Covid 19 y Vacuna Pfizer

The n e w e ng l a n d j o u r na l of m e dic i n e
Original Article
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*
A BS T R AC T
BACKGROUND
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the The authors' affiliations are listed in the
resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people Appendix. Address reprint requests to
Dr. Absalon at Pfizer, 401 N. Middletown
in a worldwide pandemic. Safe and effective vaccines are needed urgently. Rd., Pearl River, NY 10965, or at judith
.absalon@pfizer.com.
METHODS
*A complete list of investigators in the
In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy C4591001 Clinical Trial Group is pro-
trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive vided in the Supplementary Appendix,
two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg available at NEJM.org.
per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA Drs. Polack and Thomas contributed
vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full- equally to this article.
length spike protein. The primary end points were efficacy of the vaccine against This article was published on December
laboratory-confirmed Covid-19 and safety. 10, 2020, at NEJM.org.
DOI: 10.1056/NEJMoa2034577
RESULTS Copyright © 2020 Massachusetts Medical Society.
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.)
n engl j med nejm.org 1

The New England Journal of Medicine
Downloaded from nejm.org on December 12, 2020. For personal use only. No other uses without permission.
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
C
oronavirus disease 2019 (Covid-19) larly 21 days apart, as compared with placebo.
has affected tens of millions of people Adults 16 years of age or older who were healthy
globally1 since it was declared a pandemic or had stable chronic medical conditions, includ-
by the World Health Organization on March 11, ing but not limited to human immunodeficiency
2020.2 Older adults, persons with certain coex- virus (HIV), hepatitis B virus, or hepatitis C vi-
A Quick Take
is available at
isting conditions, and front-line workers are at rus infection, were eligible for participation in
NEJM.org highest risk for Covid-19 and its complications. the trial. Key exclusion criteria included a medi-
Recent data show increasing rates of severe acute cal history of Covid-19, treatment with immuno-
respiratory syndrome coronavirus 2 (SARS-CoV-2) suppressive therapy, or diagnosis with an im-
infection and Covid-19 in other populations, in- munocompromising condition.
cluding younger adults.3 Safe and effective pro- Pfizer was responsible for the design and
phylactic vaccines are urgently needed to contain conduct of the trial, data collection, data analysis,
the pandemic, which has had devastating medi- data interpretation, and the writing of the
cal, economic, and social consequences. manuscript. BioNTech was the sponsor of the
We previously reported phase 1 safety and im- trial, manufactured the BNT162b2 clinical trial
munogenicity results from clinical trials of the material, and contributed to the interpretation
vaccine candidate BNT162b2,4 a lipid nanoparticle– of the data and the writing of the manuscript.
formulated,5 nucleoside-modified RNA (modRNA)6 All the trial data were available to all the authors,
encoding the SARS-CoV-2 full-length spike, modi- who vouch for its accuracy and completeness and
fied by two proline mutations to lock it in the for adherence of the trial to the protocol, which
prefusion conformation.7 Findings from studies is available with the full text of this article at
conducted in the United States and Germany NEJM.org. An independent data and safety mon-
among healthy men and women showed that two itoring board reviewed efficacy and unblinded
30-μg doses of BNT162b2 elicited high SARS-CoV-2 safety data.
neutralizing antibody titers and robust antigen-
specific CD8+ and Th1-type CD4+ T-cell respons- Trial Procedures
es.8 The 50% neutralizing geometric mean titers With the use of an interactive Web-based sys-
elicited by 30 μg of BNT162b2 in older and young- tem, participants in the trial were randomly as-
er adults exceeded the geometric mean titer mea- signed in a 1:1 ratio to receive 30 μg of
sured in a human convalescent serum panel, de- BNT162b2 (0.3 ml volume per dose) or saline
spite a lower neutralizing response in older adults placebo. Participants received two injections, 21
than in younger adults. In addition, the reactoge- days apart, of either BNT162b2 or placebo, deliv-
nicity profile of BNT162b2 represented mainly ered in the deltoid muscle. Site staff who were
short-term local (i.e., injection site) and systemic responsible for safety evaluation and were un-
responses. These findings supported progression aware of group assignments observed partici-
of the BNT162b2 vaccine candidate into phase 3. pants for 30 minutes after vaccination for any
Here, we report safety and efficacy findings acute reactions.
from the phase 2/3 part of a global phase 1/2/3
trial evaluating the safety, immunogenicity, and Safety
efficacy of 30 μg of BNT162b2 in preventing The primary end points of this trial were solic-
Covid-19 in persons 16 years of age or older. This
ited, specific local or systemic adverse events
data set and these trial results are the basis for an
and use of antipyretic or pain medication within
application for emergency use authorization.9 Col-
7 days after the receipt of each dose of vaccine
lection of phase 2/3 data on vaccine immunoge- or placebo, as prompted by and recorded in an
nicity and the durability of the immune response electronic diary in a subset of participants (the
to immunization is ongoing, and those data are reactogenicity subset), and unsolicited adverse
not reported here. events (those reported by the participants with-
out prompts from the electronic diary) through
1 month after the second dose and unsolicited
Me thods
serious adverse events through 6 months after
Trial Objectives, Participants and Oversight the second dose. Adverse event data through ap-
We assessed the safety and efficacy of two 30-μg proximately 14 weeks after the second dose are
doses of BNT162b2, administered intramuscu- included in this report. In this report, safety
2 n engl j med nejm.org

Safety and Efficacy of the BNT162b2 Vaccine
data are reported for all participants who pro- tary Appendix, available at NEJM.org. In brief,
vided informed consent and received at least one the safety population includes persons 16 years
dose of vaccine or placebo. Per protocol, safety re- of age or older; a total of 43,448 participants
sults for participants infected with HIV (196 pa- constituted the population of enrolled persons
tients) will be analyzed separately and are not injected with the vaccine or placebo. The main
included here. safety subset as defined by the FDA, with a me-
During the phase 2/3 portion of the study, a dian of 2 months of follow-up as of October 9,
stopping rule for the theoretical concern of vac- 2020, consisted of 37,706 persons, and the reac-
cine-enhanced disease was to be triggered if the togenicity subset consisted of 8183 persons. The
one-sided probability of observing the same or a modified intention-to-treat (mITT) efficacy pop-
more unfavorable adverse severe case split (a split ulation includes all age groups 12 years of age
with a greater proportion of severe cases in vac- or older (43,355 persons; 100 participants who
cine recipients) was 5% or less, given the same were 12 to 15 years of age contributed to person-
true incidence for vaccine and placebo recipients. time years but included no cases). The number
Alert criteria were to be triggered if this probabil- of persons who could be evaluated for efficacy 7
ity was less than 11%. days after the second dose and who had no evi-
dence of prior infection was 36,523, and the
Efficacy number of persons who could be evaluated 7
The first primary end point was the efficacy of days after the second dose with or without evi-
BNT162b2 against confirmed Covid-19 with onset dence of prior infection was 40,137.
at least 7 days after the second dose in participants
who had been without serologic or virologic evi- Statistical Analysis
dence of SARS-CoV-2 infection up to 7 days after The safety analyses included all participants
the second dose; the second primary end point who received at least one dose of BNT162b2 or
was efficacy in participants with and partici- placebo. The findings are descriptive in nature
pants without evidence of prior infection. Con- and not based on formal statistical hypothesis
firmed Covid-19 was defined according to the testing. Safety analyses are presented as counts,
Food and Drug Administration (FDA) criteria as percentages, and associated Clopper–Pearson
the presence of at least one of the following 95% confidence intervals for local reactions,
symptoms: fever, new or increased cough, new or systemic events, and any adverse events after
increased shortness of breath, chills, new or in- vaccination, according to terms in the Medical
creased muscle pain, new loss of taste or smell, Dictionary for Regulatory Activities (MedDRA), ver-
sore throat, diarrhea, or vomiting, combined with sion 23.1, for each vaccine group.
a respiratory specimen obtained during the symp- Analysis of the first primary efficacy end
tomatic period or within 4 days before or after it point included participants who received the vac-
that was positive for SARS-COV-2 by nucleic acid cine or placebo as randomly assigned, had no
amplification–based testing, either at the central evidence of infection within 7 days after the
laboratory or at a local testing facility (using a second dose, and had no major protocol devia-
protocol-defined acceptable test). tions (the population that could be evaluated).
Major secondary end points included the ef- Vaccine efficacy was estimated by 100 × (1 − IRR),
ficacy of BNT162b2 against severe Covid-19. Se- where IRR is the calculated ratio of confirmed
vere Covid-19 is defined by the FDA as confirmed cases of Covid-19 illness per 1000 person-years
Covid-19 with one of the following additional of follow-up in the active vaccine group to the
features: clinical signs at rest that are indicative corresponding illness rate in the placebo group.
of severe systemic illness; respiratory failure; evi- The 95.0% credible interval for vaccine efficacy
dence of shock; significant acute renal, hepatic, and the probability of vaccine efficacy greater
or neurologic dysfunction; admission to an in- than 30% were calculated with the use of a
tensive care unit; or death. Details are provided Bayesian beta-binomial model. The final analy-
in the protocol. sis uses a success boundary of 98.6% for prob-
An explanation of the various denominator ability of vaccine efficacy greater than 30% to
values for use in assessing the results of the compensate for the interim analysis and to
trial is provided in Table S1 in the Supplemen- control the overall type 1 error rate at 2.5%.

44,820 Participants were screened
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
43,548 Underwent randomization
99 Were not vaccinated

1 Did not sign the informed
consent document
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
18,860 Received dose 1 of BNT162b2 18,846 Received dose 1 of placebo
316 Did not receive dose 2

304 Did not receive dose 2 96 Withdrew
100 Withdrew 86 Were no longer eligible
62 Were lost to follow-up 61 Were lost to follow-up
56 Had ongoing or pending 46 Had ongoing or pending
status status
51 Were no longer eligible 18 Had adverse event
28 Had adverse event 5 Were pregnant
4 Were pregnant 2 Were withdrawn by
2 Were withdrawn by physician
physician 1 Died
1 Died 1 Had medication error
(no adverse event)
18,556 Received dose 2 of BNT162b2 18,530 Received dose 2 of placebo
48 Discontinued trial after dose 2 95 Discontinued trial after dose 2

27 Withdrew 66 Withdrew
18 Were lost to follow-up 25 Were lost to follow-up
1 Died 2 Died
1 Was withdrawn by physician 1 Had other reason
1 Had medication error 1 Declined further procedures
(no adverse event)

Figure 1 (facing page). Enrollment and Randomization. analyses (estimates of vaccine efficacy and 95%
The diagram represents all enrolled participants confidence intervals) are provided for key sub-
through November 14, 2020. The safety subset (those groups.
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- R e sult s
off date. The further procedures that one participant in
the placebo group declined after dose 2 (lower right
Participants
Between July 27, 2020, and November 14, 2020,
corner of the diagram) were those involving collection
of blood and nasal swab samples. 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
Moreover, primary and secondary efficacy end (United States, 130 sites; Argentina, 1; Brazil, 2;
points are evaluated sequentially to control the South Africa, 4; Germany, 6; and Turkey, 9) in
familywise type 1 error rate at 2.5%. Descriptive the phase 2/3 portion of the trial. A total of
Table 1. Demographic Characteristics of the Participants in the Main Safety Population.*
BNT162b2 Placebo Total

Characteristic (N=18,860) (N=18,846) (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.

Figure 2. Local and Systemic Reactions Reported Mild Moderate Severe Grade 4
within 7 Days after Injection of BNT162b2 or Placebo,
According to Age Group. A Local Events
Data on local and systemic reactions and use of medi- 100 16–55 Yr of Age, Dose 1
cation were collected with electronic diaries from par- 90 83
ticipants in the reactogenicity subset (8,183 partici- 80
pants) for 7 days after each vaccination. Solicited 70
injection-site (local) reactions are shown in Panel A. 60
Pain at the injection site was assessed according to 50
the following scale: mild, does not interfere with activ- 40
ity; moderate, interferes with activity; severe, prevents 30
daily activity; and grade 4, emergency department visit
20 14
or hospitalization. Redness and swelling were mea- 6
10 5
sured according to the following scale: mild, 2.0 to 1 0
0
5.0 cm in diameter; moderate, >5.0 to 10.0 cm in di-
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ameter; severe, >10.0 cm in diameter; and grade 4,
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necrosis or exfoliative dermatitis (for redness) and ne-
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crosis (for swelling). Systemic events and medication 100 16–55 Yr of Age, Dose 2
use are shown in Panel B. Fever categories are desig- 90
nated in the key; medication use was not graded. Ad- 78
80
ditional scales were as follows: fatigue, headache, 70
chills, new or worsened muscle pain, new or worsened 60
joint pain (mild: does not interfere with activity; mod- 50
erate: some interference with activity; or severe: pre- 40
vents daily activity), vomiting (mild: 1 to 2 times in 30
24 hours; moderate: >2 times in 24 hours; or severe:
Percentage of Participants 20 12
requires intravenous hydration), and diarrhea (mild: 6 6
10
2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose 1 0
0
stools in 24 hours; or severe: 6 or more loose stools in
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24 hours); grade 4 for all events indicated an emer- 62
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gency department visit or hospitalization. I bars repre-
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sent 95% confidence intervals, and numbers above 100 >55 Yr of Age, Dose 1
the I bars are the percentage of participants who re- 90
ported the specified reaction. 80 71
70
43,448 participants received injections: 21,720 60
50
received BNT162b2 and 21,728 received placebo
40
(Fig. 1). At the data cut-off date of October 9, a
30
total of 37,706 participants had a median of at 20
least 2 months of safety data available after the 9 7
10 5
1 1
second dose and contributed to the main safety 0
data set. Among these 37,706 participants, 49%
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were female, 83% were White, 9% were Black or

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African American, 28% were Hispanic or Latinx, 100 >55 Yr of Age, Dose 2
35% were obese (body mass index [the weight in 90
kilograms divided by the square of the height in 80
70 66
meters] of at least 30.0), and 21% had at least
60
one coexisting condition. The median age was 50
52 years, and 42% of participants were older 40
than 55 years of age (Table 1 and Table S2). 30
20
8 7 7
Safety 10
1 1
Local Reactogenicity 0
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The reactogenicity subset included 8183 partici-

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pants. Overall, BNT162b2 recipients reported more

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local reactions than placebo recipients. Among Pain at Injection Redness Swelling
Site
BNT162b2 recipients, mild-to-moderate pain at

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
B Systemic Events and Use of Medication

100 16–55 Yr of Age, Dose 1
90
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50 47
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40 33 34
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30 21
20 14 12 14
11 11 11
10 4 6 6
1 1 1
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100 16–55 Yr of Age, Dose 2
90
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60 52
50 45
35 37
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30 23 24 22
20 16
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Percentage of Participants
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100 >55 Yr of Age, Dose 1
90
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70
60
50
40 34
30 23 25
18 20
20 14 12
6 8 7 8 9 6
10 3
1 0 0 1
0
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100 >55 Yr of Age, Dose 2

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60 51
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Fever Fatigue Headache Chills Vomiting Diarrhea Muscle Pain Joint Pain Use of antipyretic
medication

the injection site within 7 days after an injection than vaccine recipients to use the medications,
was the most commonly reported local reaction, regardless of age or dose. Systemic events in-
with less than 1% of participants across all age cluding fever and chills were observed with the
groups reporting severe pain (Fig. 2). Pain was first 1 to 2 days after vaccination and resolved
reported less frequently among participants old- shortly thereafter.
er than 55 years of age (71% reported pain after Daily use of the electronic diary ranged from
the first dose; 66% after the second dose) than 90 to 93% for each day after the first dose and
among younger participants (83% after the first from 75 to 83% for each day after the second
dose; 78% after the second dose). A noticeably dose. No difference was noted between the
lower percentage of participants reported injec- BNT162b2 group and the placebo group.
tion-site redness or swelling. The proportion of
participants reporting local reactions did not Adverse Events
increase after the second dose (Fig. 2A), and no Adverse event analyses are provided for all en-
participant reported a grade 4 local reaction. In rolled 43,252 participants, with variable follow-
general, local reactions were mostly mild-to-mod- up time after dose 1 (Table S3). More BNT162b2
erate in severity and resolved within 1 to 2 days. recipients than placebo recipients reported any
adverse event (27% and 12%, respectively) or a
Systemic Reactogenicity related adverse event (21% and 5%). This distri-
Systemic events were reported more often by bution largely reflects the inclusion of transient
younger vaccine recipients (16 to 55 years of age) reactogenicity events, which were reported as
than by older vaccine recipients (more than 55 adverse events more commonly by vaccine recipi-
years of age) in the reactogenicity subset and ents than by placebo recipients. Sixty-four vac-
more often after dose 2 than dose 1 (Fig. 2B). cine recipients (0.3%) and 6 placebo recipients
The most commonly reported systemic events (<0.1%) reported lymphadenopathy. Few partici-
were fatigue and headache (59% and 52%, re- pants in either group had severe adverse events,
spectively, after the second dose, among younger serious adverse events, or adverse events leading
vaccine recipients; 51% and 39% among older to withdrawal from the trial. Four related serious
recipients), although fatigue and headache were adverse events were reported among BNT162b2
also reported by many placebo recipients (23% and recipients (shoulder injury related to vaccine ad-
24%, respectively, after the second dose, among ministration, right axillary lymphadenopathy,
younger vaccine recipients; 17% and 14% among paroxysmal ventricular arrhythmia, and right leg
older recipients). The frequency of any severe paresthesia). Two BNT162b2 recipients died (one
systemic event after the first dose was 0.9% or from arteriosclerosis, one from cardiac arrest),
less. Severe systemic events were reported in less as did four placebo recipients (two from unknown
than 2% of vaccine recipients after either dose, causes, one from hemorrhagic stroke, and one
except for fatigue (in 3.8%) and headache (in 2.0%) from myocardial infarction). No deaths were con-
after the second dose. sidered by the investigators to be related to the
Fever (temperature, ≥38°C) was reported after vaccine or placebo. No Covid-19–associated deaths
the second dose by 16% of younger vaccine re- were observed. No stopping rules were met dur-
cipients and by 11% of older recipients. Only 0.2% ing the reporting period. Safety monitoring will
of vaccine recipients and 0.1% of placebo recipi- continue for 2 years after administration of the
ents reported fever (temperature, 38.9 to 40°C) af- second dose of vaccine.
ter the first dose, as compared with 0.8% and
0.1%, respectively, after the second dose. Two Efficacy
participants each in the vaccine and placebo Among 36,523 participants who had no evidence
groups reported temperatures above 40.0°C. of existing or prior SARS-CoV-2 infection, 8 cases
Younger vaccine recipients were more likely to of Covid-19 with onset at least 7 days after the
use antipyretic or pain medication (28% after second dose were observed among vaccine re-
dose 1; 45% after dose 2) than older vaccine recipients and 162 among placebo recipients. This
cipients (20% after dose 1; 38% after dose 2), case split corresponds to 95.0% vaccine efficacy
and placebo recipients were less likely (10 to 14%) (95% confidence interval [CI], 90.3 to 97.6; Ta-

Table 2. Vaccine Efficacy against Covid-19 at Least 7 days after the Second Dose.*
Posterior
Vaccine Efficacy, % Probability
(95% Credible (Vaccine Efficacy
Efficacy End Point BNT162b2 Placebo Interval)‡ >30%)§
No. of Surveillance No. of Surveillance

Cases Time (n)† Cases Time (n)†
(N=18,198) (N=18,325)
Covid-19 occurrence at least 8 2.214 (1,7411) 162 2.222 (17,511) 95.0 (90.3–97.6) >0.9999
7 days after the second
dose in participants with-
out evidence of infection
(N=19,965) (N=20,172)
Covid-19 occurrence at least 9 2.332 (18,559) 169 2.345 (18,708) 94.6 (89.9–97.3) >0.9999
7 days after the second
dose in participants with
and those without evidence
of infection
* 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.
ble 2). Among participants with and those with- Discussion

out evidence of prior SARS CoV-2 infection, 9 cases
of Covid-19 at least 7 days after the second dose A two-dose regimen of BNT162b2 (30 μg per
were observed among vaccine recipients and 169 dose, given 21 days apart) was found to be safe
among placebo recipients, corresponding to 94.6% and 95% effective against Covid-19. The vaccine
vaccine efficacy (95% CI, 89.9 to 97.3). Supple- met both primary efficacy end points, with more
mental analyses indicated that vaccine efficacy than a 99.99% probability of a true vaccine ef-
among subgroups defined by age, sex, race, eth- ficacy greater than 30%. These results met our
nicity, obesity, and presence of a coexisting condi- prespecified success criteria, which were to es-
tion was generally consistent with that observed tablish a probability above 98.6% of true vaccine
in the overall population (Table 3 and Table S4). efficacy being greater than 30%, and greatly
Vaccine efficacy among participants with hyper- exceeded the minimum FDA criteria for authori-
tension was analyzed separately but was consis- zation.9 Although the study was not powered to
tent with the other subgroup analyses (vaccine definitively assess efficacy by subgroup, the
efficacy, 94.6%; 95% CI, 68.7 to 99.9; case split: point estimates of efficacy for subgroups based
BNT162b2, 2 cases; placebo, 44 cases). Figure 3 on age, sex, race, ethnicity, body-mass index, or
shows cases of Covid-19 or severe Covid-19 with the presence of an underlying condition associ-
onset at any time after the first dose (mITT popu- ated with a high risk of Covid-19 complications
lation) (additional data on severe Covid-19 are are also high. For all analyzed subgroups in
available in Table S5). Between the first dose and which more than 10 cases of Covid-19 occurred,
the second dose, 39 cases in the BNT162b2 group the lower limit of the 95% confidence interval
and 82 cases in the placebo group were observed, for efficacy was more than 30%.
resulting in a vaccine efficacy of 52% (95% CI, The cumulative incidence of Covid-19 cases
29.5 to 68.4) during this interval and indicating over time among placebo and vaccine recipients
early protection by the vaccine, starting as soon begins to diverge by 12 days after the first dose,
as 12 days after the first dose. 7 days after the estimated median viral incuba-

Table 3. Vaccine Efficacy Overall and by Subgroup in Participants without Evidence of Infection before 7 Days after Dose 2.
Efficacy End-Point BNT162b2 Placebo Vaccine Efficacy, %

Subgroup (N=18,198) (N=18,325) (95% CI)†
Surveillance Surveillance
No. of Time No. of Time
Cases (No. at Risk)* Cases (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 (8762) 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.
tion period of 5 days,10 indicating the early onset The favorable safety profile observed during
of a partially protective effect of immunization. phase 1 testing of BNT162b24,8 was confirmed in
The study was not designed to assess the efficacy the phase 2/3 portion of the trial. As in phase 1,
of a single-dose regimen. Nevertheless, in the reactogenicity was generally mild or moderate,
interval between the first and second doses, the and reactions were less common and milder in
observed vaccine efficacy against Covid-19 was older adults than in younger adults. Systemic
52%, and in the first 7 days after dose 2, it was reactogenicity was more common and severe
91%, reaching full efficacy against disease with after the second dose than after the first dose,
onset at least 7 days after dose 2. Of the 10 cases although local reactogenicity was similar after
of severe Covid-19 that were observed after the the two doses. Severe fatigue was observed in
first dose, only 1 occurred in the vaccine group. approximately 4% of BNT162b2 recipients,
This finding is consistent with overall high ef- which is higher than that observed in recipients
ficacy against all Covid-19 cases. The severe case of some vaccines recommended for older adults.12
split provides preliminary evidence of vaccine- This rate of severe fatigue is also lower than that
mediated protection against severe disease, al- observed in recipients of another approved viral
leviating many of the theoretical concerns over vaccine for older adults.13 Overall, reactogenicity
vaccine-mediated disease enhancement.11 events were transient and resolved within a couple

2.4
0.5 Placebo
0.4
2.0
0.3
0.2
1.6 0.1
Cumulative Incidence (%)
0.0
0 3 6 9 12 15 18 21
1.2
0.8
0.4
BNT162b2
0.0
0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119
Days after Dose 1
Efficacy End-Point Subgroup BNT162b2, 30 µg (N=21,669) Placebo (N=21,686) VE (95% CI)

No. of participants Surveillance time No. of participants Surveillance time
person-yr (no. at risk) person-yr (no. at risk) percent
Covid-19 occurrence
After dose 1 50 4.015 (21,314) 275 3.982 (21,258) 82.0 (75.6–86.9)
After dose 1 to before dose 2 39 82 52.4 (29.5–68.4)
Dose 2 to 7 days after dose 2 2 21 90.5 (61.0–98.9)
≥7 Days after dose 2 9 172 94.8 (89.8–97.6)
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.
of days after onset. Lymphadenopathy, which pants with a median follow-up time of 2 months
generally resolved within 10 days, is likely to after the second dose, the study has more than
have resulted from a robust vaccine-elicited im- 83% probability of detecting at least one adverse
mune response. The incidence of serious adverse event, if the true incidence is 0.01%, but it is not
events was similar in the vaccine and placebo large enough to detect less common adverse events
groups (0.6% and 0.5%, respectively). reliably. This report includes 2 months of follow-
This trial and its preliminary report have up after the second dose of vaccine for half the
several limitations. With approximately 19,000 trial participants and up to 14 weeks’ maximum
participants per group in the subset of partici- follow-up for a smaller subset. Therefore, both

the occurrence of adverse events more than 2 to investment of resources. The development of
3.5 months after the second dose and more BNT162b2 was initiated on January 10, 2020,
comprehensive information on the duration of when the SARS-CoV-2 genetic sequence was re-
protection remain to be determined. Although leased by the Chinese Center for Disease Control
the study was designed to follow participants for and Prevention and disseminated globally by the
safety and efficacy for 2 years after the second GISAID (Global Initiative on Sharing All Influ-
dose, given the high vaccine efficacy, ethical and enza Data) initiative. This rigorous demonstration
practical barriers prevent following placebo re- of safety and efficacy less than 11 months later
cipients for 2 years without offering active im- provides a practical demonstration that RNA-based
munization, once the vaccine is approved by vaccines, which require only viral genetic sequence
regulators and recommended by public health information to initiate development, are a major
authorities. Assessment of long-term safety and new tool to combat pandemics and other infec-
efficacy for this vaccine will occur, but it cannot tious disease outbreaks. The continuous phase
be in the context of maintaining a placebo group 1/2/3 trial design may provide a model to reduce
for the planned follow-up period of 2 years after the protracted development timelines that have
the second dose. These data do not address delayed the availability of vaccines against other
whether vaccination prevents asymptomatic in- infectious diseases of medical importance. In
fection; a serologic end point that can detect a the context of the current, still expanding pan-
history of infection regardless of whether symp- demic, the BNT162b2 vaccine, if approved, can
toms were present (SARS-CoV-2 N-binding anti- contribute, together with other public health mea-
body) will be reported later. Furthermore, given sures, to reducing the devastating loss of health,
the high vaccine efficacy and the low number of life, and economic and social well-being that has
vaccine breakthrough cases, potential establish- resulted from the global spread of Covid-19.
ment of a correlate of protection has not been Supported by BioNTech and Pfizer.
feasible at the time of this report. Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
This report does not address the prevention A data sharing statement provided by the authors is available
of Covid-19 in other populations, such as young- with the full text of this article at NEJM.org.
er adolescents, children, and pregnant women. We thank all the participants who volunteered for this study;
and the members of the C4591001 data and safety monitoring
Safety and immune response data from this trial board for their dedication and their diligent review of the data.
after immunization of adolescents 12 to 15 years We also acknowledge the contributions of the C4591001 Clinical
of age will be reported subsequently, and addi- Trial Group (see the Supplementary Appendix); Tricia Newell
and Emily Stackpole (ICON, North Wales, PA) for editorial sup-
tional studies are planned to evaluate BNT162b2 port funded by Pfizer; and the following Pfizer staff: Greg Ad-
in pregnant women, children younger than 12 ams, Negar Aliabadi, Mohanish Anand, Fred Angulo, Ayman
years, and those in special risk groups, such as Ayoub, Melissa Bishop-Murphy, Mark Boaz, Christopher Bowen,
Salim Bouguermouh, Donna Boyce, Sarah Burden, Andrea Ca-
immunocompromised persons. Although the wein, Patrick Caubel, Darren Cowen, Kimberly Ann Cristall,
vaccine can be stored for up to 5 days at stan- Michael Cruz, Daniel Curcio, Gabriela Dávila, Carmel Devlin,
dard refrigerator temperatures once ready for use, Gokhan Duman, Niesha Foster, Maja Gacic, Luis Jodar, Stephen
Kay, William Lam, Esther Ladipo, Joaquina Maria Lazaro, Marie-
very cold temperatures are required for shipping Pierre Hellio Le Graverand-Gastineau, Jacqueline Lowenberg,
and longer storage. The current cold storage re- Rod MacKenzie, Robert Maroko, Jason McKinley, Tracey Melle-
quirement may be alleviated by ongoing stability lieu, Farheen Muzaffar, Brendan O’Neill, Jason Painter, Eliza-
beth Paulukonis, Allison Pfeffer, Katie Puig, Kimberly Rarrick,
studies and formulation optimization, which Balaji Prabu Raja, Christine Rainey, Kellie Lynn Richardson,
may also be described in subsequent reports. Elizabeth Rogers, Melinda Rottas, Charulata Sabharwal, Vilas
The data presented in this report have sig- Satishchandran, Harpreet Seehra, Judy Sewards, Helen Smith,
David Swerdlow, Elisa Harkins Tull, Sarah Tweedy, Erica Weaver,
nificance beyond the performance of this vac- John Wegner, Jenah West, Christopher Webber, David C. Whrit-
cine candidate. The results demonstrate that enour, Fae Wooding, Emily Worobetz, Xia Xu, Nita Zalavadia,
Covid-19 can be prevented by immunization, Liping Zhang, the Vaccines Clinical Assay Team, the Vaccines
Assay Development Team, and all the Pfizer colleagues not
provide proof of concept that RNA-based vac- named here who contributed to the success of this trial. We
cines are a promising new approach for protect- also acknowledge the contributions of the following staff at
ing humans against infectious diseases, and BioNTech: Corinna Rosenbaum, Christian Miculka, Andreas
Kuhn, Ferdia Bates, Paul Strecker, Ruben Rizzi, Martin Bexon,
demonstrate the speed with which an RNA- Eleni Lagkadinou, and Alexandra Kemmer-Brück; and the fol-
based vaccine can be developed with a sufficient 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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What was the study design of the clinical trial?

What was the study design of the clinical trial?

What were the primary endpoints of the clinical trial?

What were the primary endpoints of the clinical trial?

The n e w e ng l a n d j o u r na l of m e dic i n e

Safety and Efficacy of the BNT162b2 mRNA

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The New England Journal of Medicine

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44,820 Participants were screened

1272 Did not undergo randomization

43,548 Underwent randomization

99 Were not vaccinated

43,448 Were injected with vaccine or placebo

37,706 Received vaccine or placebo

18,860 Received dose 1 of BNT162b2 18,846 Received dose 1 of placebo

316 Did not receive dose 2

18,556 Received dose 2 of BNT162b2 18,530 Received dose 2 of placebo

48 Discontinued trial after dose 2 95 Discontinued trial after dose 2

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Table 1. Demographic Characteristics of the Participants in the Main Safety Population.*

BNT162b2 Placebo Total

* Percentages may not total 100 because of rounding.

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were female, 83% were White, 9% were Black or

The reactogenicity subset included 8183 partici-

pants. Overall, BNT162b2 recipients reported more

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B Systemic Events and Use of Medication

100 >55 Yr of Age, Dose 2

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No. of Surveillance No. of Surveillance

ble 2). Among participants with and those with- Discussion

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Efficacy End-Point BNT162b2 Placebo Vaccine Efficacy, %

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The New England Journal of Medicine

Efficacy End-Point Subgroup BNT162b2, 30 µg (N=21,669) Placebo (N=21,686) VE (95% CI)

Figure 3. Efficacy of BNT162b2 against Covid-19 after the First Dose.

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* Percentages may not total 100 because of rounding.

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