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BNT162b2
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Page 1REQUEST FOR PRIORITY REVIEW
COVID -19 Vaccine (BNT162, PF -07302048)
BLA 125742
MAY 2021
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Page 2TABLE OF CONTENTS
ABBREVIAT IONS ................................ ................................ ................................ ................... 3
1. OVERVIEW ................................ ................................ ................................ .......................... 5
1.1. Rationale for Priority Review ................................ ................................ .................... 5
1.2. Serious and L ife-threatening Disease ................................ ................................ ........ 5
1.2.1. Background and Clinical Presentation of COVID -19 ................................ ..5
1.2.2. I ncidence and Prevalence of COVID-19 ................................ ...................... 6
1.3. Unmet Medical Need ................................ ................................ ................................ 6
1.4. Signi ficant Improvement in Safety and Effectiveness through Prevention of
COVID -19 Disease ................................ ................................ ................................ ......6
1.4.1. Overview of Nonclinical Data ................................ ................................ ......6
1.4.2. Overview of Completed and Ongoing Clinical Trials ................................ ..7
1.4.2.1. Safet y................................ ................................ ........................... 8
1.4.2.2. Efficacy ................................ ................................ ..................... 10
1.4.2.3. I mmunogenicity ................................ ................................ ........ 13
1.4.3. Vaccine Effectivness ................................ ................................ .................. 13
1.4.4. Overview of Post- authorization Safety Data ................................ .............. 14
1.5. Conclusions ................................ ................................ ................................ ............. 14
2. REFERENCES ................................ ................................ ................................ .................... 16
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Page 3ABBREVIATIONS
Abbreviation Definition
ADR adverse drug reaction
AE adverse event
AESI adverse event of special interest
BLA Biologics License Application
CDC Centers for Disease Control and Prevention
CI confidence interval
COVID -19 Coronavirus Disease 2019
DART Developmental and Reproductive Toxicology
EUA Emergency Use Authorization
FDA (US) Food and Drug Administration
FIH first-in-human
GLP Good Laboratory Practice
GMC geometric mean concentration
GMT geometric mean titer
HCS human convalescent serum
HIV human immunodeficiency virus
IFN interferon -gamma
IgG immunoglobulin G
IL-2 interleukin -2
IM intramuscular(ly)
IND Investigational New Drug
LTCF long term care facility
NHP non-human primate
PDUFA Prescription Drug User Fee Act
RNA ribonucleic acid
SAE serious adverse event
SARS -CoV-2 severe acute respiratory syndrome Coronavirus -2; virus causing the disease COVID -19
SOC System Organ Class
US United States
Th1 helper T cell type 1
VAED vaccine -associated enhanced disease
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Page 4Abbreviation Definition
VE vaccine efficacy
WHO World Health Organization
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Page 51.OVERVIEW
In accordance with theprovisions 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 BNT162b2 .BNT162b2 is a proph ylactic vaccine that targets severe
acute respiratory syndrome Coronavirus-2 ( SARS- CoV -2), which causes Coronavirus Disease
2019 ( COVID -19). The proposed indication for the candidate v accine is active immunization to
prevent COVID -19disea se caused b ySARS -CoV -2 in individuals ≥16years 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)for
BNT162b2 was effective on 29 April 2020. Fast Track Designation was granted on 07 July 2020
for individuals 18 y ears of age and older (a cop y of the Fast Track Designation Grant Letter is
provided in Module 1.7.4). On 11 December 2020, Emergency Use Authorization (EUA 27034)
for active immunization to prevent COVID -19 in individuals 16years of age and older was
issued for this vaccine (EUA product identified as Pfizer-BioNTech COVID- 19 Vaccine).
1.1.Rationale for Priority Review
Pfizer and BioNTech are seekingUS licensure of BNT162b2 for use in individuals ≥16years of
age. The Biologics License Application (BLA) 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 aserious and life -
threatening condition (COVID -19) and, if approved, would provide a significant improvement in
safet y andeffectiveness because there are currently no vaccines licensed for the prevention of
COVID -19in the US (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 has 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 remain s a significant challenge to public
health and economic stability worldwide, for which for a licensed proph ylactic vaccine is a
necessary and critical mitigation.
COVID -19 presentation is generall y with cough and fever, with chest radiograph y showing
ground -glass opacities or patch y shadowing .2However, many patients present without fever or
radiographic changes, and infections may be as ymptomatic which isrelevant to controlling
transmission. For sy mptomatic patients, disease progression may lead to a cute respiratory
distress sy ndrome requiring ventilation , subsequent multi -organ failure , and death .2
Common 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
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Page 61.2.2. Incidence and Prevalence of COVID-19
On 25April 2021, The Center for S ystems Science and Engineering at Johns Hopkins University
reported more than 1 46.7 million cases globall y, with over 3.1 million deaths from 192
countries /regions . The US ( United States) has reported 32 million cases and over 572 ,000
deaths.3
1.3.Unmet Medical Need
There are no vaccines licensed in the US for the prevention of COVID -19 disease.4
The FDA issued an EUA for t he Pfizer -BioNTech COVID -19 Vaccine and Moderna COVID -19
Vaccine on 11 and 18 December 202 0, respectively . An EUA was issued for the Janssen
COVID -19 Vaccine on 27 February 2021. T hese vaccines have been , and continue to be,
rigorousl y tested in large safet y and efficacy studies that meet regulatory requirements in the US ;
however, the EUA place slimitations on eligibility and access to the vaccines.
Mass immunization with a safe and effective vaccine against COVID -19 can dramaticall yalter
the trajectory ofthe pandemic. According to policy briefing by theInstitute for Health Metrics
and Evaluation published on 31 March 2021, COVID -19 remains a leading cause of death in the
US with up to 100,000 additional deaths projected in the US between March and July 2021,
many of which can likely be prevented with COVID -19 vaccination .5,6Vaccination against
COVID -19 began with EUA/conditional approvals in December 2020, in a phased rollout
defined b y national/regional guidance. However, there continue to be concerning trends that may
counteract the impacts of this vaccination effort, including:
limitations in access to obtaining a vaccine due to infrastructure challenges (ie, clinic and
appointment capacity and sy stems)7
increasi ng viral transmission fueled by relaxed compliance with mitigations as the pandemic
surpasses the 1- year mark (ie, masks, phy sical distancing, limiting travel)5,7
increasing circulation of emerging variants of concern (which are currentl y driving continued
spread of viral infection in Europe despite extensive mitigation mandat es).5,7
1.4.Significant Improvement in Safety and Effectiveness through Prevention of COVID-19
Disease
1.4.1. Overview of Nonclinical Data
Key nonclinical evaluation sof BNT162b2 included pharmacology (mouse immunogenicit y
studies, non-human primate [ NHP ]immunogenicity and challenge studies) and toxicity
(two Good Laborator y Practice [ GLP] rat repeat- dose toxicity studies )invitro and in vivo.
Adevelopmental and reproductive toxicity (DART )study was completed in rats.
Nonclinical studies in mice and NHP demonstrate that BNT162b2 elicits a rapid antibody
response with measurable SARS -CoV -2 neutralizing titers after a single dose and substantial
increases in titers after a second dose that exceed titers in sera from SARS -CoV - 2/COVID -19-
recovered individuals. A Th1 -dominant T cell response was evident in both mice and NHPs.
S-specific CD8+ T cell responses were also detectable in BNT162b2 -immunized animals. The
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Page 7strongl y Th1 -biased CD4+ T cell response and interferon- γ (IFNγ)+ CD8+ T cell response after
immunization with BNT162b2 is a pattern favored for vaccine safet y and ef ficacy and provided
added reassurance for clinical safet y.8In aSARS -CoV -2 rhesus challenge model, BNT162b2
provided complete protection from the presence of detectable viral RNA in the lungs compared
to the saline control with no clinical, radiological ,or histopathological evidence of vaccine -
elicited disease enhancement.9
Administration of BNT162b2 by IM injection to male and female Wistar Han rats once every
week, for a total of 3 weekly cycles of dosing, was tolerated without evidence of s ystemic
toxicity in GL P-compliant repeat -dose toxicity studies .
In a DART stud y, 0.06 mL of a vaccine formulation containing the same quantity of nucleoside -
modified mRNA (30 µg) and other ingredients included in a single human dose of BNT162b2
was administered to fe male rats b y the IMroute on four occasions: 21 and 14 days prior to
mating, and on gestation day s 9 and 20. No vaccine -related adverse effects on female fertility ,
fetal development ,or postnatal development were reported in the study .
In summary , the nonclinical package summarized above supports BNT162b2 administered twice
by IM injection at a dose of 30 µg RNA. Additional details of nonclinical studies are provided in
Module 2.4.
1.4.2. Overview of Completed and Ongoing Clinical Trials
The COVID -19 vaccine ca ndidate is currentl y being studied in a global clinical trial
(Study C4591001 and other clinical trials under BB -IND 19736, as well as a German clinical
trial (Study BNT162 -01, not under the IND).
The German first-in-human ( FIH) Phase 1/2 study (BNT162- 01) was conducted to gather safet y
and immunogenicit y data on several BNT162 vaccine candidates to inform the overall clinical
development of a COVID -19 vaccine. Phase 1 of Study C4591001 evaluated 2 vaccine
candidates , and safet y and immunogenicit y result s led to the selection of a single candidate,
BNT162b2 (30 µg). The first 360 Phase 2/3 subjects comprised the Phase 2 portion of the study ;
these subjects c ontribute dto efficacy , immunogenicity , and safet y endpoints . Study C4591001 is
currentl y in Phase 3 and available results as of the latest data cutoff dates are summarized in the
sections below.
Efficacy anal yses are event -driven in pivotal Study C4591001 Phase 2/3 participants ≥12 y ears of
age. Prespecified anal yses were conducted on 94 confirmed COVI D-19 cases (interim anal ysis data
cutoff date: 04November 2020 )and 170confirmed cases (final anal ysis data cutoff date :
14November 2020 ) reported in participants without prior evidence of SARS- CoV -2 infection
before or during the vaccine regimen . Updat ed analy ses of 1165 confirmed cases in blinded
placebo- controlled follow -up from Dose 1 to a data cutoff date of 13 March 2021 evaluated
duration of protection.
Immunogenicit y anal yses of adults (18 to 85 y ears of age) in Study C4591001 include data up to
1 month after Dose 2 in Phase 2, and up to 6 months after Dose 2 in Phase 1.
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Page 8Safety data are collected cumulatively in Study C4591001 . Some participants ≥16 y ears of age
have been unblinded to treatment assignment; therefore , safet y data are presented separatel y for
blinded placebo -controlled and open- label periods. Key safety data in the BLA submission
include:
Blinded placebo -controlled period : Dose 1 to 1 month after Dose 2 and to unblinding date:
Phase 1 participants randomized to BNT162b2 30 µg (to ~6 months after Dose 2)
Phase 2/3 participants ≥16 y ears of age including HIV+ subset (to ~5 months after Dose 2)
Open -label observational period : from unblinding dat eto data cutoff date:
Phase 2/3 participants ≥16 y ears of age originall y randomized to BNT162b2
Phase 2/3 participants ≥16 y ears of age originall y randomized to placebo who then
received BNT162b2 after being unblinded
Cumulative follow -up from Dose 1 to 6 months after Dose 2 : Phase 2/3 participants
originall y randomized to BNT162b 2 (inclusive of blinded data and open- label data), comprised
of at least 3000 in each adult age group (16 to 55 y ears of age, >55 y ears of age)
Supportive analy sesfrom Study BNT162- 01 are provided in this submission for immunogenicity
data including T cel l responses, and safety data including reactogenicit y and adverse events
(AEs), for adult participants in the Phase 1 portion of the study .
Further e fficacy , immunogenicity, and safety details are summarized in the Clinical Overview in
Module 2.5.
1.4.2.1. Safety
1.4.2.1.1. Phase 1 Safety
Based on Phase 1 data from the FIH Stud y BNT162 -01, BNT162b1 and BNT162b2 were safe
and well -tolerated in healthy adults 18 to 55 y ears of age, with no unanticipated safety findings.
Reactogenicit y and AEs tended to increase in incidence and /or severity with increasing dose of
BNT162b2. Reactogenicity was mostl y mild to moderate and short -lived after dosing (eg, arose
and resolved within the first 1 to 2 day s after dosing), and the AE profile and clinical laboratory
results did not suggest an y safet y concerns.
Based on Phase 1 data from Study C4591001 and Study BNT162-01 , BNT162b1 and BNT162b2
were safe and well -tolerated in y ounger healthy adults 18 to 85 y ears of age, with no
unanticipated safet y findings. Reactogenicity and AEs were general ly milder and less frequent in
participants in the older group compared with the y ounger group and overall tended to increase
with increasing BNT162b2 dose. Reactogenicity was mostly mild to moderate and short -lived
after dosing, and the AE profile did not suggest any safet y concerns , including up to
approximately 6 months after Dose 2 for BNT162b2 30 µg groups . Clinical laboratory
evaluations showed a transient decrease in l ymphocy tes that was observed in all age and dose
groups after Dose 1, which resolve d within approximately 1 week , were not associated with an y
other clinical sequelae, and were not considered clinically relevant.
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Page 9Ribonucleic acid (RNA )vaccines are known to induce t ype I interferon,10and ty peI interferons
regulate l ymphocy te recirculati on and are associated with transient migration and/or
redistribution of ly mphocy tes.11This rapid rebound of ly mphocy tes supports that the
lymphocy tes are not depleted, but temporaril y migrated out of the peripheral blood, and
subsequently re-entered the bl oodstream b y the time of the next assessment.
1.4.2.1.2. Phase 2/3 Safety
Based on Phase 2/3 data from approximately 44,000 participants ≥16 y ears 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 across age groups . Reactogenicit y and AEs were generall y milder and less
frequent in participants in the older group ( >55years of age) compared with the y ounger group
(≤55 y ears of age). Reactogenicity was mostly mild to moderate and short -lived after dosing for
both y ounger and older age groups (ie, median onset between 1 to 4 days after dosing and
resolution within 1 to 2 day s after onset), and the AE profile did not suggest any serious safet y
concerns. The incidence of serious adverse eve nts (SAEs )and deaths were low in the context of
the number of participants enrolled and comparable between BNT162b2 and placebo. The
incidence of discontinuations due to AEs was also generall y low and similar between BNT162b2
and placebo groups.
Cumulati ve safety follow -up to at least 6 months after Dose 2 for approximately 12,000 Phase
2/3 participants originally randomized to BNT162b2, comprising the combined blinded and
open -label periods, showed no new safet y signals or suggested an ynew safety concer ns arising
from longer -term follow -up.
Similarly , open -label follow -up of participants randomized to placebo from the time of
unblinding to receive BNT162b2 until the data cutoff da te showed no new safet y signals or
concerns.
Safety anal ysis results for subgroups based on demographics (age, race, ethnicity ) and b y
baseline SARS -CoV -2 positive versus negative status have not shown an y clinically important
differences in the BNT162b2 safet y profile. Anal ysis of the subset of individuals with stable
human im munodeficiency virus (HIV)did not suggest any safet y concerns in this population.
Analy sis of participants originall y randomized to placebo who then received BNT162b2 (Dose
3) by demographic subgroups and based on prior evidence of SARS -CoV -2 infection or prior
COVID -19 did not suggest any safet y concerns.
Phase 2/ 3 safet y data were generally concordant with safety data in Phase 1 of the study , both
overall and with regard to y ounger and older participants.
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Page 101.4.2.2. Efficacy
1.4.2.2.1. Phase 2/3 Efficacy Final Analysis
Evalua ble Efficacy Population
In the final efficacy analy sis, among participants without evidence of SARS -CoV -2 infection
before and during vaccination regimen, vaccine efficacy (VE)against confirmed COVID -19
occurring at least 7 days after Dose 2 was 95.0%, with 8 COVI D-19 cases in the BNT162b2
group compared to 162 COVID -19 cases in the placebo group. The 95% credible interval for the
vaccine efficacy was 90.3% to 97.6%.
For the s econd primary endpoint, VE against confirmed COVID -19 occurring at least 7 days
after Dose 2 in participants with or without evidence of SARS -CoV -2 infection before and
during vaccination regimen was 94.6%, with 9 and 169 cases in the BNT162b2 and placebo
groups respectively . The posterior probability of >99.99% for the true VE greater than 30% met
the prespecified success criterion of >98.6% for this endpoint. The 95% credible interval for the
vaccine efficacy was 89.9% to 97.3%.
Observed VE was very high for the first primary efficacy endpoint across subgroups of age, sex,
race, ethnicity , and country , as VE was >93% in all subgroups, with the exception of “all others”
race group (89.3% VE) and Brazil (87.7% VE).
For the secondary efficacy endpoint anal yses, observed VE against confirmed COVID-19
occurring at least 14 day s after Dose 2 in participants without evidence of SARS -CoV -2
infection before and during vaccination regimen, was 94.2%, with 8 and 139 cases in the
BNT162b2 and placebo groups respectivel y. The posterior probability of >99.99% for the true
VE >30% met the prespecified success criterion of >98.6% for this endpoint. The 95% credible
interval for the vaccine efficacy was 88.7% to 97.2%.
Similarly , among participants with or without evidence of SARS -CoV -2 infection before and
during vaccination regimen, VE against confirmed COVID -19 occurring at least 14 day s after
Dose 2 was 94.4%, with 8 and 144 cases in the BNT162b2 and placebo groups respectivel y. The
posterior probability of >99.99% for t he true VE >30% met the prespecified success criterion of
>98.6% for this endpoint. The 95% credible interval for the vaccine efficacy was 89.1% to
97.3%.
Among participants without evidence of SARS -CoV -2 infection before and during vaccination
regimen, observed VE of 66.3% against severe COVID- 19 occurring at least 7 days after Dose 2
did not meet the prespecified success criterion of the posterior probability >98.6%, due to the
small number of severe cases (1 in the BNT162b2 group, 3 in the placebo group) observed after
Dose 2 in the study .
The efficacy anal yses using Centers for Disease Control and Prevention (CDC )defined
symptoms to identify a COVID -19 case gave similar efficacy results as the primary endpoints.
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Page 11All-Available Efficacy Population
The early onset of protection is readily apparent from cumulative incidence curves, which show
that disease onset tracks conjointly for BNT162b2 and placebo until approximately 14 day s after
Dose 1, at which point the curves diverge, with cases steadily accumulating in the placebo group,
while remaining virtually flat after BNT162b2.
Among all participants (regardless of evidence of infection before or during the vaccination
regimen) 50 cases of COVID -19 occurred after Dose 1 in the BNT162b2 group compared with
275 cases in the placebo group, indicating an estimated VE of 82% (2 -sided 95% confidence
interval [CI]: 75.6%, 86.9%) against confirmed COVID -19 occurring after Dose 1, with VE of
52.4% (95% CI: 29.5%, 68.4%) between Dose 1 and Dose 2.
Among the tota l of 10 severe COVID -19 cases observed after Dose 1, onl y 1 severe case was
seen in BNT162b2 recipients compared to 9 severe COVID -19 cases in placebo recipients; these
results, as well as case splits between Dose 1 and Dose 2 and after Dose 2, were consis tent with
overall efficacy seen against COVI D-19. Similar results were observed when using the CDC
definition of severe disease.
Overall Conclusions
Final efficacy results show that BNT162b2 at 30 µg provided protection against COVID -19 in
participants with or without evidence of prior infection with SARS -CoV -2, including across
demographic subgroups, with severe cases observed predominantl y in the placebo group.
1.4.2.2.2. Phase 2/3 Efficacy Updated An alysis
Updated Analysis –Efficacy Against Confirmed COVID -19
In the updated descriptive efficacy anal ysis (data cutoff date :13 March 2021), among
participants in the evaluable efficacy population without evidence of SARS -CoV -2 infection
before and during the vaccination regimen, the estimated VE against confirmed COVID-19
occurring at least 7 days after Dose 2 was 91.3% ( 2-sided 95% CI: 89.0%, 93.2%), with 77 cases
in the BNT162b2 group and 850 cases in the placebo group. Among participants with or without
evidence of SARS -CoV -2 infection before and during the vaccination regimen, the estimated VE
against confirmed COVID -19 occurring at least 7 day s after Dose 2 was 91. 1% (2 -sided 95% CI :
88.9%, 93.0%), with 81and 873cases in the BNT162b2 and placebo gro ups,respectivel y.
All cases of confirmed COVID -19 are accounted for in the anal yses of VE in the Dose 1
all-available (modified intention -to-treat) population , regardless of evidence of infection before
or during the vaccination regimen. In this anal ysis,the estimated VE against all cases occur ring
at an y time after Dose 1 was 87.8% (2 -sided 95% CI : 85.3%, 89.9%), with 131 cases in the
BNT162b2 group and 1034 cases in the placebo group.
In this same Dose 1 all -available (modified intention -to-treat) population, the estimated VE
against all cases occurring ≥7days after Dose 2 was 9 1.2%. The estimated VE was 91.7% from
≥11 day s after Dose 1 to before Dose 2, 96.2% for cases occurring from ≥7 days after Dose 2 to
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Page 12<2 months after Dose 2, 90.1%for the period from ≥2 months to <4 months after Dose 2, and
83.7% for the period ≥4 months after Dose 2.
Efficacy in Subgroups
Among participants without evidence of SARS -CoV -2 infection before and dur ing the
vaccination regimen (efficacy evaluable population) ,VE against COVID -19 occurring at least
7days after Dose 2 was evaluated for demographic and risk subgroups , as follows:
Estimated VE was ≥90% in most demographic subgroups, similar to 91.3% over all VE.
High estimated VE was observed across age subgroups :
100.0% in participants 12 to 15 years of age
90.6% in participants 16to 64 y ears of age
94.5% in participants ≥65years of age
96.2% in participants ≥75years of age.
Estimated VE by country was 86.5% in Argentina; 86.2% in Brazil ;92.6% in the US; and
100.0% in South Africa, German y, and Turkey .
The estimated VE was similar for participants at risk (91.6%) and those not at risk (91.0%). The
estimated VEfor participants ≥65 y ears of age who were at risk was 91.8%, as compared with
98.1% for those ≥65 y ears of age andnot at risk. The estimated VE was similar in obese (91.6%) and
non-obese (91.1%) participants. When evaluated by type of comorbidity ,the estimated VE was
>85% for participants w ith each comorbidit y evaluated, including an y malignancy, cardiovascular
disease, chronic pulmonary disease, diabetes, obesity , and h ypertension.
Efficacy Against Severe Disease
Among participants without evidence of SARS -CoV -2 infection before and duri ng the
vaccination regimen (evaluable efficacy population), t he estimated VE against FDA -defined
severe COVID -19 (protocol definition) occurring at least 7 days after Dose 2 was 95.3% (2- sided
95% CI : 71.0%, 99.9%), with 1 and 21 cases in the BNT162b2 and placebo groups, respectively .
Similarly , the estimated VE was also 95.3% (2-sided 95% CI: 70.9%, 99.9%) among participants
with or without evidence of SARS -CoV -2 infection, also with 1 and 21 cases in the BNT162b2
and placebo groups, respectivel y.
Among pa rticipants without evidence of SARS -CoV -2 infection before and during the
vaccination regimen (evaluable efficacy population) , the estimated VEagainst CDC -defined
severe COVID -19 occurring at least 7 days after Dose 2 was 100.0% (2-sided 95% CI: 88.1%,
100.0%), with 0 and 32 cases in the BNT162b2 and placebo groups, respectively .Similarly , the
estimated VE was also 100.0% (2-sided 95% CI: 88.0%, 100.0%) among participants with or
without evidence of SARS -CoV -2 infection before and during the vaccination r egimen, also with
0and 32cases in the BNT162b2 and placebo groups, respectivel y.
Among participants in the Dose 1 all-available (modified intention -to-treat) population , regardless of
evidence of infection before or during the vaccination regimen, the estimated VE against
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Page 13FDA -defined severe cases of COVID -19 occurring at any time after Dose 1 was 96.7% (2 -sided 95%
CI: 80.3%, 99.9%), with 1 case of severe COVID- 19 in the BNT162b2 group compared to 30 cases
in the placebo group.
1.4.2.3. Immunogenicity
1.4.2.3.1. Phase 1 Immunogenicity
Study BNT162-01 provides evidence for robust T cell- mediated immunity , with antigen induced
interferon -gamma (IFNexpression demonstrating a Th1 CD4+ and CD8+ phenoty pe following
the second dose of either BNT162b1 or BNT162b2. I mmunogeni city data from Study
BNT162 -01 were generally concordant with results in pivotal Study C4591001, showing robust
SARS CoV -2 neutralization following the second dose and complimentary T cell immune
response data for both younger and older adults . The durabil ity of T cell responses to BNT162b2
vaccination was evident from maintenance of the Th1 phenoty pe and persistent IFN and IL -2
production by CD4+ and CD8+ T cells up to approximately 6 months.
In Stud y C4591001, both BNT162b1 and BNT162b2 elicited robust SARS -CoV -2 neutralizing
antibody response starting from 7 day s after Dose 2 in y ounger and older adults. Responses were
generall y stronger in younger adults than in older adults. Neutralizing antibody response was
maintained through Day 52 and was similar f or the candidates within the corresponding age and
dose groups. Comparisons of SARS -CoV -2 neutraliz ingtiters for both vaccine candidates with a
panel of HCS support the benefit of a two -dose vaccine regimen with a dose response up to 30 µg .
For the groups that received BNT162b2 at 30 µg, persistence of the immune response was
observed through 6 months after Dose 2. SARS -CoV -2 serum neutralizing titers and serum
S1-binding IgG concentrations at 6 months after Dose 2 had decreased relative to those observed
at 1 month after Dose 2 butremained above pre-vaccination and placebo levels.
The Phase 1 immunogenicity data from both the pivotal and supportive study collectively
showed robust immunogenicity elicited by BNT162b2 in both y ounger and old er adults at the
30µg dose level, which was ultimately selected to proceed to Phase 2/3 development.
1.4.2.3.2. Phase 2 Immunogenicity
Based on immunogenicity results from 360 participants in Phase 2 of Study C4591001,
BNT162b2 at 30 µg elicited robust SARS -CoV -2 ne utralization and S1 -binding IgG antibody
responses at 1 month after Dose 2 similar to those previously observed in Phase 1 of the stud y.
Notably , SARS -CoV -2 neutralizing titers were higher in the y ounger adult compared to the older
adult cohort. Of note, geometric mean titer s (GMTs )for younger and older participants at
1 month after Dose 2 were comparable to the GMTs of a comparative panel of human
convalescent serum (HCS ). S1-binding geometric mean concentration s (GMCs )were generally
higher in the younge r age cohort compared to the older age cohort, again concordant with
observations in the Phase 1 portion of the study .
1.4.3. Vaccine Effectivness
Recent data have confirmed effectiveness of BNT162b2 in the real world: in a nationwide study
among individuals aged >16 y ears in I srael (population 9.1M) reported VE at >7 day s after
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Page 14second dose was 95.3% (95% CI 94.9- 97.7%) and at >14 day s after second dose was 96.5%
(95% CI 96.3- 96.8%)12; in a prospective cohort of healthcare workers in the United Kingdom,
which repor ted VE at >7 day s after second dose of 86% (95% CI 76 -97%)13; in a retrospective
nationwide registry study of healthcare workers in Denmark, which reported VE at >7 day s after
second dose of 90% (95% CI 82-95%)14; in a test- negative case control study of individuals aged
>80 y ears in England, which reported VE at >14 day s after second dose of 89% (95% CI 85 -
93%)15; in a retrospective cohort study of long term care facility (LTCF) -residents after an
COVID -19 outbreak in a LTCF in Kentucky caused by SARS -CoV -2 variant R.1 with the
E484K mutation, which reported VE at >7 day s after second dose of 64.4% (95% CI 38.5-
79.5)16; in a retrospective registry study of individuals aged 18- 64 years in Sweden, which
reported VE at >7 day s after the second dose of 86% (95% CI 72 -94%) .17
1.4.4. 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 literature, cases from Pfizer -sponsored marketing programs, non- interventional
studies, and cases of serious AEs repor ted from clinical studies regardless of causalit y
assessment. Through 28 February 2021 (data lock point aligned with Pharmacovigilance Plan),
there were a total of 42,086 case reports (25,379 medically confirmed and 16,707 non -medicall y
confirmed) containing 158,893 events. Cases were received from 63 countries.
Consistent with what was seen in Phase 2/3 of Study C4591001, m ost reported AEs were in
System Organ Class es(SOCs) with reactogenicity events : general disorders and administration
site conditions ( 51,335), nervous s ystem disorders (25,957), musculoskeletal and connective
tissue disorders (17,283), andgastrointestinal disorders (14,096) . Post -authorization data have
also informed the addition of adverse drug reactions ( ADRs )related to the experienc e of
reactogenicity to the product labeling.
Aside from addition of anaphy laxis and hypersensitivity , the analyses of cumulative post -
authorization safety data, including a review of adverse events of special interest ( AESIs ),are
consistent with the analysis of this pivotal clinical trial. Review of post -authorization data has
not revealed an ynovel safety concerns, except for anaph ylaxis, and has confirmed the favorable
benefit -risk profile of the vaccine.
Further details regarding the cumulative an alysis of post -authorization safety data are presented
in Module 5.3.6 .
1.5.Conclusions
The BLA for BNT162b2 fulfills the criteria for priority review designation. BNT162b2 prevents
aserious and life -threatening condition (COVID -19) and, if approved, would pr ovide a
significant improvement in safet y and effectiveness because there are currently no vaccines
licensed for the prevention of COVID- 19 in the US .
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Page 15The available clinical evidence for BNT162b2 (30 µg) effectiveness includes induction of strong
immune responses and overwhelmingly high vaccine efficacy , suggesting the vaccine confers
protection against COVID- 19 in individuals ≥16years of age.
The potential risks are based on the observed safety profile to date, which shows mostly mild
reactogenicity , low incidence of severe or serious events, and no clinicall y concerning safet y
observations or safet y concerns. The vaccine appears to be safe and well -tolerated across the
safet y population comprising approximately 44,000 study participants ≥16 y ears of age, among
whom approximately 12,000 have been followed for at least 6 months after completing the two -
dose regimen. Safety analy ses have also included demographic subgroups based on age, sex, race,
ethnicity , and baseline SARS -CoV -2 status and the subset with stable HIV . The confinement of
severe cases of COVID -19 predominantly to the placebo group versus the BNT162b2 group
suggests no evidence of vaccine -associated enhanced disease (VAED ).Post-authorization safet y
review reinforces that BNT162b2 is safe and tolerable.
Vaccine efficacy was remarkabl y high, ≥95% for participants without prior evidence of
SARS -CoV -2 infection and >94% for those with or without prior infection, in the prespecified
interim and /orfinal anal yses. Updated anal yses with all confirmed cases accrued up to
approximately 6 months after Dose 2 showed persistence of protection with estimated VE of
≥91.1%. O verall, o bserved VE was >90% across subgroups identified b y age, sex, race, ethnicity ,
country , and risk factors and remained high in the updated anal ysis. Severe cases have been confined
overwhelmingly to the placebo group in all efficacy analy ses. Efficacy data suggest highl y effective
protection against COVID- 19 in a broad pop ulation of individuals across demographic
characteristics, with durable immune responses and protection from COVID- 19 disease observed up
to approximately 6months after completing the vaccination regimen.
Avaccine program must be implemented expediently and rapidly expanded to have a significant
impact on the pandemic course.6,18Licensure of BNT162b2 is likely to enhance vaccine uptake
by facilitating suppl y of vaccine from Pfizer/BioNTech directl y to pharmacies and healthcare
providers/facilities. The greatest impact of BNT162b2 licensure may be direct suppl y to
healthcare providers who serve vulnerable populations such as elderl y pati ents and those who
live in rural and underserved communities (ie, individuals who might be unable to navigate the
challenges of securing vaccine access using the s ystems in place for EUA). Expansion of vaccine
via licensure would ultimately improve the pro spect of achieving population herd immunity to
bring the pandemic under control.19
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Page 162.REFERENCE S
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