The new engl and jour nal of medicine
n engl j med 385;3  nejm.org  July 15, 2021 239
From Cincinnati Children’s Hospital, Cincinnati
(R.W.F.); Kaiser Permanente Vaccine
Study Center, Oakland (N.P.K.), and
the California Research Foundation, San
Diego (D.M.B.) — both in California; Vaccine
Research and Development, Pfizer,
Hurley, United Kingdom (N.K., S.L., R.B.);
Vaccine Research and Development,
Pfizer, Pearl River (A.G., J.A., K.A.S., K.K.,
W.V.K., D.C., P.R.D., K.U.J., W.C.G.), and
SUNY Upstate Medical University, Syracuse
(S.J.T.) — both in New York; Vaccine
Research and Development (J.L.P., H.M.,
X.X.) and Worldwide Safety, Safety Surveillance
and Risk Management (S.M.),
Pfizer, Collegeville, PA; Duke Human
Vaccine Institute, Durham, NC (E.B.W.);
Senders Pediatrics, South Euclid, OH (S.S.);
Clinical Research Professionals, Chesterfield,
MO (T.J.); BioNTech, Mainz, Germany
(Ö.T., U.Ş.); and Worldwide Safety,
Safety Surveillance and Risk Management,
Pfizer, Groton, CT (D.B.T.). Address
reprint requests to Dr. Gurtman at Vaccine
Research and Development, Pfizer,
401 N. Middletown Rd., Pearl River, NY
10965, or at ­alejandra​.­gurtman@​­pfizer
​.­com.
*The members of C4591001 Clinical Trial
Group are listed in the Supplementary
Appendix, available at NEJM.org.
This article was published on May 27, 2021,
at NEJM.org.
N Engl J Med 2021;385:239-50.
DOI: 10.1056/NEJMoa2107456
Copyright © 2021 Massachusetts Medical Society.
BACKGROUND
Until very recently, vaccines against severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) had not been authorized for emergency use in persons younger
than 16 years of age. Safe, effective vaccines are needed to protect this population,
facilitate in-person learning and socialization, and contribute to herd immunity.
METHODS
In this ongoing multinational, placebo-controlled, observer-blinded trial, we randomly
assigned participants in a 1:1 ratio to receive two injections, 21 days apart,
of 30 μg of BNT162b2 or placebo. Noninferiority of the immune response to
BNT162b2 in 12-to-15-year-old participants as compared with that in 16-to-25-yearold
participants was an immunogenicity objective. Safety (reactogenicity and adverse
events) and efficacy against confirmed coronavirus disease 2019 (Covid-19;
onset, ≥7 days after dose 2) in the 12-to-15-year-old cohort were assessed.
RESULTS
Overall, 2260 adolescents 12 to 15 years of age received injections; 1131 received
BNT162b2, and 1129 received placebo. As has been found in other age groups,
BNT162b2 had a favorable safety and side-effect profile, with mainly transient mildto-moderate
reactogenicity (predominantly injection-site pain [in 79 to 86% of participants],
fatigue [in 60 to 66%], and headache [in 55 to 65%]); there were no vaccinerelated
serious adverse events and few overall severe adverse events. The geometric
mean ratio of SARS-CoV-2 50% neutralizing titers after dose 2 in 12-to-15-year-old
participants relative to 16-to-25-year-old participants was 1.76 (95% confidence interval
[CI], 1.47 to 2.10), which met the noninferiority criterion of a lower boundary of the
two-sided 95% confidence interval greater than 0.67 and indicated a greater response
in the 12-to-15-year-old cohort. Among participants without evidence of previous
SARS-CoV-2 infection, no Covid-19 cases with an onset of 7 or more days after dose 2
were noted among BNT162b2 recipients, and 16 cases occurred among placebo recipients.
The observed vaccine efficacy was 100% (95% CI, 75.3 to 100).
CONCLUSIONS
The BNT162b2 vaccine in 12-to-15-year-old recipients had a favorable safety profile,
produced a greater immune response than in young adults, and was highly effective
against Covid-19. (Funded by BioNTech and Pfizer; C4591001 ClinicalTrials.gov
number, NCT04368728.)
ABSTR ACT
Safety, Immunogenicity, and Efficacy of the
BNT162b2 Covid-19 Vaccine in Adolescents
Robert W. Frenck, Jr., M.D., Nicola P. Klein, M.D., Ph.D., Nicholas Kitchin, M.D.,
Alejandra Gurtman, M.D., Judith Absalon, M.D., Stephen Lockhart, D.M.,
John L. Perez, M.D., Emmanuel B. Walter, M.D., Shelly Senders, M.D.,
Ruth Bailey, B.Sc., Kena A. Swanson, Ph.D., Hua Ma, Ph.D., Xia Xu, Ph.D.,
Kenneth Koury, Ph.D., Warren V. Kalina, Ph.D., David Cooper, Ph.D.,
Timothy Jennings, D.O., Donald M. Brandon, M.D., Stephen J. Thomas, M.D.,
Özlem Türeci, M.D., Dina B. Tresnan, D.V.M., Ph.D., Susan Mather, M.D.,
Philip R. Dormitzer, M.D., Ph.D., Uğur Şahin, M.D., Kathrin U. Jansen, Ph.D.,
and William C. Gruber, M.D., for the C4591001 Clinical Trial Group*​​
Original Article
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n engl j med 385;3  nejm.org  July 15, 2021240
The new engl and jour nal of medicine
A
s of May 21, 2021, the coronavirus
disease 2019 (Covid-19) pandemic has
caused more than 165 million infections
across all ages globally, as well as more than
3.4 million deaths.1
BNT162b2 (Pfizer–BioNTech)
is a Covid-19 vaccine containing nucleoside-modified
messenger RNA encoding the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2)
spike glycoprotein.2
In healthy adults, two 30-μg
doses of BNT162b2 elicited high neutralizing
titers and robust, antigen-specific CD4+ and
CD8+ T-cell responses against SARS-CoV-2.3,4
In
the phase 2–3 part of an ongoing global, phase
1–2–3 randomized, controlled trial involving participants
16 years of age or older, BNT162b2 had
a favorable safety profile characterized by transient
mild-to-moderate injection-site pain, fatigue,
and headache and was 95% effective in preventing
Covid-19 from 7 days after dose 2.5
On the
basis of these findings, BNT162b2 received emergency
use authorization from the Food and
Drug Administration on December 11, 2020, for
Covid-19 prevention in persons 16 years of age
or older.6
On May 10, 2021, the emergency use
authorization was expanded to include persons
12 years of age or older on the basis of data
presented in this report.7
Other vaccines against
SARS-CoV-2 are authorized for emergency use1,8‑10
;
however, BNT162b2 is the only one currently
authorized for use in persons younger than 16
years of age.
Although children and adolescents generally
have milder Covid-19 than adults, severe illness
can occur in this population, especially in those
with underlying medical conditions.11
Adolescents
may play an important role in SARS-CoV-2 trans-
mission.12,13
Thus, their vaccination may prevent
disease and contribute to herd immunity. Furthermore,
with immunization of older persons,
younger persons account for an increased proportion
of Covid-19 infections.14,15
The pandemic
has interrupted the education and social development
of students and has simultaneously burdened
caregivers.16-18
Safe, efficacious vaccines for
younger populations are therefore paramount.
Methods
Objectives, Participants, and Oversight
We conducted a randomized, placebo-controlled,
observer-blinded, phase 3 trial as part of a phase
1–2–3 trial assessing BNT162b2 safety, immunogenicity,
and efficacy in healthy persons 12 years
of age or older. This report presents findings from
12-to-15-year-old participants enrolled in the
United States, including descriptive comparisons
of safety between participants in that age cohort
and those who were 16 to 25 years of age and an
evaluation of the noninferiority of immunogenicity
in the 12-to-15-year-old cohort to that in
the 16-to-25-year-old cohort. Data were collected
through the cutoff date of March 13, 2021.
Eligible participants were healthy or had stable
preexisting disease (including hepatitis B,
hepatitis C, or human immunodeficiency virus
infection). Persons with a previous clinical or virologic
Covid-19 diagnosis or SARS-CoV-2 infection,
previous coronavirus vaccination, diagnosis
of an immunocompromising or immunodeficiency
disorder, or treatment with immunosuppressive
therapy (including cytotoxic agents and systemic
glucocorticoids) were excluded.
The ethical conduct of the trial is summarized
in the Supplementary Appendix, available
with the full text of this article at NEJM.org.
Additional details of the trial are provided in the
protocol, available at NEJM.org. Pfizer was responsible
for the trial design and conduct, data
collection, data analysis, data interpretation, and
writing of the manuscript that was submitted.
Both Pfizer and BioNTech manufactured the
vaccine and placebo. BioNTech was the regulatory
sponsor of the trial and contributed to data
interpretation and writing of the manuscript. All
data were available to the authors, who vouch for
their accuracy and completeness and for the
adherence of the trial to the protocol.
Procedures
Randomization was conducted with the use of
an interactive Web-based response system. Participants
were assigned in a 1:1 ratio to receive two
intramuscular injections of 30 μg of BNT162b2
or placebo (saline) 21 days apart. For evaluation
of immediate vaccine-associated reactions, participants
were observed in the clinic for 30 minutes
after vaccination.
Safety
Safety objectives included the assessment of local
or systemic reactogenicity events, which were recorded
by the participants in an electronic diary
(e-diary) for 7 days after each dose. Unsolicited
adverse events (i.e., those reported by the particiThe
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n engl j med 385;3  nejm.org  July 15, 2021 241
BNT162b2 Vaccine in Adolescents
pant without e-diary prompting) and serious adverse
events were also recorded from receipt of
the first dose through 1 month and 6 months
after dose 2, respectively.
Immunogenicity
Immunogenicity assessments (SARS-CoV-2 serum
neutralization assay and receptor-binding
domain [RBD]–binding or S1-binding IgG direct
Luminex immunoassays) were performed before
vaccination and 1 month after dose 2, as described
previously.3
The immunogenicity objective
was to show noninferiority of the immune
response to BNT162b2 in 12-to-15-year-old participants
as compared with that in 16-to-25year-old
participants. Noninferiority was assessed
among participants who had no evidence of previous
SARS-CoV-2 infection with the use of the
two-sided 95% confidence interval for the geometric
mean ratio of SARS-CoV-2 50% neutralizing
titers in 12-to-15-year-old participants as compared
with 16-to-25-year-old participants 1 month
after dose 2. BNT162b2 immunogenicity was
evaluated in participants with and those without
serologic or virologic evidence of previous SARSCoV-2
infection. Corresponding end points were
the geometric mean SARS-CoV-2 neutralizing titers
at baseline (i.e., immediately before receipt
of the first injection) and 1 month after dose 2
and geometric mean fold rises (GMFRs) in titers
from baseline to 1 month after dose 2.
Efficacy
The efficacy of BNT162b2 against confirmed
Covid-19 with an onset 7 or more days after dose
2 was summarized in participants who did not
have evidence of previous SARS-CoV-2 infection,
as well as in all vaccinated participants. Surveillance
for potential Covid-19 cases was undertaken
throughout the trial; if acute respiratory
illness developed in a participant, the participant
was tested for SARS-CoV-2. Methods for identifying
SARS-CoV-2 infections and Covid-19 diagnoses
are summarized in the Supplementary
Appendix.
Statistical Analysis
The safety population included all participants
who received at least one dose of BNT162b2 or
placebo. The reactogenicity subset included all
12-to-15-year-old participants and a subset of
16-to-25-year-old participants (those who received
an e-diary to record reactogenicity events). Safety
end points are presented descriptively as counts,
percentages, and associated Clopper–Pearson twosided
95% confidence intervals, with adverse
events and serious adverse events described according
to terms in the Medical Dictionary for Regulatory
Activities, version 23.1, for each group.
Immunogenicity was assessed in a random
subset of participants in each age cohort with
the use of a simple random-sample selection
procedure. For immunogenicity assessments, all
participants in both age cohorts were from U.S.
sites. The dose 2 immunogenicity population
that could be evaluated included participants
who underwent randomization and received two
BNT162b2 doses in accordance with the protocol,
received dose 2 within the prespecified
window (19 to 42 days after dose 1), had at least
one valid and determinate immunogenicity result
from a blood sample obtained within 28 to
42 days after dose 2, and had no major protocol
deviations. Noninferiority of the immune response
to BNT162b2 in 12-to-15-year-old participants
as compared with that in 16-to-25-yearold
participants was assessed on the basis of the
geometric mean ratio of SARS-CoV-2 50% neutralizing
titers. A sample of 225 BNT162b2 recipients
who could be evaluated (or 280 BNT162b2
recipients overall) in each age cohort was estimated
to provide 90.8% power for declaring
noninferiority (defined as a lower limit of the
95% confidence interval for the geometric mean
ratio of >0.67). A testing laboratory supply limitation
of the qualified viral lot used for assay
validation and clinical testing resulted in the
trial having fewer participants than anticipated
for the immunogenicity analyses. Calculations of
the geometric mean ratios, geometric mean titers,
and GMFRs are described in the Supplementary
Appendix.
Although the formal evaluation of efficacy
was to be based on the overall results obtained
across all age cohorts, the statistical analysis
plan specified that descriptive efficacy summaries
would be provided for each age cohort (the
stratification factor). The efficacy analysis for
the 12-to-15-year-old cohort was planned as a
descriptive analysis because the number of cases
that would occur in the age subgroups was unknown.
The efficacy population that could be
evaluated included all eligible 12-to-15-year-old
participants who underwent randomization and
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n engl j med 385;3  nejm.org  July 15, 2021242
The new engl and jour nal of medicine
2264Underwentrandomization
2306Participantswerescreened
42Didnotundergo
randomization
39Didnotmeet
eligibilitycriteria
1Withdrew
2Hadotherreason
1134Wereassigned
toreceiveBNT162b2
1130Wereassigned
toreceiveplacebo
3DidnotreceiveBNT162b2
2Nolongermet
eligibilitycriteria
1Hadotherreason
1Didnotreceiveplacebo
forunknownreason
1131Receiveddose11129Receiveddose1
1Waswithdrawnby
parentorguardian
afterdose2
1118Completed
vaccinationperiod
1102Completed
vaccinationperiod
7Receiveddose1but
notdose2
3Nolongermet
eligibilitycriteria
2Hadadverseevent
1Waswithdrawnby
physician
1Hadotherreason
12Receiveddose1but
notdose2
10Nolongermet
eligibilitycriteria
1Hadprotocoldeviation
1Hadunknownreason
1124Receiveddose21117Receiveddose2
3788Underwentrandomization
3881Participantswerescreened
93Didnotundergo
randomization
84Didnotmeet
eligibilitycriteria
3Withdrew
6Hadotherreason
1875Wereassigned
toreceiveBNT162b2
1913Wereassigned
toreceiveplacebo
6DidnotreceiveBNT162b2
4Withdrew
1Hadadverseevent
1Nolongermeteligibility
criteria
7Didnotreceiveplacebo
3Withdrew
1Hadprotocoldeviation
1Nolongermet
eligibilitycriteria
1Hadotherreason
1Hadunknownreason
1869Receiveddose11906Receiveddose1
22Discontinuedparticipation
intrialafterdose2
10Withdrew
9Werelosttofollow-up
1Waswithdrawnby
physician
1Hadprotocoldeviation
1Hadotherreason
20Discontinuedparticipation
intrialafterdose2
10Werelosttofollow-up
9Withdrew
1Waswithdrawnby
parentorguardian
1803Completed
vaccinationperiod
1807Completed
vaccinationperiod
43Receiveddose1but
notdose2
18Werelosttofollow-up
10Withdrew
6Hadunknownreason
5Nolongermet
eligibilitycriteria
2Werepregnant
1Hadadverseevent
1Hadotherreason
70Receiveddose1but
notdose2
26Nolongermet
eligibilitycriteria
23Werelosttofollow-up
10Withdrew
5Hadotherreason
3Werepregnant
2Werewithdrawn
byphysician
1Hadadverseevent
1826Receiveddose21836Receiveddose2
A12–15YrofAgeB16–25YrofAge
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n engl j med 385;3  nejm.org  July 15, 2021 243
BNT162b2 Vaccine in Adolescents
received two doses of BNT162b2 or placebo, received
dose 2 within the prespecified window
(19 to 42 days after dose 1), and had no major
protocol deviations. The all-available efficacy
population included all participants who received
one or two doses. Vaccine efficacy was defined
as 100 × (1 − IRR), where IRR is the ratio of the
rate of a first confirmed Covid-19 illness in the
BNT162b2 group to the corresponding rate in
the placebo group. Two-sided Clopper–Pearson
95% confidence intervals were calculated (not adjusted
for multiple comparisons). Because the
number of participants who reported symptoms
but were missing a valid polymerase-chain-reaction
test result was small, data for these participants
were not imputed in the analysis.
Results
Participants
Between October 15, 2020, and January 12, 2021,
a total of 2306 adolescents 12 to 15 years of age
were screened for inclusion, and 2264 underwent
randomization across 29 U.S. sites; 2260 participants
received injections, with 1131 receiving
BNT162b2 and 1129 receiving placebo (Fig. 1).
More than 97% of the BNT162b2 recipients received
dose 2. In the reactogenicity subset, all
the 12-to-15-year-old participants were from the
United States and the 16-to-25-year-old participants
were recruited globally (Table 1). Although
documented previous Covid-19 was an exclusion
criterion, approximately 5% of the participants
were SARS-CoV-2–positive at baseline, possibly
because of previous asymptomatic infection. In
the immunogenicity subset, all the participants
in both age cohorts were from the United States.
Among the 2260 participants who were 12 to 15
years of age, 51% were male, 86% were White,
and 12% were Hispanic or Latinx. Overall, 1308
participants (58%) had at least 2 months of follow-up
after their second vaccine dose. The trial
populations are summarized in Table S1 in the
Supplementary Appendix.
Safety
Reactogenicity
In both age cohorts, BNT162b2 recipients reported
more local and systemic events than placebo recipients
(Fig. 2). Local and systemic events were
generally mild to moderate in severity, reported
at similar frequencies in both age cohorts, and
typically resolved within 1 or 2 days. In both age
cohorts, injection-site pain was the most common
local reaction. Severe injection-site pain
after any BNT162b2 dose was reported in 1.5%
of 12-to-15-year-old participants and in 3.4% of
16-to-25-year-old participants; no severe pain was
reported after placebo administration.
In both age cohorts, headache and fatigue
were the most frequently reported systemic events.
After BNT162b2 injection, severe headache and
severe fatigue were reported in a lower percentage
of 12-to-15-year-old participants than of
16-to-25-year-old participants. Fever (oral body
temperature, ≥38°C) occurred after dose 2 of
BNT162b2 in 20% of 12-to-15-year-old recipients
and in 17% of 16-to-25-year-old recipients. The
use of antipyretic agents was slightly more frequent
among BNT162b2 recipients who were 12
to 15 years of age than among those who were
16 to 25 years of age (37% vs. 32% after dose 1,
and 51% vs. 46% after dose 2). Fever with a temperature
higher than 40°C occurred in 1 (0.1%)
of the 12-to-15-year-old participants 1 day after
BNT162b2 dose 1. In general, systemic events
were reported more often after BNT162b2 dose
2 than after dose 1. No differences in reactogenicity
were noted between participants who were
SARS-CoV-2–positive at baseline and those who
were SARS-CoV-2–negative at baseline (Fig. S1).
Adverse Events
Among 12-to-15-year-old participants, adverse
events occurring from dose 1 through 1 month
after dose 2 were reported by 6% of BNT162b2
Figure 1 (facing page). Screening, Randomization, and
Vaccine and Placebo Administration.
Participants who received dose 1 but not dose 2 could
continue to be evaluated for safety. Participants were
considered to have completed the vaccination period if
they had completed the follow-up visit 1 month after
dose 2 as of the data-cutoff date. As of the data-cutoff
date, some participants had not yet completed their
1-month follow-up visit after dose 2. Some participants
became eligible for a vaccine according to local or national
recommendations before the 1-month follow-up
visit after dose 2. These participants could choose to
be made aware of their randomly assigned injection,
and those who had received placebo could then choose
to receive BNT162b2. Participants who had originally
received placebo and chose to receive BNT162b2 as
part of the trial would then follow a different visit
schedule.
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The new engl and jour nal of medicine
and placebo recipients; slightly more BNT162b2
recipients than placebo recipients reported related
adverse events (3% vs. 2%) (Table S2). Among
16-to-25-year-old BNT162b2 recipients, 11% reported
any adverse event and 6% had vaccinerelated
adverse events. Among BNT162b2 recipients,
severe adverse events were reported in 0.6%
of those who were 12 to 15 years of age and in
1.7% of those who were 16 to 25 years of age.
One BNT162b2 recipient in the 12-to-15-yearTable
1. Demographic Characteristics of the Participants.*
Characteristic BNT162b2 Placebo
12–15 Yr
(N = 1131)
16–25 Yr
(N = 537)
12–15 Yr
(N = 1129)
16–25 Yr
(N = 561)
Male sex — no. (%) 567 (50.1) 255 (47.5) 585 (51.8) 269 (48.0)
Race or ethnic group — no. (%)†
White 971 (85.9) 445 (82.9) 962 (85.2) 466 (83.1)
Black or African American 52 (4.6) 47 (8.8) 57 (5.0) 50 (8.9)
American Indian or Alaska
Native
4 (0.4) 7 (1.3) 3 (0.3) 1 (0.2)
Asian 72 (6.4) 22 (4.1) 71 (6.3) 21 (3.7)
Native Hawaiian or other
Pacific Islander
3 (0.3) 3 (0.6) 0 1 (0.2)
Multiracial 23 (2.0) 12 (2.2) 29 (2.6) 19 (3.4)
Not reported 6 (0.5) 1 (0.2) 7 (0.6) 3 (0.5)
Hispanic or Latinx ethnic group —
no. (%)†
Hispanic or Latinx 132 (11.7) 112 (20.9) 130 (11.5) 105 (18.7)
Non-Hispanic or non-Latinx 997 (88.2) 423 (78.8) 996 (88.2) 456 (81.3)
Not reported 2 (0.2) 2 (0.4) 3 (0.3) 0
Country — no. (%)
Argentina 0 20 (3.7) 0 28 (5.0)
Brazil 0 24 (4.5) 0 19 (3.4)
Germany 0 11 (2.0) 0 20 (3.6)
South Africa 0 34 (6.3) 0 45 (8.0)
Turkey 0 12 (2.2) 0 15 (2.7)
United States 1131 (100) 436 (81.2) 1129 (100) 434 (77.4)
Age at vaccination — yr
Mean 13.6±1.11 19.4±3.26 13.6±1.11 19.6±3.33
Median (range) 14.0 (12–15) 18.0 (16–25) 14.0 (12–15) 19.0 (16–25)
Baseline SARS-CoV-2 status
— no. (%)‡
Positive 46 (4.1) 30 (5.6) 47 (4.2) 34 (6.1)
Negative 1028 (90.9) 497 (92.6) 1023 (90.6) 522 (93.0)
Missing 57 (5.0) 10 (1.9) 59 (5.2) 5 (0.9)
*	Plus–minus values are means ±SD. Results are for the reactogenicity subset of the safety population, which included
all participants in the 12-to-15-year-old cohort and a subset of participants in the 16-to-25-year-old cohort. Percentages
may not total 100 because of rounding.
†	Race and ethnic group were reported by the participants.
‡	A positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) status required a positive N-binding antibody
result at vaccination visit 1, a positive nucleic acid amplification test (NAAT) result at vaccination visit 1, or a medical
history of coronavirus disease 2019 (Covid-19).
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n engl j med 385;3  nejm.org  July 15, 2021 245
BNT162b2 Vaccine in Adolescents
old cohort discontinued vaccination because of a
vaccine-related adverse event: a temperature greater
than 40°C (described above) in a 14-year-old boy
who was SARS-CoV-2–negative at baseline, had
no reported medical history, and had no other
symptoms. He received BNT162b2 dose 1 and
had fever (temperature, 40.4°C) 1 day after vaccination,
which resolved 2 days later. The participant
did not receive dose 2 but remained in
the trial for safety follow-up. One BNT162b2 recipient
in the 16-to-25-year-old cohort discontinued
vaccination because of severe vaccine-related
injection-site pain and headache, both of which
were reported 1 day after dose 1 and resolved
within 1 day. Lymphadenopathy was reported in
9 of 1131 BNT162b2 recipients (0.8%) and in 2 of
1129 placebo recipients (0.2%) who were 12 to
15 years of age, as compared with in 1 of 536
BNT162b2 recipients (0.2%) and in no placebo
recipients who were 16 to 25 years of age. Appendicitis
was reported in 2 participants: 1 BNT162b2
recipient in the 16-to-25-year-old cohort and 1
placebo recipient in the 12-to-15-year-old cohort.
No thromboses or hypersensitivity adverse events
or vaccine-related anaphylaxis was seen. Few participants
in any cohort (≤0.4% through 1 month
after dose 2) had serious adverse events, and none
were considered by the investigators to have been
vaccine-related. No deaths were reported.
Immunogenicity
The immune response to BNT162b2 in 12-to-15year-old
adolescents was noninferior to that observed
in 16-to-25-year-old young adults. The
geometric mean ratio of the BNT162b2 neutralizing
geometric mean titer in 12-to-15-year-old
participants to that in 16-to-25-year-old participants
1 month after dose 2 was 1.76 (95% confidence
interval [CI], 1.47 to 2.10) (Table 2), which
met the noninferiority criterion (i.e., a lower
boundary of the two-sided 95% confidence interval
of >0.67). The lower boundary of the twosided
95% confidence interval for the geometric
mean ratio was greater than 1, indicating a greater
response in adolescents than in young adults.
Among all participants regardless of serologic
evidence of previous SARS-CoV-2 infection,
the serum-neutralizing geometric mean titer 1 month
after BNT162b2 dose 2 was 1283.0 in the 12-to-
15-year-old cohort and 730.8 in the 16-to-25-yearold
cohort (Fig. S2). The corresponding geometric
mean titers at 1 month among placebo recipients
were 15.1 and 10.7. Substantial increases in the
50% neutralizing titer from baseline were observed,
with GMFRs from baseline to 1 month
after dose 2 of 118.3 among 12-to-15-year-old
participants and 71.2 among 16-to-25-year-old
participants. The corresponding GMFRs among
placebo recipients were 1.4 and 1.1.
Efficacy
Among the 1983 participants in the 12-to-15year-old
cohort who could be evaluated and did
not have evidence of previous SARS-CoV-2 infection,
no cases of Covid-19 with an onset of 7 or
more days after dose 2 were observed among
BNT162b2 recipients and 16 cases were observed
among placebo recipients, which corresponded
to an observed vaccine efficacy of 100% (95% CI,
75.3 to 100) (Table 3). Similarly, in the group that
included all 2229 participants in the 12-to-15year-old
cohort who could be evaluated, regardless
of whether they had evidence of previous
SARS-CoV-2 infection, vaccine efficacy from 7 days
after dose 2 was 100% (95% CI, 78.1 to 100), with
no Covid-19 cases observed among BNT162b2
recipients and 18 cases observed among placebo
recipients. After dose 1 and before dose 2, there
were 3 Covid-19 cases noted (within 11 days after
dose 1) among BNT162b2 recipients, as compared
with 12 cases among placebo recipients
(vaccine efficacy, 75%; 95% CI, 7.6 to 95.5) (Table
S3). No cases of severe Covid-19 were observed
in this age cohort.
Discussion
A two-dose regimen of 30 μg of BNT162b2 administered
21 days apart to adolescents 12 to 15
years of age was safe and immunogenic and resulted
in an observed vaccine efficacy of 100%
against Covid-19 from 7 days after dose 2.
BNT162b2 elicited a high immune response in
adults,3
which translated to a 95% vaccine efficacy
among participants in the phase 2–3 trial
who were 16 years of age or older.5
Noninferiority
of immunogenicity in 12-to-15-year-old adolescents,
as shown in our trial, was initially planned
as the primary assessment of vaccine effectiveness
through “immunobridging,” an approach in
which the effectiveness of a vaccine is inferred
from immunogenicity data. The efficacy analysis
was descriptive because a sufficient number of
Covid-19 cases was not anticipated. However,
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n engl j med 385;3  nejm.org  July 15, 2021246
The new engl and jour nal of medicine
20 17
1 0
66 66
23
65 61
24 24
42 40
7 4 3 3 1 2
6 8
4 5
32
41
8 10
16
22
5 4
25
51
46
9
12
10 7
1 1
60 60
41 39
55 54
35 37
28 25
10 9
3 2 1 2
8
11
7
11
24
27
13 14
10
13
7 5
37
32
10 11
6 6
1 1
7 8
1 1
86 83
23
16
5 6
1 0
5 7
1 0
79 78
18
12
PercentofParticipants
100
80
90
70
60
40
30
10
50
20
0
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
Redness Swelling Pain at Injection Site
C Systemic Events and Use of Medication, Dose 1
A Local Events, Dose 1
Mild; temperature 38.0 to 38.4°C Moderate; temperature >38.4 to 38.9°C Severe; temperature >38.9 to 40.0°C Grade 4; temperature >40.0°C
PercentofParticipants
100
80
90
70
60
40
30
10
50
20
0
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
Redness Swelling Pain at Injection Site
B Local Events, Dose 2
PercentofParticipants
100
80
90
70
60
40
30
10
50
20
0
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
Fever Fatigue Headache Chills Vomiting Diarrhea Muscle Pain Joint Pain Antipyretic Use
PercentofParticipants
100
80
90
70
60
40
30
10
50
20
0
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
BN
T162b2,12–15
Yr
BN
T162b2,16–25
Yr
Placebo,12–15
Yr
Placebo,16–25
Yr
D Systemic Events and Use of Medication, Dose 2
Fever Fatigue Headache Chills Vomiting Diarrhea Muscle Pain Joint Pain Antipyretic Use
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n engl j med 385;3  nejm.org  July 15, 2021 247
BNT162b2 Vaccine in Adolescents
given the number of cases and the precision of
vaccine efficacy estimates, the vaccine efficacy
in this trial provides a high level of certainty
about the efficacy results. The lower limit of the
95% confidence interval for vaccine efficacy,
which was greater than 75%, provides substantial
evidence of efficacy in this age group and is
consistent with the high efficacy previously reported
in participants 16 years of age or older.5
Although BNT162b2 is a two-dose regimen,
early protection after a single dose has been reported
in clinical trials and on the basis of realworld
data.5,19,20
It is reassuring that early protection
is also observed in this age group, given the
important public health implications for pandemic
control.
Evaluation of BNT162b2 in younger adolescents
was undertaken for several reasons. The
incidence of Covid-19 is reported to be higher
among 12-to-17-year-old adolescents than among
younger children.21
In addition, children, especially
from low-income families, have been negatively
affected by the lack of in-person learning during
the pandemic.17,18
Therefore, a demonstration of
efficacy and safety in 12-to-15-year-old adolescents
is important in order to expand the emergency use
authorization to include children 12 years of age
or older and make a critical step toward achieving
herd immunity. Finally, the favorable safety
and side-effect profile and high efficacy, along
with the acceptable risk-to-benefit ratio in adoFigure
2 (facing page). Local Reactions and Systemic
Events Reported within 7 Days after Administration
of BNT162b2 or Placebo.
The results shown are for the reactogenicity subset of
the safety population, which included all participants in
the 12-to-15-year-old cohort and the subset of participants
in the 16-to-25-year-old cohort who had electronic
diary data available. Pain at the injection site was
graded as mild (does not interfere with activity), moderate
(interferes with activity), severe (prevents daily
activity), or grade 4 (led to an emergency department
visit or hospitalization). Redness and swelling were
graded as mild (>2.0 to 5.0 cm in diameter), moderate
(>5.0 to 10.0 cm in diameter), severe (>10.0 cm in diameter),
or grade 4 (necrosis or exfoliative dermatitis
for redness and necrosis for swelling). Fever categories
are designated in the key. Fatigue, headache, chills, new
or worsened muscle pain, and new or worsened joint
pain were graded as mild (does not interfere with activity),
moderate (some interference with activity), or severe
(prevents daily routine activity). Vomiting was
graded as mild (one or two times in 24 hours), moderate
(more than two times in 24 hours), or severe (requires
intravenous hydration), and diarrhea as mild
(two or three loose stools in 24 hours), moderate (four
or five loose stools in 24 hours), or severe (six or more
loose stools in 24 hours). Grade 4 for all systemic
events indicated an emergency department visit or hospitalization.
I bars indicate 95% confidence intervals.
The numbers above the I bars are the overall percentages
of the participants in each group who reported
the specified local reaction or systemic event. No participant
had a grade 4 local reaction. With regard to
systemic events, there was one incident of fever with a
temperature higher than 40°C in a 12-to-15-year-old
participant after dose 1 of BNT162b2.
Table 2. SARS-CoV-2 Serum Neutralization Assay Results 1 Month after Dose 2 of BNT162b2 among Participants
without Evidence of Infection.*
Age Group
No. of
Participants
Geometric Mean 50% Neutralizing
Titer (95% CI)†
Geometric Mean Ratio (95% CI),
12 to 15 Yr vs. 16 to 25 Yr‡
12–15 yr 190 1239.5 (1095.5–1402.5) 1.76 (1.47–2.10)
16–25 yr 170 705.1 (621.4–800.2) —
*	Results are for the subset of participants in the dose 2 immunogenicity population that could be evaluated (i.e., participants
who underwent randomization and received two BNT162b2 doses in accordance with the protocol, received dose
2 within the prespecified window, had at least one valid and determinate immunogenicity result from a blood sample
obtained within 28 to 42 days after dose 2, and had no major protocol deviations) who had no evidence of previous
SARS-CoV-2 infection. Participants without evidence of previous infection were those who had no serologic or virologic
evidence (up to 1 month after receipt of the last dose) of past SARS-CoV-2 infection (i.e., N-binding antibody [serum]
negative at vaccination visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at vaccination visits 1 and 2) and
had negative NAAT results (nasal swab) at any unscheduled visit up to 1 month after dose 2.
†	Geometric mean titers and two-sided 95% confidence intervals were calculated by exponentiating the mean logarithm
of the titers and the corresponding confidence intervals (based on the Student’s t distribution). Assay results below the
lower limit of quantitation were set to 0.5 times the lower limit of quantitation.
‡	The geometric mean ratio and two-sided 95% confidence intervals were calculated by exponentiating the mean difference
of the logarithms of the titers (the 12-to-15-year-old cohort minus the 16-to-25-year-old cohort) and the corresponding
confidence intervals (based on the Student’s t distribution). The noninferiority criterion was met, since the
lower boundary of the two-sided confidence interval for the geometric mean ratio was greater than 0.67.
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n engl j med 385;3  nejm.org  July 15, 2021248
The new engl and jour nal of medicine
lescents, now justify vaccine evaluation in younger
age groups.22
The favorable safety profile of BNT162b2,
which was seen in adults in the pivotal trial and
through ongoing pharmacovigilance after vaccine
introduction, was also observed in 12-to-15year-old
recipients.5,23
Adherence was high, with
more than 97% of BNT162b2 recipients receiving
dose 2. As previously reported for vaccine recipients
16 years of age or older, systemic events
in 12-to-15-year-old BNT162b2 recipients were
reported more often after dose 2 than after dose
1.5
Antipyretic use after both doses was slightly
higher in the 12-to-15-year-old cohort than in
the 16-to-25-year-old cohort. This favorable safety
profile is important, because a precedent exists
for vaccines being increasingly reactogenic
when administered to younger people. In the small
percentage of participants who were SARS-CoV-2–
positive at baseline, no differences in reactogenicity
from those who were SARS-CoV-2–negative
at baseline were noted, which supports immunization
without screening for evidence of previous
SARS-CoV-2 infection.
These results have several implications. Vaccination
of adolescents is likely to confer the direct
benefit of preventing disease along with indirect
benefits, including community protection.24
Although children generally have a lower burden
of symptomatic Covid-19 than adults, schools,
youth sports, and other community gatherings
may represent important sources of ongoing outbreaks
and transmission, despite high rates of
adult immunization.13,14,25
Vaccination of adolescents
will allow them to reintegrate into society
and resume in-person learning safely, which are
especially important outcomes given the severe
mental health effects of the Covid-19 pandemic
on this group.18,22,26
Recent real-world data suggest
that BNT162b2 prevents asymptomatic in-
fection.19,27
Given the observed immunogenicity
and efficacy, it is likely that vaccination will also
prevent asymptomatic infection in children,
thereby broadening community protection.
This analysis has some limitations. The efficacy
analysis was prespecified as descriptive
because an accurate sample size to assess vaccine
efficacy could not be calculated before the
start of the trial, given uncertainties about the
incidence of SARS-CoV-2 infection. Therefore,
the primary basis for the establishment of efficacy
in 12-to-15-year-old adolescents was a neutralizing
antibody response that was found to be
noninferior to that in vaccine recipients 16 years
Table 3. Vaccine Efficacy against Covid-19 in Participants 12 to 15 Years of Age.*
Efficacy End Point† BNT162b2 Placebo
% Vaccine Efficacy
(95% CI)‡
No. of Participants
with Event/Total
No.§
Surveillance Time
(No. at Risk)¶
No. of Participants
with Event/Total
No.§
Surveillance Time
(No. at Risk)¶
Covid-19 occurrence at least
7 days after dose 2 in participants
without evidence of
previous infection
0/1005 0.154 (1001) 16/978 0.147 (972) 100 (75.3–100)
Covid-19 occurrence at least
7 days after dose 2 in participants
with or without evidence
of previous infection
0/1119 0.170 (1109) 18/1110 0.163 (1094) 100 (78.1–100)
*	Results are for the efficacy population that could be evaluated, which included all eligible 12-to-15-year-old participants who received two
doses of BNT162b2 or placebo as randomly assigned, with dose 2 received within the prespecified window, and had no major protocol de-
viations.
†	Participants without evidence of previous infection were those who had no serologic or virologic evidence of past SARS-CoV-2 infection before
7 days after dose 2 (i.e., N-binding antibody testing [serum] negative at vaccination visit 1 and SARS-CoV-2 not detected by NAAT [nasal
swab] at vaccination visits 1 and 2) and had negative NAAT results (nasal swab) at any unscheduled visit before 7 days after dose 2.
‡	The 95% confidence interval for vaccine efficacy was derived on the basis of the Clopper–Pearson method with adjustment for surveillance
time.
§	The number of participants with a first occurrence of Covid-19 at 7 or more days after dose 2 and the total number of participants with data
are shown.
¶	Total surveillance time in 1000 person-years for the given end point across all participants within each group of participants who were at
risk for the end point is shown. The period for Covid-19 case accrual was from 7 days after dose 2 to the end of the surveillance period.
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n engl j med 385;3  nejm.org  July 15, 2021 249
BNT162b2 Vaccine in Adolescents
of age or older, for whom efficacy had been
shown.5
This report includes safety data through
1 month of follow-up after dose 2 for some participants.
Data on longer-term safety and the
duration of efficacy and antibody responses in
children are not yet available.
Although racial and ethnic diversity was
lower among the 12-to-15-year-old participants
than among those who were 16 years of age or
older, vaccine efficacy in the latter age cohort is
consistent among racial and ethnic subgroups,5
and a similar pattern is likely in the younger
cohort. All 12-to-15-year-old participants in this
trial were enrolled at U.S. sites, whereas the
16-to-25-year-old participants were recruited globally.
In the immunogenicity subset, however, all
participants in both age cohorts were from the
United States. The testing laboratory supply
limitation resulted in fewer than anticipated
participants in the immunogenicity analyses;
however, even with the smaller sample size and
lower power, the trial still established noninferiority
of the immune response. Although some
participants received other vaccinations during
the trial period, we did not formally examine
concomitant vaccination with BNT162b2 and
other vaccines received during adolescence. These
results do not determine whether BNT162b2 vaccination
prevents asymptomatic infection or transmission
of SARS-CoV-2; asymptomatic surveillance
is ongoing in this age group.
Given the safety, immune response, and efficacy
of the BNT162b2 vaccine in adolescents
12 to 15 years of age reported in this analysis,
studies are ongoing to evaluate these measures
in younger children and in other special populations,
such as pregnant women.
Supported by BioNTech and Pfizer.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
We thank Sheena Hunt, who wrote the first draft of the manuscript
under direction from the authors, and Tricia Newell and
Philippa Jack (all from ICON) for medical writing and editorial
assistance with an earlier version of the manuscript, which was
funded by Pfizer; all the participants who volunteered for this
trial; the members of the data and safety monitoring committee
— Jonathan Zenilman, Kathryn Edwards, Lawrence Stanberry,
Robert Belshe, and Steven G. Self — who have been reviewing
the trial safety data on a weekly basis; Greg Adams,
Negar Aliabadi, Mohanish Anand, Fred Angulo, Ayman Ayoub,
Melissa Bishop-Murphy, Mark Boaz, Christopher Bowen, Salim
Bouguermouh, Donna Boyce, Sarah Burden, Andrea Cawein,
Patrick Caubel, Darren Cowen, Kimberly Ann Cristall, Michael
Cruz, Daniel Curcio, Carmel Devlin, Niesha Foster, Luis Jodar,
Stephen Kay, Esther Ladipo, Marie-Pierre Hellio Le GraverandGastineau,
Juleen Gayed, Jacqueline Lowenberg, Rod MacKenzie,
Robert Maroko, Jason McKinley, Tracey Mellelieu, Brendan
O’Neill, Jason Painter, Sohil Patel, Elizabeth Paulukonis, Allison
Pfeffer, Katie Puig, Kimberly Rarrick, Balaji Prabu Raja, Kellie
Lynn Richardson, Elizabeth Rogers, Melinda Rottas, Charulata
Sabharwal, Vilas Satishchandran, Harpreet Seehra, Judy
Sewards, Helen Smith, Uzma Sarwar, David Swerdlow, Elisa
Harkins Tull, Sarah Tweedy, Erica Weaver, John Wegner, Jenah
West, David C. Whritenour, Fae Wooding, Emily Worobetz, Nita
Zalavadia, Liping Zhang, and Lefteris Zolotas, all from Pfizer,
for their contributions to this work; the Pfizer Vaccines Clinical
Assay Team, the Pfizer Vaccines Assay Development Team, and
all of the Pfizer colleagues not named here who contributed to
the success of this trial; Corinna Rosenbaum, Christian Miculka,
Andreas Kuhn, Ferdia Bates, Paul Strecker, Ruben Rizzi,
Martin Bexon, Eleni Lagkadinou, and Alexandra Kemmer-Brück
(all from BioNTech); and Dietmar Katinger and Andreas Wagner
(both from Polymun).
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n engl j med 385;3  nejm.org  July 15, 2021250
BNT162b2 Vaccine in Adolescents
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