heart rate (n=2) or increased respiratory rate (n=3), all of which were considered by
the investigator as not clinically significant based on examination at the illness visit and
contributing circumstances such as the participant crying during examination. All cases occurred
post Dose 2 (range 32-208 days post Dose 2). The final severe COVID-19 case in a BNT162b2
recipient occurred 99 days post-Dose 2 in a 2-year-old participant who had increased
respiratory rate (RR), decreased SpO2 as severe case criteria and was hospitalized due to
COVID-19. The participant reported fever, new or increased cough, and new or increased
shortness of breath, with at least 1 symptom ongoing as of the last report. During the urgent
care visit, the participant had hypoxemia and was hospitalized with wheeze on lung
auscultation. BioFire testing was positive for parainfluenza virus 3, in addition to the positive
central laboratory COVID-19 result. The participant received oxygen via nasal canula, inhaled
salbutamol and oral steroids while hospitalized, then was discharged home 3 days later.
In the placebo group, a 2-year-old participant met severe criteria because of decreased SpO2
(88% on room air) with symptoms of new or increased cough and nasal congestion.
Multiple cases of confirmed COVID-19

Six participants 6-23 months of age (3 BNT162b2 recipients and 3 placebo recipients)
developed more than one virologically and clinically confirmed episodes of symptomatic COVID-
19 disease. All BNT162b2 recipients received 3 doses of assigned study intervention, 1 placebo
recipient received 2 doses of placebo only, and 2 original placebo recipients received 2 doses of
placebo followed by 3 doses of open-label BNT162b2. The interval between the episodes
ranged from 1-4 months, with shorter intervals if the first episode occurred in January 2022 or
later (during Omicron circulation). All participants with multiple episodes were negative at
baseline for prior SARS-CoV-2 infection. Coinfections with other respiratory viruses were
present in 1 BNT162b2 recipient (enterovirus) and 3 placebo recipients (adenovirus,
enterovirus, endemic coronavirus, RSV).
Six participants 2-4 years of age (5 BNT162b2 recipients and 1 placebo recipient) developed
more than one virologically and clinically confirmed episode of symptomatic COVID-19 disease.
All of these participants received 3 doses of assigned study intervention, except for one
participant in the BNT162b2 group who received 2 doses of BNT162b2. The interval between
the episodes ranged from 1-4 months, with shorter intervals if the first episode occurred in
January 2022 or later (during Omicron circulation). All participants with multiple episodes were
negative at baseline for prior SARS-CoV-2 infection.
4.2.6.3. Post hoc efficacy analyses

Vaccine efficacy from Dose 1
An analysis of the number of confirmed COVID-19 cases following Dose 1 was conducted with
the all-available efficacy population, for all participants regardless of evidence of prior infection
through 7 days after Dose 3, at selected time intervals during and following completion of the
primary series.
38
Table 19. First COVID-19 Occurrence Any Time After Dose 1, Blinded Follow-Up Period,
Participants 6-23 Months of Age, All-Available Efficacy Population, Study C4591007
BNT162b2 3 μg
(Na=1178) Placebo
Cases, n1b (Na=598) Vaccine
Surveillance Timec, Cases, n1b Efficacy %
Efficacy Endpoint (n2d) Surveillance Timec, (n2d) (95% CIe)
First COVID-19 98 58 14.0
occurrence after Dose 1 0.456, (1027) 0.232, (524) (-21.2, 38.4)
13 5 -29.7
Dose 1 to before Dose 2
0.063, (1027) 0.032, (524) (-364.7, 56.6)
Dose 2 to <7 days after 3 3 48.4
Dose 2 0.019, (1002) 0.010, (517) (-285.0, 93.1)
≥7 Days after Dose 2 to 80 48 14.5
before Dose 3 0.338, (998) 0.173, (512) (-24.9, 41.0)
Dose 3 to <7 days after 1 0 UND
Dose 3 0.006, (336) 0.003, (147) (NA, NA)
1 2 75.5
≥7 Days after Dose 3
0.030, (277) 0.015, (139) (-370.1, 99.6)
Source: EUA 27034.554 Efficacy 508 tables. Table E.D.1.
Abbreviations: NA=not applicable; VE=Vaccine Efficacy; UND=Undefined.
a. N=number of participants in the specified group.
b. n1=Number of participants meeting the endpoint definition.
c. Total surveillance time in 1,000 person-years for the given endpoint across all participants within each group at risk for the
endpoint. Time period for COVID-19 case accrual is from Dose 1 to the end of the surveillance period for the overall row and from
start to the end of range stated for each interval.
d. n2=Number of participants at risk for the endpoint.
e. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.
Table 20. First COVID-19 Occurrence Any Time After Dose 1, Participants 2 to <5 Years of Age, All-
Available Efficacy Population, Study C4591007
BNT162b2 3 μg Placebo
(Na=1835) (Na=915) Vaccine
Cases, n1b Cases, n1b Efficacy %
Efficacy Endpoint Surveillance Timec, (n2d) Surveillance Timec, (n2d) (95% CIe)
First COVID-19 127 92 32.6
occurrence after Dose 1 0.661, (1673) 0.323, (834) (10.8, 48.8)
Dose 1 to before Dose 21 8 -32.1
2 0.100, (1673) 0.050, (834) (-244.8, 43.8)
Dose 2 to <7 days 4 5 60.1
after Dose 2 0.031, (1639) 0.016, (819) (-85.6, 92.1)
≥7 Days after Dose 2 100 74 33.6
to before Dose 3 0.464, (1630) 0.228, (814) (9.1, 51.3)
Dose 3 to <7 days 0 0
NE
after Dose 3 0.010, (553) 0.004, (222)
2 5 82.3
≥7 Days after Dose 3
0.056, (481) 0.025, (209) (-8.0, 98.3)
Source: EUA 27034.554 Efficacy 508 tables. Table E.D.2.
Abbreviations: NE=not estimable; VE=Vaccine Efficacy.
a. N=number of participants in the specified group.
b. n1=Number of participants meeting the endpoint definition.
c. Total surveillance time in 1,000 person-years for the given endpoint across all participants within each group at risk for the
endpoint. Time period for COVID-19 case accrual is from Dose 1 to the end of the surveillance period for the overall row and from
start to the end of range stated for each interval.
d. n2=Number of participants at risk for the endpoint.
e. Confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted to the surveillance time.
39
The estimated VE for the prevention of COVID-19 disease after Dose 1 in the all-available
efficacy population is 14.0% (95% CI: -21.2%-38.3%) for participants 6-23 months of age and
32.6% (95% CI: 10.8%-48.8%) for participants 2-4 years of age.
The post-hoc analysis of cases accumulated after Dose 1, after Dose 2 and before Dose 3,
suggests modest protection against COVID-19 following two doses in the older age group, but
interpretation is limited by wide confidence intervals. It is not possible to conclude a difference
between efficacy post-Dose 3 as compared to efficacy post-Dose 2 based on COVID-19 cases
accrued in the study as of the April 29, 2022, cutoff date.
Cumulative incidence curves

Based on the cumulative incidence curves for the all-available efficacy population after Dose 1,
(Figure 1 and Figure 2), COVID-19 disease onset appears to occur similarly for both BNT162b2
and placebo groups until after Dose 3, at which time point, the curves begin to diverge.
Participants 6-23 Months, All-Available Efficacy Population
Source: Source: EUA 27034.554 Efficacy 508 tables.
40
Participants 2-4 Years, All-Available Efficacy Population
Source: Source: EUA 27034.554 Efficacy 508 tables.
4.2.7. Phase 2/3 safety results
4.2.7.1. Phase 2/3 overview of adverse events

From Dose 1 to the data cutoff or participant unblinding (whichever was earlier) among
BNT162b2 recipients 6 months through 4 years of age, the frequency of immediate unsolicited
AEs after any dose was <0.5%, frequencies of solicited injection site reactions within 7 days
after any dose ranged from 20.5%-36.3%, and frequencies of solicited systemic reactions after
any dose ranged from 30.8%-61.0%. Six BNT162b2 recipients and 1 placebo recipient withdrew
from the study due to AEs. SAEs were reported in 17 BNT162b2 recipients 6-23 months of age,
and none were considered by the study investigator or FDA to be related to the vaccine. Of the
12 BNT162b2 recipients 2-4 years of age. There were no deaths reported. See Table 21 and
Table 22 below for summary counts and frequencies of adverse events after each dose.
Table 21. Adverse Events in Participants 6-23 Months of Age, Blinded Follow-Up, Phase 2/3 Safety
Event BNT162b2 3 μg Placebo
Immediate unsolicited AE within 30 minutes after vaccination, n/N (%) -- --
Dose 1 3/1178 (0.3) 0/598 (0)
Dose 2 3/1166 (0.3) 3/596 (0.5)
Dose 3 0/386 (0) 0/184 (0)
41

Solicited injection site reaction within 7 days, n/N (%) -- --
Dose 1 279/1173 (23.8) 104/595 (17.5)
Dose 2 248/1147 (21.6) 79/591 (13.4)
Dose 3 75/365 (20.5) 26/170 (15.3)
Solicited systemic reaction within 7 days, n/N (%) -- --
Dose 1 715/1173 (61.0) 346/595 (58.2)
Dose 2 640/1147 (55.8) 298/591 (50.4)
Dose 3 188/365 (51.5) 77/170 (45.3)
From Dose 1 through 1 month after Dose 3, n/N (%) -- --
Any AE 355/1178 (30.1) 162/598 (27.1)
Unsolicited non-serious AE 343/1178 (29.1) 157/598 (26.3)
From Dose 1 through cutoff date or participant unblinding, n/N (%) -- --
Withdrawal due to AEs 3/1178 (0.3) 0/598 (0)
SAE 17/1178 (1.4) 14/598 (2.3)
Death 0/1178 (0) 0/598 (0)
Source: EUA 27024.554 Safety-Immunogenicity_508_Tables. Table Q1, Page 15.
Abbreviations: AE=adverse event; n=number of participants with the specified characteristic. N=number of administered participants
in the specified group (the denominator for the percentage calculations); SAE=serious adverse event.
Note: Medical Dictionary for Regulatory Activities (v25.0) coding dictionary applied.
Note: Immediate AE refers to an AE reported in the 30-minute observation period after vaccination.
%: n/N
Table 22. Adverse Events in Participants 2-4 Years of Age, Blinded Follow-Up, Phase 2/3 Safety
Immediate unsolicited AE within 30 minutes after vaccination, n/N (%) -- --
Dose 1 5/1835 (0.3) 3/915 (0.3)
Dose 2 4/1819 (0.2) 1/907 (0.1)
Dose 3 0/606 (0) 0/280 (0)
Solicited injection site reaction within 7 days, n/N (%) -- --
Dose 1 648/1825 (35.5) 229/909 (25.2)
Dose 2 645/1779 (36.3) 205/878 (23.3)
Dose 3 174/552 (31.5) 41/262 (15.6)
Solicited systemic reaction within 7 days, n/N (%) -- --
Dose 1 693/1825 (38.0) 354/909 (38.9)
Dose 2 599/1779 (33.7) 283/878 (32.2)
Dose 3 170/552 (30.8) 77/262 (29.4)
From Dose 1 through 1 month after Dose 3, n/N (%) -- --
Any AE 344/1835 (18.7) 171/915 (18.7)
Unsolicited non-serious AE, n/N (%) 339/1835 (18.5) 169/915 (18.5)
From Dose 1 through cutoff date or participant unblinding, n/N (%) -- --
Withdrawal due to AEs 3/1835 (0.2) 1/915 (0.1)
SAE 12/1835 (0.7) 8/915 (0.9)
Death 0/1835 (0) 0/915 (0)
Source: EUA 27024.554 Safety-Immunogenicity_508_Tables. Table Q2, Page 16.
Abbreviations: AE=adverse event; n=number of participants with the specified characteristic. N=number of administered participants
in the specified group (the denominator for the percentage calculations); SAE=serious adverse event.
Note: Medical Dictionary for Regulatory Activities (v25.0) coding dictionary applied.
Note: Immediate AE refers to an AE reported in the 30-minute observation period after vaccination.
%: n/N
Analyses that included adverse events reported after a participant was unblinded did not
suggest any meaningful differences in the safety profile. No events that were reported after
unblinding were serious or considered possibly related to study intervention.
42
4.2.7.2. Immediate adverse events

Of 1,178 BNT162b2 recipients 6-23 months of age, 3 participants reported AEs within 30
minutes after Dose 1: vomiting, injection site erythema and hematoma (n=1 each). After Dose 2,
3 BNT162b2 recipients reported injection site erythema, injection site swelling and rash.
Of 1,835 BNT162b2 recipients 2-4 years of age, 5 participants reported immediate AEs
following received Dose 1: erythema in 2 participants, and injection site bruising, injury
associated with device and skin abrasion in 1 participant each. Following Dose 2, four
immediate reactions were reported by 1 BNT162b2 recipient each: injection site pain, injection
site erythema, rash erythematous and urticaria.
None of the BNT162b2 recipients in either age group reported an immediate AE after Dose 3, or
anaphylaxis/severe allergic reaction within 30 minutes after any dose.
4.2.7.3. Solicited adverse reactions

Overall, frequencies of any solicited local adverse reaction (AR) were higher in BNT162b2
recipients than placebo recipients, and frequencies were similar after Dose 1 and 2 but slightly
lower after Dose 3. Tenderness at the injection site was the most frequently reported local
reaction after each BNT162b2 dose (15.0%-16.6%), with redness (7.1%-10.6%) and swelling
(2.7%-3.7%) at the injection site reported less frequently. Frequencies of any solicited systemic
AR in BNT162b2 recipients were generally similar after Dose 1, 2 or 3, and included irritability
(43.6%-51.2%), drowsiness (19.9%-27.0%), decreased appetite (20.2%-22.2%) and fever
(6.8%-7.4%). Most local and systemic reactions were mild to moderate in severity, with median
onset of 1-2 days postvaccination, and resolved within 1-2 days after onset. Solicited local and
systemic reactions in BNT162b2 recipients that were graded as severe occurred in ≤1.1% of
participants across groups and doses, and all but one were systemic reactions. No Grade 4
local or systemic reactions were reported after any dose.
Rates of local ARs in participants 6-23 months of age (3 µg dose level) were all lower than
those in individuals 5-11 years of age 49 (10 µg dose level) enrolled in the same study. Fever
was reported more frequently and with higher severity in participants 6-23 months of age
compared to individuals 5-11 years of age. Three vaccine recipients 6-23 months of age
reported a fever >40.0°C:
• a 19-month-old with fever of 40.6°C on Day 2 after Dose 1, with fevers of 39°C and 38.1°C
on the subsequent days, and a concurrent nonserious AE of exanthema subitum reported
on Day 2 after Dose 1 (attributed to a viral infection) that resolved in 4 days;
• an 11-month-old with fever starting on Day 1 after Dose 2 and persisting through Day 5
(temperatures on Days 1 to 5 were: 39.2°C, 39.5°C, 40.5°C, 38.4°C, 39.1°C), Grade 3
drowsiness on Days 1-2 and Days 5-6 post-Dose 2, and Grade 3 irritability on Days 2 and 5
post-Dose 2; the participant was diagnosed with roseola at an unscheduled illness visit;
• a 13-month-old with fever of 40.5°C on Day 3 and 39.5°C on Day 4 after Dose 3, with
resolution of fever by Day 6 (no temperature reported on Day 5).
The frequencies of local and systemic ARs within 7 days after each vaccination in participants
with evaluable e-diary data are summarized in Table 23 and Table 24. The characteristics of the
systemic and local reactions are presented in Table 25.
43
Table 23. Frequency of Solicited Local Reactions, by Severity, Within 7 Days After Each Dose in
Participants 6-23 Months of Age, Phase 2/3 Safety Populationa, Study C4591007
BNT162b2 Placebo BNT162b2 Placebo BNT162b2 Placebo
Dose 1 Dose 1 Dose 2 Dose 2 Dose 3 Dose 3
Event N=1159-1173 N=591-595 N=1137-1147 N=590-591 N=362-365 N=170
Tenderness at the
-- -- -- -- -- --
injection siteb, %
Any d
16.6 11.2 15.0 8.5 16.0 11.8
Mild 15.6 10.3 13.5 7.1 14.1 10.0
Moderate 0.9 0.8 1.4 1.4 1.9 1.8
Severe 0 0 0.1 0 0 0
Rednessc, % -- -- -- -- -- --
Anyd 10.6 7.4 9.3 6.6 7.1 5.3
Mild 9.7 6.9 8.5 6.1 4.7 4.7
Moderate 0.9 0.5 0.9 0.5 2.2 0.6
Severe 0 0 0 0 0.3 0
Swellingc, % -- -- -- -- -- --
Anyd 3.9 2.5 3.9 1.5 2.7 1.8
Mild 3.4 2.2 3.4 1.4 1.9 1.8
Moderate 0.5 0.3 0.5 0.2 0.8 0
Severe 0 0 0 0 0 0
Any local reactiond 23.8 17.5 21.6 13.4 20.5 15.3
Source: EUA 27034.556 c4594007-dose3-tables-ns-listings-6mo-4yr-safety.pdf. Pages 128-132.
%: n/N. n=number of participants in the specified age group with the specified reaction. N=number of participants in the specified
age group reporting at least 1 yes or no response for the specified reaction after the specified dose.
a. All participants in the specified age group who received at least 1 dose of the study intervention with evaluable e-diary data.
b. Mild: does not interfere with activity; moderate: interferes with activity; severe: prevents daily activity.
c. Mild: 0.5 to ≤2.0 cm; moderate: 2.0 to ≤7.0 cm; severe: >7.0 cm.
d. Any local reaction: any redness >0.5 cm, any swelling >0.5 cm, or any pain at the injection site.
Table 24. Frequency of Solicited Systemic Reactions, by Severity, Within 7 Days After Each Dose
in Participants 6-23 Months of Age, Phase 2/3 Safety Populationa, Study C4591007
Event N=1159-1173 N=591-595 N=1137-1147 N=590-591 N=362-365 N=170
Fever, % -- -- -- -- -- --
≥38.0°C 7.2 7.2 7.4 6.1 6.8 5.9
≥38.0°C to 38.4°C 3.6 3.7 3.6 3.0 3.8 4.1
>38.4°C to 38.9°C 2.0 2.4 1.7 1.9 1.4 1.2
>38.9°C to 40.0°C 1.6 1.0 2.0 1.2 1.4 0.6
>40.0°C 0.1 0.2 0.1 0 0.3 0
Irritabilityb, % -- -- -- -- -- --
Anye 51.2 47.2 47.4 40.7 43.6 37.6
Mild 21.1 17.9 18.7 15.1 15.5 15.9
Moderate 29.4 29.3 28.1 24.7 27.9 21.8
Severe 0.6 0 0.6 0.8 0.3 0
Drowsinessc, % -- -- -- -- -- --
Anye 27.0 29.3 23.8 21.2 19.9 12.9
Mild 21.7 22.0 17.7 16.6 13.8 8.8
Moderate 5.2 6.9 5.8 4.4 5.8 3.5
Severe 0.2 0.3 0.4 0.2 0.3 0.6
44

Event N=1159-1173 N=591-595 N=1137-1147 N=590-591 N=362-365 N=170
Decreased Appetited, % -- -- -- -- -- --
Anye 22.2 21.2 22.2 18.0 20.2 13.5
Mild 11.9 12.4 13.8 10.7 11.6 7.6
Moderate 10.0 8.6 8.0 7.1 7.5 5.9
Severe 0.3 0.2 0.4 0.2 1.1 0
Any systemic evente 61.0 58.2 55.8 50.4 51.5 45.3
Use of antipyretic or
24.0 19.7 21.2 18.8 19.2 16.5
pain medicationf, %
Source: EUA 27034.556 c4594007-dose3-tables-ns-listings-6mo-4yr-safety.pdf. Pages 202, 215.
%: n/N. n=Number of participants with the specified reaction. N=Number of participants reporting at least 1 yes or no response for
the specified reaction after the specified dose.
b. Mild: easily consolable; Moderate: requiring increased attention; Severe: inconsolable; crying, cannot be comforted.
c. Mild: increased or prolonged sleeping bouts; Moderate: slightly subdued, interfering with daily activity; Severe: disabling; not
interested in usual daily activity.
d. Mild: decreased interest in eating; Moderate: decreased oral intake; Severe: refusal to eat.
e. Any systemic event: any fever ≥38.0℃, any fatigue, any vomiting, any chills, any diarrhea, any headache, any new or worsened
muscle pain, or any new or worsened joint pain.
f. Severity was not collected for use of antipyretic or pain medication.
Table 25. Characteristics of Solicited Local and Systemic Reactions in Participants 6-23 Months of
Age, Phase 2/3 Safety Populationa, Study C4591007
Event Dose 1 Dose 1 Dose 2 Dose 2 Dose 3 Dose 3
Any solicited local
-- -- -- -- -- --
reaction
Day of onset, median 1.0 1.0 1.0 1.0 1.0 1.0
(min, max) (1, 6) (1, 4) (1, 5) (1, 6) (1, 4) (1, 6)
Duration, median 1.0 1.0 1.0 1.0 1.0 1.0
(min, max) (1, 10) (1, 6) (1, 6) (1, 10) (1, 9) (1, 5)
Persisted beyond 7
3/1173 (<0.1) 0 0 2/591 (0.3) 1/365 (0.3) 0
days, n/N (%)
Any solicited systemic
-- -- -- -- -- --
reaction
(min, max) (1, 7) (1, 7) (1, 7) (1, 7) (1, 7) (1, 7)
Duration, median 2.0 2.0 2.0 2.0 2.0 2.0
(min, max) (1, 39) (1, 21) (1, 29) (1, 34) (1, 19) (1, 52)
Persisted beyond 7
45/1173 (3.8) 30/595 (5.0) 37/1147 (3.2) 21/591 (3.6) 9/365 (2.5) 7/170 (4.1)
days, n/N (%)
Source: EUA 27034.556 c4594007-dose3-tables-ns-listings-6mo-4yr-safety.pdf. Pages 202, 215.
Abbreviations: AR=adverse reaction; max=maximum; min=minimum; n=number of participants with the specified reaction persisted
beyond 7 days; N=number of participants reporting at least one yes or no response for the specified reaction after the specified
dose.

Solicited local and systemic ARs in BNT162b2 recipients generally occurred at similar
frequencies after Dose 1, 2 or 3. Pain at the injection site was the most frequently reported local
reaction after each BNT162b2 dose (26.7%-31.0%). Most local and systemic reactions were
mild to moderate in severity, with median onset 1-2 days postvaccination, and resolved within
1-2 days after onset. ARs in BNT162b2 recipients that were graded as severe were <0.5% after
any dose. No Grade 4 reactions were reported after any dose.
45
Rates of local ARs in participants 2-4 years of age (3 µg dose level) were all lower than those in
individuals 5-11 years of age 50 (10 µg dose level) enrolled in the same study. Systemic ARs
such as fatigue, headache, chills, and muscle pain were generally reported less frequently and
were milder in severity in 2-4-year-old participants compared to 5-11-year-old participants.
Fever was reported more frequently and with higher severity in 2-4-year-old participants than in
5-11-year-old participants. Three vaccine recipients 2-4 years of age reported a fever >40.0°C:
• a 3-year-old was reported to have fever of 40.8°C on Day 2 after Dose 1, which persisted
with fevers of 40.7°C, 40.5°C and 38.4°C on the subsequent days and resolved on Day 6
without other concurrent AEs reported. The fever was also reported as a nonserious AE of
pyrexia considered as related to study intervention by the investigator and led to withdrawal.
• a 4-year-old was reported to have fever starting on Day 3 after Dose 2 and persisting
through Day 7 (temperatures on Days 1 to 5 were: 39.2°C, 39.5°C, 40.5°C, 38.4°C, 39.1°C)
with a concurrent Grade 2 SAE of calf pain on Day 6 and a nonserious Grade 2 AE of rash
(chest, upper back, and ear) on Day 7 after Dose 2. When the participant defervesced, the
rash then developed, which indicated a possible viral infection. (See Section 7.3.7.6 for
additional details of SAEs)
• A 4-year-old was reported to have fever on Days 5 through 7 post-Dose 2, ranging from
38.7°C to 40.3°C. No other AEs were reported, and no medication use was reported.
The frequencies of local and systemic ARs within 7 days after each vaccination in participants
with evaluable e-diary data are summarized in Table 26 and Table 27. The characteristics of the
systemic and local reactions are presented in Table 28.
Table 26. Frequency of Solicited Local Reactions, Within 7 Days After Each Dose in Participants 2-
4 Years of Age, Phase 2/3 Safety Populationa, Study C4591007
Event N=1813-1825 N=905-909 N=1772-1779 N=877-878 N=547-552 N=262
Pain at the injection
-- -- -- -- -- --
siteb, %
Any d
30.8 20.6 31.0 20.3 26.7 13.4
Mild 28.8 19.7 29.0 19.3 23.8 12.6
Moderate 2.0 0.8 2.0 0.9 2.9 0.8
Severe 0 0.1 0 0.1 0 0
Rednessc, % -- -- -- -- -- --
Anyd 8.8 8.5 11.4 5.7 10.9 3.4
Mild 7.5 7.4 9.6 4.9 9.6 2.7
Moderate 1.2 1.0 1.7 0.8 1.3 0.8
Severe 0.1 0.1 0.1 0 0 0
Swellingc, % -- -- -- -- -- --
Anyd 3.7 2.9 5.7 2.1 3.1 1.1
Mild 3.2 2.3 4.6 1.8 2.9 1.1
Moderate 0.4 0.6 1.2 0.2 0.2 0
Severe 0 0 0 0 0 0
Any local reactiond 35.5 25.2 36.3 23.3 31.5 15.6
46
Table 27. Frequency of Solicited Systemic Reactions, Within 7 Days After Each Dose in
Participants 2-4 Years of Age, Phase 2/3 Safety Populationa, Study C4591007
Event N=1813-1825 N=905-909 N=1772-1779 N=877-878 N=547-552 N=262
Fever, % -- -- -- -- -- --
≥38.0°C 5.2 5.3 4.9 5.2 5.1 4.2
≥38.0°C to 38.4°C 3.1 2.6 2.3 1.9 2.9 1.5
>38.4°C to 38.9°C 1.3 1.8 1.5 2.4 1.4 1.5
>38.9°C to 40.0°C 0.7 0.9 1.1 0.9 0.7 1.1
>40.0°C 0.1 0 0.1 0 0 0
Fatigueb, % -- -- -- -- -- --
Anye 29.7 30.6 25.7 22.9 24.5 21.8
Mild 18.5 19.4 15.1 13.7 15.9 13.4
Moderate 10.9 10.6 10.2 8.9 8.2 8.4
Severe 0.3 0.6 0.5 0.3 0.4 0
Headacheb, % -- -- -- -- -- --
Anye 4.5 4.9 4.6 4.1 4.9 4.2
Mild 3.5 3.9 3.6 2.6 3.5 3.8
Moderate 1.0 0.9 1.0 1.4 1.5 0.4
Severe 0 0.1 0 0.1 0 0
Chillsb, % -- -- -- -- -- --
Anye 2.3 2.4 3.0 2.6 3.3 2.7
Mild 1.5 1.8 2.0 1.9 2.6 2.7
Moderate 0.6 0.7 1.0 0.7 0.5 0
Severe 0.2 0 0 0 0.2 0
Vomitingc, % -- -- -- -- -- --
Anye 3.0 2.7 3.4 3.3 1.6 3.8
Mild 2.4 1.5 3.1 3.0 1.3 3.4
Moderate 0.6 1.1 0.3 0.3 0.4 0.4
Severe 0 0 0 0 0 0
Diarrhead, % -- -- -- -- -- --
Anye 7.7 8.0 6.7 7.3 5.1 5.0
Mild 7.2 7.1 5.9 6.5 3.8 3.8
Moderate 0.5 0.9 0.7 0.8 1.3 1.1
Severe 0 0 0.1 0 0 0
New or worsened
-- -- -- -- -- --
muscle painb, %
Any e
2.4 1.7 2.6 2.4 2.0 1.5
Mild 1.8 1.4 1.9 1.9 1.9 1.5
Moderate 0.5 0.2 0.7 0.5 0.5 0
Severe 0.1 0 0 0 0 0
47

Event N=1813-1825 N=905-909 N=1772-1779 N=877-878 N=547-552 N=262
New or worsened
-- -- -- -- -- --
joint painb, %
Anye 0.8 2.0 1.4 1.0 1.3 0.8
Mild 0.7 1.4 1.0 0.7 0.9 0.8
Moderate 0.1 0.6 0.3 0.3 0.2 0
Severe 0 0 0 0 0.2 0
Any systemic
38.0 38.9 33.7 32.2 30.8 29.4
reactione
Use of antipyretic or
10.8 9.1 9.9 8.4 8.5 6.9
pain medicationf, %
b. Mild: does not interfere with activity; Moderate: some interference with activity; Severe: prevents daily activity.
c. Mild: 1 to 2 times in 24 hours; Moderate: >2 times in 24 hours; Severe: requires intravenous hydration.
d. Mild: 2 to 3 loose stools in 24 hours; Moderate: 4 to 5 loose stools in 24 hours; Severe: 6 or more loose stools in 24 hours.
Table 28. Characteristics of Solicited Local and Systemic Reactions in Participants 2-4 Years of
Age, Phase 2/3 Safety Populationa, Study C4591007
Event Dose 1 Dose 1 Dose 2 Dose 2 Dose 3 Dose 3
Any solicited local
-- -- -- -- -- --
reaction
(min, max) (1, 7) (1, 6) (1, 7) (1, 6) (1, 6) (1, 7)
Duration, median 1.0 1.0 1.0 1.0 1.0 1.0
(min, max) (1, 9) (1, 20) (1, 31) (1, 10) (1, 14) (1, 11)
Persisted beyond 7
4/1825 (0.2) 3/909 (0.3) 11/1779 (0.6) 2/878 (0.2) 1/552 (0.2) 1/262 (0.4)
days, n/N (%)
Any solicited systemic
-- -- -- -- -- --
reaction
(min, max) (1, 7) (1, 7) (1, 7) (1, 7) (1, 7) (1, 7)
Duration, median 1.0 1.0 1.0 1.0 1.0 1.0
(min, max) (1, 26) (1, 18) (1, 29) (1, 32) (1, 15) (1, 9)
Persisted beyond 7
23/1825 (1.3) 13/909 (1.4) 21/1779 (1.2) 8/878 (0.9) 4/552 (0.7) 3/262 (1.1)
days, n/N (%)
Source: EUA 27034.556 c4594007-dose3-tables-ns-listings-6mo-4yr-safety.pdf. Pages 153, 160, 207
Abbreviations: max=maximum; min=minimum; n=number of participants with the specified reaction persisted beyond 7 days;
N=number of participants reporting at least one yes or no response for the specified reaction after the specified dose.
Additional analyses of the solicited local and systemic reactions that included any e-diary data
reported after a participant was unblinded did not suggest any meaningful differences in the
reactogenicity profile when including post-unblinding events.
A total of 120 participants with e-diary data received 3 µg BNT162b2 Dose 1 and 2, turned 5
years of age, then were unblinded and received Dose 3 at the 10 µg dose level in an open-label
manner. In a separate analysis of these participants, there was a dose level dependent increase
48
in local reactions after Dose 3 compared to after Dose 2 (Table 29). There was also a dose
level-dependent increase in certain systemic reactions after Dose 3 compared to after Dose 2,
including fever, fatigue and headache, while other systemic reactions remained similar or
showed no clear pattern after each subsequent dose (Table 30).
Table 29. Frequency of Solicited Local Reactions, Within 7 Days After Dose 2 and 3 in Participants
2-4 Years of Age and Participants Who Turned 5 Years of Age and Received BNT162b2 10 µg Dose
3, Phase 2/3 Safety Populationa, Study C4591007
2-4 Years 5 Years
3 µg Dose 2 10 µg Dose 3
Event N=120 N=111
Pain at the injection siteb, % -- --
Anyd 35.0 53.2
Mild 34.2 44.1
Moderate 0.8 8.1
Severe 0 0.9
Rednessc, % -- --
Anyd 11.7 16.2
Mild 10.8 8.1
Moderate 0 8.1
Severe 0.8 0
Swellingc, % -- --
Anyd 4.2 6.3
Mild 3.3 3.6
Moderate 0.8 2.7
Severe 0 0
Any local reactiond 40.0 58.6
Source: Adapted from EUA 27034.556 c4591007-dose3-tables-ns-listings-6mo-4yr-safety.pdf. Table p148.
Table 30. Frequency of Solicited Systemic Reactions, Within 7 Days After Dose 3 in Participants 2-
4 Years of Age and Participants Who Turned 5 Years of Age and Received BNT162b2 10 µg Dose
3, Phase 2/3 Safety Populationa, Study C4591007
2-4 Years 5 Years
Event N=120 N=111
Fever, % -- --
≥38.0°C 2.5 12.6
≥38.0°C to 38.4°C 0.8 6.3
>38.4°C to 38.9°C 1.7 5.4
>38.9°C to 40.0°C 0 0.9
>40.0°C 0 0
Fatigueb, % -- --
Anye 24.2 34.2
Mild 17.5 17.2
Moderate 6.7 16.2
Severe 0 0.9
49
2-4 Years 5 Years

Event N=120 N=111
Headacheb, % -- --
Anye 4.2 12.6
Mild 4.2 9.9
Moderate 0 2.7
Severe 0 0
Chillsb, % -- --
Anye 4.2 2.7
Mild 2.5 1.8
Moderate 0.8 0.9
Severe 0 0
Vomitingc, % -- --
Anye 3.3 2.7
Mild 2.5 1.8
Moderate 0.8 0.9
Severe 0 0
Diarrhead, % -- --
Anye 8.3 3.6
Mild 7.5 3.6
Moderate 0.8 0
Severe 0 0
New or worsened muscle painb, % -- --
Anye 5.0 3.6
Mild 4.2 1.8
Moderate 0.8 1.8
Severe 0 0
New or worsened joint painb, % -- --
Anye 1.7 0
Mild 1.7 0
Moderate 0 0
Severe 0 0
Any systemic reactione 35.0 45.0
Use of antipyretic or pain
8.4 6.9
medicationf, %
Source: Adapted from EUA 27034.556 c4591007-dose3-tables-ns-listings-6mo-4yr-safety.pdf. Table p198.
b. Mild: does not interfere with activity; Moderate: some interference with activity; Severe: prevents daily activity.
c. Mild: 1 to 2 times in 24 hours; Moderate: >2 times in 24 hours; Severe: requires intravenous hydration.
d. Mild: 2 to 3 loose stools in 24 hours; Moderate: 4 to 5 loose stools in 24 hours; Severe: 6 or more loose stools in 24 hours.
4.2.7.4. Unsolicited adverse events

Information about unsolicited AEs was collected from Dose 1 through 1 month after each dose.
The frequencies of unsolicited non-serious AEs reported were similar in the BNT162b2 and
placebo groups in both age groups: 29.1% vs. 26.3% in participants 6-23 months of age and
18.5% vs. 18.5% in participants 2-4 years of age, respectively. The most commonly observed
AEs were consistent with those reported as solicited ARs (local and systemic reactogenicity)
50
and/or were consistent with events frequently reported in this age group, including infections
and injuries, that were not considered related to study vaccination.
Adverse events considered related to BNT162b2 included lymphadenopathy and

hypersensitivity are discussed in Section 4.2.7.6 with Adverse events of clinical interest. SAEs
are discussed in Section 4.2.7.5.
4.2.7.5. Serious adverse events

Information about SAEs was collected from Dose 1 up to 6 months post-Dose 3.

Among participants 6-23 months of age, SAEs were reported in 17 (3.1%) participants in the
BNT162b2 group and 14 (2.3%) in the placebo group, most of which were gastrointestinal or
respiratory illnesses/infections that occur commonly in this age group.
SAEs reported in the BNT162b2 group included RSV bronchiolitis (5 participants), pneumonia
(2 participants), gastroenteritis (2 participants), lower respiratory tract infection (2 participants),
and the following events were each reported once (a participant can report more than one
event): anal abscess, anaphylaxis, lower respiratory tract infection, viral lower respiratory tract
infection, metapneumovirus infection, rhinovirus infection, rotavirus gastroenteritis, viral
gastroenteritis, accidental overdose, febrile convulsion, seizure. None of the SAEs in the
BNT162b2 group were considered by the study investigator or by FDA to be related to
vaccination, given the time to onset after vaccination and/or plausible alternate etiology.
SAEs reported in the placebo group included bronchiolitis or RSV bronchiolitis (3 participants)
and cyanosis (2 participants) the following events were each reported once (a participant can
report more than one event): vomiting, anaphylaxis, norovirus gastroenteritis, rotavirus
gastroenteritis, tonsillitis, viral infection, pneumomediastinum, respiratory distress, feeding
intolerance, hypoglycemia, head injury, second degree burns, and thermal burns.
Narratives for SAEs of clinical interest in BNT162b2 recipients are as follows:

• One 21-month-old BNT162b2 recipient was reported to have an SAE of anaphylaxis 14
days after Dose 1. The participant had a known history of nut allergy and was taken to the
emergency department for treatment of an anaphylactic reaction (hives, wheezing, nausea
and vomiting) one day after eating nuts. FDA agrees that this SAE was unrelated to
BNT162b2
• One 6-month-old BNT162b2 recipient was reported to have an SAE of seizure (eye rolling
upwards) that occurred 2 days after Dose 2, preceded by symptoms of a respiratory tract
infection and temperature of 38.0°C. The participant was evaluated in the emergency
department and admitted to the hospital for evaluation of seizure: with eye rolling upwards
noted once on an otherwise normal physical/neurological examination. A head ultrasound
was normal and SARS-CoV-2 “swab” was negative. Laboratory abnormalities included a
slightly elevated C-reactive protein (20 mg/L, normal range not provided), and elevated
white blood cells (20.8K). An electroencephalogram (EEG) was performed during
physiologic sleep and showed focal evidence of seizure activity. No further information was
provided about management of symptoms, including use of antipyretic medications prior to
or during the acute presentation of seizure. The participant went home from the hospital the
same day, with follow-up appointment in neurology clinic. The parent noticed a few episodes
of eye rolling per day, with resolution of symptoms 17 days after onset; the participant was
withdrawn from the study by parental request. During follow-up in neurology clinic 2 months
51
after the event, the final diagnosis was convulsions, not elsewhere classified. While the
clinical presentation suggests that the seizure may have been related to an infectious
process that began prior to Dose 2, a febrile seizure related to vaccination cannot be
definitively excluded based on available information.
• One 21-month-old BNT162b2 recipient was reported to have an SAE of febrile convulsion
which occurred 38 days post Dose 1, which was attributed to ear inflammation and resolved
the next day. FDA agrees that this SAE was unrelated to BNT162b2.

Among participants 2-4 years of age, SAEs were reported by 12 (0.7%) participants in the
BNT162b2 group: appendicitis (2 participants), dehydration (2 participants), and the following
events were each reported once (a participant can report more than one event): pyrexia, pain in
the extremity, focal peritonitis, status epilepticus, epilepsy, febrile convulsion, rotavirus
gastroenteritis, viral gastroenteritis, dehydration, gastroenteritis, diarrhea, upper respiratory tract
infection and lower respiratory tract infection. Two SAEs reported by the same participant were
considered at least possibly related to vaccination by the study investigator (see narrative
below). The remaining SAEs were considered by the study investigator and by FDA to be
unrelated to the study vaccine due to the time to onset after vaccination and/or plausible
alternative etiology. The 8 (0.9%) placebo recipients who had SAEs reported the following:
adenovirus gastroenteritis, gastroenteritis, rotavirus gastroenteritis, foreign body, papilledema,
epilepsy, febrile convulsion, and bronchial hyperactivity.
• A 4-year-old BNT162b2 recipient was reported to have SAEs of pyrexia and pain in the
extremity. Fever (Tmax of 40.3°C) started 2 days after Dose 2. The participant was brought
to the emergency department for further evaluation of fever and discharged the same day.
The fever persisted for another 3 days, and the participant was hospitalized for further
evaluation of fever, with new onset moderate pain in extremity (right calf pain characterized
as an SAE), causing a limp. Physical examination was otherwise normal. Labs included
white blood cells 1.8K, platelets 137K, creatinine phosphokinase 491 International Units/L
(to 1,878 on Day 7, normal range not provided), erythrocyte sedimentation rate 17 (normal
0-15). Evaluation for other specific viral infections and urine culture for bacteria were
negative. Treatment included oral ibuprofen and paracetamol for fever and pain. The fever
resolved on Day 7, followed by appearance of a non-pruritic urticarial “purpura”-type rash on
face, chest, and upper back. The participant was discharged from the hospital on Day 7.
The rash resolved on Day 8, calf pain resolved on Day 9, and the participant fully recovered
on Day 10 and returned to daycare without medications. A final diagnosis was not provided.
Based on the temporal relationship to BNT162b2 Dose 2, the study investigator considered the
pyrexia to be related to vaccination and the calf pain possibly related to the study vaccine.
Given the constellation and progression of symptoms, FDA considered the events to be
consistent with symptoms due to an unspecified viral infection, e.g., viral myositis.
Two BNT162b2 recipients reported SAEs of appendicitis, both of which were considered by the
study investigator and FDA to be unrelated to vaccination; narratives are provided below:
• A 4-year-old was reported to have SAEs of acute appendicitis (moderate in severity) and
mild localized peritonitis, both with onset on 105 days post-Dose 2. This participant was
subsequently unblinded upon turning 5 years of age and received open-label Dose 3 of
BNT162b2 10-μg approximately 6 months after Dose 2 and no AEs were reported post-
Dose 3.
52
• A 4-year-old was reported to have an SAE of severe appendicitis with onset 11 days post-
Dose 2. The event was reported as resolved the same day following appendectomy. This
participant reported no other AEs after any dose.
The three SAEs of status epilepticus, febrile convulsion, and epilepsy were considered by the
study investigator and FDA to be unrelated to vaccination; narratives are provided below.
• A 4-year-old BNT162b2 recipient with a history of seizures, failure to thrive,
gastroesophageal reflux, hypotonia, and lissencephaly was reported to have an SAE of
status epilepticus with onset Day 18 after Dose 1. The participant was diagnosed with a
urinary tract infection that was considered by the study investigator to have precipitated the
seizures; the event resolved within 3 days. The participant was also diagnosed with a non-
serious AE of hypoglycemia on Day 18 that resolved within 2 days. This participant withdrew
from the study due to the AE before receiving Dose 2.
• A 2-year-old BNT162b2 recipient had a febrile convulsion 21 days post-Dose 1, which
resolved the same day, with unknown cause after evaluation in an emergency department.
The participant received Dose 2 3 days later without additional AEs reported.
• A 4-year-old BNT162b2 recipient, with a family history of febrile seizures, experienced
seizure-like activity 47 days after BNT162b2 Dose 2 and went to the emergency
department. The participant had received influenza vaccine 3 days prior to the onset of
symptoms. The participant was hospitalized, and no further seizures were noted. EEG
subsequently showed abnormal results. An SAE of suspected epilepsy was reported,
considered by the study investigator as unrelated to the BNT162b2 vaccine but possibly
related to influenza vaccination.
4.2.7.6. Adverse events of clinical interest

FDA conducted Standardized MedDRA Queries (SMQs) to evaluate for constellations of
unsolicited AEs among vaccine recipients 6 months through 4 years of age in Phase 2/3 of
study C4591007 through the April 29, 2022, cutoff date. SMQs (narrow and broad in scope)
were conducted using PTs that could represent various conditions, including but not limited to
angioedema, arthritis, convulsions, demyelination, hypersensitivity, peripheral neuropathy, and
vasculitis.
No new or unexpected ARs were identified based on these SMQ results for either age group.
No cases of myocarditis/pericarditis or vaccine-related anaphylaxis were reported in either age
group through the data cutoff.

SMQ analyses of Angioedema and Hypersensitivity throughout the follow up period yielded
similar incidence of events in vaccine and placebo recipients [n=9 (0.8%) vs. n=4 (0.7%) and
n=25 (2.1%) vs. n=12 (2.0%), respectively, for Angioedema and Hypersensitivity], with urticaria
as the primary PT under the SMQ Angioedema [n=8 (0.7%) vaccine vs. n=3 (0.5%) placebo
recipients]. Most (n=21, 1.8%) events in the SMQ Hypersensitivity were common skin and
subcutaneous tissue disorders for this age, such as rash, eczema/atopic dermatitis, maculo-
papular rash, erythematous rash, and contact dermatitis.
Two unrelated events of anaphylaxis occurred in one BNT162b2 recipient with known peanut
allergy, attributed to a reaction to walnut exposure, and in one placebo recipient with known
food allergies, which was attributed to egg allergy; both were also reported as SAEs.
Additionally, an unrelated event of serum sickness (full body rash) was reported in 1 BNT162b2
53
recipient, 31 days after Dose 2, which was attributed to amoxicillin treatment. FDA concurs with
the investigators that these events were unlikely to be related to vaccination.
Lymphadenopathy was reported by 2 (0.2%) BNT162b2 recipients 6-23 months of age and no
placebo recipients.
• A 12-month-old was noted to have a neck mass 24 days after Dose 2, which was
considered not related to the vaccine by the study investigator. A diagnosis of swollen lymph
node of unknown etiology was made with an ultrasound. No other symptoms were reported,
and the status of the event was ongoing at the time of the data cutoff. FDA concurs with the
investigator’s assessment.
• A 19-month-old had mild enlarged left groin lymph node 2 days after Dose 2, administered
in the left thigh, which resolved after 3 days. The event was considered related to
vaccination by the study investigator and by FDA.
Convulsions were reported at a similar incidence in the BNT162b2 (n=4, 0.3%) and placebo
(n=1, 0.2%) groups. These included: 2 events of seizure in the BNT162b2 group, one of which
occurred 3 days post-Dose 2 and was reported as an SAE (Section 4.2.7.5), and the other was
a nonserious event with onset 164 days post-Dose 2; and 2 events of febrile convulsion in the
BNT162b2 group, one of which was reported as an SAE (Section 4.2.7.5), and both of which
occurred >30 days after vaccination. All were considered by the study investigator and by FDA
as not related to study intervention.

SMQ analyses of Angioedema throughout the follow up period yielded similar incidences of
events between vaccine and placebo recipients [n=7 (0.4%) vs n=4 (0.5%)]. SMQ analyses of
Hypersensitivity yielded more events in the BNT162b2 group compared to the placebo group
[n=16 (0.9%) vs n=4 (0.4%)]. Most (n=11, 0.6%) events in the SMQ for Hypersensitivity were
common skin and subcutaneous tissue disorders for this age, such as rash, eczema/atopic
dermatitis, and contact dermatitis.
Lymphadenopathy was reported by 1 BNT162b2 recipient and no placebo recipients 2-4 years
of age. The lymphadenopathy occurred behind the left ear of a 2-year-old participant 2 days
after Dose 2, with resolution in 6 days, and was considered related to vaccination by the study
investigator and by FDA.
Convulsions were reported at the same incidence in the BNT162b2 (n=4, 0.2%) and placebo
(n=2, 0.2%) groups. In the BNT162b2 group, 1 event of status epilepticus occurred 18 days
post-Dose 1 in a participant with history of seizures, in the setting of a urinary tract infection
(also reported as an unrelated SAE which led to withdrawal). In the BNT162b2 group, this also
included 1 event of epilepsy reported 48 days post-Dose 2 as an SAE, and 2 events of febrile
convulsion, one of which occurred 21 days post-Dose 1 (reported as an SAE); the other event
(non-serious) occurred 42 days post-Dose 2. All events were considered by the study
investigator and FDA as not related to study intervention. SAEs are discussed in Section
4.2.7.5.
Two events of appendicitis were reported, both in the BNT162b2 group and both reported as
SAEs (Section 4.2.7.5). In one case, the participant had acute appendicitis and localized
peritonitis with onset 105 days post-Dose 2 with resolution the next day. In the other case, the
participant had appendicitis with onset 11 days post-Dose 2 that resolved the same day. Both
events were considered by the study investigator and FDA as not related to study intervention.
54
4.2.7.7. Adverse events leading to study withdrawal

Study withdrawals due to AEs in participants 6 months through 4 years of age were reported in
6 BNT162b2 recipients and 1 placebo recipient.

Among participants 6-23 months of age, 3 BNT162b2 recipients and no placebo recipients
withdrew from the study due to an AE. One BNT162b2 recipient developed fever (>40°C) 2
days post-Dose 1 that resolved in 3 days, with concurrent exanthema subitem (viral infection)
that resolved in 4 days. Another BNT162b2 recipient with a history of eczema developed a
generalized rash 5 days after receiving Dose 1, which resolved by Day 9. Additionally, 1
BNT162b2 recipient reported pyrexia 3 days post Dose 3 that resolved in 3 days. All adverse
events were considered related to the vaccine by the study investigator and FDA.

Among participants 2-4-years of ag, 3 BNT162b2 recipients and 1 placebo recipient withdrew
from the study due to an AE. One BNT162b2 recipient with a history of seizures was
hospitalized for status epilepticus (attributed to a urinary tract infection) that occurred 18 days
post-Dose 1. Another BNT162b2 participant experienced a non-serious AE of pyrexia
(maximum temperature 40.8°C), which occurred 2 days post-Dose 1 and resolved in 5 days;
this AE was considered by the study investigator and FDA to be related to vaccination.
Additionally, 1 BNT162b2 recipient had a nonserious AE of mild urticaria which occurred 2 days
post Dose 1 and resolved in 4 days which led to study withdrawal; this AE was considered
related to vaccination by the study investigator and FDA.
4.2.7.8. Subgroup analyses of safety

Subgroup analyses were performed for solicited local and systemic ARs, unsolicited AEs, and
serious AEs, comparing BNT162b2 and placebo groups by sex, race and ethnicity. No notable
differences were observed between subgroups, although certain subgroups such as Black or
African American race and Hispanic/Latino ethnicity had too few participants to draw meaningful
conclusions.
The percentage of participants 6-23 months old and 2-4 years old who reported e-diary data
and who were baseline SARS-CoV-2 positive was 7.5% and 12.6%, respectively. Subgroup
analyses of solicited ARs in each age group, by baseline SARs-CoV-2 status, showed similar
reactogenicity profiles. No notable differences were found in the type, frequency and severity of
unsolicited AEs or serious AEs in this age group in seropositive subjects relative to seronegative
subjects.
4.3. Summary of study C4591007 Phase 2/3
This EUA request included data from 1,178 BNT162b2 recipients and 598 placebo recipients 6-
23 months of age and 1,835 BNT162b2 recipients and 915 placebo recipients 2-4 years of age
in the Phase 2/3 portion of an ongoing clinical trial, C4591007. Among participants 6 months
through 4 years of age, the median follow up was 2.1 months after Dose 3 (inclusive of both
blinded and open-label follow-up) at the time of the April 29, 2022, data cutoff.
Immunobridging success criteria were met for both age groups of 6-23 months and 2-4 years
based on SARS-CoV-2 neutralizing antibody GMTs and seroresponse rates at 1-month post-
Dose 3 evaluated against the USA_WA1/2020 reference strain and compared to participants
16-25 years of age randomly selected from study C4591001. Subgroup immunogenicity
55
analyses by age, gender, race, and ethnicity showed no notable differences compared to the
overall study population, although some subgroups were too small to draw meaningful
conclusions, and participants seropositive for SARS-CoV-2 at baseline had higher post-Dose 3
antibody titers than participants seronegative for SARS-CoV-2 at baseline. Additional
descriptive immunogenicity analyses, based on 50% FFRNT, showed that post-Dose 3
neutralizing antibody GMTs against the Omicron variant were lower than those against the
ancestral strain and Delta variant.
In a preliminary descriptive efficacy analysis of 3 COVID-19 cases in participants 6-23 months

of age, VE against COVID-19 at least 7 days post-Dose 3 was 75.6% (95% CI: -369.1%,
99.6%), with 1 COVID-19 case in the BNT162b2 group and 2 in the placebo group (2:1
randomization BNT162b2 to placebo). In a similar preliminary descriptive efficacy analysis of 7
COVID-19 cases in participants 2-4 years of age with and without evidence of prior SARS-CoV-
2 infection, VE was 82.4% (95% CI: -7.6%, 98.3%) with 2 cases in the BNT162b2 group and 5
in the placebo group (2:1 randomization BNT162b2 to placebo). In a combined analysis of both
age groups, VE was 80.4% (95% CI: 14.1%, 96.7%) with 3 cases in the BNT162b2 group and 7
cases in the placebo group. All COVID-19 cases in these analyses occurred in participants
without evidence of prior SARS-CoV-2 infection, during February 2022 through April 2022, when
the Omicron variant was prevalent in the United States. From Dose 1 through the data cutoff, 1
placebo recipient 6-23 months of age and 7 participants 2-4 years of age (6 BNT162b2
recipients and 1 placebo recipient) met the criteria for severe COVID-19, with only one
hospitalization for severe COVID-19 disease in a BNT162b2 recipient 99 days post-Dose 2.
Solicited local ARs generally occurred at similar frequencies after each dose and solicited
systemic ARs occurred at slightly decreasing frequencies with each successive dose. The most
commonly reported solicited ARs after any dose for participants 6-23 months of age were
irritability (51.2%), drowsiness (27.0%), decreased appetite (22.2%), and tenderness at the
injection site (16.6%). The most commonly reported solicited ARs after any dose for participants
2-4 years of age were pain at the injection site (30.8%), fatigue (29.7%), and injection site
redness (11.4%). Most local and systemic reactions were mild to moderate in severity, with
median onset 1-2 days post vaccination, and a median duration of 1-2 days after onset.
Subgroup safety analyses of reactogenicity by baseline SARS-CoV-2 status showed no notable
differences as compared with the overall study population.
In participants 6-23 months of age, the frequencies of unsolicited non-serious AEs reported
were similar in the BNT162b2 and placebo groups (29.1% versus 26.3%). In participants 2-4
years of age, the frequencies of unsolicited non-serious AEs reported were the same in the
BNT162b2 and placebo groups (18.7% versus 18.7%). The most commonly observed
unsolicited AEs were consistent with those reported as solicited adverse events (local and
systemic reactogenicity) and/or were consistent with events frequently reported in this age
group, including infections and injuries. Lymphadenopathy was observed following vaccination
in two BNT162b2 recipients 6-23 months of age and one BNT162b2 recipient 2-4 years of age;
no cases were reported in the placebo group. From the combined safety database of 3,013
BNT162b2 recipients 6 months through 4 years of age, 1% of participants (n=29) reported
SAEs, as compared to 1.5% of participants (n=22) in the combined safety database of 1,513
placebo recipients 6 months through 4 years of age. Two SAEs (pyrexia [>40°C] and pain in
extremity) which occurred in the same participant were considered by the study investigator as
possibly related to vaccination; FDA considers viral myositis to be a plausible alterative etiology.
Three participants in the BNT162b2 group withdrew from the study due to pyrexia (>40°C);
these AEs were classified as non-serious. There were no reports of myocarditis/pericarditis, no
cases of anaphylaxis considered caused by vaccination, and no deaths.
56
5. Pharmacovigilance activities
Pfizer submitted a revised pharmacovigilance plan to monitor safety concerns that could be
associated with BNT162b2 in individuals 6 months through 4 years of age. The PVP includes
the important identified risks of anaphylaxis, myocarditis, and pericarditis. Pfizer-BioNTech
plans to conduct passive and active surveillance to monitor the post-authorization safety for the
Pfizer-BioNTech COVID-19 Vaccine, including:
Mandatory reporting by the Sponsor under the EUA for the following events to VAERS
within 15 days: SAEs (irrespective of attribution to vaccination); COVID-19 disease resulting
in hospitalization or death; multisystem inflammatory syndrome
Adverse event reporting in accordance with regulatory requirements for the licensed
vaccine, Comirnaty
Additionally, following approval of Comirnaty, the Sponsor was also asked to submit reports of
myocarditis and pericarditis as 15-day reports to VAERS.
The Sponsor will submit periodic safety reports containing an aggregate review of safety data
including assessment of adverse events; vaccine administration errors, whether or not
associated with an adverse event; and newly identified safety concerns.
Post-authorization observational studies will be conducted, which encompass the evaluation of

children 6 months through 4 years of age, and include active surveillance safety studies using
large health insurance claims and/or electronic health record database(s):
Study C4591009: A non-interventional post-approval safety study of the Pfizer-BioNTech

COVID-19 mRNA Vaccine in the United States
Objective: To assess the occurrence of safety events of interest, including myocarditis

and pericarditis, in the general US population of all ages, pregnant women, the
immunocompromised, and persons with a prior history of COVID-19 within selected data
sources participating in the US Sentinel System.
Study C4591021: Post-conditional approval active surveillance study among individuals in

Europe receiving the Pfizer-BioNTech Coronavirus Disease 2019 (COVID-19) Vaccine
Objective: To determine whether an increased risk of prespecified AESI, including

myocarditis/pericarditis, exists following the administration of at least one dose of the
Pfizer-BioNTech COVID-19 Vaccine.
Study C4591021 Substudy (currently C4591038): Substudy to describe the natural history of
myocarditis and pericarditis following administration of Comirnaty
Objective: To describe the clinical course of myocarditis/pericarditis, including treatment,

survival, hospitalization, and long-term cardiac outcomes of myocarditis and pericarditis
among individuals diagnosed with myocarditis and/or pericarditis after receiving at least
one dose of the Pfizer-BioNTech COVID-19 Vaccine and among individuals diagnosed
with myocarditis and/or pericarditis who had no prior COVID-19 vaccination, using a
cohort study design.
57
Study C4591036: Prospective cohort study with at least 5 years of follow-up for potential
long-term sequelae of myocarditis after vaccination (in collaboration with Pediatric Heart
Network [PHN]).
Objective: To characterize the clinical course, risk factors, resolution, long-term

sequelae, and quality of life in children and young adults <21 years with acute post-
vaccine myocarditis/pericarditis.
Pfizer-BioNTech also plans to include vaccine effectiveness analyses among individuals 6

months through 4 years of age in study C4591014 entitled “Pfizer-BioNTech COVID-19
BNT162b2 Vaccine Effectiveness Study Kaiser Permanente Southern California.”
6. Benefit-risk in the context of the proposed EUA for Pfizer-BioNTech COVID-19 Vaccine
in children 6 months through 4 years of age
6.1. Known and potential benefits
Available data support the effectiveness of the Pfizer-BioNTech COVID-19 Vaccine 3-dose
primary series (3 µg each dose) in preventing COVID-19 in the age group of 6 months through 4
years. For each of the age groups of 6-23 months and 2-4 years, vaccine effectiveness was
inferred by immunobridging, based on a comparison of neutralizing antibody responses with
formal hypothesis testing, to a comparator group of participants 16-25 years of age from a
clinical endpoint efficacy study in which observed VE was 91.2% (95% CI: 88.3, 93.5) in
participants 16-55 years of age. 51 Post-licensure and post-authorization observational studies of
Comirnaty and Pfizer-BioNTech COVID-19 Vaccine, respectively, have demonstrated
decreased effectiveness of a primary series against the currently predominant Omicron variant
compared with effectiveness against the ancestral strain and variants (Alpha, Delta) that were
predominant during pre-authorization trials in adults and older pediatric age groups. Consistent
with this observation, descriptive immunogenicity analyses based on an exploratory 50%
FFRNT in participants 6 months through 4 years of age indicate lower neutralizing titers against
the Omicron variant than against the ancestral strain and Delta variant. Available preliminary
descriptive VE data from the ongoing Phase 2/3 study from 555 participants 6-23 months of age
and 860 participants 2-4 years of age who received 3 doses of BNT162b2 were suggestive of
greater effectiveness against COVID-19 disease due to Omicron than following the first 2 doses
of the primary series, but definitive conclusions are limited by a small number of cases that
precluded a reliable estimate of post-Dose 3 VE.
Among infants and children 6 months through 4 years of age, rates of hospitalization and death
due to COVID-19 are higher than among children and adolescents 5-17 years of age, and
comparable to individuals 18-25 years of age, underscoring the benefit of an effective COVID-
19 vaccine in this age group. In older pediatric age groups, the vaccine has been demonstrated
to prevent hospitalization and other serious sequelae such as MIS-C with greater effectiveness
against these more serious outcomes, including during the current Omicron-predominant period.
Given the uncertainty of the COVID-19 pandemic and likelihood of continued SARS-CoV-2
transmission during the ensuing months, deployment of the vaccine for use among children 6
months through 4 years of age will likely have a beneficial effect on COVID-19 associated
morbidity and mortality in this age group. 52
58
6.2. Uncertainties related to benefits
The uncertainties associated with benefits of the Pfizer-BioNTech COVID-19 vaccine when
used in children 6 months through 4 years of age include the following:
• Duration of vaccine effectiveness: the blinded, placebo-controlled evaluation period for

descriptive efficacy analyses was limited, and waning of protection following a primary series
has been observed in older age groups.
• Need for a booster dose: based on experience with adults, it is likely that a booster dose will
be needed in addition to the three-dose primary series to increase robustness, breadth, and
duration of protection against currently circulating and emerging SARS-CoV-2 variants in
children 6 months through 4 years of age. A booster dose could be considered for
authorization with submission of supportive data in a future amendment to the EUA.
• Effectiveness in certain populations at high risk of severe COVID-19, including
immunocompromised individuals.
• Benefits in individuals previously infected with SARS-CoV-2: descriptive post-Dose 3
efficacy analyses do not include cases in previously infected participants. However,
observational data with other COVID-19 vaccines have demonstrated an added benefit of
vaccination to protection conferred by natural immunity. 53 Additionally, for individuals
previously infected with the Omicron variant of SARS-CoV-2, a vaccine based on the
ancestral strain S protein could provide a greater breadth of protection against SARS-CoV-2
variants.
• Effectiveness in preventing post-acute sequelae of COVID-19: available data are not
conclusive on the effectiveness of COVID-19 vaccines currently in use against long-term
sequelae of COVID-19 among individuals who are infected despite vaccination. Additional
evaluation is needed to assess the effect of this vaccine in preventing long-term effects of
COVID-19, including data from clinical trials and from the vaccine’s use post-authorization.
• Future vaccine effectiveness as influenced by characteristics of the pandemic, including
emergence of new variants: the continued evolution of the pandemic, including changes in
the virus infectivity, antigenically significant mutations to the S protein, and changes in
practice of nonpharmacologic interventions to mitigate against transmission, will likely
influence vaccine effectiveness over time. Continued evaluation of vaccine effectiveness
following issuance of an EUA and/or licensure will be critical.
• Vaccine effectiveness against asymptomatic infection and transmission of SARS-CoV-2:
Available data for COVID-19 vaccines currently in use has demonstrated that effectiveness
against asymptomatic infection is lower and less durable than effectiveness against
symptomatic COVID-19. Available data also do not indicate high-level or durable
effectiveness against transmission of SARS-CoV-2 from vaccinated individuals with
breakthrough infections.
6.3. Known and potential risks
In study participants 6 months through 4 years of age, there were numerically higher rates of
solicited local and systemic ARs in BNT162b2 recipients than in placebo recipients. Overall, the
rates of these ARs reported among participants 6 months through 4 years of age were lower
than those reported among older age groups and likely reflect the lower vaccine mRNA content
evaluated in participants 6 months through 4 years of age. In considering unsolicited AEs
reported among participants 6 months through 4 years of age, the available safety data from a
total database of over 3,000 vaccine recipients do not suggest any new safety concerns
compared with the safety profile described in older age groups.
59
Anaphylaxis, primarily among individuals with a history of severe allergic reactions to other
medications or foods, has been documented to occur at a rate of approximately 6 cases per
million doses among BNT162b2 recipients 16 years of age and older (similar in magnitude to
reported rates of anaphylaxis following other licensed preventive vaccines). Risk of allergic
reactions, including the potential for severe allergic reactions and the need for vaccine providers
to be able to manage them should they occur and a contraindication for use in individuals with
known allergy to any component of the vaccine, are described in the vaccine Fact Sheets and
Prescribing Information. Additionally, risk of anaphylaxis/severe allergic reactions will be further
evaluated as part of the PVP for the vaccine.
Myocarditis/pericarditis, in particular in the first week following Dose 2, is a known risk

associated with the Pfizer-BioNTech COVID-19 Vaccine and is greatest among adolescent
males 16-17 years of age compared with both younger and older age groups. In contrast to
myocarditis in the pre-COVID era, most reported cases of vaccine-associated myocarditis have
involved rapid resolution of symptoms with conservative management; however, the long-term
sequelae of vaccine-associated myocarditis, if any, remain to be determined. The risk of
vaccine-associated myocarditis/pericarditis among children 6 months through 4 years of age is
unknown at this time. No cases of myocarditis or pericarditis were reported among over 3,000
vaccine recipients in the clinical trial, some of whom had at least 1 month of follow-up post-Dose
3. However, this safety database is not large enough to quantify the frequency of this
uncommon AR. Data supporting that the risk of vaccine-associated myocarditis may be lower
among children 6 months through 4 years of age compared with adolescents 16-17 years of age
include a lower rate of vaccine-associated myocarditis reported to VAERS in males 5-11 years
of age than for males 12-15 and 16-17 years of age, and lower rates of systemic reactogenicity
in participants 6 months through 4 years of age associated with the lower vaccine mRNA
content intended for use in this age group.
6.4. Uncertainties related to risks
The uncertainties associated with risks of the Pfizer-BioNTech COVID-19 vaccine when used in
children 6 months through 4 years of age include the following:
• Risk of myocarditis/pericarditis, as described in detail in Section 6.3 above, including:

o Incidence of myocarditis/pericarditis in children 6 months through 4 years of age.
o Short-term and potential long-term sequelae and outcomes in affected individuals
o Whether the vaccine is associated with subclinical myocarditis, and if so, whether there
are long-term sequelae.
o Mechanism of action by which the vaccine could cause myocarditis and pericarditis has
not been established.
• Safety in certain subpopulations
o Available data are insufficient to make conclusions about the safety of the vaccine in
certain subpopulations such as immunocompromised children.
o Safety data in children previously infected with SARS-CoV-2 are limited; however,
available data do not suggest increased reactogenicity or other safety concerns among
previously infected children.
• Adverse reactions that are very uncommon or that require longer follow-up to be detected.
Active and passive safety surveillance will continue during the post authorization period to
detect new safety signals, Section 5, Pharmacovigilance Activities.
60
7. Topic for VRBPAC Discussion
The VRBPAC will convene on June 15, 2022, to discuss whether, based on the totality of
scientific evidence available, the benefits of the Pfizer-BioNTech COVID-19 Vaccine, when
administered as a three-dose primary series, outweigh its risks for use in infants and children 6
months through 4 years of age.
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63
9. Appendix A: Study C4591007 Phase 1 information
9.1. Phase 1: Dose-finding and dose selection design
For Phase 1, BNT162b2 was evaluated in children in the US who were not at high risk of SARS-
CoV-2 exposure, did not have medical conditions that represented risk factors for severe
COVID-19, and did not have serologic/virologic evidence of prior SARS-CoV-2 infection.
BNT162b2 dose levels of 3 µg and 10 µg were evaluated in an age de-escalation, open-label
manner for each age group (2-4-years first, followed by 6-23 months), sequentially based upon
the safety evaluation and recommendation by the internal review committee to either advance to
the subsequent dose level or terminate a specific dose level, with the plan to administer 2
doses, 3 weeks apart to all participants. Safety evaluation included reactogenicity (solicited local
reactions and systemic events) 7 days after each dose and AEs through 1 month after Dose 2,
for each dose level. The data analysis cutoff date for Phase 1 was July 16, 2021. SARS-CoV-2
50% neutralizing GMTs (SARS-CoV-2 mNG microneutralization assay) were assessed at an
early timepoint (at 7 days after Dose 2) to facilitate dose selection.
Based on the 10-µg safety assessments for children 5-11 years of age in C4591007, dose
finding was initiated at 10 µg in 2-4-year-olds. Following review by the internal review
committee of safety data in 2-4-year-olds for up to 7 days after Dose 1, dosing commenced at
the 3-μg dose level in participants 6-23 months of age.
9.2. Phase 1: Safety results

Two dose levels (3 μg and 10 μg) were evaluated in 48 participants 2-4 years of age (n=16 for 3
μg and n=32 for 10 μg). Solicited local and systemic ARs were mostly mild to moderate and
short-lived. In general, the frequency and/or severity of solicited ARs increased with increasing
dose level and number of injections.
Pain at the injection site was the most commonly reported local reaction for both dose levels.
The proportion of participants with pain at the injection site was higher in the 10-μg group
compared to the 3-μg group after Dose 1 and Dose 2: 10 μg (62.5% and 53.1%) versus 3 μg
(31.3% and 37.5%). Participants in the 10-μg group reported redness and swelling within 7 days
after Dose 1 and Dose 2 [redness: 10 μg (28.1% and 15.6%); swelling: 10 μg (9.4% and 3.1%)];
none of the participants in the 3-μg group reported redness or swelling within 7 days after either
dose. No Grade 4 local reactions were reported.
Fatigue was the most commonly reported systemic reaction for both dose levels. The proportion
of participants with fatigue was higher in the 10-μg compared to the 3-μg dose level group after
Dose 1 and Dose 2: 10 μg (46.9% and 59.4%) versus 3 μg (25.0% and 25.0%).
Fever was more common and more severe in the 10-μg group than in the 3-μg group after Dose
1 and Dose 2: 10 μg (18.8% and 18.8%) versus 3 μg (0% and 6.3%). Severe fever (>38.9°C to
40°C) was reported in the 10-μg group by 2 (6.3%) participants within 7 days after Dose 1 and 2
(6.3%) participants and none in the 3-μg group. All systemic events except fever were mild or
moderate in severity post-Dose 1 and 2.
From Dose 1 to 1 month after Dose 2, one or more AEs were reported by 25.0% of participants
in the 3-μg group and 37.5% of participants in the 10-μg group. A higher proportion of AEs in
the 10-μg group than in the 3-μg dose level group were considered by the study investigator as
64
related to study intervention (21.9% vs. 12.5%). In the 10-μg group, the AEs reported were
injection site pain (n=3), costochondritis (n=1), lymphadenopathy (n=1), abdominal discomfort
(n=1), abdominal pain (n=1), and injection site bruising (n=1), whereas the 3-μg group reported
only injection site pain (n=2). None of the participants reported a severe AE or SAE, and no
deaths were reported during the study.

The 3-μg dose level was evaluated in 16 participants 6-23 months of age. Local and systemic
reactogenicity were mostly mild and resolved within 1 or 2 days. Redness (18.8%) and swelling
(6.3%) were the most common local reactions within 7 days after Dose 1. Tenderness at
injection site (6.3%) was the only local reaction within 7 days after Dose 2. All local reactions
were mild in severity. Drowsiness (25.0%) and irritability (43.8%) were the most frequent
systemic events reported within 7 days after Dose 1. Irritability (31.3%), fever (12.5%), and
decreased appetite (12.5%) were more common within 7 days after Dose 2. All systemic events
within 7 days after Dose 1 were mild or moderate in severity, and those within 7 days after Dose
2 were mild in severity.
From Dose 1 to 1 month after Dose 2 in participants 6-23 months of age, one or more AEs were
reported by 12.5% of participants who received 3 μg BNT162b2. One 16-month-old participant
reported Grade 1 urticaria on Day 1 post-Dose 1, which resolved in 2 days and was considered
related to the study intervention. No severe AEs, SAEs or deaths were reported.
9.3. Phase 1: Immunogenicity results
For both age groups (6-23 months, 2-4 years), the SARS-CoV-2 neutralizing GMTs SARS-CoV-
2 neutralizing GMTs at the 3-μg level were similar, and numerically higher than GMTs at 1
month post-Dose 2 (30 μg) from participants 16-25 years of age (study C4591001). In
participants 2-4 years of age, the SARS-CoV-2 neutralizing antibody response was dose-
dependent, and SARS-CoV-2 neutralizing GMTs at 7 days post-Dose 2 at the 10-μg level were
similar to GMTs at 1 month post-Dose 2 (30 μg) from adolescents 12-15 years of age (study
C4591001) and numerically higher than GMTs post-Dose 2 (30 μg) in participants 16-25 years
of age (study C4591001). Sera from participants in study C4591007 and the comparator groups
were tested contemporaneously with the same assay.
9.4. Phase 1: Dose selection decision
Because the 3-μg dose level was better tolerated than the 10-μg dose level in children 2-4 years
of age, the 3-μg dose level was selected for evaluation in children 6-23 months of age. The 3-μg
dose selected for both age groups in the Phase 2/3 portion of study C4591007 was also
supported by the preliminary immunogenicity results.
65
10. Appendix B: COVID-19 case definitions
COVID-19
The case definition for a confirmed case of COVID-19 was the presence of at least one of the
following symptoms and a positive SARS-CoV-2 nucleic acid amplification test within 4 days of
the symptomatic period:
• Fever
• New or increased cough
• New or increased shortness of breath
• Chills
• New or increased muscle pain
• New loss of taste or smell
• Sore throat
• Diarrhea
• Vomiting
• Inability to eat/poor feeding
Severe COVID-19
The case definition for a severe COVID-19 case included a confirmed COVID-19 case with at
least one of the following:
• Clinical signs at rest indicative of severe systemic illness (RR and HR, by age, 1 SpO2≤93%
on room air at sea level, or PaO2/FiO2 <300 mm Hg)
• Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation,
mechanical ventilation, or ECMO)
• Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm
Hg, or requiring vasopressors)
• Significant acute renal, hepatic, or neurologic dysfunction
• Admission to an ICU
• Death
For participants <5 years of age, positive RT-PCR cases confirmed by the central laboratory or
valid local test also underwent BioFire testing for coinfection with other respiratory pathogens.
1
Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and respiratory rate in children from birth to 18 years of
age: a systematic review of observational studies. Lancet. 2011;377(9770):1011-8.
66

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Vaccines and Related Biological Products Advisory Committee Meeting

June 15, 2022

FDA Briefing Document

EUA amendment request for Pfizer-BioNTech COVID-19 Vaccine

Table 1. Study C4591007 in Participants 6 Months Through 4 Years of Age (3 µg BNT162b2) 16

In study C4591007, vaccine effectiveness was inferred by immunobridging based on SARS-

without evidence of prior SARS-CoV-2 infection at baseline. Otherwise, subgroup analyses of

2.1. SARS-COV-2 virus and COVID-19 disease

Following observation of an increased incidence of myocarditis in 2020 compared with 2019,

2.2. Authorized and approved vaccines and therapies for COVID-19

2.2.1. Comirnaty and Pfizer-BioNTech COVID-19 Vaccine

Comirnaty (COVID-19 Vaccine, mRNA) made by BioNTech Manufacturing GmbH (in

2.2.2. Spikevax and Moderna COVID-19 Vaccine

Spikevax (COVID-19 Vaccine, mRNA), manufactured by Moderna, is approved for active

2.2.3. Janssen COVID-19 Vaccine

2.2.4. Therapies for COVID-19

adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or

Other pharmacological products for pre-exposure prophylaxis of COVID-19, post-exposure

SARS-CoV-2-targeting monoclonal antibodies: Bebtelovimab is authorized under EUA for the

Immune modulators: Baricitinib is authorized for the treatment of COVID-19 in hospitalized

2.3. Post-licensure/post-authorization experience with Comirnaty and Pfizer-BioNTech

2.3.1. Vaccine effectiveness against SARS-CoV-2 variants of concern

2.3.2. Post-EUA and post-licensure safety surveillance

Myocarditis and pericarditis

Although some cases of vaccine-associated myocarditis/pericarditis have required intensive

Vaccine Formulation for children 6 months through 4 years of age

3. EUA requirements, guidance and considerations pertaining to COVID-19 vaccines

3.1. US requirements to support issuance of an EUA for a biological product

3.2. FDA guidance for industry related to COVID-19 vaccines

3.3. Regulatory considerations for clinical development of COVID-19 vaccines in

4. FDA review of clinical safety and effectiveness data

4.1. Overview of study C4591007

Table 1. Study C4591007 in Participants 6 Months Through 4 Years of Age

4.2. Phase 2/3

4.2.1. Phase 2/3 study design

4.2.1.1. Phase 2/3 immunogenicity evaluation

4.2.1.2. Phase 2/3 efficacy evaluation

4.2.1.3. Phase 2/3 safety evaluation

Unsolicited adverse events

Adverse events of clinical interest

4.2.2. Phase 2/3 analysis populations

Data analysis cutoff dates:

4.2.3. Phase 2/3 disposition

Participants 2-4 years of age

Participants 2-4 years of age

Participants 6-23 months of age

Participants 2-4 years of age

4.2.4. Phase 2/3 comorbidities at baseline

Participants 6-23 months of age

Participants 2-4 years of age

4.2.5. Phase 2/3 demographic and baseline characteristics

Participants 2-4 years of age

Immunogenicity and efficacy populations

Comparator groups for immunogenicity

4.2.6. Phase 2/3 vaccine effectiveness results

4.2.6.1. Primary immunogenicity objectives

Participants 6-23 months of age

Participants 2-4 years of age