Document text
BNT162b2
1.2 Request for Priority Review
CONFIDENTIAL
Page 1REQUEST FOR PRIORITY REVIEW
COVID -19 Vaccine (BNT162, PF -07302048)
sBLA 125742/45
DECEMBER 2021
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Page 2TABLE OF CONTENTS
LIST OF FIGURES ................................ ................................ ................................ ................... 2
ABBREVIAT IONS ................................ ................................ ................................ ................... 3
1. OVERVIEW ................................ ................................ ................................ .......................... 4
1.1. Rationale for Priority Review ................................ ................................ .................... 4
1.2. Serious and L ife-threatening Disease ................................ ................................ ........ 4
1.2.1. Background and Clinical Presentation of COVID -19 ................................ ..4
1.2.2. I ncidence and Prevalence of COVID-19 ................................ ...................... 5
1.3. Unmet Medical Need ................................ ................................ ................................ 6
1.4. Significant Improvement in Safety and Effectiveness through P revention of
COVID -19 Disease ................................ ................................ ................................ ......6
1.4.1. Overview of Immunogenicity ................................ ................................ .......6
1.4.2. Overview of Efficacy –Updated Anal ysis................................ ................... 7
1.4.3. Overview of Safety................................ ................................ ....................... 7
1.4.4. Overview of Supportive Real World and Post -Authorization Data
Following Use of BNT162 b2 in Children 12 -15 Years of Age ......................... 8
1.4.5. Overview of Post- authorization Safety Data ................................ ................ 9
1.5. Conclusions ................................ ................................ ................................ ............. 10
2. REFERENCES ................................ ................................ ................................ .................... 12
LIST OF FIGURES
Figure 1 Trends in Total Deaths in The United States Reported to CDC................. 5
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Page 3ABBREVIATIONS
Abbreviation Definition
AE adverse event
BLA Biologics License Application
CDC Centers for Disease Control and Prevention
CFR case fatality rates
CI confidence interval
COVID -19 Coronavirus Disease 2019
CSR Clinical Study Report
EUA Emergency Use Authorization
FDA (US) Food and Drug Administration
GMFR geometric mean -fold rise
GMT geometric mean titer
ICU intensive care unit
IM intramuscular(ly)
IND Investigational New Drug
IQR interquartile range
SAE serious adverse event
SARS -CoV-2 severe acute respiratory syndrome Coronavirus -2; virus causing the disease COVID -19
sBLA supplemental Biologics License Application
SOC System Organ Class
US United States
VAERS Vaccine Adverse Event Reporting System
VE vaccine efficacy
VOC Variant of Concern
VOI Variant of Interest
WHO World Health Organization
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Page 41. OVE RVIEW
In accordance with the provisions outlined in the Prescription Drug User Fee Act (PDUFA) and
the Food and Drug Administration ( FDA )Guidance for Industry Expedited Programs for Serious
Conditions –Drugs and Biologics (May 2014)1, Pfizer and BioNTech are requesting Priority
Review Designation for the expansion of licensure of BNT162b 2 (COMIRNATY) to individuals
12-15 years of age .BNT162b2 is a prophy lactic vaccine that targets severe acute respiratory
syndrome Coronavirus- 2 (SARS -CoV -2), which causes Coronavirus Disease 2019 ( COVID -19).
The proposed expanded indication for the candidate vaccine is active immunization to prevent
COVID -19disea se caused by SARS -CoV -2 in individuals ≥12years of age. The proposed
dosage is 30 µg via intramuscular (IM) injection following a dosing regimen of two 0.3 -mL
doses given 3 weeks apart. The Investigational New Drug Application ( IND 19736 )for
BNT162b2 was effective on 29 April 2020. Emergency use authorization (EUA 27034) for
active immunization to prevent COVID -19 caused by SARS -CoV -2was initially issued for
BNT162b2 (Pfizer -BioNTech COVID -19 Vaccine) on 11 December 202 0 for individuals 16
years of age and older. Emergency use authorization was extended to individuals 12 through 15
years of age on 10 May 202 1.BNT162b2 was licensed for use in individuals 16 y ears of age and
older on 23 August 2021 (BLA 125742). The BLA was granted Priorit y Review Designation.
Pfizer and BioNTech are presentl y seeking expansion of licensure of BNT162b2 to include
individuals 12 -15 years of age and are requesting priority review .
1.1.Rationale for Priority Review
The supplemental Biologics L icense Application ( sBLA) for BNT162b2 meets the criteria for
priority review designation , as outlined i n the 2014 Guidance for Industry : Expedited Programs
for Serious Conditions –Drugs and Biologics ,because BNT162b2 prevents a serious and
life-threatening condition (COVID -19) in individuals 12-15 years of age and, if approved, would
provide a significant improvement in safet y andeffectiveness because there are currentl y no
vaccines licensed for the prevention of COVID-19 in the US for this age group (Section 1.2and
Section 1.4).1
1.2.Serious and Life -threatening Disease
1.2.1. Background and Clinical Presentation of COVID-19
COVID -19 is caused by SARS -CoV -2, a zoonotic virus that first emerged as a human pathogen
in China and ha s rapidl y spread around the world by human -to-human transmission. SARS -CoV -
2 infections and the resulting disease COVID -19 have spread globall y, and on 11 March 2020
the World Health Organization ( WHO )characterized the COVID -19 outbreak as a pandemic. At
the time of this submission, the ongoing pandemic remains a significant challenge to public
health and economic stability worldwide, for which for a licensed prophy lactic vaccine is a
necessary and critical mitigation.
COVID -19 presentation is generall y with cough and fever, with chest radiography showing
ground -glass opacities or patch y shadowing.2However, man y patients present without fever or
radiographic changes, and infections may be as ymptomatic which is relevant to controlling
transmission. For sy mptomatic patients, disease progression may lead to acute respiratory distress
syndrome requiring ventilation, subsequent multi- organ failure, and death.2
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Page 5Common sy mptoms in hospitalized patients (in order of highest to lowest frequency ) include
fever, dry cough, shortness of breath, fatigue, my algias, nausea/vomiting or diarrhea, headache,
weakness, and rhinorrhea.2Anosmia (loss of smell) or ageusia (loss of taste) may be the sole
presenting s ymptom in approximately 3% of individuals who have COVID-19.2
The US Centers for Disease Control and Prevention (CDC) defined COVID- 19 sy mptoms as
including 1 or more of the following:3fever, 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, fatigue, headache, nasal congestion or runny nose, or nausea.
All ages may present with the disease, with case fatalit y rates (CFR) elevated in persons
>60years of age.4Comorbidities are associated with increased CFR, including cardiovascular
disease, diabetes, hy pertension, and chronic respiratory disease.5Healthcare workers are over -
represented among COVID -19 patient s due to occupational exposure to infected patients.5In the
US, the death total has risen to almost 800,000 as of 12 December 2021 (Figure 1).6
Figure 1Trends in Total Deaths in The United States Reported to CDC
1.2.2. Incidence and Prevalence of COVID-19
With the widespread availability of COVID -19 vaccines in the United States, the disease burden
has shifted to increasingly impact younger age groups, particularl y pediatric and adolescent
populations who remain largel y unvaccinated.7As of the week ending October 16, 2021, the age
groups 5 -11, 12 -15, and 16 -17 years had among the highest weekl y case rates per 100,000
population (164.1, 154.0, and 163.8 per 100,000, respectivel y).8Although the hospitalization rate
among those 12 -17 years of age is low relative to other age groups (1.6/100,000 or lower since
Octo ber 2021)9, among those who are hospitalized, the risk of progression to severe disease
(requiring ICU admission, invasive mechanical ventilation, or in -hospital death) in this age group
is approximately 30-34%.10,11,12
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Page 61.3.Unmet Medical Need
Vaccination is the m ost effective medical countermeasure to decrease risk and mitigate spread of
the SARS -CoV -2 virus. Immunization with a safe and effective COVID -19 vaccine is a critical
component of the nation’s strategy to reduce COVID -19-related illnesses, hospitalizatio ns, and
deaths and to help restore societal functioning.
Data from pre -clinical and clinical studies on tolerability , safety, immunogenicity , and efficacy
of Pfizer -BioNTech COVID-19 Vaccine have shown the known and potential benefits outweigh
the known and potential risks for individuals 16 y ears of age and older, and formed the basis of
approval of Pfizer -BioNTech COVID -19 Vaccine in the US. As of December 2021, BNT162b2
30-µg has received temporary authorization for emergency use, conditional marketing
authorization approval, or full approval in >90 countries globall y.
Licensure of Pfizer -BioNTech COVID -19 Vaccine for use in individuals 12- 15 years of age at
this time addresses an urgent public health need. These adolescents have experienced
unprecedented prolonged disruption to education and social development for over a year during
the SARS -CoV -2 pandemic, due to infection risk in congregate settings; this in turn creates
significant challenges for families and communities, in particular whe re the pandemic has
exacerbated pre -existing socio- economic disparities.13,14Education is a key determinant of health
and a driver of economic opportunity . Expanding COVID -19 vaccination eligibility to include
adolescents, in addition to individuals 16 years of age and older, would further protect
communities (eg, support a safe return to in -person learning for schools and increase vaccination
rates overall ). Licensure of Pfizer -BioNTech COVID- 19 Vaccine in individuals 12 -15years of
age, based on demonstrat ed effectiveness (via immunobridging), efficacy , and safet y data from
approximately 2200 individuals in this age group in pivotal Study C4591001, would address
critical and dual unmet needs for public health and education.
1.4.Significant Improvement in Safety and Effectiveness through Prevention of COVID-19
Disease
1.4.1. Overview of Immunogenicity
Refer to Section 11.3 of the adolescent interim CSR dated 14 April 2021 (through data cutoff
date of 13 March 2021, Module 5.3.5.1 C4591001 Adolescent Interim CSR ) for full details of
immunogenicit y anal yses for adolescent participants 12- 15 years of age, including results for
additional immunogenicity endpoints which were anal yzed for SARS -CoV -2 serum neutralizing
titers (GMTs, GMFRs, and s eroresponse rates).
Immune response to BNT162b2 30 µg in SARS- CoV -2 50% neutralizing titers in adolescents
12-15 years of age was noninferior to (and in fact exceeded) the immune response in y oung
adults 16-25 years of age, which provides immunobridging for adolescents. Substantial increases
over baseline in neutralizing GMTs and high seroresponse rates were observed at 1 month after
Dose 2 in both age groups, which were observed for participants with baseline SARS -CoV -2
positive and negative status. The vast majority of BNT162b2 recipients in both age groups
achieved a ≥4-fold rises from before vaccination to 1 month after Dose 2.
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Page 71.4.2. Overview of Efficacy – Updated Analysis
Refer to Section 11 of the adolescent 6-month update interim CSR dated 12December 2021
(Module 5.3.5.1 C4591001 Adolescent 6 -Month Update Interim CSR ) for full details of updated
efficacy analyses for adolescent participants 12 -15 years of age . Descriptive efficacy anal yses
were conducted for the adolescent group on cases accrued during b linded placebo -controlled
follow -up period through the data cutoff date of 02 September 2021.
In the adolescent group, in efficacy anal yses in the evaluable efficacy population based on cases
reported from at least 7 days after Dose 2 through the data cut off date (02 September 2021), the
estimated VE against confirmed COVID -19 was 100% (95% CI: 86.8%, 100%) for individuals
without evidence of prior SARS -CoV -2 infection before and during vaccination regimen, and
100% (2 -sided 95% CI: 87.5%, 100%) for those with or without evidence of prior SARS -CoV -2
infection before and during vaccination regimen.
Among participants without and with or without evidence of SARS -CoV -2 infection before and
during the vaccination regimen (evaluable efficacy population), VE aga inst COVI D-19 occurring
at least 7 day s after Dose 2 was evaluated for demographic and risk subgroups, and the estimated
VE was 100.0% for all subgroups.
The efficacy anal ysis for the Dose 1 all -available (modified intention -to-treat) population,
included 3 cases in the BNT162b2 group (all occurring within <11 day s after Dose 1 and in
participants who had baseline SARS -CoV -2 negative status) and 48 cases in the placebo group,
with an estimated VE against all cases occurring at an y time after Dose 1 of 94.0% (2-sided 95%
CI: 81.3%, 98.8%).
No severe cases were reported in the 12- 15 years of age group as of the data cutoff date
(02September 2021).
Most variants sequenced were neither Variant of Interest (VOI) nor Variant of Concern (VOC)
except for the B.1.1. 7 (Alpha) found in 23.3% of placebo participants. All of the cases in the
efficacy anal yses occurred between 02 November 2020 to 19 May 2021, which is before the
Delta surge in the US.
Overall, these updated efficacy data strongl y support BNT162b2 use in a dolescents 12-15 years
of age.
1.4.3. Overview of Safety
Refer to Section 1 2of the adolescent 6 -month update interim CSR dated 12 December 2021
(through data cutoff date of 02 September 2021, Module 5.3.5.1 C4591001 Adolescent 6 -Month
Update Interim CSR ) for ful l details of updated safety analyses for adolescent participants 12 -15
years of age.
Based on Phase 3 data from 2260 participants 12- 15 years of age with up to at least 6 months of
follow -up after Dose 2 in Study C4591001, BNT162b2 at 30 µg was safe and well- tolerated and
aligned with that previously demonstrated for 16 yrs and older. The AE profile did not suggest
any new safet y concerns. The incidence of SAEs was low in the context of the number of
participants enrolled and compar able in the BNT162b2 and placebo groups. Only 1 participant
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Page 8discontinued from the study due to an AE (related nonserious AE of py rexia [previously
reported]), and there were no deaths.
Cumulative safety follow -up from Dose 1 to 6 months after Dose 2 for 11 13 adolescent
participants originally randomized to BNT162b2 (comprising the combined blinded
placebo- controlled and open -label observational periods), and from the open -label follow -up of
1010 adolescent participants originall y randomized to placebo (from the time of unblinding to
receive BNT162b2 until the data cutoff date), showed no new safet y signals or suggested an y
new safety concerns arising from this period of follow -up.
Similarly , anal yses of new AEs since the EUA data snapshot showed no new safet y signals or
concerns.
Safety anal ysis results for subgroups based on demographics (age, race, ethnicity , and sex) and
by baseline SARS -CoV -2 status (positive vs negative) have not shown an y clinically important
differences in the BNT162b2 safet y profile.
Adolescent Phase 3 safety data were generall y concordant with previousl y reported adult safet y
data ( ≥16 y ears of age) in Phases 1- 3 of the stud y.
1.4.4. Overview of Supportive Real World and Post -Authorization Data Following Use of
BNT162b2 in Children 12 -15 Yea rs of Age
The Phase 3 Study C4591001 updated efficacy results are supported b y contemporaneous real -
world data from Israel and the United States demonstrating high vaccine effectiveness (90%) of
two doses of BNT162b2 against sy mptomatic COVID -19 in the ado lescent
population.15,16,17,18,19,20
Two studies from Israel examined short -term VE against infection up to 3- 4 weeks after the
second dose among adolescents without prior SARS- CoV -2 infection.15,16Among individuals
aged 12 -15 years who received their second dose between July 1, 2021 and July 24, 2021 (i.e.,
during the earl y stages of the delta variant outbreak in I srael), adjusted VE against infection in
the 8- 28 day s after the second dose was 92% (95% CI : 88-94).15Similarly, in another study of
adolescents aged 12 -18 years vaccinated between June 8 -September 14, 2021, a time period
when the delta variant accounted for over 95% of all new cases in Israel, VE in the 7 -21 day s
after the second dose was 90% (95% CI: 88 -92) against infection and 93% (95% CI : 88-97)
against sy mptomatic COVID -19.16
Results from two studies reporting VE against infection among US adolescents are remarkabl y
consistent with the results observed in Israel.17,18Among Kaiser Permanente Southern California
(KPSC) members aged 12- 15 years, the adjus ted VE against infection through August 8, 2021
was 91% (95% CI: 88 -93). Further, protection against infection remained high through 3 months
following the second dose (the latest follow -up available with sufficient sample size for
evaluation); adjusted VE at <1 month, 1 to <2 months, and 2 to <3 months was 91% (95%: 86 -
94), 92% (95% CI: 88- 94), and 88% (95% CI : 68-96), respectively .17In another US study
examining Kaiser Permanente Northwest enrollees during July 4-September 11, 2021, a period
of delta predominance, the incidence rate ratio for infection comparing vaccinated ( ≥2 doses)
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Page 9versus unvaccinated adolescents aged 12 -17 years was 8.9 (95% CI: 6.6 -11.9), which can be
calculated as a VE against infection of approximately 91%.18
Two CDC studies that assessed protection against hospitalization among the adolescent
population reported VE estimates of approximately 90%.19,20Among US patients aged 12 -18
years hospitalized at 19 pediatric hospitals across 16 states, adjusted VE against hospitalization
during June 1 -September 30, 2021 was 93% (95% CI : 83-97). Results were similar when
stratified by age group; VE was 91% (95% CI : 74-97) among patients aged 12 -15 years and 94%
(95% CI : 78-99) among patients aged 16 -18 years. The median (interquartile range [IQR])
duration between the second dose and illness onset was 72 (45- 97) day s.19The second stud y
estimated the risk of hospitalization by vaccination status among adolescents aged 12 -17 years
from June 20- July 31, 2021. This study reported an incidence rate ratio of 10.1 ( 95% CI : 3.7-
27.9), which can be calculated as a VE of approximately 90%. It should be noted, however, that
the sample size of this analy sis was small (n=68).20
Overall, real -world effectiveness data to date indicate high VE against infection and
hospitalization following two doses of BNT162b2 in individuals 12 -15 years of age of
approximately 90%.
Real-world safet y surveillance data has shown that ra re cases of post- vaccination my ocarditis
may occur in individuals 12− 15 years of age (21.5 per million second doses administered based
on VAERS).21These events tend to occur more frequently after the second dose and among
males (39.9 vs 3.9 per million sec ond doses administered in males versus females,
respectivel y).21
1.4.5. Overview of Post -authorization Safety Data
Post-authorization safety data are continuall y monitored by Pfizer and BioNTech for
pharmacovigilance and risk management purposes. Pfizer’s safet y database contains cases of
AEs reported spontaneously to Pfizer, cases reported by the health authorities, cases published in
the medical liter ature, cases from Pfizer -sponsored marketing programs, non- interventional
studies, and cases of serious AEs reported from clinical studies regardless of causalit y
assessment. Cumulatively, out of the 629,525 total reports received through 30 September 2021 ,
there was a total of 3320 post -marketing reports containing 10,050 events occurred in pediatric
individuals aged between 12 and 15 y ears of age.
Consistent with events in Phase 2/3 of Study C4591001, most reported AEs were in SOCs with
reactogenicity events. T he SOCs that contained the greatest number (≥ 5%) of events included
General disorders and administration site conditions (2545 AEs), Nervous sy stem disorders (1606),
Injury , poisoning and procedural complications (1131), Gastrointestinal disorders (8 30), Skin and
subcutaneous tissue disorders (599), Musculoskeletal and connective tissue disorders (584),
Respiratory , thoracic and mediastinal disorders (495), Cardiac disorders (362), Investigation (350),
Infections and infestations (229), Psychiatric di sorders (188) and Vascular disorders (167).
The safet y profile of BNT162b2 remains aligned with the approved label. There was no new
significant information emerging from the close monitoring for anaph ylaxis and
myocarditis/pericarditis, and the anal yses of cumulative post -authorization safet y data, including
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Page 10a review of AESIs, are consistent with the analy sis of the pivotal clinical study (C4591001) and
has confirmed the favorable benefit -risk profile of the vaccine.
Further details regarding the cumulati ve anal ysis of post -authorization safety data are presented
in Module 5.3.6.
1.5.Conclusions
The sBLA meets the criteria for priority review designation, as outlined in the 2014 Guidance for
Industry: Expedited Programs for Serious Conditions – Drugs and Biologics because BNT162b2
prevents a serious and life -threatening condition (COVID -19) and, if approved, would provide a
significant improvement in safet y and effectiveness because there are currently no vaccines
licensed for the prevention of COVID -19 in the US for individuals 12 -15 years of age .1
The available and updated clinical data for BNT162b2 effectiveness includes induction of strong
immune respo nses and overwhelmingly high vaccine efficacy with a satisfactory safet y profile,
suggesting that the vaccine confers safe and effective protection against COVID -19 in
individuals ≥12 y ears of age.
The potential risks are based on the observed clinical st udy safet y profile to date, which shows low
incidence of severe or serious events, and no new clinically concerning safety observations or
safet y concerns (and mostly mild reactogenicity , as previously reported). The vaccine has been
shown to be safe and w ell-tolerated irrespective of prior infection with SARS- CoV -2. In this
adolescent age group, no AEs were reported that suggested an y potential cases of severe
COVID -19.
The safet y profile of BNT162b2 remains aligned with the approved label. There was no new
significant information emerging from the close monitoring for anaph ylaxis and my ocarditis.
Review of post -authorization data did not identify any additional or unexpected risks associated
with BNT162b2 and confirms the favorable benefit -risk balance observed in the clinical study .
Post-marketing surveillance activities will continue.
The currently available evidence on real- world effectiveness strongl y supports a positive benefit-
risk profile for v accination of individuals 12−15 years of age with BNT162b2 to protect against
COVID -19 and add another important lay er of community protection as the US struggles to turn
the corner on the pandemic, ensure that the success of the vaccination program achiev ed to date
is not undone, and resume normal life.
Efficacy data suggest highly effective protection against COVID -19 in a broad population of
individuals across demographic characteristics including age and prior SARS -CoV -2 infection,
with 100% VE observe d in adolescents 12- 15 years of age.
Overall, the potential risks and benefits in adolescents, as assessed b y the updated safety and
efficacy profiles of BNT162b2, are balanced in favor of the potential benefits to prevent
COVID -19 in immunized individual s 12- 15 years of age. Important risks of BNT162b2 are
described in the Pharmacovigilance Plan and will continue to be assessed and minimized as
described in the updated Pharmacovigilance Plan . The public health impacts that include
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Page 11individual and com munity health, education, and socio -economic outcomes also weigh in favor
of expediting full licensure of BNT162b2 for immunization of individuals 12 -15 years of age.
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Page 122.REFERENCE S
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