Document text
Interim Clinical Study Report
Protocol C4591001
CLINICAL STUDY REPORT SYNOPSIS
CONFIDENTIAL
Page 1Vaccine Name and Compound Number: BNT162 RNA -Based COVID -19 Vaccines,
Compound Number: PF-07302048
Report Title: Interim Report –Adolescents : A Phase 1/2/3, Placebo -Controlled,
Randomized, Observer -Blind, Dose -Finding Study to Evaluate the Safety , Tolerability ,
Immunogenicit y, and Efficacy of SARS -COV -2 RNA Vaccine Candidates Against
COVID -19 in Healthy Individuals
Protocol Number: C4591001
Sponsor: BioNTech SE
Sponsor Agent : Pfizer Inc
Phase of Development: Phase 1/2/3
First Subject First Visit: 29 April 2020
Last Subject Last Visit: Not applicable
Data Cutoff Date: 13 March 2021
Serology Completion Date: 22 March 2021 (Phase 2/3 , Visit 3 [post- Dose 2 blood draw]
assay completed for participants 12 through 25 years of age )
Coordinating Investigator(s): Stephen Thomas, MD, SUNY Upstate Medical Universit y,
725Irving Ave, Ste. 311, Sy racuse, NY 13210
Refer to Appendix 16.1.4.1 for a list of investigators involved in this study .
Study Center(s): 131 in the United States (US) , 9in Turkey , 6in Germany , 4in South
Africa, 2in Brazil, and 1 in Argentina . Refer to Appendix 16.1.4.1 for a list of sites involved
in this study .
Phase 3 participants ≥16 y ears of age were enrolled at sites in the US, Brazil, Argentina,
Turkey , South Africa, and German y. Participants 12- 15 years of age were enrolled at sites in
the US.
Date of Current Version: 14April 2021
Date(s) of Previous Rep ort(s): Not applicable
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Page 2OBJECTIVES
Study Objectives and Endpoints:
Phase 1
Phase 1 results are not presented in this report.
Phase 2/3
The study objective , estimands, and endpoints presented in Table S1are from Protocol
Amendment 14.Those previously reported in the final anal ysis interim C4591001 clinical
study report (CSR) sy nopsis dated 03 December 2020, are based on Protocol Amendment 9.
Final efficacy anal yses were completed and reported in the final anal ysis interim CSR dated
03December 2020 along with safet y and immunogenicity data available at that time (data
cutoff date 14 November 2020). This prior CSR reported prespecified efficacy (event -driven)
in participants ≥12 y ears of age and ongoing safety data in participants ≥16 years of age with
a median of at least 2 months of f ollow -up after Dose 2 and up to the data cutoff date.
The current CSR presents safet y,efficacy , and immunogenicit y data for adolescents
12through 15 years of age up to the data cutoff date (13 March 2021). Data are included
from y oung adults 16 through 2 5 years of age for immunobridging anal yses and descriptive
safet y analysis comparisons. L onger -term reference safet y data are also presented from the
adult 16 through 55 years of age stratum up to the date of participant unblinding. Note, these
data are for comparative purposes and do not include a full independent safety evaluation.
This study is ongoing; results for objectives outside of the scope of this CSR, including full
independent safet y evaluation for participants ≥16years of age, will be reported separatel y at
a later time (Table S1).
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Page 3Table S1. Phase 2/3 Objectives, Estimands, and Endpoints
Objectivesa Estimands Endpoints Reference
Primary Efficacy
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
coronavirus disease 2019 (COVID -19)
occurring from 7 days after the second
dose in participants without evidence of
infection before vaccinationIn participants complying with the key
protocol criteria (evaluable participants) at
least 7 days after receipt of the second dose
of study interv ention: 100 × (1 –illness
rate ratio [ IRR
])
[ratio of active vaccine to placebo]COVID -19 incidence per 1000 person -years
of follow -up based on central laboratory or
locally confirmed nucleic acid applification
test (NAAT )in participants with no
serolo gical or virological evidence (up to
7days after receipt of the second dose) of
past severe acute respiratory syndrome
coronavirus 2 (SARS -CoV -2)infectionPrespecified complete efficacy data
are reported in final analysis interim
CSR dated 03 December 20 20.
Updated efficacy data for participants
12 through 15 years of age only are
reported in this CSR.
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 occurring from 7 days after
the second dose in participants with and
without evidence of infection before
vaccinationIn participants complying with the key
protocol criteria (evaluable participants) at
least 7 days after receipt of the second dose
of study intervention: 100 × (1 – IRR)
[ratio of active vaccine to placebo]COVID -19 incidence per 1000 person -years
of follow -up based on central laboratory or
locally confirmed NAATInterim data are reported in final
analysis interim CSR dated
03December 2020.
Updated efficacy data for participants
12 through 15 years of age only are
reported in this CSR.
Primary Safety
To define the safety profile of
prophylactic BNT162b2 in the first
360participants randomized (Phase 2)In participants receiving at least 1 dose of
study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
Adverse events ( AEs) from Dose 1 to
7 days after the second dose
Serious adverse events ( SAEs )from
Dose 1 to 7 days after the second doseLocal react ions (pain at the injection site,
redness, and swelling)
Systemic events (fever, fatigue, headache,
chills, vomiting, diarrhea, new or worsened
muscle pain, and new or worsened joint
pain)
AEs
SAEsInterim data are reported in final
analysis interim CSR da ted
03December 2020.
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Page 4Table S1. Phase 2/3 Objectives, Estimands, and Endpoints
Objectivesa Estimands Endpoints Reference
To define the safety profile of
prophylactic BNT162b2 in all
participants randomized in Phase 2/3In participants receiving at least 1 dose of
study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 month after the
second dose
SAEs from Dose 1 to 6 months after the
second doseAEs
SAEs
In a subset of at least 6000 participants:
o Local reactions (pain at the
injection site, redness, and
swelling)
o Systemic events (fever, fatigue,
headache, chills, vomiting, diarrhea,
new or worsened muscle pain, and
new or worsened joint pain)Interim data are reported up to
1month after Dose 2 and to the data
cutoff date (14 November 2020) in
final analysis interim CSR dated
03December 2020.
Interim data for local reactions and
systemic events reported up to 7 days
after each dose, and AEs and SAEs
are reported from Dose 1 to 1 month
after Dose 2 and to the unblinding
date are reported in this CSR.
To define the safety profile of
prophylactic BNT162b2 in participants
12 to 15 years of age in Phase 3In participants receiving at least 1 dose of
study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 month after the
second dose
SAEs from Dose 1 to 6 months after
the second dose Local reactions (pain at the injection
site, redness, and swelling )
Systemic events (fever, fatigue,
headache, chills, vomiting, diarrhea, new
or worsened muscle pain, and new or
worsened joint pain)
AEs
SAEsData from Dose 1 to 1 month after
Dose 2 are reported in this CSR.
Interim data for local reactions and
systemic events reported up to 7 days
after each dose, and AEs and SAEs are
reported from Dose 1 to 1 month after
Dose 2 and to the cutoff date are
reported in this CSR.
To describe the safety and tolerability
profile of BNT162b2 SAgiven as 1 or 2
doses to BNT162b2 -experienced
participants, or as 2 doses to
BNT162b2 -naïve participants
To describe the safety and tolerability
profile of BNT162b2 given as a third
dose to BNT162b2 -experienced
participantsIn participants receiving at least 1 dose of
study intervention, the percentage of
participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 month after the
last dose
SAEs from Dose 1 to 5 or 6 months
after the last doseLocal reactions (pain at the injection site,
redness, and swelling)
Systemic events (fever, fatigue, headache,
chills, vomiting, diarrhea, new or
worsened muscle pain, and new or
worsened joint pain)
AEs
SAEsData will be reported at a later time.
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Page 5Table S1. Phase 2/3 Objectives, Estimands, and Endpoints
Objectivesa Estimands Endpoints Reference
Prim ary Immunogenicity
BNT162b2 -experienced participants
To demonstrate the noninferiority of the
anti–reference strain immune response
after a third dose of BNT162b2
compared to after 2 doses of
BNT162b2, in the same individualsGeometric mean ratio ( GMR )of reference
strain NT 1 month after the third dose of
BNT162b2 to 1 month after the second
dose of BNT162b2
The difference in percentages of
participants with seroresponse to the
reference strain at 1 month after the third
dose of BNT162b2 and 1 month after the
second dose of BNT162b2SARS -CoV -2 reference strain neutralizing
titers (NTs )in participants with no
serological or virological evidence (up to
1 month after receipt of the third dose of
BNT162b2) of past SA RS-CoV -2 infectionData will be reported at a later time.
To demonstrate the noninferiority of the
anti-SA immune response after 1 dose
of BNT162b2 SAcompared to the anti–
reference strain immune response after
2 doses of BNT162b2, in the same
individualsGMR of SA NT 1 month after 1 dose of
BNT162b2 SAto the reference strain NT 1
month after the second dose of BNT162b2
The difference in percentages of
participants with seroresponse to the SA
strain at 1 month after 1 dose of
BNT162b2 SAand seroresponse to the
reference strain at 1 month after the second
dose of BNT162b2SARS -CoV -2 SA and reference strain NTs in
participants with no serological or virological
evidence (up to 1 month after receipt of
1dose of BNT162b2 SA) of past SARS -CoV -2
infectionData wi ll be reported at a later time.
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Page 6Table S1. Phase 2/3 Objectives, Estimands, and Endpoints
Objectivesa Estimands Endpoints Reference
BNT162b2 -naïve participants
To demonstrate the noninferiority of the
anti-SA immune response after 2 doses
of BNT162b2 SAcompared to the anti–
reference strain immune response after
2 doses of BNT162b2 GMR of SA NT 1 month after the second
dose of BNT162b2 SAto the reference strain
NT 1 month after the second dose of
BNT162b2
The difference in percentages of
participants with seroresponse to the SA
strain at 1 month after the second dose of
BNT162b2 SAand seroresponse to t he
reference strain at 1 month after the second
dose of BNT162b2SARS -CoV -2 SA and reference strain NTs in
participants with no serological or virological
evidence (up to 1 month after receipt of the
second dose of BNT162b2 SAor BNT162b2 as
appropriate) of past SARS -CoV -2 infectionData will be reported at a later time.
Secondary Efficacy
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 occurring from 14 days
after the second dose in participants
without evidence of infection before
vaccinationIn participants complying with the key
protocol criteria (evaluable participants) at
least 14 days after receipt of the second
dose of study intervention:
100 × (1 –IRR) [ratio of active vaccine to
placebo]COVID -19 incidence per 1000 person -years
of follow -up based on central laboratory or
locally confirmed NAAT in participants with
no serological or virological evidence (up to
14 days after receipt of the second dose) of
past SARS -CoV -2 infectionPrespecified complete efficacy data
are reported in final analysis interim
CSR dated 03 December 2020.
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 occurring from 14 days
after the second dose in participants
with and without evidence of infection
before vaccinationIn participants complying with the key
protocol criteria (evaluable participants) at
least 14 days after receipt of the second
dose of study intervention:
100 × (1 –IRR) [ratio of active vaccine to
placebo]COVID -19 incidence per 1000 p erson -years
of follow -up based on central laboratory or
locally confirmed NAATPrespecified complete efficacy data
are reported in final analysis interim
CSR dated 03 December 2020.
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed sever e
COVID -19 occurring from 7 days and
from 14 days after the second dose in
participants without evidence of
infection before vaccinationIn participants complying with the key
protocol criteria (evaluable participants)
at least 7 days
and
at least 14 days
after receipt of the second dose of study
intervention: 100 × (1 –IRR)
[ratio of active vaccine to placebo]Confirmed severe COVID -19 incidence per
1000 person -years of follow -up in
participants with no serological or virological
evidence (up to 7 days and up to 14 days after
receipt of the second dose) of past
SARS -CoV -2 infectionPrespecified complete efficacy data
are reported in final analysis interim
CSR dated 03 December 2020.
Updated efficacy data occurring from
at least 7 days after the sec ond dose
for participants 12 through 15 years
of age only are reported in this CSR.
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Page 7Table S1. Phase 2/3 Objectives, Estimands, and Endpoints
Objectivesa Estimands Endpoints Reference
To evaluate the efficacy of prophylactic
BNT162b2 against confirmed severe
COVID -19 occurring from 7 days and
from 14 days after the second dose in
participants with and without evidence
of infection before vaccinationIn participants complying with the key
protocol criteria (evaluable participants)
at least 7 days
and
at least 14 days
after receipt of the second dose of study
intervention: 100 × (1 –IRR)
[ratio of ac tive vaccine to placebo]Confirmed severe COVID -19 incidence per
1000 person -years of follow -upPrespecified complete efficacy data
are reported in final analysis interim
CSR dated 03 December 2020.
Updated efficacy data occurring from
at least 7 days aft er the second dose
for participants 12 through 15 years
of age only are reported in this CSR.
To describe the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 (according to the
CDC -defined symptoms) occurring
from 7 days and from 14 days after the
second dose in participants without
evidence of infection before vaccinationIn participants complying with the key
protocol criteria (evaluable participants)
at least 7 days
and
at least 14 days
after receipt of the second dose of study
interventio n: 100 × (1 –IRR)
[ratio of active vaccine to placebo]COVID -19 incidence per 1000 person -years
of follow -up based on central laboratory or
locally confirmed NAAT in participants with
no serological or virological evidence (up to
7days and up to 14 days after receipt of the
second dose) of past SARS-CoV -2 infectionPrespecified complete efficacy data
are reported in final analysis interim
CSR dated 03 December 2020.
To describe the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 (according to the
CDC -defined symptoms) occurring
from 7 days and from 14 days after the
second dose in participants with and
without evidence of infection before
vaccinationIn participants complying with the key
protocol criteria (evaluable participants)
at least 7 days
and
at least 14 days
after receipt of the second dose of study
intervention: 100 × (1 –IRR)
[ratio of active vaccine to placebo]COVID -19 incidence per 1000 person -years
of follow -up based on central laboratory or
locally confirmed NAATPrespecified complete efficacy data
are reported in final analysis interim
CSR dated 03 December 2020.
To evaluate the efficacy of prophylactic
BNT162b2 against non -S
seroconversion to SARS -CoV -2 in
participants without evidence of
infection or confirme d COVID -19In participants complying with the key
protocol criteria (evaluable participants):
100 × (1 –IRR) [ratio of active vaccine to
placebo]Incidence of asymptomatic SARS -CoV -2
infection per 1000 person -years of follow -up
based on SARS -CoV -2nucleoprotein binding
(N-binding )antibody seroconversion in
participants with no serological or virological
evidence of past SARS -CoV -2 infection or
confirmed COVID -19Data will be reported at a later time.
To evaluate the efficacy of prophylactic
BNT16 2b2 against asymptomatic
SARS -CoV -2 infection in participants
without evidence of infection up to the
start of the asymptomatic surveillance
periodIn participants complying with the key
protocol criteria (evaluable participants):
100 × (1 –IRR) [ratio of active vaccine to
placebo]Incidence of asymptomatic SARS -CoV -2
infection per 1000 person -years of follow -up
based on central laboratory –confirmed
NAAT in participants with no serological or
virological evidence (up to the start of the Data will be reported at a later time.
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Page 8Table S1. Phase 2/3 Objectives, Estimands, and Endpoints
Objectivesa Estimands Endpoints Reference
asymptomatic survei llance period) of past
SARS -CoV -2 infection
Secondary Immunogenicity
To demonstrate the noninferiority of the
immune response to prophylactic
BNT162b2 in participants 12 to 15
years of age compared to participants
16 to 25 years of ageGMR, estimated by the ratio of the
geometric mean of SARS -CoV -2
neutralizing titers in the 2 age groups
(12-15 years of age to 16 -25 years of age)
1 month after completion of vaccinationSARS -CoV -2 neutralizing titers in
participants with no serological or virological
evidence (up to 1 month after receipt of the
second dose) of past SARS -CoV -2 infectionData are reported in this CSR .
BNT162b2 -experienced participants
To demonstrate the noninferiority of the
anti-South African variant (SA)
immune response after a third dose of
BNT162b2 compared to the anti –
reference strain immune response after
2 doses of BNT162b2, in the same
individuals GMR of SA NT 1 month after the third
dose of BNT162b2 to the reference strain
NT 1 month after the second dose of
BNT162b2
The difference in percentages of
participants with seroresponse to the SA
strain at 1 month after the third dose of
BNT162b2 and seroresponse to the
reference strain at 1 month after the second
dose of BNT162b2SARS -CoV -2 SA an d reference strain NTs in
participants with no serological or virological
evidence (up to 1 month after receipt of the
third dose of BNT162b2) of past SARS -CoV -2
infectionData will be reported at a later time.
To demonstrate the noninferiority of the
anti–reference strain immune response
after 1 dose of BNT162b2 SAcompared
to after 2 doses of BNT162b2, in the
same individuals GMR of reference strain NT 1 month after
1 dose of BNT162b2 SAto 1month after the
second dose of BNT162b2
The difference in p ercentages of
participants with seroresponse to the
reference strain at 1 month after 1 dose of
BNT162b2 SAand 1 month after the second
dose of BNT162b2SARS -CoV -2 reference strain NTs in
participants with no serological or virological
evidence (up to 1 mo nth after receipt of 1
dose of BNT162b2 SA) of past SARS -CoV -2
infectionData will be reported at a later time.
To descriptively compare the anti-SA
immune response after 1 dose of
BNT162b2 SAand a third dose of
BNT162b2 GMR of SA NT 1 month after 1 dose of
BNT162b2 SAto 1month after the third
dose of BNT162b2
The difference in percentages of
participants with seroresponse to the SA
strain at 1 month after 1 dose of SARS -CoV -2 SA NT in participants with no
serological or virological evidence (up to
1month after receipt of 1 dose of
BNT162b2 SAor the third dose of BNT162b2)
of past SARS -CoV -2 infectionData will be reported at a later time.
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Page 9Table S1. Phase 2/3 Objectives, Estimands, and Endpoints
Objectivesa Estimands Endpoints Reference
BNT162b2 SAand 1 month after the third
dose of BNT162b2
To descriptively compare the anti-SA
immune response after 2 doses of
BNT162b2 SAand the anti –reference
strain immune response after 2 doses of
BNT162b2, in the same individuals GMR of SA NT 1 month after the second
dose of BNT162b2 SAto the reference strain
NT 1 month after the second dose of
BNT162b2
The difference in percentages of
participants with seroresponse to the SA
strain at 1 month after the second dose of
BNT162b2 SAand seroresponse to the
reference strain at 1 month after the second
dose of BNT162b2SARS -CoV -2 SA and reference strain NTs in
participants with no serological or virological
evidence (up to 1 month after receipt of the
second dose of BNT162b2 SA) of past
SARS -CoV -2 infectionData will be reported at a later time.
BNT162b2 -naïve participants
To demonstrate a statistically greater
anti-SA immune response after 2 doses
of BNT162b2 SAcompared to after 2
doses of BNT162b2 GMR of SA NT 1 month after the second
dose of BNT162b2 SAto 1month after the
second dose of BNT162b2
The difference in percentages of
participants with seroresponse to the SA
strain at 1 month after the second dose of
BNT162b2 SAand 1 month after the second
dose of BNT162b2SARS -CoV -2 SA NTs in participants with no
serological or virological evidence (up to 1
month after receipt of the second dose of
BNT1 62b2 SAor BNT162b2 as appropriate)
of past SARS -CoV -2 infectionData will be reported at a later time.
To descriptively compare the anti–
reference strain immune response after
2 doses of BNT162b2 SAand after 2
doses of BNT162b2 GMR of reference strain NT 1 month after
the second dose of BNT162b2 SAto
1month after the second dose of
BNT162b2
The difference in percentages of
participants with seroresponse to reference
strain at 1 month after the second dose of
BNT162b2 SAand 1 month after the second
dose of BNT162b2SARS -CoV -2 reference strain NTs in
participants with no serological or virological
evidence (up to 1 month after receipt of the
second dose of BNT162b2 SAor BNT162b2 as
appropriate) of past SARS-CoV -2 infectionData will be reported at a later time.
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Page 10Table S1. Phase 2/3 Objectives, Estimands, and Endpoints
Objectivesa Estimands Endpoints Reference
Exploratory
To describe the efficacy of prophylactic
BNT162b2 against confirmed
COVID -19 occurring from 7 days after
the second dose through the blinded
follow -up period in participants
without, and with and without, evidence
of infection before vaccinationIn participants complying with the key
protocol criteria (evaluable participants)
after receipt of the second dose of study
intervention:
100 × (1 –IRR) [ratio of active vaccine to
placebo]COVID -19 incidence per 1000 person -years
of blinded f ollow -up based on central
laboratory or locally confirmed NAATData will be reported at a later time.
To describe the incidence of confirmed
COVID -19 through the entire study
follow -up period in participants who
received BNT162b2 at initial
randomization or subsequentlyIn participants who received BNT162b2
(atinitial randomization or subsequently):
Incidence per 1000 person-ye ars of
follow -upCOVID -19 incidence per 1000 person -years
of follow -up based on central laboratory or
locally confirmed NAATData will be reported at a later time.
To evaluate the immune response over
time to prophylactic BNT162b2 and
persistence of immune response in
participants with and without
serological or virological evidence of
SARS -CoV -2 infection before
vaccinationGeometric mean concentration
(GMC )/geometric mean titer ( GMT )and
geometric mean fold rise ( GMFR )at
baseline and 1, 6, 12, and 24 months after
completion of vaccinationFull-length S -binding or S1 -binding
immunoglobulin G (IgG)levels
SARS -CoV -2 neutralizing titersGMTs and GMFRs of SARS -CoV -2
neutralizing titers up to 1 month after
Dose 2 in participants 12 through 15
and 16 through 25 are reported in this
CSR.
To describe the incidence of non -S
seroconversion to SARS -CoV -2
through the entire study follow-up
period in participants who received
BNT162b2 at initial randomization In participants who received BNT162b2 at
initial randomization:
Incidence per 1000 per son-years of
follow -upIncidence of asymptomatic SARS -CoV -2
infection per 1000 person -years of follow -up
based on N -binding antibody seroconversion
in participants with no serological or
virological evidence of past SARS -CoV -2
infection or confirmed COVID -19Data will be reported at a later time.
To describe the efficacy of prophylactic
BNT162b2 against asymptomatic
SARS -CoV -2 infection in participants
with evidence of infection up to the
start of the asymptomatic surveillance
periodIn participants complying with the key
protocol criteria (evaluable participants):
100 × (1 –IRR) [ratio of active vaccine to
placebo]Incidence of asymptomatic SARS -CoV -2
infection per 1000 person -years of follow -up
based on central laboratory –confirmed
NAAT in particip ants with serological or
virological evidence (up to the start of the
asymptomatic surveillance period) of past
SARS -CoV -2 infectionData will be reported at a later time.
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Objectivesa Estimands Endpoints Reference
To describe the serological responses to
the BNT vaccine candidate and
characterize the SARS -CoV -2 isolate in
cases of:
Confirmed COVID-19
Confirmed severe COVID -19
SARS -CoV -2 infection without
confirmed COVID -19Full S -binding or S1 -binding IgG levels
SARS -CoV -2 neutralizing titers
Identification of SARS -CoV -2 variants(s)Data will be reported at a later time.
To describe the safety, immunogenicity,
and efficacy of prophylactic BNT162b2
in individuals with confirmed stable
HIV diseaseAll safety, immunogenicity, and efficacy
endpoints described aboveData will be reported at a later time.
To describe the safety and
immunogenicity of prophylactic
BNT162b2 in individuals 16 to 55 years
of age vaccinated with study
intervention produced by manufacturing
“Process 1” or “Process 2” AEs
SAEs
SARS -CoV -2 neutralizing titersData will be re ported at a later time.
To describe the immune response to
any variants of concern ( VOCs )not
already specifiedGeometric mean NT for any VOCs not
already specified, after any dose of
BNT162b2 SAor BNT162b2 SARS -CoV -2 NTs for any VOCs not
already specifiedData will be reported at a later time.
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Page 12Table S1. Phase 2/3 Objectives, Estimands, and Endpoints
Objectivesa Estimands Endpoints Reference
To describe the cell -mediated immune
response, and additional humoral
immune response parameters, to the
reference strain and SA in a subset of
participants:
7 Days and 1 and 6 months after
BNT162b2 SAgiven as 1 or 2 doses
to BNT162b2 -experienced
participants
7 Days and 1 and 6 months after
BNT162b2 SAgiven as 2 doses to
BNT162b2 -naïve participants
7 Days and 1 and 6 months after
BNT162b2 given as a third dose to
BNT162b2 -experienced
participantsData will be reported at a later time.
a.HIV-positive participants in Phase 3 were not included in analyses of the objectives, w ith the exception of the specific explorat ory objective.
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Page 13METHODS
Study Design: This is a Phase 1/2/3, randomized, multinational, placebo -controlled,
observer -blind, dose -finding, vaccine candidate– selection, and efficacy study in healthy
individuals.
The study consists of 2 parts: Phase 1 to identify preferre d vaccine candidate(s) and dose
level(s); and Phase 2/3 as an expanded cohort and efficacy part. These parts, and the
progression between them, are detailed in Figure S1.
Figure S1.Study Schema
Phase 1 For each vaccine candidate (4:1 randomization active:placebo)
Age: 18-55 y Age: 65-85 y
Low-dose -level 2 -dose group (n=15)
IRC (safety) IRC (safetyLow-dose -level 2 -dose group (n=15)after Dose 1)
Mid-dose -level 2 -dose group (n=15)
IRC (safety)IRC (safetyMid-dose -level 2 -dose group (n=15)after Dose 1)
High -dose -level 2 -dose group (n=15)
IRC (safetyHigh -dose -level 2 -dose group (n=15)after Dose 1)
IRC choice of group(s) for Phase 2/3
(safety & immunogenicity after Doses 1 and 2)
Phase 2/3 Single vaccine candidate (1:1 randomization active:placebo)
Safety and immunogenicity analysis of
Phase 2 data (first 360 participants)
byunblinded team (these participants
will also be included in Phase 3
analyses)Age: ≥12
(Stratified 12 -15, 16-55, or >55)
BNT162b2 30 µg or placebo 2 doses
(n~21,999 per group, total n~43,998)
Abbreviation: IRC = internal review committee
Note: Participants ≥16 years of age who originally received placebo w ereoffered the opportunity to receive BNT162b2 at
defined points as part of the study.
The study evaluated the safet y, tolerability , and immunogenicit y of 3 different SARS -CoV -2
ribonucleic acid ( RNA )vaccine candidates against COVID -19 and the Phase 2/3 efficacy of
1 selected candidate based on Phase 1 results:
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Page 14As a 2 -dose (separated by 21 day s) schedule;
At various dose levels in Phase 1;
As a booster; (data will be reported at a later time)
In various age groups:
Phase 1: 18 to 55 and 65 to 85 y ears of age;
Phase 2: ≥18 years of age (stratified as 18 to 55 years and >55 to 85 years);
Phase 3: ≥12 years of age (stratified as 12 to 15, 16 to 55, or >55 y ears of age).
To facilitate rapid review of data in real time, Pfizer and BioNTech staff were unblinded to
vaccine allocation for the participants in Phase 1, and remain blinded for the Phase 2/3
portion of study except those who were designated for unblinded activities following the
protocol and the data blinding plan .
Inthis report , interim data are presented up to 1 month after Dose 2 and up to the data cutoff
date for blinded follow -uponly (13 March 2021) and summarizes the following participant
age groups:
Adolescents (12 through 15 years of age): immunobridging and safet y
(median ≥2months follow -up); descriptive efficacy anal yses during blinded placebo -
controlled follow -up period conducted on all confirmed COVID -19 cases accrued up
to the data cutoff date of 13 M arch 2021
Young adults (16 through 25 years of age): reference group for 12 through 15 years
immunogenicit y and descriptive safet y analysis comparisons
Adults (16 through 55 years of age): prot ocol specified ‘y ounger adult’ age stratum,
to provide referenc e safety data from anal yses of participants with longer- term
follow -up. Note, these data are for comparative purposes and do not include a full
independent safet y evaluation.
A full independent safet y evaluation of Phase 2/3 participants ≥16 years of age w ill be
reported separatel yat a later time .
Planned Booster and Variant Strain Evaluation
Planned booster and variant of concern ( VOC )vaccine evaluation sare not included in this
report and will be reported at a later time.
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Page 15Unblinding Considerations
The study was unblinded in stages once all ongoing participants either had been individually
unblinded or had concluded their 6 -month post –Dose 2 study visit, as follows:
Phase 1 (after Visit 8).
Phase 2/3, ≥16 y ears of age (after Visit 4).
Phase 3, 12 through 15 years of age (after Visit 4).
Original Phase 3 participants rerandomized to assess boostability and protection against
emerging VOCs (after Visit 306) (data will be reported at a later time).
Participants ≥16 y ears of age who originall y received placebo and became eligible for receipt
of BNT162b2 according to recommendations detailed separately , and available in the
electronic stud y reference portal, had the opportunity to receive BNT162b2 in a phased
manner as part of the study . The investigator ensure d the participant met at least 1 of the
recommendation criteria.
Adolescents 12 through 15 y ears of age remain blinded in this study , as BNT162b2
vaccination eligibility in all markets/regions is currently for 16 years of age and older. Note
that a few pa rticipants in the 12 through 15 years of age group turned 16 years of age after
study enrollment and thus became eligible for unblinding to treatment assignment and
vaccination under the emergency use or conditional authorization in their country /region.
Phase 1
Phase 1 safet y follow -up is ongoing, and p articipants were expected to participate for up to a
maximum of approximately 26 months . This interim report only describes Phase 2/3
adolescents 12 through 15 y ears of age, with reference comparison to y oung adults
16through 25 years of age and adults 16 through 55 y ears of age.
Phase 2/3
Safety and immunogenicity data generated during the Phase 1 portion of this study and the
BioNTech study conducted in Germany (BNT162 -01) supported BNT162b2 at a dose of
30µg as the vaccine candidate to proceed into Phase 2/3.
The Phase 2 part of the study was comprised of the first 360 participants enrolled
(1:1randomization between BNT162b2 and placebo, stratified by age groups [18 t hrough
55years and >55 t hrough 85 years] with approximately 50% in each age stratum) to assess
safety data through 7 days after Dose 2 and immunogenicity data through 1 month after
Dose 2 from these Phase 2 360 participants. Enrollment continued during Phase 2 and these
participants ar e included in the efficacy evaluation in the Phase 3 part of the study .
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Page 16Participants in the ongoing Phase 3 part of the study are ≥12 years of age (stratified as
12through 15, 16 through 55, or >55 years of age) . The 12- through 15-year stratum
comprise dup to approximately 2200 participants enrolled at selected investigational sites . It
was planned to enroll a minimum of 40% of participants in the > 55 yearsof age stratum .
Participants in Phase 3 were randomized 1:1 to receive either active vaccine or p lacebo .
Efficacy anal yses for Phase 2/3 part of the study were event -driven. The prespecified interim
analysis was conducted on an accrued 94 evaluable COVID -19 cases (data cutoff date:
04November 2020) , and the final anal ysis was conducted on an accrued 170evaluable
COVID -19 cases (data cutoff date : 14November 2020 ). These data are reported in the final
analysis interim CSR dated 03 December 2020 and included all study participants in the
efficacy populations ≥12 y ears of age .
At the time of the final analy sis of efficacy , few participants 12 through 15 y ears of age had
enrolled in the study ,and no COVID -19 cases reported in this age group accrued at that time .
Updated efficacy analy ses during blinded placebo- controlled follow -up period were
conducted on cases accrued in the 12 through 15 years of age group up to the data cutoff date
of 13 March 2021. This report presents these analyses of all confirmed COVID -19 cases and
any cases meeting protocol -and CDC -defined criteria for severe disease for parti cipants 12
through 15 years of age.
Noninferiorit y (NI) of immune response to prophylactic BNT162b2 in participants
12through 15 years of age to response in participants 16 through 25 years of age w ere
assessed based on the GMR of SARS -CoV -2 neutralizing titers 1 month after Dose 2 using a
1.5-fold NI margin.
Safety data are included for adolescents 12 through 15 y ears of age through 1 month after
Dose 2 and to the data cutoff date (13 March 2021) and include descriptive comparisons to
participants (react ogenicity subset) in the group 16 through 25 years of age. Safety data from
participants 16 through 55 y ears of age are included for comparative purposes ,and afull
independent safet y evaluation of this age group along with participants >55 y ears of age w ill
be reported separatel yat a later time .
It is planned that p articipants would participate for approximately 26months .
Inclusion/Exclusion Criteria: Inclusion and exclusion criteria presented are reflected
through Protocol Amendment 13 for this ongoing study . Updated inclusion and exclusion
criteria of the subset of participants receiving the booster dose against emerging VOCs based
on Protocol Amendme nt 14 are not analy zedin this report, and therefore ,are not presented in
this sy nopsis.
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Page 17Participants were eligible to be included in the study only if all of the following criteria
apply :
Inclusion Criteria:
Age and Sex:
1.Male or female participants betwe en the ages of 18 and 55 y ears, inclusive, 65 and
85years, inclusive (Phase 1), or ≥12 y ears (Phase 2/3), at randomization. Note that
participants <18 years of age cannot be enrolled in the European Union ( EU).
Type of Participant and Disease Characterist ics:
2.Participants who were willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifesty le considerations, and other study procedures.
3.Health y participants who were determined b y medical history, ph ysical examination
(ifrequired), and clinical judgment of the investigator to be eligible for inclusion in the
study .
Note : Healthy participants with preexisting stable disease, defined as disease not requiring
significant change in therapy or hospitalization for worsening disease during the 6 weeks
before enrollment, could be included.
4.Phase 2/3 only: Participants who, in the judgment of the investigator, were at higher risk
for acquiring COVID -19 (including, but not limited to, use of mass transportation,
relevant demographic s, and frontline essential workers).
Informed Consent:
5. Capable of giving personal signed informed consent/have parent(s)/legal guardian capable
of giving signed informed consent which included compliance with the requirements and
restrictions listed in the informed consent document (I CD) and in the protocol.
Exclusion Criteria:
Participants were excluded from the stud y if an y of the following criteria applied:
Medical Conditions:
1.Other medical or psy chiatric condition including recent (within the past y ear)or active
suicidal ideation/behavior or laboratory abnormality that increased the risk of study
participation or, in the investigator’s judgment, made the participant inappropriate for the
study .
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Page 182.Phases 1 and 2 only: Known infection with human immunodeficiency virus (HIV),
hepatitis C virus (HCV), or hepatitis B virus (HBV).
3.History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaph ylaxis) to any component of the study intervention(s).
4.Receipt of medications intended to prevent COVID -19.
5.Previous clinical (based on COVID -19 s ymptoms/signs alone, if a SARS -CoV -2 NAAT
result was not available) or microbiological (based on COVID -19 s ymptoms/signs and a
positive SARS -CoV -2 NAAT result) diagnosis of COVID-19.
6.Phase 1 only: Individuals at high risk for severe COVID -19, including those with any of
the following risk factors:
Hypertension
Diabetes mellitus
Chronic pulmonary disease
Asthma
Current vaping or smoking
History of chronic smoking within the prior y ear
Chronic liver disease
Stage 3 or worse chronic kidney disease (glomerular filtration rate <60 mL/min/1.73 m2)
Resident in a long- term facility
Body mass index (BMI) >30 kg/m2
Anticipating the need for immunosuppressive treatme nt within the next 6 months
7.Phase 1 only: Individuals currentl y working in occupations with high risk of exposure to
SARS -CoV -2 (eg, healthcare worker, emergency response personnel).
8. Immunocompromised individuals with known or suspected immunodeficiency , as
determined b y history and/or laboratory /physical examination.
9.Phase 1 only: Individuals with a history of autoimmune disease or an active autoimmune
disease requiring therapeutic intervention, including but not limited to: sy stemic or
cutaneous lupus ery thematosus, autoimmune arthritis/rheumatoid arthritis, Guillain -Barré
syndrome, multiple sclerosis, Sjögren’s s yndrome, idiopathic thrombocytopenia purpura,
glomerulonephritis, autoimmune thy roiditis, giant cell arteritis (temporal arteritis),
psoriasis, a nd insulin -dependent diabetes mellitus (type 1).
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Page 1910. Bleeding diathesis or condition associated with prolonged bleeding that would, in the
opinion of the investigator, contraindicate intramuscular injection.
11.Women who are pregnant or breastfeeding.
Prior/Conco mitant Therapy:
12.Previous vaccination with any coronavirus vaccine.
13.Individuals who received treatment with immunosuppressive therapy , including cy totoxic
agents or s ystemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throug hout the study . If systemic corticosteroids were administered short term
(<14 days) for treatment of an acute illness, participants should not have been enrolled
into the study until corticosteroid therapy had been discontinued for at least 28 day s
before study intervention administration. I nhaled/nebulized (except for participants in
Phase 1 – see exclusion criterion 14), intra- articular, intrabursal, or topical (skin or ey es)
corticosteroids were permitted.
14.Phase 1 only: Regular receipt of inhaled/nebulized corticosteroids.
15.Receipt of blood/plasma products or immunoglobulin, from 60 day s before study
intervention administration or planned receipt throughout the stud y.
Prior/Concurrent Clinical Study Experience:
16.Participation in other studies involving study intervention within 28 day s prior to study
entry and/or during study participation.
17.Previous participation in other studies involving study intervention containing lipid
nanoparticles.
Diagnostic Assessments:
18.Phase 1 only: Positive serological test f or SARS -CoV -2 immunoglobulin M (IgM)
and/or IgG antibodies at the screening visit.
19.Phase 1 only: Any screening hematology and/or blood chemistry laboratory value that
meets the definition of a ≥Grade 1 abnormality .
Note: With the exception of bilirubin, participants with any stable Grade 1 abnormalities
(according to the toxicity grading scale) may be considered eligible at the discretion of
the investigator. (Note: A “stable” Grade 1 laboratory abnormalit y is defined as a report
of Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on a
second sample from the same participant.)
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Page 2020.Phase 1 only: Positive test for HIV, hepatitis B surface antigen (HBsAg), hepatitis B
core antibodies (HBc Abs), or hep atitis C virus antibodies (HCV Abs) at the screening
visit.
21.Phase 1 only: SARS -CoV -2 NAAT -positive nasal swab within 24 hours before receipt of
study intervention.
Other Exclusions:
22.Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of
the study , site staff otherwise supervised by the investigator, and their respective famil y
members.
Vaccines Administered: The vaccine candidate selected for Phase 2/3 evaluation was
BNT162b2 at a dose of 30 µg.The stud y evaluated a 2 -dose (separated b y 21 day s) schedule of
the following for active immunization against COVID -19 or saline placebo in participants
12through 15 years of age and reference groups ( 16 through 25 and 16 through 55 years of age) :
BNT162b2 (BNT162 RNA -LNP vaccine containing modRNA that encodes
SARS -CoV -2 full -length, P2 mutant, prefusion spike gl ycoprotein [ P2 S]): 30 µg
Normal saline (0.9% sodium chloride solution for injection)
A list of the study interventions administered in this study and their representative lot
numbers is provided in Table S2.
Table S2. Investigational Product Lot Numbers – Interim – Adolescents
Investigational
Product Phase ManufacturerVendor Lot Number
(Manufacturer)
Lot Numbera(Pfizer)
BNT162b2 (30 µg) 2/3 BioNTech BCV40420 -A
BCV40420 -A
BCV40420 -A
BCV40420 -A
BCV40420 -A
BCV40620 -A
BCV40620 -AE220395 -
0006L003/P220395 -
0012L
E220395 -
0035L002/P220395 -
0048L
E220395 -
0035L003/P220395 -
0048L
EU2065896/E220395 -
0004L
PA2070104/P220395 -
0008L
PA2071394/P220395 -
0029L
PA2072393/P220395 -
0019L
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Page 21Table S2. Investigational Product Lot Numbers – Interim – Adolescents
BCV40620 -B
BCV40620 -B
BCV40620 -C
BCV40620 -C
BCV40620 -D
BCV40620 -D
BCV40720 -A
BCV40720 -A
BCV40720 -B
BCV40720 -C
ED3938PA2071395/P220395 -
0016L
PA2072396/P220395 -
0016L
PA2071396/P22039 5-
0047L
PA2072439/P220395 -
0047L
PA2072442/P220395 -
0042L
PA2072765/P220395 -
0042L
PA2074172/P220395 -
0053L
PA2074998/P220395 -
0060L
PA2074173/P220395 -
0051L
PA2074071/P220395 -
0052L
PA2074300/P220395 -
0021L
ED3938
ED3938
ED3938
EE3813
EE3813
EE8493Z
EE3813
EE3813
EE3813
EJ0553ZEU2074330/E220395 -
0036L
PA2074300/P220395 -
0022L
PA2074300/P220395 -
0023L
PA2074838/P220395 -
0024L
PA2074838/P220395 -
0020L
PA2077905/P220395 -
0026L
NC2075485/P220395 -
0068L
NC2075485/P220395 -
0074L
NC2075485/P220395 -
0077L
PA2085061/P220395 -
0070L
Normal saline (0.9%
sodium chloride
solution for injection)2/3 Pfizer DK1589;20 -001592
DK1589;20 -001776
DK2074;20 -002029
DK2074;20 -002108PA2064251/P220395 -
0005L
PA2065311/P220395 -
0007L
PA2067775/P220395 -
0030L
PA2067774/P220395 -
0013L
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Page 22Table S2. Investigational Product Lot Numbers – Interim – Adolescents
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221PA2069407/P220395 -
0031L
PA2069407/P220395 -
0032L
PA2069407/P220395 -
0033L
PA2069407/P220395 -
0034L
PA2069407/P220395 -
0044L
PA2069407/P220395 -
0045L
PA2069407/P220395 -
0046L
PA2069407/P220395 -
0054L
PA2069407/P22039 5-
0055L
PA2069407/P220395 -
0056L
PA2069407/P220395 -
0062L
PA2069407/P220395 -
0065L
PA2069407OTH/E220395 -
0049L
Note: C4591001 End of Study Information and Quality Control (QC) Record for Study Drug Appendix (Section D)
dated 07Apr 2021 was used to create this table.
a. Lot number assigned to the investigational product by Pfizer Global Clinical Supply.
Protocol C4591001 Investigational Product Lot Numbers Table – Interim –Adolescents, Final , Version 2.0,
09Apr 2021.
Efficacy and Immunogenicity Evaluations: Efficacy (prespecified) was assessed for
potential cases of COVID -19and described in the final anal ysis interim C4591001 CSR
dated 03 December 2020. The prespecified interim analy sis was conducted on an accrued
94evaluable COVID -19 cases (data cutoff date: 04November 2020) , and the final anal ysis
was conducted on an accrued 170evaluable COVID -19 cases (data cutoff date :
14November 2020 ).These anal yses included data from all participants in Phase 3 age
groups ( 12-15, 16 -55, and >55 y ears of age) at the time of the anal yses.Prespecified primary
and secondary efficacy endpoint analy ses were completed per protocol as of 14 November
2020, and no additional formal hypothesis testing of clinically confirmed COVID -19 cases is
planned. At the time of the final anal ysis, there were few participants 12- 15 years of age
enrolled in the study and no COVID -19 cases reported in this age group accrued at that time
(14 November 2020) .In this report, efficacy was assessed based on all cases in participants
12 through 15 y ears of age accrued in blinded follow -up to a data cutoff date of
13March 2021 .
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Page 23Confirmed COVID -19: presence of at least 1 of the following s ymptoms and SARS -CoV -2
NAAT -positive during, or within 4 day s before or after, the s ymptomatic period, either at the
central laboratory or at a local testing facility (using an acceptable test):
Fever;
New or increased cough;
New or increased shortness of breath;
Chills;
New o r increased muscle pain;
New loss of taste or smell;
Sore throat;
Diarrhea;
Vomiting.
The second definition, which may be updated as more is learned about COVID -19, include s
the following additional sy mptoms defined b y the CDC (listed at
https://www.cdc.g ov/coronavirus/2019 -ncov/s ymptoms- testing/sy mptoms.html):
Fatigue;
Headache;
Nasal congestion or runny nose;
Nausea.
Confirmed severe COVID- 19: confirmed COVID -19 and presence of at least 1 of the
following:
Clinical signs at rest indicative of severe s ystemic illness (RR ≥30 breaths per minute,
HR ≥ 125 beats per minute, SpO 2≤93% on room air at sea level, or PaO 2/FiO 2
<300 mm Hg);
Respiratory failure (defined as needing high -flow oxy gen, noninvasive ventilation,
mechanical ventilation, or ECMO);
Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors);
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Page 24Significant acute renal, hepatic, or neurologic d ysfunction;
Admission to an intensive care unit ( ICU);
Death.
In addition to the ab ove specified definition of severe COVID -19, an efficacy anal ysis for
any severe COVID -19 cases was conducted using the CDC definition of severe COVID-19
(hospitalization, admission to the I CU, intubation or mechanical ventilation, or death ).
For i mmunogen icity testing, the following assay s were performed inparticipants 12 through
15 years of age :SARS -CoV -2 neutralization assay ( reference strain).
Safety Evaluations:
Local Reactions and Sy stemic Events: All participants 12 through 15 years of age and a
subset of participants 16 through 55 years of age (including the y oung adults 16 through
25years of age )were asked to monitor and record local reactions, sy stemic events, and
antipy retic/pain medication usage for 7 days following administration of the study
intervention using an e -diary . All other participants didnot complete a n e-diary but hadtheir
local reactions and s ystemic events reported as AEs .
For local reactogenicit y, during the reactogenicit y e-diary reporting period, participants were
asked to assess redness, swelling, and pain at the injection site and to record the sy mptoms in
the reactogenicit y e-diary. If a local reaction persisted bey ond the end of the reactogenicity
e-diary period following vaccination, the participant was requeste d to report that information.
Redness and swelling were measured and recorded in measuring device units (range: 1to21)
and then categorized during anal ysis as absent, mild, moderate, or severe based on the
grading scale. Pain at the injection site was as sessed by the participant as absent, mild,
moderate, or severe according the grading scale.
For s ystemic reactogenicity , during the reactogenicity e-diary reporting period, participants
were asked to assess vomiting, diarrhea, headache, fatigue, chills, n ew or worsened muscle
pain, and new or worsened joint pain and to record the sy mptoms in the reactogenicit y
e-diary . The sy mptoms were assessed by the participant as absent, mild, moderate, or severe
according to the grading scale.
Temperature was collected in the reactogenicit y e-diary in the evening daily during the
reactogenicity e-diary reporting period and at an y time during the reactogenicity e-diary data
collection periods when fever was suspected. Fever is defined as an oral temperature of ≥38.0 °C
(100.4°F). The highest temperature for each day was recorded in the reactogenicity e-diary .
The investigator or designee obtained stop dates from the participant for any ongoing local
reactions, s ystemic events, or use of antipy retic medication on the las t day that the
reactogenicity e-diary was completed.
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Page 25AEs and SAEs : AEs were reported b y the participant (or, when appropriate, by a caregiver,
surrogate, or the participant's legally authorized representative). The time period for activel y
eliciting and c ollecting AEs and SAEs (“active collection period”) for each participant began
from the time the participant provided informed consent, which was obtained before the
participant’s participation in the study (ie, before undergoing any study -related procedur e
and/or receiving study intervention), through and including Visit 3 (1 month after Dose 2) for
Phase 2/3 participants. In addition, any AEs occurring up to 48 hours after each subsequent
blood draw were recorded on the CRF. SAEs were collected from the time the participant
provides informed consent to approximately 6 months after the last dose of study
intervention ( Visit 4 for Phase 2/3 participants).
Acute reactions (immediate AEs) were collected within the first 30 minutes after
administration of the study intervention.
Statistical Methods:
Efficacy Analysis: The efficacy assessment in Phase 2/3 portion of the study was
event -driven. Vaccine efficacy (VE)with respect to the first primary efficacy endpoint was
assessed at the first interim analy sis (a t least 62 cases) at 94 cases (data cutoff date:
04November 2020) and met success criteria on the first primary endpoint .At the final
analysis (at least 164 cases) vaccine efficacy with respect to all efficacy endpoints was
assessed on an accrued 170 evaluable COVID -19 cases (data cutoff date :
14November 2020) for both primary and all secondary efficacy endpoints. No additional
formal hy pothesis testing of clinically confirmed COVID -19 cases isplanned .
Assessment of VE of BNT162b2 was performed for confirmed COVID -19 cases observed at
least 7 day s after the receipt of Dose 2 onwards among participants either without or with or
without serological or virological evidence before or during vaccination regimen (up to
7days after receip t of the second dose) of past SARS -CoV -2 infection. VE was estimated b y
100% × (1 –IRR), where I RR was the ratio of COVID -19 illness rate in the BNT162b2
group to the corresponding illness rate in the placebo group.
Updated efficacy analy ses during blinded placebo -controlled follow -up were conducted for
participants 12 through 15 y ears of age based on the data cutoff date of 13 March 2021. The
point estimate of VE in the blinded follow- up period and associated 2 -sided 95% CI was
derived using the Clopper Pearson method adjusted for surveillance time. In addition to the
protocol definition of severe COVID-19, supportive anal yses using the CDC definition of
severe COVID -19 was also performed .
Immunogenicity Analysis: For participants randomized to the BNT162b2 groups with no
serological or virological evidence (up to 1 month after receipt of the second dose) of past
SARS -CoV -2 infection, the GMR of SARS -CoV -2 50% neutralizing titers in participants
12through 15 years of age to those i n participants 16 through 25 years of age and 2 -sided
95% CI s were provided at 1 month after Dose 2 for NIassessment. The GMR and its 2- sided
95% CI werederived by calculating differences in means and CIs on the natural log scale of
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Page 26the titers based on the Student’s t-distribution and then exponentiating the results. The
difference in means on the natural log scale w ere12 through 15 years minus 16 through
25years. Noninferiorit y wasdeclared if the lower bound of the 2- sided 95% CI for the GMR
wasgreater than 0.67 , using 1.5- fold NI margin. In addition, the difference in percentages of
participants (12 through 15 years – 16 through 25 years) achieving a ≥4-fold rise in SARS -
CoV -2 neutralizing titers from before vaccination to 1 month after Dose 2 were provided.
The associated 2 -sided 95% CI for the difference in percentage was calculated using the
Miettinen and Nurminen method.
For immunogenicity results of SARS -CoV -2 neutralizing titers, the GMT w ascomputed
along with associated 95% CIs. The GMT w ascalculated as the means of assay results after
making the logarithm transformation and then exponentiating the mean sto express results on
the original scale. Two -sided 95% CIs were obtained by taking log transforms of assay
results , calculating the 95% CIswith reference to Student’s t -distribution, and then
exponentiating the confidence limits.
The GMFR was calculated by exponentiating the mean of the difference of logarithmicall y
transformed assay results (later time point – earlier time point). Two -sided CIs were obtained
by calculating CIs using Student’s t -distribution for the mean difference of the
logarithmicall y transformed assay results and exponentiating the confidence limits.
The exact 95% CIs for binary endpoints were computed using the F distribution
(Clopper -Pearson method).
Titers below the lower limit of quantitation (LLOQ) or denoted as below the level of
quantitation (BLQ) were set to 0.5 × LLOQ for analy sis.
Safety Analysis: The primary safet y objective was evaluated b y descriptive summa ry
statistics for local reactions, sy stemic events, and AEs/SAEs for each vaccine group. A 3-tier
approach was used to summarize AEs in Phase 2/3. Under this approach ,AEs were classified
into 1 of 3 tiers:
Tier 1 events are prespecified events of clinical importance and are identified in a list in the
product’s S afety Review Plan; there are no Tier 1 AEs identified for this program.
Tier 2 events were those that were not Tier 1 but were considered “relative ly common”;
a MedDRA preferred term is defined as a Tier 2 event if there are at least 1% of participants
with the AE term in at least 1 vaccine group .
Tier 3 events were those that were neither Tier 1 nor Tier 2.
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Page 27RESULTS
Participant Disposition and Demography:
Participants 12 Through 15 Years of Age :
Study population characteristics are provided for adolescents 12 to 15 y ears of age, and those
of young adults 16 through 25 y ears of age are included for comparison. Note that for safet y
endpoint anal ysesof adolescents that included comparative data from y oung adults, the
young adult group anal yzed was the reactogenicit y subset (ie, those participants in the young
adult group who completed an e -diary for reactogenicity in addition to AE reporting).
The di sposition of adolescents (12 through 15 years of age) and young adults (16 through
25years of age) was similar in BNT162b2 and placebo groups through 1 month after Dose 2.
Most participants randomized in both age groups (≥97.4%) received Dose 1 and Dose 2 .
Among adolescents, 7 participants (0.6%) in the BNT162b2 group and 17 participants (1.5%)
in the placebo group discontinued from the vaccination period and are continuing in the study
for safety follow -up. Most participants across age groups completed th e visit at 1 month after
Dose 2 (≥94.5%). Among adolescents who discontinued from vaccination period but
continued in the study up to the 1 month post Dose 2 visit , 2 participants discontinued due to
AEs, both in the BNT162b2 group (p yrexia considered b y the investigator as related to stud y
intervention, and unrelated anxiety/depression) and none in the placebo group.
No adolescents in the BNT162b2 and 2 participan ts in the placebo group withdrew from the
study before the 1 month post Dose 2 visit.
The median duration of follow -up for adolescents was >2 months after Dose 2. Almost all
(98.3%) of adolescent participants had at least 1 month of follow -up after Dose 2 , and
1308 out of 2260 enrolled adolescents (57.9%) had at least 2 months of follow -up after
Dose 2.
A total of 49 adolescent participants withdrew from the vaccination period when they turned
16years of age after entering the stud y and became eligible to be unblinded to receive
BNT162b2 vaccination; of these, 19/49 received Dose 3 and Dose 4 (BNT162b2).
Participants originall y randomized to placebo who received Dose 3 of BNT162b2 (per
protocol) continued in open- label follow -up in the study , but their dat a were censored at the
time of unblinding with regard to analy ses in this submission. Information for these
participants are provided for SAEs or other significant AEs.
Demographic characteristics for adolescents (12 through 15 y ears of age) and y oung adul ts
(16 through 25years of age) were similar in the corresponding BNT162b2 and placebo
groups in the safety population. Overall, most adolescent participants in the BNT162b2
group were White ( 85.9%), with 4.6% Black participants and 6.4% Asian participants , and
other racial groups were <3.0 %. There were 11.7% Hispanic/Latino participants. The m edian
age in the BNT162b2 group was 14.0 years and 50.1% were male. Obese adolescents (based
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Page 28on age -and sex -specific body mass index) made up 11.3% (placebo group) t o 12.6%
(BNT162b2 group) of this age group in the safet y population.
Demographic characteristics for the adolescents and y oung adults in the reactogenicit y subset
were similar to those in the safet y population .
Participants 16 Through 55 Years of Age :
Thedisposition of randomized adult participants (16 through 55 years of age) was similar in
the BNT162b2 and placebo groups during the blinded follow -up period. Most participants
randomized ( 97.7%) received Dose 1 and Dose 2. There were 278 (2.1%) participan ts in the
BNT162b2 group and 388(3.0%)participants in the placebo group who discontinued from
the vaccination period. Most participants (95.8%) completed the 1 month post Dose 2 visit
and 25.5% of the BNT162b2 group participants completed the 6 months po st Dose 2 (25.5%)
visit as of the data cutoff date. There were 608 participants in the BNT162b2 and placebo
groups who were withdrawn from the study (2.0% and 2.7%, respectivel y), most ly due to lost
to follow -up (1.2%) or withdrawn by subject (0.9%).
Duration of follow- up was ≥4 months after Dose 2 for 57.8% of adult participants
(16through 55 years of age) during the blinded placebo- controlled follow -up period. As of
the data cutoff date (13 March 2021), the proportion of participants in this age group wi th
blinded follow -up to at least 6 months after Dose 2 included 10.4% in the BNT162b2 group
and 8.2% in the placebo group. When total exposure time from Dose 2 to the data cutoff date
is considered, 6666 participants in this age group (51.0%) had ≥6 months of follow -up time.
Demographic characteristics for Phase 2/3 adults in the 16 through 55 years of age group
were similar in the BNT162b2 and placebo groups .Overall, most adult participants were
White ( 78.2%), with 11.0% Black participants and 5.4% Asian participants, and other racial
groups were < 6.0%. There were 30.8% Hispanic/Latino participants. The m edian age was
40.0 years and 49.9% of participants were male. Obese adults made up 33.7 % of this safet y
population.
Efficacy Results:
Participants 12 Through 15 Years of Age:
Descriptive efficacy analy ses were conducted for the adolescent group on cases accrued
during blinded follow -up period through the data cutoff date of 13 March 2021.
In the adolescent group, in the efficacy anal yses in the evaluable efficacy population based
on cases reported from at least 7 days after Dose 2 through the data cutoff date, the observed
VE was 100% ( 0 and 16 cases in the BNT162b2 and placebo group ,respectively ,with
2-sided 95% CI: 75.3%, 100%) for individuals without evidence of prior SARS -CoV -2
infection before and during vaccination regimen, and 100% ( 0 and 18 cases in the BNT 162b2
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Page 29and placebo group respectively with 2-sided 95% CI : 78.1%, 100%) for those with or without
evidence of prior SARS -CoV -2 infection before and during vaccination regimen.
The efficacy anal ysis for the Dose 1 all -available (modified intention -to-treat) population
included 3 cases in the BNT162b2 group and 35 cases in the placebo group, with an observed
VE of 91.6% (2 -sided 95% CI : 73.5%, 98.4%), with no cases reported in the BNT162b2
group starting from ≥11 day s after Dose 1.
No severe cases were reported in the 12- 15 years of age group as of the date cutoff date.
Overall, these efficacy data strongl y support BNT162b2 us e in adolescents 12-15 years of
age.
Immunogenicity Results –Participants 12 Through 15 Years of Age :
Noninferiorit y of Immune Response to Prophylactic BNT 162b2 in Participants 12Through
15 Years Compared with Participants 16 Through 25 Years of Age :
Geometric Mean Ratio (GMR) in Neutralization Titers
The immune response to BNT162b2 in adolescents 12 through 15 years of age was noninferior
to that observed in young adults 16 through 25 years of age, based on SARS -CoV -2 50%
neutralizing titers at 1 month after Dose 2, in participants without prior evidence of
SARS -COV -2 infection, and in fact greatl y exceeded the response observed in y oung adults.
TheGMT ratio of adolescents to y oung adults was 1.76 (2-sided 95% CI : 1.47, 2.10), meeting
the 1.5- fold noninferiority (NI)criterion (ie, lower bound of the 2 -sided 95% CI for GMR
>0.67). Of note, the lower bound of the 2- sided 95% CI for the GMR is >1 which indicates a
statistically greater response in the adolescents than that of y oung adults.
Seroresponse
Among participants without prior e vidence of SARS- CoV -2 infection up to 1 month after
Dose 2 of BNT162b2, high proportions (97.9% of adolescents and 100.0% of y oung adults)
had a ≥4-fold rise (seroresponse) in SARS -CoV -2 50% neutralizing titers from before
vaccination to 1 month after Dose 2. The difference in proportions of participants who had a
≥4-fold rise between the two age groups (adolescents – young adults) was -2.1% (2 -sided
95% CI : -6.0%, 0.9%).
Geome tric Mean Titers (GMT s):
At 1 month after Dose 2 (Day 52) of BNT162b2, substantial increases above baseline in
SARS -CoV -2 50% neutralizing GMTs were observed in both age groups, with a greater
magnitude of increase in the adolescent group compared with the young adult group.
Theneutralizing GMT in adolescents at 1 month after Dose 2 was approximately 1.76 -fold
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Page 30that of the young adult group. As expected, the neutralizing GMTs were low in both placebo
groups.
Geometric Mean Titers (GMTs) by Baseline SARS -CoV-2 Status
Vaccination with BNT162b2 induced an increased immune response (GMTs) at 1 month
after Dose 2 for all participants, regardless of baseline SARS- CoV -2 positive or negative
status. Adolescents who were baseline SARS- CoV -2 positive had SARS -CoV -2 50%
neutralizing GMTs approximately 1.89 -fold that of adolescents who were baseline negative.
Asimilar pattern was observed for baseline SARS -CoV -2 positive versus negative y oung
adults.
Geometric Mean Fold Rise s(GMFR s):
The GMFRs of SARS -CoV -2 50% serum neutralizing titers from before vaccination to
1 month after Dose 2 of BNT162b2 were robust, with a greater magnitude of rise in the
adolescent group (118.3) compared with the young adult group (71.2).
GMFR in Titers by Baseline SARS -CoV-2 Status
The GMFRs were higher in the adolescent compared to y oung adult group 1 month after the
second dose. Given the limited sample size for those positive at baseline, the GMFRs were
numericall y higher in those who were negative at baseline .
Seroresponse Rate
Proportions of participants with a ≥4-fold rise in SARS -CoV -2 50% neutralizing titers from
before vaccination to 1 month after Dose 2 of BNT162b2 (seroresponse rate) were 98.1% in
adolescents and 99.3% in y oung adults. As expected, very few placebo participants reached a
≥4-fold rise in SARS -CoV -2 neutralizing titers from before to 1 month after Dose 2.
Seroresponse Rate by Basel ine SARS -CoV-2 Status
Adolescents who were baseline SARS -CoV -2 positive or negative had similar seroresponse
rates (100.0% vs 97.9%) .
Safety Results:
Participants 12 Through 15 Years of Age:
Phase 3 data from approximately 2200 adolescents 12 through 15 years of age with a median
follow -up time of at least 2 months after Dose 2 showed BNT162b2 at 30 µg was safe and well-
tolerated. Safety in young adults 16 through 25 years of age (reactogenicity subset) were
evaluated for descriptive comparison.
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Page 31Local Rea ctions and Systemic Events
Reactogenicit y in adolescents 12 through 15 y ears of age was mostly mild to moderate and
short -lived after dosing (ie, median onset mostly between 1 to 3days after dosing and
resolution within 1 to 3days after onset), similar t o the reactogenicit y data in the young
adults 16 through 25 years of age. Local reactions presented predominantly as injection site
pain with minimal effect of dose number, and sy stemic events generall y increased in
frequency and/or severit y with increasing dose number; also similar to findings in the 16
through 25 ye ars of age group. Adolescents tended to have less severe local reactions and
systemic events after each vaccine dose compared with y oung adults. The rate of fever was
somewhat higher i n the adolescent group compared to the y oung adult group (10.1% vs 7.3%
after Dose 1, respectivel y), especially after the second dose (19.6% vs 17.2 %, respectively ),
but fevers were mostl y mild to moderate in severity.
The observed AE profile did not sugg est an y serious safet y concerns for BNT162b2
vaccination of adolescents 12 through 15 years of age. Overall, AEs reported in the study for
adolescents and young adults reflect age -appropriate events consistent with the general
population.
AEs From Dose 1 to 1 Month After Dose 2
From Dose 1 to 1 month after Dose 2, severe AEs, SAEs, and AEs leading to withdrawal
were reported b y ≤1.7%, ≤0.4%, and ≤0.4%, respectively , in both groups. No reported SAEs
were considered b y the investigator as related to study intervention. Most of the AEs were
reactogenicity events reported as AEs (ie, headache, nausea, and diarrhea) in both age groups
and were frequentl y reported in the reactogenicit y SOCs of general disorders and
administration site conditions , musculoskeletal and connective tissue disorders , nervous
system disorders, and gastrointestinal disorders. Similarly , most related AEs were also
reactogenicity events and in the SOC of general disorders and administration site conditions .
Immediate AEs were reported in the BNT162b2 groups after Dose 2 only , were low in
frequency (≤0.4%) ,and most were in the SOC of general disorders and administration site
conditions.
AEs From Dose 1 to the Data Cutoff Date
Safety data up to the cutoff date (13 March 2021) were summarized for adolescent s 12 through
15 years of age ; due to variable unblinding dates among participants 16 through 25 years of
age, young adult data could not be compared with blinded adolescent data up to the cutoff date.
From Dose 1 to the data cutoff date, the number of adolescents with any AEwas similar in the
BNT162b2 and placebo groups. Severe AEs, SAEs, and AEs leading to withdrawal were
reported b y ≤0.8%, ≤0.4%, and ≤0.2%, respectively , in both groups. No reported SAEs among
adolescents were considered b y the investigator as related to stud y intervention. The most
frequentl y reported AEs included lymphadenopathy (0.8% ), injection site pain (0.6%), fatigue
(0.6%), p yrexia (0.4%), nausea (0.4%), and headache (0.4%).
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Page 32As of the data cutoff date (13 March 2021 ), there were very few AEs of clinical interest
corresponding to the CDC list of AESI s reported in adolescents. Lymphadenopathy has been
identified as related to BNT162b2 in study participants ≥16 y ears of age and is also identified
as related to BNT162b2 in the 12 -15 year old adolescent group . No cases of Bell’s
palsy /facial paral ysis were reported in adolescents as of the data cutoff date (13 March 2021).
No AEs of appendicitis were considered as related to the study intervention.
The incidence of SAEs was low in the context of the number of adolescent participants
enrolled and comparable between BNT162b2 (≤0.4% from Dose 1 to 1month after Dose 2
and to the data cut offdate)and placebo (≤0.4%, from Dose 1 to 1 month after Dose 2, and
≤0.2%from Dose 1 to the data cutoff date) . The incidence of withdrawals due to AEs was
also low and similar between BNT162b2 and placebo groups.
No deaths were reported in adolescents 12 through 15 years of age or in young adults
16through 25 years of age included in the safet y analyses.
Participants 16 Through 55 Years of Age:
The adult (16-25 years of age and 16- 55 years of age) safety data included for reference
purposes in the context of this report arefrom approximately 26,000 adults 16 through
55years of age, among whom a majority in the BNT162b2 group had at least 6 months of
blinded follow -up after Dose 2 in Phase 2/3 of this study . These data show BNT162b2 at
30µg was safe and well -tolerated in this adult age group. Reactogenicity was mostly mild to
moderate and short -lived after dosing (ie, median onset between 1 to 2days after dosing and
resolution within 1 to 2 days after onset), with local reactions presenting predominantly as
injection site pain with minimal effect of dose num ber, and s ystemic events generall y
increasing in frequency and/or severit y with increasing dose number.
Review of AEs and SAEs in the adult (16 through 55 y ears of age) population presented in
this report did not suggest new safet y concerns to date . A full and independent safet y
evaluation of the adult population is being conducted and will be included in a full clinical
study report in support of licensing/marketing application submissions including a BLA
planned in second quarter of 2021.
Comparing adole scents (12 through 15 years of age) to young adults (16 through 25 years of
age) and adults (16 through 55 y ears of age )identifies very similar reactogenicity profiles.
Reactogenicit y after each dose was observed in all groups with similar patterns after Dose 1
and Dose 2. Fever was highest for the adolescent group compared to the young adult group
but was still within tolerable limits. Arthralgia and muscle pain were higher in the y oung
adult group than the adolescent group for both doses of BNT162b2. Ove rall, the differences
in reported AEs were age -appropriate and not related to vaccination.
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Page 33Overall Conclusion (s):
In Phase 2/3, BNT162b2 at 30 µg provided protection against COVID- 19 in adolescents
12through 15 years of age irrespective of evidence of prior infection with SARS -CoV -2
(100% VE) , with no severe cases observed in this age group. The immune responses in
adolescent participants were noninferior to the immune responses in young adults , and in fact
were statisticall y greater than that observed in young adults . The tolerability and safet y
profile was acceptable and supports BNT162b2 at 30 µg administered as a 2- dose regimen
(21 day s apart) to adolescents 12 through 15 years of age for the prevention of COVID -19.
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