The
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established in 1812
December 31, 2020
vol. 383
no. 27
The authors’ affiliations are listed in the
Appendix. Address reprint requests to
Dr. Absalon at Pfizer, 401 N. Middletown
Rd., Pearl River, NY 10965, or at judith
.absalon@pfizer.com.
*A complete list of investigators in the
C4591001 Clinical Trial Group is pro-
vided in the Supplementary Appendix,
available at NEJM.org.
Drs. Polack and Thomas contributed
equally to this article.
This article was published on December
10, 2020, and updated on December 16,
2020, at NEJM.org.
N Engl J Med 2020;383:2603-15.
DOI: 10.1056/NEJMoa2034577
Copyright © 2020 Massachusetts Medical Society.
BACKGROUND
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the
resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people
in a worldwide pandemic. Safe and effective vaccines are needed urgently.
METHODS
In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy
trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive
two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg
per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA
vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-
length spike protein. The primary end points were efficacy of the vaccine against
laboratory-confirmed Covid-19 and safety.
RESULTS
A total of 43,548 participants underwent randomization, of whom 43,448 received
injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of
Covid-19 with onset at least 7 days after the second dose among participants as-
signed to receive BNT162b2 and 162 cases among those assigned to placebo;
BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to
97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups
defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of
coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first
dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety
profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the
injection site, fatigue, and headache. The incidence of serious adverse events was
low and was similar in the vaccine and placebo groups.
CONCLUSIONS
A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in
persons 16 years of age or older. Safety over a median of 2 months was similar to
that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov
number, NCT04368728.)
abstr act
Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine
Fernando P. Polack, M.D., Stephen J. Thomas, M.D., Nicholas Kitchin, M.D., Judith Absalon, M.D.,
Alejandra Gurtman, M.D., Stephen Lockhart, D.M., John L. Perez, M.D., Gonzalo Pérez Marc, M.D.,
Edson D. Moreira, M.D., Cristiano Zerbini, M.D., Ruth Bailey, B.Sc., Kena A. Swanson, Ph.D.,
Satrajit Roychoudhury, Ph.D., Kenneth Koury, Ph.D., Ping Li, Ph.D., Warren V. Kalina, Ph.D., David Cooper, Ph.D.,
Robert W. Frenck, Jr., M.D., Laura L. Hammitt, M.D., Özlem Türeci, M.D., Haylene Nell, M.D., Axel Schaefer, M.D.,
Serhat Ünal, 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*
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C
oronavirus disease 2019 (Covid-19)
has affected tens of millions of people
globally
1
since it was declared a pandemic
by the World Health Organization on March 11,
2020.
2
Older adults, persons with certain coex-
isting conditions, and front-line workers are at
highest risk for Covid-19 and its complications.
Recent data show increasing rates of severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2)
infection and Covid-19 in other populations, in-
cluding younger adults.
3
Safe and effective pro-
phylactic vaccines are urgently needed to contain
the pandemic, which has had devastating medi-
cal, economic, and social consequences.
We previously reported phase 1 safety and im-
munogenicity results from clinical trials of the
vaccine candidate BNT162b2,
4
a lipid nanoparticle–
formulated,
5
nucleoside-modified RNA (modRNA)
6
encoding the SARS-CoV-2 full-length spike, modi-
fied by two proline mutations to lock it in the
prefusion conformation.
7
Findings from studies
conducted in the United States and Germany
among healthy men and women showed that two
30-μg doses of BNT162b2 elicited high SARS-CoV-2
neutralizing antibody titers and robust antigen-
specific CD8+ and Th1-type CD4+ T-cell respons-
es.
8
The 50% neutralizing geometric mean titers
elicited by 30 μg of BNT162b2 in older and young-
er adults exceeded the geometric mean titer mea-
sured in a human convalescent serum panel, de-
spite a lower neutralizing response in older adults
than in younger adults. In addition, the reactoge-
nicity profile of BNT162b2 represented mainly
short-term local (i.e., injection site) and systemic
responses. These findings supported progression
of the BNT162b2 vaccine candidate into phase 3.
Here, we report safety and efficacy findings
from the phase 2/3 part of a global phase 1/2/3
trial evaluating the safety, immunogenicity, and
efficacy of 30 μg of BNT162b2 in preventing
Covid-19 in persons 16 years of age or older. This
data set and these trial results are the basis for an
application for emergency use authorization.
9
Col-
lection of phase 2/3 data on vaccine immunoge-
nicity and the durability of the immune response
to immunization is ongoing, and those data are
not reported here.
Methods
Trial Objectives, Participants and Oversight
We assessed the safety and efficacy of two 30-μg
doses of BNT162b2, administered intramuscu-
larly 21 days apart, as compared with placebo.
Adults 16 years of age or older who were healthy
or had stable chronic medical conditions, includ-
ing but not limited to human immunodeficiency
virus (HIV), hepatitis B virus, or hepatitis C vi-
rus infection, were eligible for participation in
the trial. Key exclusion criteria included a medi-
cal history of Covid-19, treatment with immuno-
suppressive therapy, or diagnosis with an im-
munocompromising condition.
Pfizer was responsible for the design and
conduct of the trial, data collection, data analysis,
data interpretation, and the writing of the
manuscript. BioNTech was the sponsor of the
trial, manufactured the BNT162b2 clinical trial
material, and contributed to the interpretation
of the data and the writing of the manuscript.
All the trial data were available to all the authors,
who vouch for its accuracy and completeness and
for adherence of the trial to the protocol, which
is available with the full text of this article at
NEJM.org. An independent data and safety mon-
itoring board reviewed efficacy and unblinded
safety data.
Trial Procedures
With the use of an interactive Web-based sys-
tem, participants in the trial were randomly as-
signed in a 1:1 ratio to receive 30 μg of
BNT162b2 (0.3 ml volume per dose) or saline
placebo. Participants received two injections, 21
days apart, of either BNT162b2 or placebo, deliv-
ered in the deltoid muscle. Site staff who were
responsible for safety evaluation and were un-
aware of group assignments observed partici-
pants for 30 minutes after vaccination for any
acute reactions.
Safety
The primary end points of this trial were solic-
ited, specific local or systemic adverse events
and use of antipyretic or pain medication within
7 days after the receipt of each dose of vaccine
or placebo, as prompted by and recorded in an
electronic diary in a subset of participants (the
reactogenicity subset), and unsolicited adverse
events (those reported by the participants with-
out prompts from the electronic diary) through
1 month after the second dose and unsolicited
serious adverse events through 6 months after
the second dose. Adverse event data through ap-
proximately 14 weeks after the second dose are
included in this report. In this report, safety
A Quick Take
is available at
NEJM.org
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Safety and Efficacy of the BNT162
b
2 Vaccine
data are reported for all participants who pro-
vided informed consent and received at least one
dose of vaccine or placebo. Per protocol, safety re-
sults for participants infected with HIV (196 pa-
tients) will be analyzed separately and are not
included here.
During the phase 2/3 portion of the study, a
stopping rule for the theoretical concern of vac-
cine-enhanced disease was to be triggered if the
one-sided probability of observing the same or a
more unfavorable adverse severe case split (a split
with a greater proportion of severe cases in vac-
cine recipients) was 5% or less, given the same
true incidence for vaccine and placebo recipients.
Alert criteria were to be triggered if this probabil-
ity was less than 11%.
Efficacy
The first primary end point was the efficacy of
BNT162b2 against confirmed Covid-19 with onset
at least 7 days after the second dose in participants
who had been without serologic or virologic evi-
dence of SARS-CoV-2 infection up to 7 days after
the second dose; the second primary end point
was efficacy in participants with and partici-
pants without evidence of prior infection. Con-
firmed Covid-19 was defined according to the
Food and Drug Administration (FDA) criteria as
the presence of at least one of the following
symptoms: fever, new or increased cough, new or
increased shortness of breath, chills, new or in-
creased muscle pain, new loss of taste or smell,
sore throat, diarrhea, or vomiting, combined with
a respiratory specimen obtained during the symp-
tomatic period or within 4 days before or after it
that was positive for SARS-CoV-2 by nucleic acid
amplification–based testing, either at the central
laboratory or at a local testing facility (using a
protocol-defined acceptable test).
Major secondary end points included the ef-
ficacy of BNT162b2 against severe Covid-19. Se-
vere Covid-19 is defined by the FDA as confirmed
Covid-19 with one of the following additional
features: clinical signs at rest that are indicative
of severe systemic illness; respiratory failure; evi-
dence of shock; significant acute renal, hepatic,
or neurologic dysfunction; admission to an in-
tensive care unit; or death. Details are provided
in the protocol.
An explanation of the various denominator
values for use in assessing the results of the
trial is provided in Table S1 in the Supplemen-
tary Appendix, available at NEJM.org. In brief,
the safety population includes persons 16 years
of age or older; a total of 43,448 participants
constituted the population of enrolled persons
injected with the vaccine or placebo. The main
safety subset as defined by the FDA, with a me-
dian of 2 months of follow-up as of October 9,
2020, consisted of 37,706 persons, and the reac-
togenicity subset consisted of 8183 persons. The
modified intention-to-treat (mITT) efficacy pop-
ulation includes all age groups 12 years of age
or older (43,355 persons; 100 participants who
were 12 to 15 years of age contributed to person-
time years but included no cases). The number
of persons who could be evaluated for efficacy
7 days after the second dose and who had no
evidence of prior infection was 36,523, and the
number of persons who could be evaluated
7 days after the second dose with or without
evidence of prior infection was 40,137.
Statistical Analysis
The safety analyses included all participants
who received at least one dose of BNT162b2 or
placebo. The findings are descriptive in nature
and not based on formal statistical hypothesis
testing. Safety analyses are presented as counts,
percentages, and associated Clopper–Pearson
95% confidence intervals for local reactions,
systemic events, and any adverse events after
vaccination, according to terms in the
Medical
Dictionary for Regulatory Activities
(MedDRA), ver-
sion 23.1, for each vaccine group.
Analysis of the first primary efficacy end
point included participants who received the vac-
cine or placebo as randomly assigned, had no
evidence of infection within 7 days after the
second dose, and had no major protocol devia-
tions (the population that could be evaluated).
Vaccine efficacy was estimated by 100 × (1 − IRR),
where IRR is the calculated ratio of confirmed
cases of Covid-19 illness per 1000 person-years
of follow-up in the active vaccine group to the
corresponding illness rate in the placebo group.
The 95.0% credible interval for vaccine efficacy
and the probability of vaccine efficacy greater
than 30% were calculated with the use of a
Bayesian beta-binomial model. The final analy-
sis uses a success boundary of 98.6% for prob-
ability of vaccine efficacy greater than 30% to
compensate for the interim analysis and to
control the overall type 1 error rate at 2.5%.
Moreover, primary and secondary efficacy end
points are evaluated sequentially to control the
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familywise type 1 error rate at 2.5%. Descriptive
analyses (estimates of vaccine efficacy and 95%
confidence intervals) are provided for key sub-
groups.
Results
Participants
Between July 27, 2020, and November 14, 2020,
a total of 44,820 persons were screened, and
43,548 persons 16 years of age or older under-
went randomization at 152 sites worldwide
(United States, 130 sites; Argentina, 1; Brazil, 2;
South Africa, 4; Germany, 6; and Turkey, 9) in
the phase 2/3 portion of the trial. A total of
43,448 participants received injections: 21,720
received BNT162b2 and 21,728 received placebo
(Fig. 1). At the data cut-off date of October 9, a
total of 37,706 participants had a median of at
least 2 months of safety data available after the
second dose and contributed to the main safety
data set. Among these 37,706 participants, 49%
were female, 83% were White, 9% were Black or
African American, 28% were Hispanic or Latinx,
35% were obese (body mass index [the weight in
kilograms divided by the square of the height in
meters] of at least 30.0), and 21% had at least
one coexisting condition. The median age was
52 years, and 42% of participants were older
than 55 years of age (Table 1 and Table S2).
Safety
Local Reactogenicity
The reactogenicity subset included 8183 partici-
pants. Overall, BNT162b2 recipients reported more
local reactions than placebo recipients. Among
BNT162b2 recipients, mild-to-moderate pain at
the injection site within 7 days after an injection
was the most commonly reported local reaction,
with less than 1% of participants across all age
groups reporting severe pain (Fig. 2). Pain was
reported less frequently among participants old-
er than 55 years of age (71% reported pain after
the first dose; 66% after the second dose) than
among younger participants (83% after the first
dose; 78% after the second dose). A noticeably
lower percentage of participants reported injec-
tion-site redness or swelling. The proportion of
participants reporting local reactions did not
increase after the second dose (Fig. 2A), and no
participant reported a grade 4 local reaction. In
general, local reactions were mostly mild-to-mod-
erate in severity and resolved within 1 to 2 days.
Systemic Reactogenicity
Systemic events were reported more often by
younger vaccine recipients (16 to 55 years of age)
than by older vaccine recipients (more than 55
years of age) in the reactogenicity subset and
more often after dose 2 than dose 1 (Fig. 2B).
The most commonly reported systemic events
were fatigue and headache (59% and 52%, re-
spectively, after the second dose, among younger
vaccine recipients; 51% and 39% among older
recipients), although fatigue and headache were
also reported by many placebo recipients (23% and
24%, respectively, after the second dose, among
younger vaccine recipients; 17% and 14% among
older recipients). The frequency of any severe
systemic event after the first dose was 0.9% or
less. Severe systemic events were reported in less
than 2% of vaccine recipients after either dose,
except for fatigue (in 3.8%) and headache (in 2.0%)
after the second dose.
Fever (temperature, ≥38°C) was reported after
the second dose by 16% of younger vaccine re-
cipients and by 11% of older recipients. Only 0.2%
of vaccine recipients and 0.1% of placebo recipi-
ents reported fever (temperature, 38.9 to 40°C) af-
ter the first dose, as compared with 0.8% and
0.1%, respectively, after the second dose. Two
participants each in the vaccine and placebo
groups reported temperatures above 40.0°C.
Younger vaccine recipients were more likely to
use antipyretic or pain medication (28% after
dose 1; 45% after dose 2) than older vaccine re-
cipients (20% after dose 1; 38% after dose 2),
and placebo recipients were less likely (10 to 14%)
than vaccine recipients to use the medications,
Figure 1 (facing page).
Enrollment and Randomization.
The diagram represents all enrolled participants
through November 14, 2020. The safety subset (those
with a median of 2 months of follow-up, in accordance
with application requirements for Emergency Use Au-
thorization) is based on an October 9, 2020, data cut-
off date. The further procedures that one participant in
the placebo group declined after dose 2 (lower right
corner of the diagram) were those involving collection
of blood and nasal swab samples.
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Safety and Efficacy of the BNT162
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2 Vaccine
1272 Did not undergo randomization
1152 Did not meet eligibility criteria
64 Had other reason
33 Withdrew
13 Underwent randomization
after cutoff
5 Had unspecified reason
4 Were withdrawn by physician
1 Was lost to follow-up
99 Were not vaccinated
1 Did not sign the informed
consent document
316 Did not receive dose 2
96 Withdrew
86 Were no longer eligible
61 Were lost to follow-up
46 Had ongoing or pending
status
18 Had adverse event
5 Were pregnant
2 Were withdrawn by
physician
1 Died
1 Had medication error
(no adverse event)
304 Did not receive dose 2
100 Withdrew
62 Were lost to follow-up
56 Had ongoing or pending
status
51 Were no longer eligible
28 Had adverse event
4 Were pregnant
2 Were withdrawn by
physician
1 Died
18,556 Received dose 2 of BNT162b2
18,530 Received dose 2 of placebo
43,448 Were injected with vaccine or placebo
21,720 Were assigned to receive BNT162b2
21,728 Were assigned to receive placebo
37,706 Received vaccine or placebo
and had median follow-up of 2 mo
43,548 Underwent randomization
44,820 Participants were screened
18,860 Received dose 1 of BNT162b2
18,846 Received dose 1 of placebo
48 Discontinued trial after dose 2
27 Withdrew
18 Were lost to follow-up
1 Died
1 Was withdrawn by physician
1 Had medication error
(no adverse event)
95 Discontinued trial after dose 2
66 Withdrew
25 Were lost to follow-up
2 Died
1 Had other reason
1 Declined further procedures
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regardless of age or dose. Systemic events in-
cluding fever and chills were observed within
the first 1 to 2 days after vaccination and re-
solved shortly thereafter.
Daily use of the electronic diary ranged from
90 to 93% for each day after the first dose and
from 75 to 83% for each day after the second
dose. No difference was noted between the
BNT162b2 group and the placebo group.
Adverse Events
Adverse event analyses are provided for all en-
rolled 43,252 participants, with variable follow-
up time after dose 1 (Table S3). More BNT162b2
recipients than placebo recipients reported any
adverse event (27% and 12%, respectively) or a
related adverse event (21% and 5%). This distri-
bution largely reflects the inclusion of transient
reactogenicity events, which were reported as
adverse events more commonly by vaccine recipi-
ents than by placebo recipients. Sixty-four vac-
cine recipients (0.3%) and 6 placebo recipients
(<0.1%) reported lymphadenopathy. Few partici-
pants in either group had severe adverse events,
serious adverse events, or adverse events leading
to withdrawal from the trial. Four related serious
adverse events were reported among BNT162b2
recipients (shoulder injury related to vaccine ad-
ministration, right axillary lymphadenopathy,
paroxysmal ventricular arrhythmia, and right leg
Table 1.
Demographic Characteristics of the Participants in the Main Safety Population.*
Characteristic
BNT162b2
(N=18,860)
Placebo
(N=18,846)
Total
(N=37,706)
Sex — no. (%)
Male
9,639 (51.1)
9,436 (50.1)
19,075 (50.6)
Female
9,221 (48.9)
9,410 (49.9)
18,631 (49.4)
Race or ethnic group — no. (%)
†
White
15,636 (82.9)
15,630 (82.9)
31,266 (82.9)
Black or African American
1,729 (9.2)
1,763 (9.4)
3,492 (9.3)
Asian
801 (4.2)
807 (4.3)
1,608 (4.3)
Native American or Alaska Native
102 (0.5)
99 (0.5)
201 (0.5)
Native Hawaiian or other Pacific Islander
50 (0.3)
26 (0.1)
76 (0.2)
Multiracial
449 (2.4)
406 (2.2)
855 (2.3)
Not reported
93 (0.5)
115 (0.6)
208 (0.6)
Hispanic or Latinx
5,266 (27.9)
5,277 (28.0)
10,543 (28.0)
Country — no. (%)
Argentina
2,883 (15.3)
2,881 (15.3)
5,764 (15.3)
Brazil
1,145 (6.1)
1,139 (6.0)
2,284 (6.1)
South Africa
372 (2.0)
372 (2.0)
744 (2.0)
United States
14,460 (76.7)
14,454 (76.7)
28,914 (76.7)
Age group — no. (%)
16–55 yr
10,889 (57.7)
10,896 (57.8)
21,785 (57.8)
>55 yr
7,971 (42.3)
7,950 (42.2)
15,921 (42.2)
Age at vaccination — yr
Median
52.0
52.0
52.0
Range
16–89
16–91
16–91
Body-mass index
‡
≥30.0: obese
6,556 (34.8)
6,662 (35.3)
13,218 (35.1)
* Percentages may not total 100 because of rounding.
† Race or ethnic group was reported by the participants.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
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Safety and Efficacy of the BNT162
b
2 Vaccine
paresthesia). Two BNT162b2 recipients died (one
from arteriosclerosis, one from cardiac arrest),
as did four placebo recipients (two from unknown
causes, one from hemorrhagic stroke, and one
from myocardial infarction). No deaths were con-
sidered by the investigators to be related to the
vaccine or placebo. No Covid-19–associated deaths
were observed. No stopping rules were met dur-
ing the reporting period. Safety monitoring will
continue for 2 years after administration of the
second dose of vaccine.
Efficacy
Among 36,523 participants who had no evidence
of existing or prior SARS-CoV-2 infection, 8 cases
of Covid-19 with onset at least 7 days after the
second dose were observed among vaccine re-
cipients and 162 among placebo recipients. This
case split corresponds to 95.0% vaccine efficacy
(95% confidence interval [CI], 90.3 to 97.6; Ta-
ble 2). Among participants with and those with-
out evidence of prior SARS CoV-2 infection, 9 cases
of Covid-19 at least 7 days after the second dose
were observed among vaccine recipients and 169
among placebo recipients, corresponding to 94.6%
vaccine efficacy (95% CI, 89.9 to 97.3). Supple-
mental analyses indicated that vaccine efficacy
among subgroups defined by age, sex, race, eth-
nicity, obesity, and presence of a coexisting condi-
tion was generally consistent with that observed
in the overall population (Table 3 and Table S4).
Vaccine efficacy among participants with hyper-
tension was analyzed separately but was consis-
tent with the other subgroup analyses (vaccine
efficacy, 94.6%; 95% CI, 68.7 to 99.9; case split:
BNT162b2, 2 cases; placebo, 44 cases). Figure 3
shows cases of Covid-19 or severe Covid-19 with
onset at any time after the first dose (mITT popu-
lation) (additional data on severe Covid-19 are
available in Table S5). Between the first dose and
the second dose, 39 cases in the BNT162b2 group
and 82 cases in the placebo group were observed,
resulting in a vaccine efficacy of 52% (95% CI,
29.5 to 68.4) during this interval and indicating
early protection by the vaccine, starting as soon
as 12 days after the first dose.
Discussion
A two-dose regimen of BNT162b2 (30 μg per
dose, given 21 days apart) was found to be safe
and 95% effective against Covid-19. The vaccine
met both primary efficacy end points, with more
than a 99.99% probability of a true vaccine ef-
ficacy greater than 30%. These results met our
prespecified success criteria, which were to es-
tablish a probability above 98.6% of true vaccine
efficacy being greater than 30%, and greatly
exceeded the minimum FDA criteria for authori-
zation.
9
Although the study was not powered to
definitively assess efficacy by subgroup, the
point estimates of efficacy for subgroups based
on age, sex, race, ethnicity, body-mass index, or
the presence of an underlying condition associ-
ated with a high risk of Covid-19 complications
are also high. For all analyzed subgroups in
which more than 10 cases of Covid-19 occurred,
the lower limit of the 95% confidence interval
for efficacy was more than 30%.
The cumulative incidence of Covid-19 cases
over time among placebo and vaccine recipients
begins to diverge by 12 days after the first dose,
7 days after the estimated median viral incuba-
tion period of 5 days,
10
indicating the early onset
of a partially protective effect of immunization.
The study was not designed to assess the efficacy
of a single-dose regimen. Nevertheless, in the
interval between the first and second doses, the
observed vaccine efficacy against Covid-19 was
52%, and in the first 7 days after dose 2, it was
91%, reaching full efficacy against disease with
onset at least 7 days after dose 2. Of the 10 cases
of severe Covid-19 that were observed after the
first dose, only 1 occurred in the vaccine group.
This finding is consistent with overall high ef-
ficacy against all Covid-19 cases. The severe case
split provides preliminary evidence of vaccine-
mediated protection against severe disease, al-
leviating many of the theoretical concerns over
vaccine-mediated disease enhancement.
11
The favorable safety profile observed during
phase 1 testing of BNT162b2
4,8
was confirmed in
the phase 2/3 portion of the trial. As in phase 1,
reactogenicity was generally mild or moderate,
and reactions were less common and milder in
older adults than in younger adults. Systemic
reactogenicity was more common and severe
after the second dose than after the first dose,
although local reactogenicity was similar after
the two doses. Severe fatigue was observed in
approximately 4% of BNT162b2 recipients,
which is higher than that observed in recipients
of some vaccines recommended for older adults.
12
This rate of severe fatigue is also lower than that
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observed in recipients of another approved viral
vaccine for older adults.
13
Overall, reactogenicity
events were transient and resolved within a couple
of days after onset. Lymphadenopathy, which
generally resolved within 10 days, is likely to
have resulted from a robust vaccine-elicited im-
mune response. The incidence of serious adverse
events was similar in the vaccine and placebo
groups (0.6% and 0.5%, respectively).
This trial and its preliminary report have
several limitations. With approximately 19,000
participants per group in the subset of partici-
pants with a median follow-up time of 2 months
after the second dose, the study has more than
83% probability of detecting at least one adverse
event, if the true incidence is 0.01%, but it is not
large enough to detect less common adverse events
reliably. This report includes 2 months of follow-
up after the second dose of vaccine for half the
trial participants and up to 14 weeks’ maximum
follow-up for a smaller subset. Therefore, both
Figure 2.
Local and Systemic Reactions Reported
within 7 Days after Injection of BNT162b2 or Placebo,
According to Age Group.
Data on local and systemic reactions and use of medi-
cation were collected with electronic diaries from par-
ticipants in the reactogenicity subset (8,183 partici-
pants) for 7 days after each vaccination. Solicited
injection-site (local) reactions are shown in Panel A.
Pain at the injection site was assessed according to
the following scale: mild, does not interfere with activ-
ity; moderate, interferes with activity; severe, prevents
daily activity; and grade 4, emergency department visit
or hospitalization. Redness and swelling were mea-
sured according to the following scale: mild, 2.0 to
5.0 cm in diameter; moderate, >5.0 to 10.0 cm in di-
ameter; severe, >10.0 cm in diameter; and grade 4,
necrosis or exfoliative dermatitis (for redness) and ne-
crosis (for swelling). Systemic events and medication
use are shown in Panel B. Fever categories are desig-
nated in the key; medication use was not graded. Ad-
ditional scales were as follows: fatigue, headache,
chills, new or worsened muscle pain, new or worsened
joint pain (mild: does not interfere with activity; mod-
erate: some interference with activity; or severe: pre-
vents daily activity), vomiting (mild: 1 to 2 times in
24 hours; moderate: >2 times in 24 hours; or severe:
requires intravenous hydration), and diarrhea (mild:
2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose
stools in 24 hours; or severe: 6 or more loose stools in
24 hours); grade 4 for all events indicated an emer-
gency department visit or hospitalization.
I
bars repre-
sent 95% confidence intervals, and numbers above
the
I
bars are the percentage of participants who re-
ported the specified reaction.
0
0
1
83
78
71
66
14
12
9
8
6
6
7
7
1
5
6
5
7
1
1
1
1
Redness
Swelling
>55 Yr of Age, Dose 2
>55 Yr of Age, Dose 1
16–55 Yr of Age, Dose 2
16–55 Yr of Age, Dose 1
100
80
90
70
60
40
30
10
50
20
0
A
Local Events
Mild
Moderate
Severe
Grade 4
Percentage of Participants
100
80
90
70
60
40
30
10
50
20
0
100
80
90
70
60
40
30
10
50
20
0
Pain at Injection
Site
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
100
80
90
70
60
40
30
10
50
20
0
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Safety and Efficacy of the BNT162
b
2 Vaccine
4
16
1
11
1
0
0
0
42
52
25
39
34
24
18
14
14
35
6
23
11
10
8
8
12
8
7
6
21
37
14
29
28
45
20
38
14
13
12
10
11
8
8
5
11
22
9
19
6
5
6
4
6
4
3
3
1
2
0
1
1
1
1
0
47
59
34
51
33
23
23
17
100
80
90
70
60
40
30
10
50
20
0
BNT162b2
Placebo
Fever
BNT162b2
Placebo
Fatigue
BNT162b2
Placebo
Headache
BNT162b2
Placebo
Chills
BNT162b2
Placebo
Vomiting
>55 Yr of Age, Dose 2
>55 Yr of Age, Dose 1
16–55 Yr of Age, Dose 2
16–55 Yr of Age, Dose 1
BNT162b2
Placebo
Diarrhea
BNT162b2
Placebo
Muscle Pain
BNT162b2
Placebo
Joint Pain
BNT162b2
Placebo
Use of Antipyretic
Medication
B
Systemic Events and Use of Medication
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
Percentage of Participants
100
80
90
70
60
40
30
10
50
20
0
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
100
80
90
70
60
40
30
10
50
20
0
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
100
80
90
70
60
40
30
10
50
20
0
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
BNT162b2
Placebo
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the occurrence of adverse events more than 2 to
3.5 months after the second dose and more
comprehensive information on the duration of
protection remain to be determined. Although
the study was designed to follow participants for
safety and efficacy for 2 years after the second
dose, given the high vaccine efficacy, ethical and
practical barriers prevent following placebo re-
cipients for 2 years without offering active im-
munization, once the vaccine is approved by
regulators and recommended by public health
authorities. Assessment of long-term safety and
efficacy for this vaccine will occur, but it cannot
be in the context of maintaining a placebo group
for the planned follow-up period of 2 years after
the second dose. These data do not address
whether vaccination prevents asymptomatic in-
fection; a serologic end point that can detect a
history of infection regardless of whether symp-
toms were present (SARS-CoV-2 N-binding anti-
body) will be reported later. Furthermore, given
the high vaccine efficacy and the low number of
vaccine breakthrough cases, potential establish-
ment of a correlate of protection has not been
feasible at the time of this report.
This report does not address the prevention
of Covid-19 in other populations, such as young-
er adolescents, children, and pregnant women.
Safety and immune response data from this trial
after immunization of adolescents 12 to 15 years
of age will be reported subsequently, and addi-
tional studies are planned to evaluate BNT162b2
in pregnant women, children younger than 12
years, and those in special risk groups, such as
immunocompromised persons. Although the
vaccine can be stored for up to 5 days at stan-
dard refrigerator temperatures once ready for use,
very cold temperatures are required for shipping
and longer storage. The current cold storage re-
quirement may be alleviated by ongoing stability
studies and formulation optimization, which
may also be described in subsequent reports.
The data presented in this report have sig-
nificance beyond the performance of this vac-
cine candidate. The results demonstrate that
Covid-19 can be prevented by immunization,
Table 2.
Vaccine Efficacy against Covid-19 at Least 7 days after the Second Dose.*
Efficacy End Point
BNT162b2
Placebo
Vaccine Efficacy, %
(95% Credible
Interval)‡
Posterior
Probability
(Vaccine Efficacy
>30%)§
No. of
Cases
Surveillance
Time (n)†
No. of
Cases
Surveillance
Time (n)†
(N=18,198)
(N=18,325)
Covid-19 occurrence at least
7 days after the second
dose in participants with-
out evidence of infection
8
2.214 (17,411)
162
2.222 (17,511)
95.0 (90.3–97.6)
>0.9999
(N=19,965)
(N=20,172)
Covid-19 occurrence at least
7 days after the second
dose in participants with
and those without evidence
of infection
9
2.332 (18,559)
169
2.345 (18,708)
94.6 (89.9–97.3)
>0.9999
* The total population without baseline infection was 36,523; total population including those with and those without prior evidence of infec-
tion was 40,137.
† The surveillance time is the total time in 1000 person-years for the given end point across all participants within each group at risk for the
end point. The time period for Covid-19 case accrual is from 7 days after the second dose to the end of the surveillance period.
‡ The credible interval for vaccine efficacy was calculated with the use of a beta-binomial model with prior beta (0.700102, 1) adjusted for the
surveillance time.
§ Posterior probability was calculated with the use of a beta-binomial model with prior beta (0.700102, 1) adjusted for the surveillance time.
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Safety and Efficacy of the BNT162
b
2 Vaccine
provide proof of concept that RNA-based vac-
cines are a promising new approach for protect-
ing humans against infectious diseases, and
demonstrate the speed with which an RNA-
based vaccine can be developed with a sufficient
investment of resources. The development of
BNT162b2 was initiated on January 10, 2020,
when the SARS-CoV-2 genetic sequence was re-
leased by the Chinese Center for Disease Control
and Prevention and disseminated globally by the
GISAID (Global Initiative on Sharing All Influ-
enza Data) initiative. This rigorous demonstration
of safety and efficacy less than 11 months later
provides a practical demonstration that RNA-based
vaccines, which require only viral genetic sequence
information to initiate development, are a major
new tool to combat pandemics and other infec-
tious disease outbreaks. The continuous phase
1/2/3 trial design may provide a model to reduce
the protracted development timelines that have
delayed the availability of vaccines against other
infectious diseases of medical importance. In
the context of the current, still expanding pan-
demic, the BNT162b2 vaccine, if approved, can
contribute, together with other public health mea-
sures, to reducing the devastating loss of health,
Table 3.
Vaccine Efficacy Overall and by Subgroup in Participants without Evidence of Infection before 7 Days after Dose 2.
Efficacy End-Point
Subgroup
BNT162b2
(N=18,198)
Placebo
(N=18,325)
Vaccine Efficacy, %
(95% CI)†
No. of
Cases
Surveillance
Time
(No. at Risk)*
No. of
Cases
Surveillance
Time
(No. at Risk)*
Overall
8
2.214 (17,411)
162
2.222 (17,511)
95.0 (90.0–97.9)
Age group
16 to 55 yr
5
1.234 (9,897)
114
1.239 (9,955)
95.6 (89.4–98.6)
>55 yr
3
0.980 (7,500)
48
0.983 (7,543)
93.7 (80.6–98.8)
≥65 yr
1
0.508 (3,848)
19
0.511 (3,880)
94.7 (66.7–99.9)
≥75 yr
0
0.102 (774)
5
0.106 (785)
100.0 (−13.1–100.0)
Sex
Male
3
1.124 (8,875)
81
1.108 (8,762)
96.4 (88.9–99.3)
Female
5
1.090 (8,536)
81
1.114 (8,749)
93.7 (84.7–98.0)
Race or ethnic group‡
White
7
1.889 (14,504)
146
1.903 (14,670)
95.2 (89.8–98.1)
Black or African American
0
0.165 (1,502)
7
0.164 (1,486)
100.0 (31.2–100.0)
All others
1
0.160 (1,405)
9
0.155 (1,355)
89.3 (22.6–99.8)
Hispanic or Latinx
3
0.605 (4,764)
53
0.600 (4,746)
94.4 (82.7–98.9)
Non-Hispanic, non-Latinx
5
1.596 (12,548)
109
1.608 (12,661)
95.4 (88.9–98.5)
Country
Argentina
1
0.351 (2,545)
35
0.346 (2,521)
97.2 (83.3–99.9)
Brazil
1
0.119 (1,129)
8
0.117 (1,121)
87.7 (8.1–99.7)
United States
6
1.732 (13,359)
119
1.747 (13,506)
94.9 (88.6–98.2)
* Surveillance time is the total time in 1000 person-years for the given end point across all participants within each group at risk for the end
point. The time period for Covid-19 case accrual is from 7 days after the second dose to the end of the surveillance period.
† The confidence interval (CI) for vaccine efficacy is derived according to the Clopper–Pearson method, adjusted for surveillance time.
‡ Race or ethnic group was reported by the participants. “All others” included the following categories: American Indian or Alaska Native,
Asian, Native Hawaiian or other Pacific Islander, multiracial, and not reported.
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2614
The
new engl and jour nal
of
medicine
life, and economic and social well-being that has
resulted from the global spread of Covid-19.
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 all the participants who volunteered for this study;
and the members of the C4591001 data and safety monitoring
board for their dedication and their diligent review of the data.
We also acknowledge the contributions of the C4591001 Clinical
Trial Group (see the Supplementary Appendix); Tricia Newell
and Emily Stackpole (ICON, North Wales, PA) for editorial sup-
port funded by Pfizer; and the following Pfizer staff: Greg Ad-
ams, Negar Aliabadi, Mohanish Anand, Fred Angulo, Ayman
Ayoub, Melissa Bishop-Murphy, Mark Boaz, Christopher Bowen,
Salim Bouguermouh, Donna Boyce, Sarah Burden, Andrea Ca-
wein, Patrick Caubel, Darren Cowen, Kimberly Ann Cristall,
Michael Cruz, Daniel Curcio, Gabriela Dávila, Carmel Devlin,
Gokhan Duman, Niesha Foster, Maja Gacic, Luis Jodar, Stephen
Kay, William Lam, Esther Ladipo, Joaquina Maria Lazaro, Marie-
Pierre Hellio Le Graverand-Gastineau, Jacqueline Lowenberg,
Rod MacKenzie, Robert Maroko, Jason McKinley, Tracey Melle-
Figure 3.
Efficacy of BNT162b2 against Covid-19 after the First Dose.
Shown is the cumulative incidence of Covid-19 after the first dose (modified intention-to-treat population). Each
symbol represents Covid-19 cases starting on a given day; filled symbols represent severe Covid-19 cases. Some
symbols represent more than one case, owing to overlapping dates. The inset shows the same data on an enlarged
y axis, through 21 days. Surveillance time is the total time in 1000 person-years for the given end point across all
participants within each group at risk for the end point. The time period for Covid-19 case accrual is from the first
dose to the end of the surveillance period. The confidence interval (CI) for vaccine efficacy (VE) is derived accord-
ing to the Clopper–Pearson method.
Cumulative Incidence (%)
2.4
1.6
2.0
1.2
0.8
0.4
0.0
0
119
112
105
98
91
84
77
70
63
56
42
28
49
35
21
14
7
Days after Dose 1
BNT162b2, 30 µg (N=21,669)
Efficacy End-Point Subgroup
Placebo (N=21,686)
VE (95% CI)
BNT162b2
Placebo
percent
person-yr (no. at risk)
Covid-19 occurrence
After dose 1
After dose 1 to before dose 2
Dose 2 to 7 days after dose 2
≥7 Days after dose 2
50
39
2
9
275
82
21
172
Surveillance time
No. of participants
4.015 (21,314)
person-yr (no. at risk)
Surveillance time
No. of participants
3.982 (21,258)
82.0 (75.6–86.9)
52.4 (29.5–68.4)
90.5 (61.0–98.9)
94.8 (89.8–97.6)
0.5
0.4
0.3
0.2
0.1
0.0
0
18
12
21
15
9
6
3
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2615
Safety and Efficacy of the BNT162
b
2 Vaccine
lieu, Farheen Muzaffar, Brendan O’Neill, Jason Painter, Eliza-
beth Paulukonis, Allison Pfeffer, Katie Puig, Kimberly Rarrick,
Balaji Prabu Raja, Christine Rainey, Kellie Lynn Richardson,
Elizabeth Rogers, Melinda Rottas, Charulata Sabharwal, Vilas
Satishchandran, Harpreet Seehra, Judy Sewards, Helen Smith,
David Swerdlow, Elisa Harkins Tull, Sarah Tweedy, Erica Weaver,
John Wegner, Jenah West, Christopher Webber, David C. Whrit-
enour, Fae Wooding, Emily Worobetz, Xia Xu, Nita Zalavadia,
Liping Zhang, the Vaccines Clinical Assay Team, the Vaccines
Assay Development Team, and all the Pfizer colleagues not
named here who contributed to the success of this trial. We
also acknowledge the contributions of the following staff at
BioNTech: Corinna Rosenbaum, Christian Miculka, Andreas
Kuhn, Ferdia Bates, Paul Strecker, Ruben Rizzi, Martin Bexon,
Eleni Lagkadinou, and Alexandra Kemmer-Brück; and the fol-
lowing staff at Polymun: Dietmar Katinger and Andreas Wagner.
Appendix
The authors’ affiliations are as follows: Fundacion INFANT (F.P.P.) and iTrials-Hospital Militar Central (G.P.M.), Buenos Aires; State
University of New York, Upstate Medical University, Syracuse (S.J.T.), and Vaccine Research and Development, Pfizer, Pearl River (J.A.,
A.G., K.A.S., K.K., W.V.K., D.C., P.R.D., K.U.J., W.C.G.) — both in New York; Vaccine Research and Development, Pfizer, Hurley,
United Kingdom (N.K., S.L., R.B.); Vaccine Research and Development (J.L.P., P.L.) and Worldwide Safety, Safety Surveillance and Risk
Management (S.M.), Pfizer, Collegeville, PA; Associação Obras Sociais Irmã Dulce and Oswaldo Cruz Foundation, Bahia (E.D.M.), and
Centro Paulista de Investigação Clinica, São Paulo (C.Z.) — both in Brazil; Global Product Development, Pfizer, Peapack, NJ (S.R.);
Cincinnati Children’s Hospital, Cincinnati (R.W.F.); Johns Hopkins Bloomberg School of Public Health, Baltimore (L.L.H.); BioNTech,
Mainz (ÖT., U.Ş.), and Medizentrum Essen Borbeck, Essen (A.S.) — both in Germany; Tiervlei Trial Centre, Karl Bremer Hospital, Cape
Town, South Africa (H.N.); Hacettepe University, Ankara, Turkey (S.Ü.); and Worldwide Safety, Safety Surveillance and Risk Manage-
ment, Pfizer, Groton, CT (D.B.T.).
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