Document text
C4591001
CONFIDENTIAL16.1.11 PUBLICATIONS BASED ON THE STUDY
1.Mulligan MJ, L yke KE, Kitchin N, et al. Phase 1/2 study of COVI D-19 RNA vaccine
BNT162b1 in adults. Nature. 2020;10.1038/s41586 -020-2639 -4.
2.Walsh EE, Frenck FW, Falsey AR, et al. Safety and immunogenicity of two RNA -based
Covid -19 vaccine candidates. N Engl J Med 2020; DOI : 10.1056/NEJMoa2027906.
3. Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA
Covid -19 Vaccine. N Engl J Med. 2020;383(27):2603 -2615. doi:10.1056/NEJMoa2034577
4.Xie X, Liu Y, Liu J, et al. Neutralization of SARS -CoV -2 spike 69/70 deletion, E484K and
N501Y variants by BNT162b2 vaccine -elicited sera. Nat Med. 2021;27(4):620-621.
doi:10.1038/s41591 -021-01270 -4
5.Liu Y, L iu J, Xia H, et al. Neutralizing Activity of BNT162b2 -Elicit ed Serum. N Engl J Med.
2021;384(15):1466 -1468. doi:10.1056/NEJMc2102017
6.Frenck RW Jr, Klein NP, Kitchin N, et al. Safety , Immunogenicity , and Efficacy of the
BNT162b2 Covid- 19 Vaccine in Adolescents. N Engl J Med. 2021;385(3):239 -250.
doi:10.1056/NEJMoa21 07456
7. Thomas SJ, Moreira ED Jr, Kitchin N, et al. Safe ty and Efficacy of the BNT162b2 mRNA
Covid -19 Vaccine through 6 Months. N Engl J Med. 2021;385(19):1761 -1773.
doi:10.1056/NEJMoa2110345
8.False y AR, Frenck RW Jr , Walsh EE, et al. SARS -CoV -2 Neutralizatio n with BNT162b2
Vaccine Dose 3. N Engl J Med. 2021;385(17):1627 -1629. doi:10.1056/NEJMc2113468
090177e1988e8d2e\Approved\Approved On: 03-Dec-2021 02:30 (GMT)
Page 1
FDA-CBER-2022-5812-0228129
Nature | Vol 586 | 22 October 2020 | 589
ArticlePhase I/II study of COVID-19 RNA vaccine
BNT162b1 in adults
Mark J. Mulligan1,2,12, Kirsten E. Lyke3,12, Nicholas Kitchin4,12, Judith Absalon5 ✉,
Alejandra Gurtman5, Stephen Lockhart4, Kathleen Neuzil3, Vanessa Raabe1,2,
Ruth Bailey4, Kena A. Swanson5, Ping Li6, Kenneth Koury5, Warren Kalina5, David Cooper5,
Camila Fontes-Garfias7, Pei-Yong Shi7, Özlem Türeci8, Kristin R. Tompkins5,
Edward E. Walsh9,10, Robert Frenck11, Ann R. Falsey9,10, Philip R. Dormitzer5, William C. Gruber5,
Uğur Şahin8 & Kathrin U. Jansen5
In March 2020, the World Health Organization (WHO) declared coronavirus disease
2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2)1, a pandemic. With rapidly accumulating numbers of cases and deaths
reported globally2, a vaccine is urgently needed. Here we report the available safety,
tolerability and immunogenicity data from an ongoing placebo-controlled, observer-blinded dose-escalation study (ClinicalTrials.gov identifier NCT04368728) among 45 healthy adults (18–55 years of age), who were randomized to receive 2 doses—separated by 21 days—of 10 μg, 30 μg or 100 μg of BNT162b1. BNT162b1 is a lipid-nanoparticle-formulated, nucleoside-modified mRNA vaccine that encodes the trimerized receptor-binding domain (RBD) of the spike glycoprotein of SARS-CoV-2. Local reactions and systemic events were dose-dependent, generally mild to moderate, and transient. A second vaccination with 100 μg was not administered because of the increased reactogenicity and a lack of meaningfully increased immunogenicity after a single dose compared with the 30-μg dose. RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titres in sera increased with dose level and after a second dose. Geometric mean neutralizing titres reached 1.9–4.6-fold that of a panel of COVID-19 convalescent human sera, which were obtained at least 14 days after a positive SARS-CoV-2 PCR. These results support further evaluation of this mRNA vaccine candidate.
In December 2019, a pneumonia outbreak of unknown cause occurred
in Wuhan, China. By January 2020, a new coronavirus was identified as
the aetiological agent. Within a month, the genetic sequence of the virus
became available (MN908947.3). Infections with SARS-CoV-2 and the
resulting disease, COVID-19, have spread globally. On 11 March 2020, the
WHO declared the COVID-19 outbreak a pandemic1. So far, the United
States has reported the highest number of cases globally2,3. No vaccines
are currently available to prevent SARS-CoV-2 infection or COVID-19.
The RNA vaccine platform has enabled rapid vaccine development
in response to this pandemic. RNA vaccines provide flexibility in the
design and expression of vaccine antigens that can mimic the structure
and expression of the antigen during natural infection. RNA is required
for protein synthesis, does not integrate into the genome, is transiently
expressed, is metabolized and eliminated by the natural mechanisms of
the body and is therefore considered safe4–7. RNA-based prophylactic
infectious-disease vaccines and RNA therapeutic agents have been
shown to be safe and well-tolerated in clinical trials. In general, vaccina -
tion with RNA elicits a robust innate immune response. RNA directs the expression of the vaccine antigen in host cells and has intrinsic adjuvant
effects8. A strength of the RNA-vaccine manufacturing platform—
irrespective of the encoded pathogen antigen—is the ability to rapidly
produce large quantities of vaccine doses against a new pathogen9,10.
Vaccine RNA can be modified by incorporating 1-methyl-
pseudouridine, which dampens innate immune sensing and increases
mRNA translation in vivo11. The BNT162b1 vaccine candidate that is cur -
rently investigated clinically incorporates such nucleoside-modified
mRNA and encodes the RBD of the spike protein of SARS-CoV-2, a key
target of virus-neutralizing antibodies12–14. The RBD antigen expressed
by BNT162b1 is modified by the addition of a T4 fibritin-derived foldon
trimerization domain to increase its immunogenicity15 by multivalent
display16. The proper folding of the RBDs in the resulting protein con-
struct has been confirmed by high resolution structural analysis (A.B.V.
et al., manuscript in preparation). The vaccine RNA is formulated in lipid
nanoparticles for more-efficient delivery into cells after intramuscular
injection17. BNT162b1 is one of several RNA-based SARS-CoV-2 vac -
cine candidates18 that are studied in parallel for selection to advance https://doi.org/10.1038/s41586-020-2639-4
Received: 29 June 2020Accepted: 4 August 2020Published online: 12 August 2020
Check for updates
1New York University Langone Vaccine Center, New York, NY, USA. 2New York University Grossman School of Medicine, New York, NY, USA. 3University of Maryland School of Medicine, Center
for Vaccine Development and Global Health, Baltimore, MD, USA. 4Vaccine Research and Development, Pfizer Inc, Hurley, UK. 5Vaccine Research and Development, Pfizer Inc, Pearl River, NY,
USA. 6Vaccine Research and Development, Pfizer Inc, Collegeville, PA, USA. 7University of Texas Medical Branch, Galveston, TX, USA. 8BioNTech, Mainz, Germany. 9University of Rochester,
Rochester, NY, USA. 10Rochester General Hospital, Rochester, NY, USA. 11Cincinnati Children’s Hospital, Cincinnati, OH, USA. 12These authors contributed equally: Mark J. Mulligan,
Kirsten E. Lyke, Nicholas Kitchin ✉e-mail: judith [email protected]
Page 2
FDA-CBER-2022-5812-0228130
590 | Nature | Vol 586 | 22 October 2020
Articleto a safety and efficacy trial. Here, we present the available data, up
to 14 days after a second dose in adults (18–55 years of age) from an
ongoing phase I/II vaccine study with BNT162b1, which is also enroll -
ing adults who are 65–85 years of age (ClinicalTrials.gov identifier,
NCT04368728).
Study design and demographics
Between 4 May 2020 and 19 June 2020, 76 participants were screened,
and 45 participants were randomized and vaccinated. Per dose level
(10 μg and 30 μg), 12 participants were vaccinated with BNT162b1
on days 1 and 21, 12 participants received a 100-μg dose on day 1 and
9 participants received placebo (Fig. 1). The study population consisted
of healthy male and female participants with a mean age of 35.4 years
(range, 19–54 years); 51.1% were male and 48.9% were female. Most
participants self-reported as white (82.2%) and non-Hispanic/
non-Latinx (93.3%) (Extended Data Table 1).
Safety and tolerability
In the 7 days after vaccination doses 1 and 2, pain at the injection site was
the most-frequent solicited local reaction, reported after the first dose
by 58.3% (7 out of 12) in the 10-μg BNT162b1 group, 100.0% (12 out of 12
each) in the 30-μg and 100-μg BNT162b1 groups, and 22.2% (2 out of 9)
in the placebo group. After the second dose, pain was reported by 83.3%
(10 out of 12) and 100.0% of individuals who received 10 μg and 30 μg
BNT162b1, respectively, and by 16.7% of individuals who received the
placebo. All local reactions were mild or moderate in severity except for
one report of severe pain after the first dose of 100 μg BNT162b1 (Fig. 2).
The most-common systemic events reported in the 7 days after each
vaccination in both BNT162b1 and placebo groups were mild to moder -
ate fatigue and headache. Reports of fatigue and headache were more
common in the BNT162b1 groups than in the placebo group. In addition,
chills, muscle pain and joint pain were reported by individuals who
received BNT162b1 but not by individuals who received the placebo.
Systemic events increased with dose level and were reported in a greater
number of participants after the second dose (10-μg and 30-μg groups).
After the first dose, fever (defined as ≥38.0 °C) was reported by 8.3%
(1 out of 12) of participants who received 10 μg and 30 μg BNT162b1 and
by 50.0% (6 out of 12) of individuals who received 100 μg BNT162b1.
After the second dose, 8.3% (1 out of 12) of participants who received
10 μg BNT162b1 and 75.0% (9 out of 12) of participants who received
30 μg BNT162b1 reported fever of ≥38.0 °C. On the basis of the reacto -
genicity reported after the first dose of 100 μg and the second dose of 30 μg, participants who received an initial 100-μg dose did not receive
a second 100-μg dose. Fevers generally resolved within 1 day of onset.
No grade 4 systemic events or fever were reported (Fig. 3a, b ). Most
local reactions and systemic events peaked by day 2 after vaccination and resolved by day 7.
Adverse events (Extended Data Table 2) were reported by 50.0%
(6 out of 12) of participants who received either 10 or 30 μg of BNT162b1,
58.3% (7 out of 12) of participants who received 100 μg of BNT162b1,
and 11.1% (1 out of 9) of placebo recipients. Two participants reported
a severe adverse event: grade 3 fever 2 days after vaccination in the
30-μg group, and sleep disturbance 1 day after vaccination in the
100-μg group. Related adverse events were reported by 25% (3 out of
12 in the 10-μg group) to 50% (6 out of 12 each in the 30-μg and 100-μg
groups) of individuals who received BNT162b1 and by 11.1% (1 out of 9)
of participants who received the placebo. No serious adverse events
were reported.
No grade 1 or greater change in routine clinical laboratory values or
laboratory abnormalities were observed for most participants after
either of the BNT162b1 vaccinations. Of those with laboratory changes,
the largest changes were decreases in the lymphocyte count after the
first dose in 8.3% (1 out of 12), 45.5% (5 out of 11) and 50.0% (6 out of
12) of participants who received 10 μg, 30 μg and 100 μg BNT162b1,
respectively. One participant each in the 10-μg (8.3% (1 out of 12)) and
30-μg (9.1% (1 out of 11)) groups and 4 participants in the 100-μg group
(33.3% (4 out of 12)) had grade 3 decreases in the lymphocyte count.
These decreases in lymphocyte count after the first dose were transient
and returned to normal 6–8 days after vaccination (Extended Data
Fig. 1). In addition, grade-2 neutropenia was noted 6–8 days after the
second dose in 1 participant each in the 10-μg and 30-μg BNT162b1
groups. These two participants continue to be followed in the study,
and no adverse events or clinical manifestations of neutropenia have
been reported to date. None of the post-vaccination abnormalities
observed were associated with clinical findings.
Immunogenicity
RBD-binding IgG concentrations and SARS-CoV-2-neutralizing titres
were assessed at baseline, at 7 and 21 days after the first dose, at 7 days
(day 28) and 14 days (day 35) after the second dose of BNT162b1. By
21 days after the first dose (for all three dose levels), geometric mean
concentrations (GMCs) of RBD-binding IgG ranged from 534 to
1,778 U ml−1 (Fig. 4a). In comparison, a panel of 38 SARS-CoV-2 infec -
tion and/or COVID-19 convalescent sera drawn at least 14 days after a
PCR-confirmed diagnosis from patients with COVID-19 (18–83 years 76 participants screened
20 participants were
not assigned11 participants did not
meet eligibility criteria
45 participants were
enrolled and randomized
12 were assigned to
10 /uni03BCg BNT162b13 were assigned
to placebo
12 (100.0%)
vaccinated with dose 1
12 (100.0%)
vaccinated with dose 23 (100.0%)
vaccinated with dose 1
3 (100.0%)
vaccinated with dose 2Study ongoing
No withdrawals12 were assigned to
30 /uni03BCg BNT162b13 were assigned
to placebo
12 (100.0%)
vaccinated with dose 1
12 (100.0%)
vaccinated with dose 23 (100.0%)
vaccinated with dose 1
3 (100.0%)
vaccinated with dose 2Study ongoing
No withdrawals12 were assigned to
100 /uni03BCg BNT162b13 were assigned
to placebo
12 (100.0%)
vaccinated with dose 1
0 vaccinated
with dose 23 (100.0%)
vaccinated with dose 1
0 vaccinated
with dose 2Study ongoing
No withdrawals
Fig. 1 | Study design. Participants who were not assigned ( n = 20) were screened but not randomized because enrolment had closed.
Page 3
FDA-CBER-2022-5812-0228131
Nature | Vol 586 | 22 October 2020 | 5910102030405060708090100
Swelling Redness PainParticipants (%)Mild
Moderate
Severe
Grade 4
10 /uni03BCg
dose 110 /uni03BCg
dose 230 /uni03BCg
dose 130 /uni03BCg
dose 2100 /uni03BCg
dose 1Placebo
any dose10 /uni03BCg
dose 110 /uni03BCg
dose 230 /uni03BCg
dose 130 /uni03BCg
dose 2100 /uni03BCg
dose 1Placebo
any dose10 /uni03BCg
dose 110 /uni03BCg
dose 230 /uni03BCg
dose 130 /uni03BCg
dose 2100 /uni03BCg
dose 1Placebo
any dose
Fig. 2 | Local reactions reported within 7 days of vaccination for all dose
levels. Solicited injection-site (local) reactions were: pain at injection site
(mild, does not interfere with activity; moderate, interferes with activity; severe, prevents daily activity; grade 4, emergency room visit or hospitalization) and redness and swelling (mild, 2.0–5.0 cm in diameter; moderate, >5.0–10.0 cm in diameter; severe, >10.0 cm in diameter; grade 4: necrosis or exfoliative dermatitis for redness, and necrosis for swelling). Data were collected with the use of electronic diaries for 7 days after each vaccination.10 /uni03BCg
30 /uni03BCg
100 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
100 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
100 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
100 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
100 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
100 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
100 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
100 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
100 /uni03BCg
Placebo10 /uni03BCg
30 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
Placebo
10 /uni03BCg
30 /uni03BCg
PlaceboMuscle pain Joint pain Medication Chills Vomiting Diarrhoea Headache Fever Fatigue
Muscle pain Joint pain Medication Chills Vomiting Diarrhoea Headache Fever Fatigue0102030405060708090100 Participants (%)
0102030405060708090100 Participants (%)Mild
Moderate
Severe
Grade 4Mild
Moderate
Severe
Grade 4a
b
Fig. 3 | Systemic events and medication use reported within 7 days after
vaccination. a, Systemic events and medication use reported within 7 days
after vaccination 1 for all dose levels. b , Systemic events and medication use
reported within 7 days after vaccination 2 for the 10-μg and 30-μg dose levels. Solicited systemic events were: fatigue, headache, chills, new or worsened muscle pain, new or worsened joint pain (mild, does not interfere with activity; moderate, some interference with activity; severe, prevents daily activity), vomiting (mild, 1–2 times in 24 h; moderate, >2 times in 24 h; severe, requires intravenous hydration), diarrhoea (mild, 2–3 loose stools in 24 h; moderate, 4–5 loose stools in 24 h; severe: 6 or more loose stools in 24 h); grade 4 for all events: emergency room visit or hospitalization; and fever (mild, 38.0–38.4 °C; moderate, 38.5–38.9 °C; severe, 39.0–40.0 °C; grade 4, >40.0 °C). Medication indicates the proportion of participants who reported the use of antipyretic or pain medication. Data were collected with the use of electronic diaries for 7 days after each vaccination.
Page 4
FDA-CBER-2022-5812-0228132
592 | Nature | Vol 586 | 22 October 2020
Articleof age) had an RBD-binding IgG GMC of 602 U ml−1. (Additional infor-
mation on the convalescent serum panel is included in the Methods.)
By 7 days after the second dose (for the 10-μg and 30-μg dose levels),
RBD-binding IgG GMCs had increased to 4,813 and to 27,872 U ml−1,
respectively. RBD-binding antibody concentrations among participants
who received one dose of 100 μg BNT162b1 did not increase further
at 21 days after the first vaccination. In the participants who received the 10-μg and 30-μg doses of BNT162b1, highly elevated RBD-binding
antibody concentrations persisted to the last time point evaluated
(day 35, 14 days after the second dose). These RBD-binding antibody
concentrations were 5,880–16,166 U ml−1 compared to 602 U ml−1 in
the panel of human convalescent sera.
For all doses, small increases in SARS-CoV-2-neutralizing geometric
mean titres (GMTs) were observed 21 days after the first dose (Fig. 4b).
Substantially greater serum neutralizing GMTs were achieved 7 days
after the second 10-μg and 30-μg dose, reaching 168–267. Neutralizing
GMTs further increased by 14 days after the second dose to 180 (10-μg
dose level) and 437 (30-μg dose level), compared to 94 for the panel of
human convalescent sera. The kinetics and durability of the neutral -
izing titres are being monitored.Discussion
The RNA-based SARS-CoV-2 vaccine candidate BNT162b1, which
was administered as 10-μg, 30-μg or 100-μg doses in healthy adults
(18–55 years of age), exhibited a tolerability and safety profile consist -
ent with those previously observed for mRNA-based vaccines5. A clear
dose-level response in elicited neutralizing titres was observed after
doses 1 and 2 in participants with a particularly steep dose response
between the 10 μg and 30 μg dose levels.
On the basis of the tolerability profile of the first dose at 100 μg and the
second dose at 30 μg, participants randomized to the 100-μg group did
not receive a second vaccination. Reactogenicity was generally greater
after the second dose in the other two dosing levels; however, symptoms
were transient and resolved within a few days. Transient decreases in
lymphocyte counts (grades 1–3) were observed within a few days after
vaccination, and returned to baseline within 6–8 days in all participants.
These laboratory abnormalities were not associated with clinical find -
ings. RNA vaccines are known to induce type-I interferon, which has been
associated with transient migration of lymphocytes into tissues19–22.
Robust immunogenicity was observed after vaccination with BNT162b1.
RBD-binding IgG concentrations were detected at 21 days after the first
dose, and these were substantially increased 7 days after the second dose
given at day 21. After the first dose, the RBD-binding IgG GMCs (10-μg
dose) were similar to those observed in a panel of 38 convalescent human
serum samples, obtained at least 14 days after a PCR-confirmed diagnosis
of SARS-CoV-2 infection and/or COVID-19. After the first dose, GMCs were
similar in the 30-μg and 100-μg groups and higher than those in the panel
of human convalescent sera. After the second dose, with 10 μg or 30 μg BNT162b1, the RBD-binding IgG GMCs were around 8.0–50-fold that of the GMC of the convalescent serum panel.
The higher RBD-binding IgG GMC elicited by the vaccine relative to
the GMC of the human convalescent serum panel may be attributed,
in part, to antibodies that bind to epitopes that are exposed on the
RNA-expressed RBD immunogen and the recombinant RBD target anti -
gen of the binding assay but are buried and inaccessible to antibodies
on the RBDs that are incorporated into the spikes of SARS-CoV-2 virions.
Neutralization provides a measure of the vaccine-elicited antibody
response that is more relevant to potential protection. Neutralization
titres were measurable after a single vaccination at day 21 for all dose
levels. At day 28 (7 days after the second dose), substantial SARS-CoV-2
neutralization titres were observed. The virus-neutralizing GMTs after
the second dose of 10 μg and 30 μg were, respectively, 1.8-fold and
2.8-fold the GMT of the convalescent serum panel. By day 35 (14 days
after the second dose)—despite a decrease in RBD-binding IgG titres
since day 28—neutralizing GMTs continued to increase, to 1.9-fold and
4.6-fold the GMT of the convalescent panel for the 10 μg and 30 μg
doses, respectively, which is consistent with affinity maturation.
Assuming that the neutralization titres that are induced by
natural infection provide protection from COVID-19, comparing
vaccine-induced SARS-CoV-2 neutralization titres to those from sera
of convalescent humans provides a benchmark for the magnitude of
the vaccine-elicited response and the potential of the vaccine to provide
protection. Because the titre at which human neutralizing antibodies
are protective remains unknown, these findings are not proof of vaccine
efficacy. Efficacy will be determined in a pivotal phase III trial. Because
the cohort that received the 100 μg dose level did not receive the booster
dose, no data for immunogenicity after a second vaccination at this dose
level are available; however, there were no substantial differences in
immunogenicity between the 30-μg and 100-μg dose levels after the first
dose. This observation suggests that a well-tolerated and immunogenic
dose level may be between 10 μg and 30 μg for this vaccine candidate.
Our study had several limitations. Although we used convalescent
sera as a comparator, the kind of immunity (T cells versus B cells or
both) and level of immunity needed to protect from COVID-19 are
unknown. Furthermore, this analysis of available data did not assess P1 72 128352 12835 17 21 28 HCS 17
P1 72 128351 72 128351 72 1 HCSTime (day)0.80.91,778
0.80.91.2
0.95344,813
5,880
1,53627,872
16,166
1,260602RBD-binding IgG (U ml–1)
0.9
10180437
Time (day)10 10 10 1010 1013168267
3394
2950% serum neutralizing titre105
104
103
102
101
103
102
101100Placeb o
10 /uni03BCg
30 /uni03BCg
100 /uni03BCg
HCS
Placeb o
10 /uni03BCg
30 /uni03BCg
100 /uni03BCg
HCS
Fig. 4 | Immunogenicity of BNT162b1. Participants in groups of 15 were
vaccinated with the indicated dose levels of BNT162b1 ( n = 12) or with placebo
(n = 3) on days 1 (all dose levels and placebo) and 21 (10-μg and 30-μg dose levels
and placebo). Reponses in individuals who received the placebo for each of the dosing groups are combined. The 28- and 35-day blood samples were obtained 7 and 14 days after the second vaccination. Sera were obtained before vaccination (day 1), and 7, 21, 28 and 35 days after the first vaccination. Human COVID-19 convalescent sera (HCS, n = 38) were obtained at least 14 days after PCR-confirmed diagnosis and at a time when the donors were asymptomatic. a, GMCs of recombinant RBD-binding IgG. Because the measured antibody
concentrations using the Luminex assay are obtained in arbitrary units, they cannot be directly translated into concentrations on a molar or mass basis. The lower limit of quantitation is 1.15. b , The 50% SARS-CoV-2-neutralizing GMTs.
Each data point represents a serum sample, and each vertical bar represents a geometric mean with 95% confidence interval. The number above the bars are either the GMC ( a) or GMT ( b) for the group. Arrows indicate the timing of
vaccination (blood was obtained before vaccination on the vaccination days).
Page 5
FDA-CBER-2022-5812-0228133
Nature | Vol 586 | 22 October 2020 | 593immune responses or safety beyond 2 weeks after the second dose
of vaccine. Both are important to inform the public health use of this
vaccine. Follow-up will continue for all participants and will include
collection of serious adverse events for 6 months and COVID-19 infec -
tion and multiple additional immunogenicity measurements for up
to 2 years. Although our population of healthy adults up to 55 years of
age is appropriate for a phase I/II study, it does not accurately reflect
the population at highest risk for COVID-19. Adults who are 65 years of
age and over have already been enrolled in this study and results will
be reported as they become available. Later phases of this study will
prioritize enrolment of more diverse populations, including those
with chronic underlying health conditions and from racial and ethnic
groups that are adversely affected by COVID-1923.
The clinical testing of BNT162b1 described here has taken place in
the context of a broader, ongoing COVID-19-vaccine-development
program. That program includes the clinical testing of three additional
vaccine candidates, including candidates that encode the full-length
spike protein, and a parallel trial in Germany, in which additional
immune responses, including neutralizing responses against variant
strains and cell-mediated responses, are being assessed24. The resulting
comparative data will allow us to address whether a full-length spike
immunogen, which presents additional epitopes, is better able to elicit
high virus-neutralizing titres that are robust to potential antigenic drift
of SARS-CoV-2 than the relatively small RBD immunogen that is encoded
by BNT162b1. The clinical findings for the BNT162b1 RNA-based vaccine
candidate are encouraging and strongly support accelerated clinical
development, including efficacy testing, and at-risk manufacturing to
maximize the opportunity for the rapid production of a SARS-CoV-2
vaccine to prevent COVID-19.
Online content
Any methods, additional references, Nature Research reporting sum-
maries, source data, extended data, supplementary information,
acknowledgements, peer review information; details of author con -
tributions and competing interests; and statements of data and code
availability are available at https://doi.org/10.1038/s41586-020-2639-4 .
1. World Health Organization. WHO Director-General’s Opening Remarks at the Media
Briefing on COVID-19. https://www.
who.int/dg/speeches/detail/who-director-general-s-
opening-remarks-at-the-media-briefing-on-covid-19---7-september-2020 (2020).
2. Coronavirus Resource Center. COVID-19 Da
shboard by the Center for Systems Science
and Engineering (CSSE) at Johns Hopkins University (JHU). https://coronavirus.jhu.edu/
map.html (Johns Hopkins University & Medicine, 2020).3. World Health Organization. Coronavirus Disease 201
9 (COVID-19) Situation Report 154.
https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200622-
covid-19-sitrep-154.pdf?sfvrsn=d0249d8d_2 (2020).
4. Alberer, M. et al. Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, pr
ospective, first-in-human phase 1 clinical trial. Lancet
390, 1511–1520 (2017).
5. Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well toler
ated in healthy adults in phase
1 randomized clinical trials. Vaccine 37, 3326–3334 (2019).
6. Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunother
apy. Nature 534, 396–401 (2016).
7. Şahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic
immunity against cancer. Nature 547, 222–226 (2017).
8. Petsch, B. et al. Protective efficacy of in vitro synthesized, specific mRNA vaccine
s against
influenza A virus infection. Nat. Biotechnol. 30, 1210–1216 (2012).
9. Rauch, S., Jasny, E., Schmidt, K. E. & Petsch, B. New vaccine technologies to combat outbre
ak situations. Front. Immunol. 9, 1963 (2018).
10. Şahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics—developing a new class of
drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014).
11. Karikó, K. et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability.
Mol. Ther. 16, 1833–1840 (2008).
12. He, Y. et al. Receptor-binding domain of SARS-CoV spike protein induces highly potent neutr
alizing antibodies: implication for developing subunit vaccine. Biochem. Biophys.
Res. Commun. 324, 773–781 (2004).
13. Zost, S. J. et al. Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the S
ARS-CoV-2 spike protein. Nat. Med. 26,
1422–1427 (2020).
14. Brouwer, P. J. M. et al. Potent neutralizing antibodies from COVID-
19 patients define
multiple targets of vulnerability. Science 369, 643–650 (2020).
15. Güthe, S. et al. Very fast folding and association of a trimerization domain from bacteriophage T4 fibritin. J
. Mol. Biol. 337, 905–915 (2004).
16. Bachmann, M. F. & Zinkernagel, R. M. Neutralizing antiviral B cell responses. Annu. Re
v.
Immunol. 15, 235–270 (1997).
17. Pardi, N. et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice b
y various routes. J. Control. Release 217, 345–351 (2015).
18. Walsh, E. E. RNA-based COVID-19 vaccine BNT162b2 selected for a pivotal efficac
y study.
Preprint at https://doi.org/10.1101/2020.08.17.20176651 (2020).
19. Foster, G. R. et al. IFN-α subtypes differentially affect human T cell motility.
J. Immunol.
173, 1663–1670 (2004).
20. Hopkins, R. J. et al. Randomized, double-blind, placebo-controlled, safety and immunogenicity study of 4 formulations of Anthrax Vaccine Adsorbed plus CPG 7
909
(AV7909) in healthy adult volunteers. Vaccine 31, 3051–3058 (2013).
21. Regules, J. A. et al. A recombinant vesicular stomatitis virus Ebola vaccine. N. Engl
. J.
Med. 376, 330–341 (2017).
22. Lai, L. et al. Emergency postexposure vaccination with vesicular stomatitis virus-vector
ed
Ebola vaccine after needlestick. J. Am. Med. Assoc. 313, 1249–1255 (2015).
23. Stokes, E. K. et al. Coronavirus disease 2019 case surveillance — U
nited States, January
22–May 30, 2020. MMWR Morb. Mortal. Wkly. Rep. 69, 759–765 (2020).
24. Şahin, U. et al. Concurrent human antibody and TH1 type T-cell responses elicited by
a COVID-19 RNA vaccine. Preprint at https://doi.org/10.1101/2020.07.17.20140533 (2020).
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
© The Author(s), under exclusive licence to Springer Nature Limited 2020
Page 6
FDA-CBER-2022-5812-0228134
ArticleMethods
Study design
This study was conducted in healthy men and women (who were not
pregnant) who were 18–55 years of age to assess the safety, tolerability
and immunogenicity of ascending dose levels of various BNT162 mRNA
vaccine candidates. In the part of the study reported here, assessment
of three dose levels (10 μg, 30 μg or 100 μg) of the BNT162b1 candidate
was conducted at two sites in the USA. This study used a sentinel cohort
design with progression and dose escalation taking place after review
of data from the sentinel cohort at each dose level. The study is regis-
tered at ClinicalTrials.gov (NCT04368728). The phase I portion of this
study was observer-blinded at the site level. Investigators were blinded
to participant-level study intervention assignment; but investigators
were not blinded to group-level assignment for the dataset included
in this Article.
Eligibility
Key exclusion criteria included individuals with known infection with
human immunodeficiency virus, hepatitis C virus or hepatitis B virus;
immunocompromised individuals and those with a history of auto -
immune disease; and those with increased risk for severe COVID-19,
previous clinical or microbiological diagnosis of COVID-19, receipt of
medications intended to prevent COVID-19, previous vaccination with
any coronavirus vaccine, a positive serological test for SARS-CoV-2
IgM and/or IgG at the screening visit, and a SARS-CoV-2 nucleic acid
amplification test-positive nasal swab within 24 h before study
vaccination.
The final protocol and informed consent document were approved by
institutional review boards for each of the participating investigational
centres. This study was conducted in compliance with all International
Council for Harmonisation good clinical practice guidelines and the
ethical principles of the Declaration of Helsinki. A signed and dated
informed consent form was required before any study-specific activity
was performed.
End points
In this report, results from the following study primary end points are
presented: the proportion of participants who reported solicited local
reactions, systemic events and use of antipyretic and/or pain medica-
tion within 7 days after vaccination, adverse events and serious adverse
events (available up to around 45 days after dose 1), and the proportion
of participants with clinical laboratory abnormalities 1 and 7 days after
vaccination and grading shifts in laboratory assessments between
baseline and 1 and 7 days after dose 1, and between dose 2 and 7 days
after dose 2. Secondary end points included: SARS-CoV-2-neutralizing
GMTs and SARS-CoV-2 RBD-binding IgG GMCs 7 and 21 days after dose
1, and 7 and 14 days after dose 2.
Procedures
Study participants were randomly assigned to a vaccine group using
an interactive web-based response technology system with each group
comprising 15 participants (12 active vaccine recipients and 3 placebo
recipients). Participants received two 0.5-ml doses of either BNT162b1
or placebo, administered by intramuscular injection into the deltoid
muscle.
BNT162b1 incorporates a good manufacturing practice-grade
mRNA drug substance that encodes the trimerized SARS-CoV-2 spike
glycoprotein RBD antigen. The coding sequence for the antigen has
been deposited with GenBank (accession number, MN908947.3). The
mRNA is formulated with lipids as the mRNA–lipid nanoparticle drug
product. The vaccine was supplied as a buffered-liquid solution for
intramuscular injection and was stored at −80 °C. The placebo was a
sterile saline solution for injection (0.9% sodium chloride injection,
in a 0.5-ml dose).Safety assessments
Safety assessments included a 4-h observation after vaccination (for
the first 5 participants vaccinated in each group), or a 30-min observa -
tion (for the remainder of participants) for immediate adverse events.
The safety assessments also included self-reporting of solicited local
reactions (redness, swelling and pain at the injection site), systemic
events (fever, fatigue, headache, chills, vomiting, diarrhoea, muscle
pain and joint pain), the use of antipyretic and/or pain medication in
an electronic diary for 7 days after vaccination, and the reporting of
unsolicited adverse events and serious adverse events after vaccination.
Haematology and chemistry assessments were conducted at screen-
ing, 1 and 7 days after the first dose, and 7 days after the second dose.
There were protocol-specified safety stopping rules for all sentinel
cohort participants. Both an internal review committee and an external
data monitoring committee reviewed all safety data. No stopping rules
were met before the publication of this report.
Human convalescent serum panel
The 38 human SARS-CoV-2 infection and/or COVID-19 convalescent
sera were drawn from participants, who were 18–83 years of age, at least
14 days after PCR-confirmed diagnosis, and at a time when participants
were asymptomatic. The mean age of the donors was 45 years of age.
Neutralizing GMTs in subgroups of the donors were as follows: ≤55 years
of age, 82 (n = 29); >55 years of age, 142 (n = 9); symptomatic infections,
90 ( n = 35); asymptomatic infections, 156 (n = 3). The antibody titre for
the one individual who was hospitalized was 618. The sera were obtained
from Sanguine Biosciences, the MT Group and Pfizer Occupational
Health and Wellness.
Immunogenicity assessments
For immunogenicity assessments, 50 ml of blood was collected before
each study vaccination, at 7 and 21 days after the first dose, and at 7 and
14 days after the second dose. In the RBD-binding IgG assay, a recombi -
nant SARS-CoV-2 RBD containing a C-terminal Avitag (Acro Biosystems,
SPD-C82E9) and no foldon domain was bound to streptavidin-coated
Luminex microspheres. In brief, 1.25 × 107 microspheres/ml were coated
with streptavidin by 1-ethyl-3-[3-dimethylaminopropyl] carbodiim -
ide hydrochloride reaction. Recombinant RBD Avitag was coupled
to streptavidin beads by incubating for 90 min at room temperature
with shaking (35 rpm). Beads were blocked in 1% BSA buffer for 30 min
at room temperature. Heat-inactivated serum from participants was
diluted 1:500, 1:5,000 and 1:50,000 in assay buffer (PBS with 0.5% BSA,
0.05% Tween-20 and 0.02% sodium azide). Following a 16–20-h incuba -
tion at 2–8 °C with shaking (300 rpm), plates were washed three times in
a solution containing 0.05% Tween-20. An R-phycoerythrin-conjugated
goat anti-human polyclonal antibody ( Jackson Labs) was then added to
plates for 90 min at room temperature with shaking (300 RPM). Plates
were then washed a final time in a solution containing 0.05% Tween-20.
Data were captured as median fluorescent intensities using a Luminex
reader and converted to U/ml antibody concentrations using a refer-
ence standard curve with arbitrary assigned concentrations of 100 U/
ml and accounting for the serum dilution factor. The reference standard
was composed of a pool of five COVID-19 convalescent serum samples
(>14 days after PCR diagnosis). Three dilutions are used to increase
the likelihood that at least one result for any sample will fall within the
usable range of the standard curve. Assay results were reported in U/
ml of IgG. The final assay results are expressed as the GMC of all sample
dilutions that produced a valid assay result within the assay range.
The SARS-CoV-2 neutralization assay used a previously described
strain of SARS-CoV-2 (USA_WA1/2020) that had been rescued by
reverse genetics and engineered by the insertion of an mNeonGreen
gene into open-reading frame 7 of the viral genome25. This reporter
virus generates similar plaque morphologies and indistinguishable
growth curves from the wild-type virus. Viral master stocks (2 × 107
Page 7
FDA-CBER-2022-5812-0228135
plaque-forming units per ml) used for the neutralization assay were
grown in Vero E6 cells as previously described25. When testing patient
convalescent serum specimens, the fluorescent neutralization assay
produced comparable results as the conventional plaque reduction
neutralization assay26. In brief, serial dilutions of heat-inactivated sera
from participants were incubated with the reporter virus to yield an
infection rate of approximately 10–30% of the Vero monolayer) for
1 h at 37 °C before inoculating Vero CCL81 cell monolayers (targeted
to have 8,000–15,000 cells per well) in 96-well plates to enable the
accurate quantification of infected cells. Total cell counts per well were
enumerated by nuclear stain (Hoechst 33342) and fluorescent virally
infected foci were detected 16–24 h after inoculation with a Cytation
7 Cell Imaging Multi-Mode Reader (BioTek) with Gen5 Image Prime
v.3.09. Titres were calculated in GraphPad Prism v.8.4.2 by generating
a four-parameter logistical fit of the percentage neutralization at each
serial serum dilution. The 50% neutralization titre was reported as the
interpolated reciprocal of the dilution that yielded a 50% reduction in
fluorescent viral foci.
Statistical analysis
The sample size for the reported part of the study was not based on
statistical hypothesis testing. The primary safety objective was evalu -
ated by descriptive summary statistics for local reactions, systemic
events, abnormal haematology and chemistry laboratory parameters,
adverse events and serious adverse events after each vaccine dose for
each vaccine group. The secondary immunogenicity objectives were descriptively summarized at the various time points. All participants
with data available were included in the safety and immunogenicity
analyses.
Reporting summary
Further information on research design is available in the Nature
Research Reporting Summary linked to this paper.
Data availability
Upon request, and subject to review, Pfizer will provide the data that
support the findings of this study. Subject to certain criteria, conditions
and exceptions, Pfizer may also provide access to the related individual
anonymized participant data. See https://www.pfizer.com/science/
clinical-trials/trial-data-and-results for more information. These data are interim data from an ongoing study for which the database is not
locked. Data have not yet been source-verified or subjected to standard
quality check procedures that would occur at the time of database lock
and may therefore be subject to change.
25. Xie, X. et al. An infectious cDNA clone of SARS-CoV-2. Cell Host Microbe 27, 841–848
(2020).
26. Muruato, A. E. et al. A high-throughput neutralizing antibody assay for COVID-1
9
diagnosis and vaccine evaluation. Nat. Commun. 11, 4059 (2020).
Acknowledgements We thank C. Monahan and D. Gantt for writing and editorial support;
H. Ma, J. Trammel and K. Challagali for statistical analysis support in the generation of this
manuscript; all of the participants who volunteered for this study; A. Kottkamp, R. Herati,
R. Pellet Madan, M. Olson, M. Samanovic-Golden, E. Cohen, A. Cornelius, L. Frye, H. Youn,
B. Fran, K. Ballani, N. Veling, J. Erb, M. Ali, L. Zhao, S. Rettig, H. Khan, H. Lambert, K. Hu, J. Hyde, M. McArthur, J. Ortiz, R. Rapaka, L. Wadsworth, G. Cummings, T. Robinson, N. Greenberg,
L. Chrisley, W. Somrajit, J. Marron, C. Thomas, K. Brooks, L. Turek, P. Farley, S. Eddington,
P. Komninou, M. Reymann, K. Strauss, B. Shrestha, S. Joshi, R. Barnes, R. Sukhavasi, M. Lee,
A. Kwon, T. Sharp, E. Pierce, M. Criddle, A. Cline, S. Parker, M. Dickey, K. Buschle, A. Cawein,
J. L. Perez, H. Seehra, D. Tresnan, R. Maroko, H. Smith, S. Tweedy, A. Jones, G. Adams, R. Malick, E. Worobetz, E. Weaver, L. Zhang, C. Devlin, D. Boyce, E. Harkins Tull, M. Boaz, M. Cruz,
C. Rosenbaum, C. Miculka, A. Kuhn, F. Bates, P. Strecker, A. Kemmer-Brück, and the Vaccines Clinical Assay Team and Vaccines Assay Development Team for their assistance during this study. Staffing services were supported in part by an NYU CTSA grant (UL1 TR001445) from the National Center for Advancing Translational Sciences, National Institutes of Health. BioNTech is the sponsor of the study. Pfizer was responsible for the design, data collection, data analysis, data interpretation and writing of the report. The corresponding authors had full access to all of the data in the study and had final responsibility for the decision to submit the data for publication. All study data were available to all authors.
Author contributions K.U.J., P.R.D., W.C.G., N.K., S.L., A.G., R.B., O.T. and U.Ş. were involved in
the design of the overall study and strategy. K.N., M.J.M., E.E.W., R.F. and A.R.F. provided feedback on the study design. W.K., D.C., K.A.S., K.R.T., C.F.-G. and P.-Y.S. performed the immunological analyses. M.J.M., K.N., E.E.W., R.F., A.R.F., K.E.L. and V.R. collected data as study investigators. P.L. and K.K. developed the statistical design and oversaw the data analysis. J.A., K.U.J., P.R.D. and W.C.G. drafted the initial version of the manuscript. All authors reviewed and edited the manuscript and approved the final version.
Competing interests N.K., J.A., A.G., S.L., R.B., K.A.S., P.L., K.K., W.K., D.C., K.R.T., P.R.D., W.C.G.
and K.U.J. are employees of Pfizer and may hold stock options. U.Ş. and Ö.T. are stock owners, management board members and employees at BioNTech and are inventors on patents and patent applications related to RNA technology. M.J.M., K.E.L., K.N., E.E.W., A.R.F., R.F. and V.R. received compensation from Pfizer for their role as study investigators. C.F.-G. and P.-Y.S. received compensation from Pfizer to perform the neutralization assay.
Additional information
Supplementary information is available for this paper at https://doi.org/10.1038/s41586-020-2639-4 .
Correspondence and requests for materials should be addressed to J.A.Peer review information Nature thanks Barbra Richardson and the other, anonymous,
reviewer(s) for their contribution to the peer review of this work.Reprints and permissions information is available at http://www.nature.com/reprints.
Page 8
FDA-CBER-2022-5812-0228136
Article
Extended Data Fig. 1 | Post vaccination changes in lymphocyte count over
time. The following time points are shown: dose 1/day 1–3, around 1 day after
dose 1; dose 1/day 6–8, around 7 days after dose 1; pre-dose 2, before dose 2; dose 2/day 6–8, around 7 days after dose 2. Symbols denote group means; circle, placebo; plus, 10 μg; cross, 30 μg; triangle, 100 μg. The box-and-whisker plots show the median (centre), first and third quartiles (lower and upper edges), and minimum and maximum values (lower and upper whiskers).
Page 9
FDA-CBER-2022-5812-0228137
Extended Data Table 1 | Demographic characteristics
N, the number of participants in the specified group or the total sample. This value is the denominator for the percentage calculations. n, the number of participants with the specified
characteristic.
Page 10
FDA-CBER-2022-5812-0228138
ArticleExtended Data Table 2 | Adverse events
N, the number of participants in the specified group or the total sample. This value is the denominator for the percentage calculations. n , the number of participants who reported at least one
occurrence of the specified adverse event category. For ‘any event’, n indicates the number of participants who reported at least one occurrence of any adverse event. Related, assessed by the
investigator as related to the investigational product.
Page 11
FDA-CBER-2022-5812-0228139
1 nature research | reporting summary April 2020
Corresponding author(s): Judith Absalon
Last updated by author(s): Jul 27, 2020
Reporting Summary
Nature Research wishes to improve the reproducibility of the work that we publish. This form provides structure for consistency and transparency
in reporting. For further information on Nature Research policies, see our Editorial Policies and the Editorial Policy Checklist .
Statistics
For all statistical analyses, confirm that the following items are present in the figure legend, table legend, main text, or Methods section.
n/a Confirmed
The exact sample size ( n) for each experimental group/condition, given as a discrete number and unit of measurement
A statement on whether measurements were taken from distinct samples or whether the same sample was measured repeatedly
The statistical test(s) used AND whether they are one or two sided
Only common tests should be described solely by name; describe more complex techniques in the Methods section.
A description of all covariates tested
A description of any assumptions or corrections, such as tests of normality and adjustment for multiple comparisons
A full description of the statistical parameters including central tendency (e.g. means) or other basic estimates (e.g. regression coefficient) AND variation (e.g. standard deviation) or associated estimates of uncertainty (e.g. confidence intervals)
For null hypothesis testing, the test statistic (e.g. F, t, r) with confidence intervals, effect sizes, degrees of freedom and P value noted
Give P values as exact values whenever suitable.
For Bayesian analysis, information on the choice of priors and Markov chain Monte Carlo settings
For hierarchical and complex designs, identification of the appropriate level for tests and full reporting of outcomes
Estimates of effect sizes (e.g. Cohen's d, Pearson's r), indicating how they were calculated
Our web collection on statistics for biologists contains articles on many of the points above.
Software and code
Policy information about availability of computer code
Data collection Inform (for data collected in the case report form) and electronic diary (Signant Health platform) for participant self reported reactogenicity
Data analysis SAS 9.4
For manuscripts utilizing custom algorithms or software that are central to the research but not yet described in published literature, software must be made available to editors and reviewers. We strongly encourage code deposition in a community repository (e.g. GitHub). See the Nature Research guidelines for submitting code & software for further information.
Data
Policy information about availability of data
All manuscripts must include a data availability statement . This statement should provide the following information, where applicable:
Accession codes, unique identifiers, or web links for publicly available datasets A list of figures that have associated raw data A description of any restrictions on data availability
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual anonymized participant data. See https://www.pfizer.com/science/clinical trials/trial data and results for more information
Page 12
FDA-CBER-2022-5812-0228140
2 nature research | reporting summary April 2020Field-specific reporting
Please select the one below that is the best fit for your research. If you are not sure, read the appropriate sections before making your selection.
Life sciences Behavioural & social sciences Ecological, evolutionary & environmental sciences
For a reference copy of the document with all sections, see nature.com/documents/nr-reporting-summary-flat.pdf
Life sciences study design
All studies must disclose on these points even when the disclosure is negative.
Sample size The sample size for this interim report was not based on statistical hypothesis testing. A total of 45 participants were enrolled in this part of
the study. For the purposes of tolerability and dose escalation study a total of 15 participants (12 receiving vaccine and 3 receiving placebo) was deemed sufficient for a dosing finding phase study.
Data exclusions All safety and immunogenicity data that were available at the time of the data snapshot were included in the interim report. No data were excluded from the analyses.
Replication This is an interim report of an ongoing human clinical trial. There was no attempt at replication of study findings
Randomization This is an randomized controlled trial. Study participants were randomly assigned to a vaccine group using an interactive web based response technology system with each group comprising 15 participants (12 active vaccine recipients and 3 placebo recipients).
Blinding This is an observer blinded study which is investigator blinded but Sponsor unblinded during Stage 1 (the stage from which data in the manuscript are presented). Investigators were unblinded to group level data but not subject level data for the purposes of interpretation and summary of the results included in this interim report.
Reporting for specific materials, systems and methods
We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response.
Materials & experimental systems
n/a Involved in the study
Antibodies
Eukaryotic cell lines
Palaeontology and archaeology
Animals and other organisms
Human research participants
Clinical data
Dual use research of concernMethods
n/a Involved in the study
ChIP seq
Flow cytometry
MRI based neuroimaging
Human research participants
Policy information about studies involving human research participants
Population characteristics Study participants were healthy men or women 18 55 years of age. Key exclusion criteria included individuals with known infection with human immunodeficiency virus, hepatitis C virus, or hepatitis B virus; immunocompromised individuals and those with a history of autoimmune disease; those with increased risk for severe COVID 19; previous clinical or microbiological diagnosis of COVID 19; receipt of medications intended to prevent COVID 19; previous vaccination with any coronavirus vaccine; a positive serological test for SARS CoV 2 IgM and/or IgG at the screening visit; and a SARS CoV 2 NAATpositive nasal swab within 24 hours before study vaccination.
Recruitment Study participants were recruited at the two individual sites and recruitment strategies were at the discretion of individual sites and could include identification of interested individuals from the sites local database or through advertising in the local community. Once recruited participants were screened for eligibility based on pre specified protocol criteria. Eligible participants were then randomized to vaccine or placebo in a blinded manner. These processes therefore did not led themselves to enrollment biases however participants who did not know about the study may have had less of an opportunity to participate.
Ethics oversight The study protocol was approved by the western institutional review board for one site and by the Langone Health New York University Institutional IRB prior to enrollment of any participants
Note that full information on the approval of the study protocol must also be provided in the manuscript.
Page 13
FDA-CBER-2022-5812-0228141
3 nature research | reporting summary April 2020Clinical data
Policy information about clinical studies
All manuscripts should comply with the ICMJE guidelines for publication of clinical research and a completed CONSORT checklist must be included with all submissions.
Clinical trial registration ClinicalTrials.gov identifier: NCT04368728
Study protocol Details of protocol elements can be accessed from clinicaltrials.gov
Data collection Data were collected at screening (up to 14 days before vaccination) and for randomized participants at the investigative site at
baseline, 1 day, 7 days and 21 days, after Dose 1, 7 days after dose 2 and up to 14 days after dose 2. Both safety and/or serum collection for immunogenicity assessments were collected for all stated time points. In addition, reactogenicity data were assessed through participant self reports via an electronic diary for 7 days after dose 1.
Outcomes In this interim report, the following study primary endpoints are presented: the proportion of participants reporting prompted local reactions, systemic events, and use of antipyretic and/or pain medication within 7 days after vaccination, AEs and serious adverse events (SAEs) (available through up to ~45 days after Dose 1), and the proportion of participants with clinical laboratory abnormalities 1 and 7 days after vaccination and grading shifts in laboratory assessments between baseline and 1 and 7 days after Dose 1 and between Dose 2 and 7 days after Dose 2. Secondary endpoints included: SARS CoV 2 neutralizing geometric mean titers (GMTs); SARS CoV 2 RBD binding IgG geometric mean concentrations (GMCs) 7 and 21 days after Dose 1 and 7 and 14 days after Dose 2
Page 14
FDA-CBER-2022-5812-0228142
090177e1954406cc\Final\Final On: 15-Oct-2020 19:54 (GMT)
Page 15
FDA-CBER-2022-5812-0228143
090177e1954406cc\Final\Final On: 15-Oct-2020 19:54 (GMT)
Page 16
FDA-CBER-2022-5812-0228144
090177e1954406cc\Final\Final On: 15-Oct-2020 19:54 (GMT)
Page 17
FDA-CBER-2022-5812-0228145
090177e1954406cc\Final\Final On: 15-Oct-2020 19:54 (GMT)
Page 18
FDA-CBER-2022-5812-0228146
090177e1954406cc\Final\Final On: 15-Oct-2020 19:54 (GMT)
Page 19
FDA-CBER-2022-5812-0228147
090177e1954406cc\Final\Final On: 15-Oct-2020 19:54 (GMT)
Page 20
FDA-CBER-2022-5812-0228148
090177e1954406cc\Final\Final On: 15-Oct-2020 19:54 (GMT)
Page 21
FDA-CBER-2022-5812-0228149
090177e1954406cc\Final\Final On: 15-Oct-2020 19:54 (GMT)
Page 22
FDA-CBER-2022-5812-0228150
090177e1954406cc\Final\Final On: 15-Oct-2020 19:54 (GMT)
Page 23
FDA-CBER-2022-5812-0228151
090177e1954406cc\Final\Final On: 15-Oct-2020 19:54 (GMT)
Page 24
FDA-CBER-2022-5812-0228152
090177e1954406cc\Final\Final On: 15-Oct-2020 19:54 (GMT)
Page 25
FDA-CBER-2022-5812-0228153
090177e1954406cc\Final\Final On: 15-Oct-2020 19:54 (GMT)
Page 26
FDA-CBER-2022-5812-0228154
090177e1954406cc\Final\Final On: 15-Oct-2020 19:54 (GMT)
Page 27
FDA-CBER-2022-5812-0228155
The new england journal of medicine
n engl j med nejm.org 1The 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, at NEJM.org.
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.)ABSTRACTSafety 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* Original Article
The New England Journal of Medicine
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
090177e195d05d30\Final\Final On: 16-Dec-2020 20:21 (GMT)
Page 28
FDA-CBER-2022-5812-0228156
n engl j med nejm.org 2The new england journal of medicine
Coronavirus 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
The New England Journal of Medicine
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
090177e195d05d30\Final\Final On: 16-Dec-2020 20:21 (GMT)
Page 29
FDA-CBER-2022-5812-0228157
n engl j med nejm.org 3Safety and Efficacy of the BNT162b2 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 evi-dence of prior infection was 36,523, and the number of persons who could be evaluated 7 days after the second dose with or without evi-dence 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%.
The New England Journal of Medicine
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
090177e195d05d30\Final\Final On: 16-Dec-2020 20:21 (GMT)
Page 30
FDA-CBER-2022-5812-0228158
n engl j med nejm.org 4The new england journal of medicine
1272 Did not undergo randomization
1152 Did not meet eligibility criteria
64 Had other reason
33 Withdrew13 Underwent randomization
after cutoff
5 Had unspecified reason4 Were withdrawn by physician1 Was lost to follow-up
99 Were not vaccinated
1 Did not sign the informed consent document
316 Did not receive dose 2
96 Withdrew86 Were no longer eligible61 Were lost to follow-up46 Had ongoing or pending
status
18 Had adverse event
5 Were pregnant2 Were withdrawn by
physician
1 Died1 Had medication error
(no adverse event)304 Did not receive dose 2
100 Withdrew
62 Were lost to follow-up56 Had ongoing or pending
status
51 Were no longer eligible28 Had adverse event
4 Were pregnant2 Were withdrawn by
physician
1 Died
18,556 Received dose 2 of BNT162b2 18,530 Received dose 2 of placebo43,448 Were injected with vaccine or placebo
21,720 Were assigned to receive BNT162b221,728 Were assigned to receive placebo
37,706 Received vaccine or placebo
and had median follow-up of 2 mo43,548 Underwent randomization44,820 Participants were screened
18,860 Received dose 1 of BNT162b2 18,846 Received dose 1 of placebo
48 Discontinued trial after dose 2
27 Withdrew18 Were lost to follow-up
1 Died1 Was withdrawn by physician1 Had medication error
(no adverse event)95 Discontinued trial after dose 2
66 Withdrew25 Were lost to follow-up
2 Died1 Had other reason1 Declined further procedures
The New England Journal of Medicine
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
090177e195d05d30\Final\Final On: 16-Dec-2020 20:21 (GMT)
Page 31
FDA-CBER-2022-5812-0228159
n engl j med nejm.org 5Safety and Efficacy of the BNT162b2 Vaccine
Moreover, primary and secondary efficacy end
points are evaluated sequentially to control the 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 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.
Table 1. Demographic Characteristics of the Participants in the Main Safety Population.*
CharacteristicBNT162b2
(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 — yrMedian 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.
The New England Journal of Medicine
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
090177e195d05d30\Final\Final On: 16-Dec-2020 20:21 (GMT)
Page 32
FDA-CBER-2022-5812-0228160
n engl j med nejm.org 6The new england journal of medicine
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 83
14
6051
78
12
6
061
71
97
151
66
8 7
17
1
Redness Swelling>55 Yr of Age, Dose 2>55 Yr of Age, Dose 116–55 Yr of Age, Dose 216–55 Yr of Age, Dose 1100
8090
70
60
40
30
1050
20
0ALocal EventsMild Moderate Severe Grade 4Percentage of Participants100
8090
70
60
40
30
1050
20
0
100
8090
70
60
40
30
1050
20
0
Pain at Injection
SiteBNT162b2Placebo
BNT162b2Placebo
BNT162b2PlaceboBNT162b2Placebo
BNT162b2Placebo
BNT162b2PlaceboBNT162b2Placebo
BNT162b2Placebo
BNT162b2PlaceboBNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
100
8090
70
60
40
30
1050
20
0Figure 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.
The New England Journal of Medicine
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
090177e195d05d30\Final\Final On: 16-Dec-2020 20:21 (GMT)
Page 33
FDA-CBER-2022-5812-0228161
n engl j med nejm.org 7Safety and Efficacy of the BNT162b2 Vaccine
4142
34
1411 122128
1411 116 61147
33
16
052
2435
1083745
13822
5 4 2 159
23
0 125
18
6 8 71420
128 9630134
23
11
039
1423
862938
10519
4 31 051
17100
8090
70
60
40
30
1050
20
0
BNT162b2Placebo
FeverBNT162b2Placebo
FatigueBNT162b2Placebo
HeadacheBNT162b2Placebo
ChillsBNT162b2Placebo
Vomiting>55 Yr of Age, Dose 2>55 Yr of Age, Dose 116–55 Yr of Age, Dose 216–55 Yr of Age, Dose 1
BNT162b2Placebo
DiarrheaBNT162b2Placebo
Muscle PainBNT162b2Placebo
Joint PainBNT162b2Placebo
Use of antipyretic
medicationBSystemic Events and Use of MedicationMild; temperature 38.0 to 38.4°C Moderate; temperature >38.4 to 38.9°C Severe; temperature >38.9 to 40.0°C Grade 4Percentage of Participants100
8090
70
60
40
30
1050
20
0
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
100
8090
70
60
40
30
1050
20
0
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
100
8090
70
60
40
30
1050
20
0
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
BNT162b2Placebo
The New England Journal of Medicine
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
090177e195d05d30\Final\Final On: 16-Dec-2020 20:21 (GMT)
Page 34
FDA-CBER-2022-5812-0228162
n engl j med nejm.org 8The new england journal of medicine
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, regardless of age or dose. Systemic events in-cluding fever and chills were observed with the first 1 to 2 days after vaccination and resolved 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 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-
The New England Journal of Medicine
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
090177e195d05d30\Final\Final On: 16-Dec-2020 20:21 (GMT)
Page 35
FDA-CBER-2022-5812-0228163
n engl j med nejm.org 9Safety and Efficacy of the BNT162b2 Vaccine
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-Table 2. Vaccine Efficacy against Covid-19 at Least 7 days after the Second Dose.*
Efficacy End Point BNT162b2 PlaceboVaccine Efficacy, %
(95% Credible
Interval)‡Posterior
Probability
(Vaccine Efficacy
>30%)§
No. of
CasesSurveillance
Time (n)†No. of
CasesSurveillance
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 infection8 2.214 (1,7411) 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 infection9 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.
The New England Journal of Medicine
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
090177e195d05d30\Final\Final On: 16-Dec-2020 20:21 (GMT)
Page 36
FDA-CBER-2022-5812-0228164
n engl j med nejm.org 10The new england journal of medicine
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.
11The favorable safety profile observed during
phase 1 testing of BNT162b24,8 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 observed in recipients of another approved viral vaccine for older adults.
13 Overall, reactogenicity
events were transient and resolved within a couple Table 3. Vaccine Efficacy Overall and by Subgroup in Participants without Evidence of Infection before 7 Days after Dose 2.
Efficacy End-Point
SubgroupBNT162b2
(N=18,198)Placebo
(N=18,325)Vaccine Efficacy, %
(95% CI)†
No. of
CasesSurveillance
Time
(No. at Risk)*No. of
CasesSurveillance
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 (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.
The New England Journal of Medicine
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
090177e195d05d30\Final\Final On: 16-Dec-2020 20:21 (GMT)
Page 37
FDA-CBER-2022-5812-0228165
n engl j med nejm.org 11Safety and Efficacy of the BNT162b2 Vaccine
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 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
1.62.0
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)BNT162b2Placebo
percent person-yr (no. at risk)
Covid-19 occurrence
After dose 1
After dose 1 to before dose 2Dose 2 to 7 days after dose 2≥7 Days after dose 25039
29275
82
21
172Surveillance 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
The New England Journal of Medicine
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
090177e195d05d30\Final\Final On: 16-Dec-2020 20:21 (GMT)
Page 38
FDA-CBER-2022-5812-0228166
n engl j med nejm.org 12The new england journal of medicine
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, 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, 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-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.
The New England Journal of Medicine
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
090177e195d05d30\Final\Final On: 16-Dec-2020 20:21 (GMT)
Page 39
FDA-CBER-2022-5812-0228167
n engl j med nejm.org 13Safety and Efficacy of the BNT162b2 Vaccine
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.).
References
1.Johns Hopkins University Coronavi-
rus Resource Center. COVID-19 dash-board by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. 2020 (https://coronavirus . jhu
. edu/ map . html).
2.World Health Organization. WHO
Director-General’s opening remarks at
the media briefing on COVID-19 —
11 March 2020 (https://www . who . int/
director - general/ speeches/ detail/ who
- director - general - s - opening - remarks - at
- the - media - briefing - on - covid - 19 - - - 11
- march - 2020).
3.Centers for Disease Control and Pre-
vention. COVID-19 information page
(https://www . cdc . gov/ coronavirus/ 2019
- ncov/ index . html).
4.Walsh EE, Frenck RW Jr, Falsey AR, et
al. Safety and immunogenicity of two RNA-
based Covid-19 vaccine candidates. N Engl J Med. DOI: 10.1056/NEJMoa2027906.5.Pardi N, Tuyishime S, Muramatsu H,
et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanopar-ticles to mice by various routes. J Control Release 2015; 217: 345-51.
6.Karikó K, Muramatsu H, Welsh FA, et
al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capaci-ty and biological stability. Mol Ther 2008; 16: 1833-40.
7.Wrapp D, Wang N, Corbett KS, et al.
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367: 1260-3.
8.Sahin U, Muik A, Derhovanessian E,
et al. BNT162b2 elicits SARS-CoV-2 neu-tralising antibodies and TH1 T cells in humans. preprint.
9. Food and Drug Administration. Guid-
ance for industry: emergency use authori-
zation for vaccines to prevent COVID-19. October 2020 (https://www . fda . gov/ media/
142749/ download).
10. Lauer SA, Grantz KH, Bi Q, et al. The
incubation period of coronavirus disease
2019 (COVID-19) from publicly reported confirmed cases: estimation and appli-cation. Ann Intern Med 2020; 172: 577-82.
11.Haynes BF, Corey L, Fernandes P, et
al. Prospects for a safe COVID-19 vac-cine. Sci Transl Med 2020; 12(568):
eabe0948.
12. Cowling BJ, Perera RAPM, Valkenburg
SA, et al. Comparative immunogenicity of several enhanced influenza vaccine options for older adults: a randomized, controlled trial. Clin Infect Dis 2020; 71: 1704-14.
13. Food and Drug Administration.
Shringrix (zoster vaccine recombinant, adjuvanted) product information. 2019 (https://www . fda . gov/ vaccines - blood
- biologics/ vaccines/ shingrix).
Copyright © 2020 Massachusetts Medical Society.
The New England Journal of Medicine
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
090177e195d05d30\Final\Final On: 16-Dec-2020 20:21 (GMT)
Page 40
FDA-CBER-2022-5812-0228168
090177e1964a7725\Final\Final On: 16-Feb-2021 01:00 (GMT)
Page 41
FDA-CBER-2022-5812-0228169
090177e1964a7725\Final\Final On: 16-Feb-2021 01:00 (GMT)
Page 42
FDA-CBER-2022-5812-0228170
090177e1964a7725\Final\Final On: 16-Feb-2021 01:00 (GMT)
Page 43
FDA-CBER-2022-5812-0228171
090177e1964a7725\Final\Final On: 16-Feb-2021 01:00 (GMT)
Page 44
FDA-CBER-2022-5812-0228172
090177e1964a7725\Final\Final On: 16-Feb-2021 01:00 (GMT)
Page 45
FDA-CBER-2022-5812-0228173
090177e1964a7725\Final\Final On: 16-Feb-2021 01:00 (GMT)
Page 46
FDA-CBER-2022-5812-0228174
CorrespondenceThe new england journal of medicine
n engl j med nejm.org 1Neutralizing Activity of BNT162b2-Elicited Serum
To the Editor: BNT162b2 is a nucleoside-modi-
fied RNA vaccine expressing the full-length pre-fusion spike glycoprotein (S) of severe acute re-spiratory syndrome coronavirus 2 (SARS-CoV-2). In a randomized, placebo-controlled clinical trial involving approximately 44,000 participants, im-munization conferred 95% efficacy against coro-navirus disease 2019 (Covid-19).
1
New, highly transmissible SARS-CoV-2 variants
that were first detected in the United Kingdom (B.1.1.7 lineage), South Africa (B.1.351 lineage), and Brazil (P.1 lineage) with mutations in the S gene
are spreading globally. To analyze effects on neu-tralization elicited by BNT162b2, we engineered S mutations from each of the three new lineages
into USA-WA1/2020, a relatively early isolate of the virus from January 2020 (Fig. S1 in the Sup-plementary Appendix, available with the full text of this letter at NEJM.org). We thereby produced three recombinant viruses representing each of these lineages and two additional ones in which we engineered subsets of mutations of the B.1.351 lineage. Thus, the first recombinant virus had all the mutations found in the S gene in the B.1.1.7
lineage (B.1.1.7-spike), the second had all the mutations found in the S gene in the P.1 lineage
(P.1-spike), the third had all the mutations found in the S gene in the B.1.351 lineage (B.1.351-spike),
the fourth had an N-terminal domain deletion found in the B.1.351 lineage and the globally dominant D614G substitution (B.1.351-Δ242-244+D614G), and the fifth had the three muta-tions from the B.1.351 lineage affecting amino acids in the receptor-binding site (K417N, E484K, and N501Y) and a D614G substitution (B.1.351-RBD+D614G). The mutant amino acid residues in the B.1.351-RBD+D614G recombinant virus are also among those in the P.1 lineage virus, al-though in the P.1 lineage virus, K417 is mutated to threonine rather than asparagine. All the mu-tant viruses yielded infectious viral titers exceed-ing 10
7 plaque-forming units per milliliter. The
B.1.1.7-spike and B.1.351-spike viruses formed plaques that were smaller than those formed by the other viruses (Fig. S2).
We performed 50% plaque reduction neutral-
ization testing (PRNT
50) using 20 serum samples
that had been obtained from 15 participants in the pivotal trial
1,2 2 or 4 weeks after the administra-
tion of the second dose of 30 μg of BNT162b2 (which occurred 3 weeks after the first immuni-zation) (Fig. S3). All the serum samples efficient-ly neutralized USA-WA1/2020 and all the viruses with variant spikes. Almost all of them did so at titers higher than 1:40. Geometric mean neutral-izing titers against USA-WA1/2020, B.1.1.7-spike, P.1-spike, B.1.351-spike, B.1.351-Δ242-244+D614G, and B.1.351-RBD+D614G viruses were 532, 663, 437, 194, 485, and 331, respectively (Fig. 1 and Table S1). Thus, as compared with neutralization of USA-WA1/2020, neutralization of B.1.1.7-spike and P.1-spike viruses was roughly equivalent, and neutralization of B.1.351-spike virus was robust but lower. Our data are also consistent with lower neutralization titers against the virus with the full set of B.1.351-spike mutations than against virus with either subset of mutations. Our findings also suggest that mutations that result in amino acid substitutions K417N, E484K, and N501Y in the receptor-binding site have a greater effect on neutralization than the 242–244 deletion affecting the N-terminal domain of the spike protein.
Limitations of the study include the potential
for mutations to alter neutralization by affecting spike function rather than antigenicity. Therefore, each neutralization assay with a different target virus is unique, and comparisons between neu-tralization titers from different assays should be interpreted with caution. Neutralizing activity against the B.1.351 lineage virus was robust at a geometric mean titer that was much higher than that obtained after one dose of BNT162b2, when strong efficacy was already observed in the C4591001 efficacy trial.
1-3 T-cell immunity may
also be involved in protection,4 and BNT162b2
The New England Journal of Medicine
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
090177e1967884c4\Final\Final On: 09-Mar-2021 16:53 (GMT)
Page 47
FDA-CBER-2022-5812-0228175
The new england journal of medicine
n engl j med nejm.org 2immunization elicits CD8+ T-cell responses that
recognize multiple variants.5 Ultimately, conclu-
sions about vaccine-mediated protection that are extrapolated from neutralization or T-cell data must be validated by real-world evidence collected in regions where the SARS-CoV-2 variants are circulating.
Yang Liu, Ph.D.
Jianying Liu, Ph.D.Hongjie Xia, Ph.D.Xianwen Zhang, B.S.Camila R. Fontes-Garfias, Ph.D.
University of Texas Medical BranchGalveston, TX
Kena A. Swanson, Ph.D.Hui Cai, Ph.D.Ritu Sarkar, M.A.Wei Chen, M.S.Mark Cutler, Ph.D.David Cooper, Ph.D.
Pfizer Vaccine Research and DevelopmentPearl River, NYScott C. Weaver, Ph.D.
University of Texas Medical Branch Galveston, TX
Alexander Muik, Ph.D. Ugur Sahin, M.D.
BioNTech Mainz, Germany
Kathrin U. Jansen, Ph.D.
Pfizer Vaccine Research and Development Pearl River, NY
Xuping Xie, Ph.D.
University of Texas Medical Branch Galveston, TX xuxie@ utmb . edu
Philip R. Dormitzer, M.D., Ph.D.
Pfizer Vaccine Research and Development Pearl River, NY philip . dormitzer@ pfizer . com
Pei-Yong Shi, Ph.D.
University of Texas Medical Branch Galveston, TX peshi@ utmb . edu
Drs. Y. Liu and J. Liu contributed equally to this letter.Figure 1. Serum Neutralization of Variant Strains of SARS-CoV-2 after the Second Dose of BNT162b2 Vaccine.
Shown are the results of 50% plaque reduction neutralization testing (PRNT 50) with the use of 20 samples obtained
from 15 trial participants 2 weeks (circles) or 4 weeks (triangles) after the administration of the second dose of the
BNT162b2 vaccine. The mutant viruses were obtained by engineering the full set of mutations in the B.1.1.7, P.1., or B.1.351 lineage or subsets of the S gene mutations in the B.1.351 lineage (B.1.351-Δ242-244+D614G and B.1.351-
RBD+D614G) into USA-WA1/2020. Each data point represents the geometric mean PRNT
50 obtained with a serum
sample against the indicated virus, including data from repeat experiments, as detailed in Table S1 in the Supple-mentary Appendix. The data for USA-WA1/2020 are from three experiments; for B.1.1.7-spike, B.1.351-Δ242-
244+D614G, and B.1.351-RBD-D614G viruses from one experiment each; and for P.1-spike and B.1.351-spike viruses
from two experiments each. In each experiment, the neutralization titer was determined in duplicate assays, and the geometric mean was taken. The heights of bars and the numbers over the bars indicate geometric mean titers. The I bars indicate 95% confidence intervals. Statistical analysis was performed with the use of the Wilcoxon signed-rank test. The statistical significance of the difference between geometric mean titers in the USA-WA1/2020 neutral-ization assay and in each variant virus neutralization assay with the same serum samples are as follows: P = 0.02 for B.1.1.7-spike; P = 0.06 for P.1-spike; P<0.001 for B.1.351-spike; P = 0.99 for B.1.351-Δ242-244+D614G; and P = 0.005 for
B.1.351-RBD+D614G. LOD denotes limit of detection.PRNT50 (log2)1280
320640
160
80
40
20
USA-WA1/2020 B.1.1.7-Spike P.1-Spike B.1.351-Spike B.1.351-Δ242-244
+D614GB.1.351-RBD
+D614G532 663
437485 331
194
LOD
The New England Journal of Medicine
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
090177e1967884c4\Final\Final On: 09-Mar-2021 16:53 (GMT)
Page 48
FDA-CBER-2022-5812-0228176
Correspondence
n engl j med nejm.org 3Supported by Pfizer and BioNTech.
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
A preliminary version of this letter was published on February 17,
2021, and was updated on March 8, 2021, at NEJM.org.
1.Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of
the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med 2020;383:2603-15.
2.Walsh EE, Frenck RW Jr, Falsey AR, et al. Safety and immuno-
genicity of two RNA-based Covid-19 vaccine candidates. N Engl J Med 2020;383:2439-50.
3.Sahin U, Muik A, Vogler I, et al. BNT162b2 induces SARS-CoV-2-neutralising antibodies and T cells in humans. December 11, 2020 (https://www . medrxiv . org/ content/ 10 . 1101/ 2020 . 12 . 09
. 20245175v1). preprint.
4.Liao M, Liu Y, Yuan J, et al. Single-cell landscape of bron-
choalveolar immune cells in patients with COVID-19. Nat Med
2020;26:842-4.
5.Skelly DT, Harding AC, Gilbert-Jaramillo J, et al. Vaccine-
induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of con-cern. February 9, 2021 (https://www.researchsquare.com/article/rs-226857/v1). preprint.
DOI: 10.1056/NEJMc2102017
Correspondence Copyright © 2021 Massachusetts Medical Society.
The New England Journal of Medicine
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
090177e1967884c4\Final\Final On: 09-Mar-2021 16:53 (GMT)
Page 49
FDA-CBER-2022-5812-0228177
090177e19751de02\Final\Final On: 16-Jun-2021 16:30 (GMT)
Page 50
FDA-CBER-2022-5812-0228178
090177e19751de02\Final\Final On: 16-Jun-2021 16:30 (GMT)
Page 51
FDA-CBER-2022-5812-0228179
090177e19751de02\Final\Final On: 16-Jun-2021 16:30 (GMT)
Page 52
FDA-CBER-2022-5812-0228180
090177e19751de02\Final\Final On: 16-Jun-2021 16:30 (GMT)
Page 53
FDA-CBER-2022-5812-0228181
090177e19751de02\Final\Final On: 16-Jun-2021 16:30 (GMT)
Page 54
FDA-CBER-2022-5812-0228182
090177e19751de02\Final\Final On: 16-Jun-2021 16:30 (GMT)
Page 55
FDA-CBER-2022-5812-0228183
090177e19751de02\Final\Final On: 16-Jun-2021 16:30 (GMT)
Page 56
FDA-CBER-2022-5812-0228184
090177e19751de02\Final\Final On: 16-Jun-2021 16:30 (GMT)
Page 57
FDA-CBER-2022-5812-0228185
090177e19751de02\Final\Final On: 16-Jun-2021 16:30 (GMT)
Page 58
FDA-CBER-2022-5812-0228186
090177e19751de02\Final\Final On: 16-Jun-2021 16:30 (GMT)
Page 59
FDA-CBER-2022-5812-0228187
090177e19751de02\Final\Final On: 16-Jun-2021 16:30 (GMT)
Page 60
FDA-CBER-2022-5812-0228188
090177e19751de02\Final\Final On: 16-Jun-2021 16:30 (GMT)
Page 61
FDA-CBER-2022-5812-0228189
The new england journal of medicine
n engl j med nejm.org 1T h e a u t h o r s ’ f u l l n a m e s , a c a d e m i c d e -
grees, and affiliations are listed in the Ap-pendix. Address reprint requests to Dr. Absalon at Pfizer, 401 N. Middletown Rd., Pearl River, NY 10965, or at judith . absalon@
pfizer . com.
*A list of the investigators in the C4591001
Clinical Trial Group is provided in the
Supplementary Appendix, available atNEJM.org.
This article was published on September 15, 2021, at NEJM.org.
DOI: 10.1056/NEJMoa2110345
Copyright © 2021 Massachusetts Medical Society.BACKGROUND
BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored severe acute respiratory syn-drome coronavirus 2 (SARS-CoV-2) full-length spike protein. BNT162b2 is highly efficacious against coronavirus disease 2019 (Covid-19) and is currently approved, conditionally approved, or authorized for emergency use worldwide. At the time of initial authorization, data beyond 2 months after vaccination were unavailable.
METHODS
In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy trial, we randomly assigned 44,165 participants 16 years of age or older and 2264 participants 12 to 15 years of age to receive two 30-μg doses, at 21 days apart, of BNT162b2 or placebo. The trial end points were vaccine efficacy against laboratory-confirmed Covid-19 and safety, which were both evaluated through 6 months after vaccination.
RESULTS
BNT162b2 continued to be safe and have an acceptable adverse-event profile. Few participants had adverse events leading to withdrawal from the trial. Vaccine ef-ficacy against Covid-19 was 91.3% (95% confidence interval [CI], 89.0 to 93.2) through 6 months of follow-up among the participants without evidence of previ-ous SARS-CoV-2 infection who could be evaluated. There was a gradual decline in vaccine efficacy. Vaccine efficacy of 86 to 100% was seen across countries and in populations with diverse ages, sexes, race or ethnic groups, and risk factors for Covid-19 among participants without evidence of previous infection with SARS-CoV-2. Vaccine efficacy against severe disease was 96.7% (95% CI, 80.3 to 99.9). In South Africa, where the SARS-CoV-2 variant of concern B.1.351 (or beta) was pre-dominant, a vaccine efficacy of 100% (95% CI, 53.5 to 100) was observed.
CONCLUSIONS
Through 6 months of follow-up and despite a gradual decline in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing Covid-19. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)ABSTRACTSafety and Efficacy of the BNT162b2 mRNA
Covid-19 Vaccine through 6 Months
S.J. Thomas, E.D. Moreira, Jr., N. Kitchin, J. Absalon, A. Gurtman, S. Lockhart,
J.L. Perez, G. Pérez Marc, F.P. Polack, C. Zerbini, R. Bailey, K.A. Swanson, X. Xu,
S. Roychoudhury, K. Koury, S. Bouguermouh, W.V. Kalina, D. Cooper,
R.W. Frenck, Jr., L.L. Hammitt, Ö. Türeci, H. Nell, A. Schaefer, S. Ünal, Q. Yang,
P. Liberator, D.B. Tresnan, S. Mather, P.R. Dormitzer, U. Şahin, W.C. Gruber, and
K.U. Jansen, for the C4591001 Clinical Trial Group* Original Article
The New England Journal of Medicine
. Copyright © 2021 Massachusetts Medical Society. All rights reserved. 090177e19814de9d\Final\Final On: 16-Se p-2021 13:02 (GMT )
Page 62
FDA-CBER-2022-5812-0228190
n engl j med nejm.org 2The new england journal of medicine
The coronavirus disease 2019 (Covid-19)
pandemic continues, with recent estimates of more than 187 million cases diagnosed
and more than 4 million deaths.
1 Vaccines are
currently available by means of full approval, conditional marketing approval, and emergency use authorization pathways.
2-5 B N T 1 6 2 b 2 i s a
lipid nanoparticle–formulated,6 nucleoside-mod-
ified RNA7 encoding the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) full-length spike glycoprotein in a prefusion stabilized con-formation.
8 To date, more than 1 billion doses
of BNT162b2 have been distributed.
We previously reported safety and efficacy
data obtained through a median of 2 months of postimmunization follow-up from a global phase 1–2–3 trial of BNT162b2 involving persons 16 years of age or older. Vaccine efficacy against Covid-19 was 95%. BNT162b2 had a favorable safety profile in diverse populations.
9 These data
formed the basis for BNT162b2 emergency or conditional authorizations globally.
10 Safety, ef-
ficacy, and immunogenicity data from partici-pants 12 to 15 years of age in this trial have been reported.
11 Here, we report safety and efficacy
findings from a prespecified analysis of the phase 2–3 portion of the trial through approxi-mately 6 months of follow-up. These additional data contributed to the full approval of BNT162b2 in the United States.
Methods
Objectives, Participants, and Oversight
This randomized, placebo-controlled, observer-blinded, phase 1–2–3 trial assessed the safety, efficacy, and immunogenicity of the BNT162b2 vaccine in adolescents and adults. The current report of the findings from the phase 2–3 portion of the trial focuses on safety assessments among participants 16 years of age or older and prespeci-fied assessments of vaccine efficacy among par-ticipants 12 years of age or older through 6 months of follow-up after immunization. Because the en-r o llm e n t o f p arti c i p an ts 12 to 1 5 y ears o f a g e began on October 15, 2020, 6-month postim-munization data are currently unavailable for this age cohort. Shorter-duration safety, immu-nogenicity, and efficacy data for participants 12 to 15 years of age are reported separately
11;
h o w ev e r , da ta f o r thi s c o h o rt ar e in c l u d e d in the analyses of vaccine efficacy in the overall population (all participants ≥12 years of age) reported here.
Participants who were healthy or had stable
chronic medical conditions were eligible. An ac-tive immunocompromising condition or recent immunosuppressive therapy was an exclusion criterion. Participants with a history of Covid-19 were excluded, although evidence of current or previous SARS-CoV-2 infection on laboratory test-ing of trial-obtained samples was not an exclu-sion criterion. Trial-related responsibilities and ethical conduct are summarized in the Supplemen-tary Appendix, available with the full text of this article at NEJM.org. The protocol contains addi-tional details of the trial and is available at NEJM.org. The first draft of the manuscript was written by the fourth author. The authors had the opportunity to review the data included in this article and confirm the accuracy of the data presented through the specified data cutoff date. The authors vouch for the accuracy and complete-ness of the data and for the fidelity of the trial to the protocol.
Procedures
T h e p a r t i c i p a n t s w e r e r a n d o m l y a s s i g n e d i n a 1:1 ratio to receive two 30-μg intramuscular injections, 21 days apart, of BNT162b2 (0.3 ml volume per dose) or saline placebo. Random-ization was performed with an interactive Web-based system. Starting in December 2020, after BNT162b2 became available under emergency or conditional use authorizations, participants 16 years of age or older who became eligible for Covid-19 vaccination according to national or local recommendations were given the option to learn their trial assignment. Those who had been randomly assigned to receive placebo were of-fered BNT162b2. After unblinding of the group assignments, participants were followed in an open-label trial period.
Safety
Safety end points included solicited, prespecified local reactions, systemic events, and antipyretic or pain medication use during the first 7 days after receipt of each vaccine or placebo dose, which were recorded in an electronic diary; unso-licited adverse events after receipt of the first dose through 1 month after the second dose; and seri-ous adverse events after receipt of the first dose through 1 and 6 months after the second dose
The New England Journal of Medicine
. Copyright © 2021 Massachusetts Medical Society. All rights reserved. 090177e19814de9d\Final\Final On: 16-Se p-2021 13:02 (GMT )
Page 63
FDA-CBER-2022-5812-0228191
n engl j med nejm.org 3Safety and Efficacy of BNT162b2 through 6 Months
was received. Safety data are presented for the
blinded follow-up and open-label periods.
Efficacy
BNT162b2 efficacy against laboratory-confirmed Covid- 19 with an onset of 7 days or more after the second dose was assessed and summarized descriptively in participants without serologic or virologic evidence of SARS-CoV-2 infection within 7 days after the second dose and in participants with or without evidence of previous infection. Efficacy against severe Covid-19 was also assessed. Lineages of SARS-CoV-2 detected in midturbinate specimens are reported here for Covid-19 cases that occurred 7 days or more after the second dose in South African participants without evi-dence of previous infection. Methods for deter-mining SARS-CoV-2 lineages and case definitions for confirmed and severe cases of Covid-19 are summarized in the Supplementary Appendix.
Statistical Analysis
The analysis populations are summarized in Table S1 in the Supplementary Appendix. Safety analyses included participants 16 years of age or older without known human immunodeficiency virus (HIV) infection who provided informed consent and received at least one BNT162b2 or placebo dose. The results of the safety analyses, which are descriptive and not based on formal hypothesis testing, are presented as counts, per-centages, and associated Clopper–Pearson 95% confidence intervals for adverse events, according to terms in the Medical Dictionary for Regulatory Ac-tivities , version 23.1, and reactogenicity events for
each trial group. Safety data that were reported up to March 13, 2021, are summarized here. The 95% confidence intervals in this report were not adjusted for multiplicity.
The analysis of vaccine efficacy during the
blinded period of the trial included all partici-pants 12 years of age or older without known HIV infection who received at least one BNT162b2 or placebo dose. Vaccine efficacy was calculated as 100 × (1 – IRR), where IRR (incidence rate ra-
tio) is the ratio of the rate (number per 1000 person-years of follow-up) of confirmed cases of Covid-19 in the BNT162b2 group to the corre-sponding rate in the placebo group. Descriptive analyses of vaccine efficacy were performed and associated 95% confidence intervals were calcu-lated with the use of the Clopper–Pearson meth-od, with adjustment for surveillance time, which accounts for potential differential follow-up be-tween the two trial groups. As described in the statistical analysis plan, available with the pro-tocol, hypothesis-testing analyses were performed with the use of a Bayesian approach, and the descriptive analyses presented here were per-formed with a frequentist approach for clarity of communication. Because the percentage of par-ticipants who reported symptoms but were miss-ing a valid polymerase-chain-reaction test result was small and slightly higher in the placebo group, data for these participants were not imputed in the analysis.
The previously reported primary efficacy ob-
jective was achieved on the basis of an analysis of 170 accrued cases of Covid-19 that could be evalu-ated (data cutoff date, November 14, 2020).
9 The
current report provides updated efficacy analyses that were performed with data from cases that had accrued up to March 13, 2021.
Results
Participants
Between July 27, 2020, and October 29, 2020, a total of 45,441 participants 16 years of age or older underwent screening, and 44,165 underwent randomization at 152 sites (130 sites in the United States, 1 site in Argentina, 2 sites in Brazil, 4 sites in South Africa, 6 sites in Germany, and 9 sites in Turkey) in the phase 2–3 portion of the trial. Of these participants, 44,060 received at least one dose of BNT162b2 (22,030 participants) or placebo (22,030), and 98% (21,759 in the BNT162b2 group and 21,650 in the placebo group) received the second dose (Fig. 1). During the blinded period of the trial, 51% of the partici-pants in each group had 4 to less than 6 months of follow-up after the second dose; 8% of the participants in the BNT162b2 group and 6% of those in the placebo group had 6 months of follow-up or more after the second dose. During the combined blinded and open-label periods, 55% of the participants in the BNT162b2 group had 6 months of follow-up or more after the second dose. A total of 49% of the participants were female, 82% were White, 10% were Black, and 26% were Hispanic or Latinx; the median age was 51 years. A total of 34% of the participants had a body-mass index (the weight in kilograms divided by the square of the height in meters) of
The New England Journal of Medicine
. Copyright © 2021 Massachusetts Medical Society. All rights reserved. 090177e19814de9d\Final\Final On: 16-Se p-2021 13:02 (GMT )
Page 64
FDA-CBER-2022-5812-0228192
n engl j med nejm.org 4The new england journal of medicine
44,165 Underwent randomization45,441 Participants underwent screening
1276 Were excluded
1173 Did not pass screening
103 Withdrew
22,085 Were assigned to receive BNT162b2 22,080 Were assigned to receive placebo
55 Did not receive BNT162b2
26 Withdrew
15 Had protocol deviation
7 No longer met eligibility criteria3 Had adverse event4 Had other reason
22,030 Received the first dose 22,030 Received the first dose
271 Discontinued trial after the first
dose and before the second dose
108 Withdrew
89 Were lost to follow-up25 No longer met eligibility criteria25 Had adverse event
6 Became pregnant3 Were withdrawn by physician2 Died2 Had medication error without
associated adverse event
11 Had other or unknown reason
167 Discontinued trial after the second
dose
81 Were lost to follow-up54 Withdrew14 Died11 Had protocol deviation
3 Were withdrawn by physician1 Had medication error without
associated adverse event
1 Was withdrawn by parent
or guardian
1 No longer met eligibility criteria1 Had other reason50 Did not receive placebo
26 Withdrew12 Had protocol deviation
3 No longer met eligibility criteria2 Had adverse event7 Had other or unknown reason
380 Discontinued trial after the first
dose and before the second dose
108 Withdrew
90 Were lost to follow-up
119 No longer met eligibility criteria
25 Had adverse event
6 Became pregnant7 Were withdrawn by physician2 Died2 Had medication error without
associated adverse event
1 Had protocol deviation
20 Had other or unknown reason
273 Discontinued trial after the second
dose
125 Withdrew
96 Were lost to follow-up24 Had protocol deviation13 Died
3 Were withdrawn by physician4 No longer met eligibility criteria1 Had adverse event1 Became pregnant6 Had other reason21,759 Received the second dose
20,334 Entered open-label follow-up21,650 Received the second dose
20,794 Entered open-label follow-up
The New England Journal of Medicine
. Copyright © 2021 Massachusetts Medical Society. All rights reserved. 090177e19814de9d\Final\Final On: 16-Se p-2021 13:02 (GMT )
Page 65
FDA-CBER-2022-5812-0228193
n engl j med nejm.org 5Safety and Efficacy of BNT162b2 through 6 Months
30.0 or more, 21% had at least one underlying
medical condition, and 3% had baseline evidence of a previous or current SARS-CoV-2 infection (Table 1 and Table S2).
Between October 15, 2020, and January 12,
2021, a total of 2306 participants 12 to 15 years of age underwent screening, and 2264 underwent randomization at 29 U.S. sites. Of these partici-pants, 2260 received at least one dose of BNT162b2 (1131 participants) or placebo (1129), and 99% (1124 in the BNT162b2 group and 1117 in the placebo group) received the second dose.
11 Among
participants who received at least one dose of BNT162b2 or placebo, 58% had at least 2 months of follow-up after the second dose, 49% were female, 86% were White, 5% were Black, and 12% were Hispanic or Latinx. Full details of the de-mographic characteristics of the participants have been reported previously.
11
Safety
Reactogenicity
The subgroup that was evaluated for reactogenic-ity in the current report, in which reactions were r e p o r t e d i n a n e l e c t r o n i c d i a ry , i n c l u d e d 9 8 3 9 participants 16 years of age or older. In this sub-gr o u p , 8 1 8 3 p arti c i p an ts ha d b e e n in c l u d e d in the previous analysis, and 1656 were enrolled after the data cutoff for that analysis.
9 The reac-
togenicity profile of BNT162b2 in this expanded subgroup did not differ substantially from that described previously.
9 This subgroup included
364 participants who had evidence of previous SARS-CoV-2 infection, 9426 who did not have evidence, and 49 who lacked the data needed to determine previous infection status.
M o r e p a r t i c i p a n t s i n t h e B N T 1 6 2 b 2 g r o u p
than in the placebo group reported local reac-tions, the most common of which was mild-to-moderate pain at the injection site (Fig. S1A). Local reactions were reported with similar fre-quency among the participants with or without evidence of previous SARS-CoV-2 infection, and the reactions were of similar severity. No local reactions of grade 4 (according to the guidelines of the Center for Biologics Evaluation and Re-search
12) were reported.
M o r e p a r t i c i p a n t s i n t h e B N T 1 6 2 b 2 g r o u p
than in the placebo group reported systemic events, the most common of which was fatigue (Fig. S1B). Systemic events were mostly mild to moderate in severity, but there were occasional severe events. Systemic reactogenicity was similar among those with or without evidence of previous S A R S - C o V - 2 i n f e c t i o n , a l t h o u g h B N T 1 6 2 b 2 r e -cipients with evidence of previous infection re-ported systemic events more often after receipt of the first dose, and those without evidence reported systemic events more often after receipt of the second dose. For example, 12% of recipi-en ts wi th evi den ce o f p revio us S ARS-Co V - 2 in -fection and 3% of those without evidence report-ed fever after receipt of the first dose; 8% of those with evidence of previous infection and 15% of those without evidence reported fever after the second dose. The highest temperature reported was a transient fever of higher than 40.0°C on day 2 after the second dose in a BNT162b2 recipient without evidence of previ-ous infection.
Adverse Events
A n a l y s e s o f a d v e r s e e v e n t s d u r i n g th e b l i n d e d period included 43,847 participants 16 years of age or older (Table S3). Reactogenicity events among the participants who were not in the re-actogenicity subgroup were reported as adverse events, which resulted in imbalances between the BNT162b2 group and the placebo group with respect to adverse events (30% vs. 14%), related adverse events (24% vs. 6%), and severe adverse events (1.2% vs. 0.7%). New adverse events at-tributable to BNT162b2 that were not previously Figure 1 (facing page). Screening, Randomization, and
Follo
w-up.
The diagram represents all enrolled participants 16
years of age or older through the data cutoff date (March 13, 2021). The diagram includes two deaths that occurred after the second dose in human immunodeficiency virus (HIV)–infected participants (one in the BNT162b2 group and one in the placebo group; these deaths were not reported in the Results section of this article because the analysis of HIV-infected participants is being conducted separately). Information on the screening, randomization, and follow-up of the participants 12 to 15 years of age has been reported previously.
11
The New England Journal of Medicine
. Copyright © 2021 Massachusetts Medical Society. All rights reserved. 090177e19814de9d\Final\Final On: 16-Se p-2021 13:02 (GMT )
Page 66
FDA-CBER-2022-5812-0228194
n engl j med nejm.org 6The new england journal of medicine
Table 1. Demographic Characteristics of the Participants at Baseline.*
CharacteristicBNT162b2
(N = 22,026)Placebo
(N = 22,021)Total
(N = 44,047)
Sex — no. (%)
Male 11,322 (51.4) 11,098 (50.4) 22,420 (50.9)
Female 10,704 (48.6) 10,923 (49.6) 21,627 (49.1)
Race or ethnic group — no. (%)†
White 18,056 (82.0) 18,064 (82.0) 36,120 (82.0)Black or African American 2,098 (9.5) 2,118 (9.6) 4,216 (9.6)Asian 952 (4.3) 942 (4.3) 1,894 (4.3)American Indian or Alaska Native 221 (1.0) 217 (1.0) 438 (1.0)Native Hawaiian or other Pacific Islander 58 (0.3) 32 (0.1) 90 (0.2)Multiracial 550 (2.5) 533 (2.4) 1,083 (2.5)Not reported 91 (0.4) 115 (0.5) 206 (0.5)
Ethnicity†
Hispanic or Latinx 5,704 (25.9) 5,695 (25.9) 11,399 (25.9)Not reported 111 (0.5) 114 (0.5) 225 (0.5)
Country — no. (%)
Argentina 2,883 (13.1) 2,881 (13.1) 5,764 (13.1)Brazil 1,452 (6.6) 1,448 (6.6) 2,900 (6.6)Germany 249 (1.1) 250 (1.1) 499 (1.1)South Africa 401 (1.8) 399 (1.8) 800 (1.8)Turkey 249 (1.1) 249 (1.1) 498 (1.1)United States 16,792 (76.2) 16,794 (76.3) 33,586 (76.3)
Age group at vaccination — no. (%)
16–55 yr 13,069 (59.3) 13,095 (59.5) 26,164 (59.4)>55 yr 8,957 (40.7) 8,926 (40.5) 17,883 (40.6)
Age at vaccination — yr
Median 51.0 51.0 51.0
Range 16–89 16–91 16–91
SARS-CoV-2 status — no. (%)‡
Positive 689 (3.1) 716 (3.3) 1,405 (3.2)Negative 21,185 (96.2) 21,180 (96.2) 42,365 (96.2)Missing data 152 (0.7) 125 (0.6) 277 (0.6)
Body-mass index — no. (%)§
≥30.0: obese 7,543 (34.2) 7,629 (34.6) 15,172 (34.4)Missing data 7 (<1) 6 (<1) 13 (<1)
* Data are summarized for participants 16 years of age or older in the safety population. The demographic characteristics
of participants 12 to 15 years of age were reported previously.
11 Percentages may not total 100 because of rounding.
SARS-CoV-2 denotes severe acute respiratory syndrome coronavirus 2.
† Race and ethnicity were reported by the participants. The categories shown are those that were used to collect the data.
‡ Positive status was defined as a positive N-binding antibody result or a positive nucleic acid amplification test (NAAT)
result at visit 1 or medical history of coronavirus disease 2019 (Covid-19). Negative status was defined as a negative N-binding antibody result or a negative NAAT result at visit 1 and no medical history of Covid-19.
§ The body-mass index is the weight in kilograms divided by the square of the height in meters.
The New England Journal of Medicine
. Copyright © 2021 Massachusetts Medical Society. All rights reserved. 090177e19814de9d\Final\Final On: 16-Se p-2021 13:02 (GMT )
Page 67
FDA-CBER-2022-5812-0228195
n engl j med nejm.org 7Safety and Efficacy of BNT162b2 through 6 Months
identified in earlier reports included decreased
appetite, lethargy, asthenia, malaise, night sweats, and hyperhidrosis. Few participants had serious adverse events or adverse events that led to trial withdrawal. No new serious adverse events were considered by the investigators to be related to BNT162b2 after the data cutoff date of the previ-ous report.
9
During the combined blinded and open-label
periods, cumulative safety data during follow-up were available through 6 months after the sec-ond dose for 12,006 participants who were origi-nally randomly assigned to the BNT162b2 group. No new safety signals relative to the previous report were observed during the longer follow-up period in the current report, which included open-label observation of the original BNT162b2 recipients and placebo recipients who received BNT162b2 after unblinding.
9
During the blinded, placebo-controlled peri-
od, 15 participants in the BNT162b2 group and 14 in the placebo group died; during the open-label period, 3 participants in the BNT162b2 group and 2 in the original placebo group who received BNT162b2 after unblinding died. None of these deaths were considered to be related to BNT162b2 by the investigators. Causes of death were bal-anced between BNT162b2 and placebo groups (Table S4).
Safety monitoring will continue according to
the protocol for 2 years after the second dose for participants who originally received BNT162b2 and for 18 months after the second BNT162b2 dose for placebo recipients who received BNT162b2 after unblinding.
Efficacy
Among 42,094 participants 12 years of age or older who could be evaluated and had no evidence of previous SARS-CoV- 2 infection, Covid- 19 with an onset of 7 days or more after the second dose was observed in 77 vaccine recipients and in 850 p l a c e b o r e c i p i e n t s u p t o t h e d a t a c u t o f f d a t e (March 13, 2021), corresponding to a vaccine ef-fi ca cy o f 9 1 . 3 % ( 9 5 % c o n fi d e n c e i n te rv al [ C I] , 89.0 to 93.2) (Table 2). Among 44,486 participants Table 2. Vaccine Efficacy against Covid-19 from 7 Days after Receipt of the Second Dose during the Blinded, Placebo-Controlled Follow-up
Period.*
Efficacy End Point BNT162b2 PlaceboVaccine Efficacy
(95% CI)‡
No. of
CasesSurveillance
Time†No. at
RiskNo. of
CasesSurveillance
Time†No. at
Risk
1000 person-yr 1000 person-yr percent
(N = 20,998) (N = 21,096)
First occurrence of Covid-19
from 7 days after receipt
of the second dose among participants without evidence of previous infection77 6.247 20,712 850 6.003 20,713 91.3
(89.0–93.2)
(N = 22,166) (N = 22,320)
First occurrence of Covid-19
from 7 days after receipt of the second dose among participants with or without evidence of previous infection81 6.509 21,642 873 6.274 21,689 91.1
(88.8–93.0)
* This analysis included participants who had no serologic or virologic evidence (within 7 days after receipt of the second dose) of previous
SARS-CoV-2 infection (i.e., negative N-binding antibody [serum] test at visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at visits1 and 2) and had a negative NAAT at any unscheduled visit up to 7 days after receipt of the second dose.
† The surveillance time is the total time (in 1000 person-years) at risk for the given end point across all participants within each group. The
time period for the accrual of Covid-19 cases was from 7 days after the second dose to the end of the surveillance period.
‡ Vaccine efficacy was calculated as 100 × (1 – IRR), where IRR (incidence rate ratio) is the ratio of the rate (number per 1000 person-years of
follow-up) of confirmed cases of Covid-19 in the BNT162b2 group to the corresponding rate in the placebo group. The 95% confidence in-terval for vaccine efficacy was derived with the use of the Clopper–Pearson method, with adjustment for surveillance time.
The New England Journal of Medicine
. Copyright © 2021 Massachusetts Medical Society. All rights reserved. 090177e19814de9d\Final\Final On: 16-Se p-2021 13:02 (GMT )
Page 68
FDA-CBER-2022-5812-0228196
n engl j med nejm.org 8The new england journal of medicine
with or without evidence of previous infection
who could be evaluated, cases of Covid-19 were o b s e r v e d i n 8 1 v a c c i n e r e c i p i e n t s a n d i n 8 7 3 placebo recipients, corresponding to a vaccine efficacy of 91.1% (95% CI, 88.8 to 93.0).
Among the participants with evidence of pre-
vious SARS-CoV-2 infection based on a positive baseline N-binding antibody test, Covid-19 was observed in 2 vaccine recipients after the first dose and in 7 placebo recipients. Among the participants with evidence of previous SARS-CoV-2 infection based on a positive nucleic acid amplification test at baseline, cases of Covid-19 were observed in 10 vaccine recipients and in 9 placebo recipients (Table S5). Covid-19 was less common among the placebo recipients with positive N-binding antibodies at trial entry (7 of 542 participants, for an incidence of 1.3%) than among those without evidence of infection at trial entry (1015 of 21,521, for an incidence of 4.7%); these findings indicate that previous infec-tion conferred approximately 72.6% protection.
Among the participants with or without
evidence of previous infection, cases of Covid-19 w e r e o b s e rv e d i n 4 6 v a c c i n e r e c i p i e n t s a n d i n 110 placebo recipients from receipt of the first dose up to receipt of the second dose, corre-sponding to a vaccine efficacy of 58.4% (95% CI, 40.8 to 71.2) (Fig. 2). During the interval from the approximate start of observed protection at 11 days after receipt of the first dose up to re-ceipt of the second dose, vaccine efficacy in-creased to 91.7% (95% CI, 79.6 to 97.4). From its peak after the second dose, observed vaccine effi-cacy declined. From 7 days to less than 2 months after the second dose, vaccine efficacy was 96.2% (95% CI, 93.3 to 98.1); from 2 months to less than 4 months after the second dose, vaccine effi-cacy was 90.1% (95% CI, 86.6 to 92.9); and from 4 months after the second dose to the data cutoff date, vaccine efficacy was 83.7% (95% CI, 74.7 to 89.9).
Severe Covid-19, as defined by the Food and
Drug Administration,
13 with an onset after receipt
of the first dose occurred in 31 participants, of whom 30 were placebo recipients; this finding corresponds with a vaccine efficacy of 96.7% (95% CI, 80.3 to 99.9) against severe Covid-19 (Fig. 2 and Table S6). Although the trial was not powered to definitively assess efficacy according to subgroup, supplemental analyses indicated that vaccine efficacy after the second dose in subgroups defined according to age, sex, race, ethnic group, presence or absence of coexisting medical conditions, and country was generally consistent with that observed in the overall population (Table 3 and Table S7).
Given the concern about the SARS-CoV-2
B.1.351 (or beta) variant, which appears to be neutralized less efficiently by BNT162b2-immune sera than many other lineages,
14 whole-viral-
genome sequencing was performed on midturbi-nate samples from Covid-19 cases observed in South Africa, where this lineage was prevalent. Nine cases of Covid-19 were observed in South African participants without evidence of previ-ous SARS-CoV-2 infection, all of whom were placebo recipients; this finding corresponds with a vaccine efficacy of 100% (95% CI, 53.5 to 100) (Table 3). Midturbinate specimens from 8 of 9 cases contained sufficient viral RNA for whole-genome sequencing. All viral genomes were the beta variant (Global Initiative on Sharing All Influenza Data accession codes are provided in the Supplementary Appendix).
Discussion
In this update to the preliminary safety and effi-cacy report of two 30-μg doses, at 21 days apart, of BNT162b2, 91.1% vaccine efficacy against Covid-19 was observed from 7 days to 6 months after the second dose in participants 12 years of age or older. Vaccine efficacy against severe dis-ease with an onset after receipt of the first dose was approximately 97%. This finding, combined with the totality of available evidence, including real-world effectiveness data,
15-18 alleviates theo-
retical concerns over potential enhancement of vaccine-mediated disease.
19
The benefit of BNT162b2 immunization start-
ed approximately 11 days after receipt of the first dose, with 91.7% vaccine efficacy from 11 days after receipt of the first dose up to receipt of the second dose. The trial cannot provide informa-tion on persistence of protection after a single dose, because 99% of the participants received the second dose as scheduled during the blinded trial period. A recent trial showed that although nonneutralizing viral antigen–binding antibody levels rise between the first and second BNT162b2 dose, serum neutralizing titers are low or unde-tectable during this interval.
20 Early protection
against Covid-19 without strong serum neutral-
The New England Journal of Medicine
. Copyright © 2021 Massachusetts Medical Society. All rights reserved. 090177e19814de9d\Final\Final On: 16-Se p-2021 13:02 (GMT )
Page 69
FDA-CBER-2022-5812-0228197
n engl j med nejm.org 9Safety and Efficacy of BNT162b2 through 6 Months
ization indicates that neutralizing titers alone do
not appear to explain early BNT162b2-mediated protection from Covid-19. Other immune mech-anisms (e.g., innate immune responses, CD4+ or CD8+ T-cell responses, B-cell memory responses, and antibody-dependent cytotoxicity) may con-tribute to protection.
21-26
Efficacy peaked at 96.2% during the interval
from 7 days to less than 2 months after the sec-ond dose and declined gradually to 83.7% from Figure 2. Efficacy of BNT162b2 against Covid-19 after Receipt of the First Dose (Blinded Follow-up Period).
The top of t
he figure shows the cumulative incidence curves for the first occurrence of coronavirus disease 2019 (Covid-19) aft er receipt
of the first dose (efficacy analysis population of participants ≥12 years of age who could be evaluated). Each symbol represent s Covid-19
cases starting on a given day, and filled symbols represent severe Covid-19 cases. Because of overlapping dates, some symbols r epre-
sent more than one case. The inset shows the same data on an enlarged y axis through 21 days. The bottom of the figure shows th e
time intervals for the first occurrence of Covid-19 in the efficacy analysis population, as well as the surveillance time, whic h is given as
the total time (in 1000 person-years) at risk for the given end point across all participants within each group. The time perio d for the ac-
crual of Covid-19 cases was from after receipt of the first dose to the end of the surveillance period for the overall row and from the start
to the end of the range stated for each time interval. Vaccine efficacy was calculated as 100 × (1 – IRR), where IRR (incidence rate ratio) is
the ratio of the rate (number per 1000 person-years of follow-up) of confirmed cases of Covid-19 in the BNT162b2 group to the c orre-
sponding rate in the placebo group. The 95% confidence interval for vaccine efficacy was derived with the use of the Clopper–Pe arson
method, with adjustment for surveillance time.Overall: first occurrence of Covid-19 after receipt of first dose
After receipt of first dose up to receipt of second dose
<11 Days after receipt of first dose
≥11 Days after receipt of first dose up to receipt of second dose
After receipt of second dose to <7 days after
≥7 Days after receipt of second dose≥7 Days after receipt of second dose to <2 mo after≥2 Mo after receipt of second dose to <4 mo after≥4 Mo after receipt of second dose% (95% CI)Vaccine Efficacy
87.8 (85.3 to 89.9)58.4 (40.8 to 71.2)18.2 (−26.1 to 47.3)91.7 (79.6 to 97.4)91.5 (72.9 to 98.3)91.2 (88.9 to 93.0)96.2 (93.3 to 98.1)90.1 (86.6 to 92.9)83.7 (74.7 to 89.9)Efficacy End PointBNT162b2
(N=23,040)
No. of
casesNo. at
riskSurveillance
time
1000 person-yr
131
46
41
53
82
12
46248.4121.339
0.6770.6620.4246.6492.9232.696
1.03022,50522,50522,50522,399
22,16322,13222,13220,81412,670
No. of
casesNo. at
riskSurveillance
time
1000 person-yrPlacebo
(N=23,037)
1034
110
506035
889
312
449
1288.124
1.331
0.6750.6560.422
6.371
2.8842.5930.89522,43422,43422,43422,36922,057
22,00122,001
20,344
11,802Cumulative Incidence (%)100.0
8.0
7.0
6.0
4.0
3.0
1.05.0
2.0
0.0
0 42 56 70 84 98 238
Days since Receipt of First Dose14 28 112 126 140 154 168 182 196 210 224Placebo
BNT162b20.40.5
0.2
0.10.3
0.0
0 9 12 15 18 21 3 6Placebo
BNT162b2
The New England Journal of Medicine
. Copyright © 2021 Massachusetts Medical Society. All rights reserved. 090177e19814de9d\Final\Final On: 16-Se p-2021 13:02 (GMT )
Page 70
FDA-CBER-2022-5812-0228198
n engl j med nejm.org 10The new england journal of medicine
Table 3. Vaccine Efficacy against Covid-19 up to 7 Days after Receipt of the Second Dose among Participants without Evidence of Infection.*
First Occurrence of
Covid-19 after Receipt of the First DoseBNT162b2
(N = 20,998)Placebo
(N = 21,096)Vaccine Efficacy
(95% CI)‡
No. of
CasesSurveillance
Time†No. at
RiskNo. of
CasesSurveillance
Time†No. at
Risk
1000 person-yr 1000 person-yr percent
Overall population 77 6.247 20,712 850 6.003 20,713 91.3 (89.0 to 93.2)
Age group — yr
16 or 17 0 0.061 342 10 0.057 331 100 (58.2 to 100)
16 to 55 52 3.593 11,517 568 3.439 11,533 91.2 (88.3 to 93.5)
≥55 25 2.499 8,194 266 2.417 8,208 90.9 (86.3 to 94.2)
≥65 7 1.233 4,192 124 1.202 4,226 94.5 (88.3 to 97.8)
≥75 1 0.239 842 26 0.237 847 96.2 (76.9 to 99.9)
Sex
Male 42 3.246 10,637 399 3.047 10,433 90.1 (86.4 to 93.0)
Female 35 3.001 10,075 451 2.956 10,280 92.4 (89.2 to 94.7)
Race or ethnic group§
White 67 5.208 17,186 747 5.026 17,256 91.3 (88.9 to 93.4)
Black or African
American4 0.545 1,737 48 0.527 1,737 91.9 (78.0 to 97.9)
Asian 3 0.260 946 23 0.248 934 87.6 (58.9 to 97.6)
American Indian or
Alaska Native0 0.041 186 3 0.037 176 100 (–119.0 to 100)
Native Hawaiian
or other Pacific Islander0 0.015 54 1 0.008 30 100 (–1961.2 to 100)
Multiracial 3 0.151 518 22 0.128 476 88.5 (61.6 to 97.8)
Not reported 0 0.026 85 6 0.030 104 100 (2.8 to 100)
Ethnicity§
Hispanic or Latinx 29 1.786 5,161 241 1.711 5,120 88.5 (83.0 to 92.4)
Non-Hispanic and
non-Latinx47 4.429 15,449 609 4.259 15,484 92.6 (90.0 to 94.6)
Not reported 1 0.032 102 0 0.033 109 NA
Country
Argentina 15 1.012 2,600 108 0.986 2,586 86.5 (76.7 to 92.7)
Brazil 12 0.406 1,311 80 0.374 1,293 86.2 (74.5 to 93.1)
Germany 0 0.047 236 1 0.048 242 100 (–3874.2 to 100)
South Africa 0 0.080 291 9 0.074 276 100 (53.5 to 100)
Turkey 0 0.027 228 5 0.025 222 100 (–0.1 to 100)
United States 50 4.674 16,046 647 4.497 16,046 92.6 (90.1 to 94.5)
* This analysis of vaccine efficacy during the blinded, placebo-controlled follow-up period included all participants who had undergone ran-
domization and were 12 years of age or older without baseline evidence of previous infection who had undergone randomization. NA de-
notes not applicable.
† Surveillance time is the total time (in 1000 person-years) at risk for the given end point across all participants within each group. The time
period for the accrual of Covid-19 cases was from 7 days after the second dose to the end of the surveillance period.
‡ Vaccine efficacy was calculated as 100 × (1 – IRR). The 95% confidence interval for vaccine efficacy was derived with the use of the Clopper–
Pearson method, with adjustment for surveillance time.
§ Race and ethnicity were reported by the participants. The categories shown are those that were used to collect the data.
The New England Journal of Medicine
. Copyright © 2021 Massachusetts Medical Society. All rights reserved. 090177e19814de9d\Final\Final On: 16-Se p-2021 13:02 (GMT )
Page 71
FDA-CBER-2022-5812-0228199
n engl j med nejm.org 11Safety and Efficacy of BNT162b2 through 6 Months
4 months after the second dose to the data cut-
off date — an average decline of approximately 6% every 2 months. Ongoing follow-up is needed to understand persistence of the vaccine effect over time, the need for booster dosing, and tim-ing of such a dose. Most participants who ini-tially received placebo have now been immunized with BNT162b2, ending the placebo-controlled period of the trial. Nevertheless, ongoing obser-vation of participants through 2 years in this trial, together with real-world effectiveness data,
15-
18 will determine whether a booster is likely to be
beneficial after a longer interval. Booster trials to evaluate safety and immunogenicity of BNT162b2 are under way to prepare for this possibility.
From 7 days after the second dose, 86 to 100%
efficacy was observed across diverse demographic profiles, including age, sex, race or ethnic group, and factors that increase the risk of Covid-19, such as high body-mass index and other coexist-ing medical conditions. BNT162b2 was also highly efficacious in various geographic regions including North America, Europe, South Africa, and Latin America. Although vaccine efficacy was slightly lower in Latin American countries, BNT162b2 had a high efficacy of approximately 86% in Argentina and Brazil. Circulation of SARS-CoV-2 variants — some of which are as-sociated with more rapid transmission and po-tentially greater pathogenicity
27 — has raised
concerns that such variants could evade vaccine-mediated protection. Our studies of in vitro neutralization of a variety of SARS-CoV-2 vari-ants have, to date, showed that all tested BNT162b2-immune sera neutralize all tested variants.
14,28-32 The beta variant, which has shown
the greatest reduction in neutralization and was the dominant strain in South Africa during the reported observation period, is still neutralized at serum titers higher than those observed at the onset of protection against Covid-19 after the first vaccine dose.
9,14,20 We found that BNT162b2
had an observed efficacy of 100% (95% CI, 53.5 to 100) against Covid-19 in South Africa (9 cases occurred in the placebo recipients and 0 cases in the BNT162b2 recipients), and 8 of 9 cases for which sequence information could be obtained involved the beta variant of SARS-CoV-2.
Safety data are now available for approxi-
mately 44,000 participants 16 years of age or older; 12,006 participants have at least 6 months of safety follow-up data after a second BNT162b2 dose. The safety profile observed at a median of 2 months after immunization was confirmed through 6 months after immunization in the cur-rent analysis. No cases of myocarditis were noted.
Before immunization, 3% of the participants
16 years of age or older had evidence of SARS-CoV-2 infection. Although this group had a slight-l y h i g h e r i n c i d e n c e o f s y s t e m i c r e a c t o g e n i c i t y events after receipt of the first dose than those without evidence of previous infection, the group had a slightly lower incidence of reactogenicity events after the second dose than those without previous infection. Thus, there was minimal ob-served difference in the overall reactogenicity profile on the basis of infection status at baseline. N i n e c a s e s o f C o v i d - 1 9 w e r e o b s e r v e d a m o n g participants with previous serologically defined natural infection: two cases were observed among the vaccine recipients and seven among the pla-cebo recipients. These data support the current practice of immunizing without screening for evidence of previous infection.
This report has several limitations. Duration
of protection and safety data that could be col-lected in a blinded, placebo-controlled manner were limited by the ethical and practical need to immunize eligible initial placebo recipients un-der emergency use authorization and according to the recommendations of public health authori-ties. The data presented here do not address whether vaccination prevents asymptomatic in-fection; however, evaluation of that question is on goin g in this trial, and real - world data sug-gest that BNT1 62b 2 prevents asymptomatic in-fection.
33,34 Preliminary analyses of breakthrough
cases have not yet identified a correlate of pro-tection, since vaccine protection rates remain high. This report does not address vaccine efficacy and safety in pregnant women and in children younger than 12 years of age. Studies evaluating BNT162b2 in these populations are ongoing.
The data in this report show that BNT162b2
prevents Covid-19 effectively for up to 6 months after the second dose across diverse populations, despite the emergence of SARS-CoV-2 variants, including the beta variant, and the vaccine con-tinues to show a favorable safety profile.
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.
The New England Journal of Medicine
. Copyright © 2021 Massachusetts Medical Society. All rights reserved. 090177e19814de9d\Final\Final On: 16-Se p-2021 13:02 (GMT )
Page 72
FDA-CBER-2022-5812-0228200
n engl j med nejm.org 12The new england journal of medicine
We thank all the participants who volunteered for this trial;
the investigators in the C4591001 Clinical Trial Group for their
contributions; the members of our data monitoring committee (Jonathan Zenilman [chair], Robert Belshe, Kathryn Edwards, Stephen Self, and Lawrence Stanberry) for their review of the data; Tricia Newell, Sheena Hunt, and Philippa Jack of ICON (North Wales, PA) for editorial support, which was funded by Pfizer; the following Pfizer staff: Greg Adams, Negar Ali-
abadi, Mohanish Anand, Fred Angulo, Ayman Ayoub, Melissa Bishop-Murphy, Mark Boaz, Christopher Bowen, Donna Boyce,
Sarah Burden, Andrea Cawein, Patrick Caubel, Darren Cowen, Kimberly Ann Cristall, Michael Cruz, Daniel Curcio, Gabriela Dávila, Carmel Devlin, Gokhan Duman, Niesha Foster, Maja Gacic, Juleen Gayed, Ahmed Hassan, Luis Jodar, Stephen Kay, William Lam, Esther Ladipo, Joaquina Maria Lazaro, Marie-Pierre Hellio Le Graverand-Gastineau, Kwok Lee, Zhenghui Li, Jacqueline Lowenberg, Hua Ma, Rod MacKenzie, Robert Ma-roko, Jason McKinley, Tracey Mellelieu, Neda Aghajani Memar, Farheen Muzaffar, Brendan O’Neill, Jason Painter, Elizabeth Paulukonis, Allison Pfeffer, Katie Puig, Kimberly Rarrick, Balaji Prabu Raja, Christine Rainey, Kellie Lynn Richardson, Elizabeth Rogers, Melinda Rottas, Charulata Sabharwal, Uzma Sarwar, Vilas Satishchandran, Harpreet Seehra, Judy Sewards, Huiqing Si, Helen Smith, David Swerdlow, James Trammel, Elisa Har-kins Tull, Sarah Tweedy, Erica Weaver, John Wegner, Jenah West, Christopher Webber, David C. Whritenour, Fae Wooding, Em-ily Worobetz, Nita Zalavadia, and Liping Zhang, as well as the Vaccines Clinical Assay Team, the Vaccines Assay Development Team, and all the Pfizer colleagues not named here who contrib-uted to the success of this trial; the following BioNTech staff: Corinna Rosenbaum, Christian Miculka, Andreas Kuhn, Ferdia Bates, Paul Strecker, Ruben Rizzi, Martin Bexon, Eleni Lagkadi-nou, and Alexandra Kemmer-Brück; and Dietmar Katinger and Andreas Wagner at Polymun.
Appendix
The authors’ full names and academic degrees are as follows: Stephen J. Thomas, M.D., Edson D. Moreira, Jr., M.D., Nicholas Kit chin,
M.D., Judith Absalon, M.D., Alejandra Gurtman, M.D., Stephen Lockhart, D M., John L. Perez, M.D., Gonzalo Pérez Marc, M.D., Fer -
nando P. Polack, M.D., Cristiano Zerbini, M.D., Ruth Bailey, B.Sc., Kena A. Swanson, Ph.D., Xia Xu, Ph.D., Satrajit Roychoudhur y,
Ph.D., Kenneth Koury, Ph.D., Salim Bouguermouh, M.D., 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., Qi Yang, Ph.D., P aul
Liberator, Ph.D., Dina B. Tresnan, D.V M., Ph.D., Susan Mather, M.D., Philip R. Dormitzer, M.D., Ph.D., Uğur Şahin, M.D., Willi am C.
Gruber, M.D., and Kathrin U. Jansen, Ph.D.
The authors’ affiliations are as follows: the 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., S.B., W.V.K., D.C., Q.Y., P.L., P.R.D., W.C.G., K.U.J.) — both in New York; Associação Obras Sociais Irmã Dulce and Oswaldo Cruz Foundation, Bahia (E.D M.), and iTrials-Hospital Militar Cent ral
(G.P M.) and Fundacion INFANT, Buenos Aires (F.P.P.) — all in Brazil; Centro Paulista de Investigação Clinica, São Paulo (C.Z.) ; Vac-
cine Research and Development, Pfizer, Hurley, United Kingdom (N.K., S.L., R.B.); Vaccine Research and Development (J.L.P., X.X.) and Worldwide Safety, Safety Surveillance, and Risk Management (D.B.T., S M.), Pfizer, Collegeville, PA; Global Product Development, Pfizer, Peapack, NJ (S.R.); Cincinnati Children’s Hospital, Cincinnati (R.W.F.); Johns Hopkins Bloomberg School of Public Healt h,
Baltimore (L.L.H.); BioNTech, Mainz (Ö.T., 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 Management, Pfizer, Groton, CT (D.B.T., S M.).
References
1.C O V I D - 1 9 d a s h b o a r d . 2 0 2 1 ( h t t p s : / /
coronavirus . jhu . edu/ map . html).
2.Food and Drug Administration.
COVID-19 vaccines. Silver Spring, MD:
Food and Drug Administration. 2021
(https://www . fda . gov/ emergency
- preparedness - and - response/ coronavirus
- disease - 2019 - covid - 19/ covid - 19
- vaccines).
3.Medicines and Healthcare Products
Regulatory Agency. Decision: conditions
of authorisation for COVID-19 vaccine As-traZeneca (regulation 174). 2021 (https://www . gov . uk/ government/ publications/
regulatory - approval - of - covid - 19 - vaccine
- astrazeneca/ conditions - of - authorisation
- for - covid - 19 - vaccine - astrazeneca).
4.Baraniuk C. What do we know about
China’s covid-19 vaccines? BMJ 2021; 373:
n912.
5.B a r a n i u k C . C o v i d - 1 9 : w h a t d o w e
know about Sputnik V and other Russian
vaccines? BMJ 2021; 372: n743.
6.Pardi N, Tuyishime S, Muramatsu H,
et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanopar-ticles to mice by various routes. J Control Release 2015; 217: 345-51.7. Karikó K, Muramatsu H, Welsh FA, et
al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capac-ity and biological stability. Mol Ther 2008; 16: 1833-40.
8.Wrapp D, Wang N, Corbett KS, et al.
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Sci-ence 2020; 367: 1260-3.
9. Polack FP, Thomas SJ, Kitchin N, et al.
Safety and efficacy of the BNT162b2 m RN A C o v i d - 1 9 v a c c i n e . N E n g l J M e d 2020; 383: 2603-15.
10.Pfizer, BioNTech. Pfizer-BioNTech
C O V I D - 1 9 v a c c i n e . F D A b r i e f i n g d o c u -ment. Presented at the Vaccines and Re-lated Biological Products Advisory Com-m i t t e e M e e t i n g , v i r t u a l , D e c e m b e r 1 0 , 2020 (https://www . fda . gov/ media/ 144245/
download).
11.Frenck RW Jr, Klein NP, Kitchin N, et
al. Safety, immunogenicity, and efficacy
of the BNT162b2 Covid-19 vaccine in ado-lescents. N Engl J Med 2021; 385: 239-50.
12.Guidance for industry: toxicity grad-
ing scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. Rockville, MD: Center for
Biologics Evaluation and Research. Sep-tember 2007 (https://www . fda . gov/ media/
73679/ download).
13.COVID-19: developing drugs and bi-
ological products for treatment or pre-
vention: guidance for industry. Silver Spring, MD: Food and Drug Administra-
tion. May 2020 (https://www . fda . gov/
regulatory - information/ search - fda
- guidance - documents/ covid - 19
- developing - drugs - and - biological
- products - treatment - or - prevention).
14.Liu Y, Liu J, Xia H, et al. Neutralizing
activity of BNT162b2-elicited serum. N Engl
J Med 2021; 384: 1466-8.
15.Haas EJ, Angulo FJ, McLaughlin JM,
et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitali-sations, and deaths following a nation-wide vaccination campaign in Israel: an observational study using national sur-veillance data. Lancet 2021; 397: 1819-29.
16. Abu-Raddad LJ, Chemaitelly H, Butt AA.
Effectiveness of the BNT162b2 Covid-19 vaccine against the B.1.1.7 and B.1.351 variants. N Engl J Med 2021; 385: 187-9.
The New England Journal of Medicine
. Copyright © 2021 Massachusetts Medical Society. All rights reserved. 090177e19814de9d\Final\Final On: 16-Se p-2021 13:02 (GMT )
Page 73
FDA-CBER-2022-5812-0228201
n engl j med nejm.org 13Safety and Efficacy of BNT162b2 through 6 Months
17.Lopez Bernal J, Andrews N, Gower C,
et al. Effectiveness of the Pfizer-BioNTech
and Oxford-AstraZeneca vaccines on cov-id-19 related symptoms, hospital admis-sions, and mortality in older adults in England: test negative case-control study. BMJ 2021; 373: n1088.
18. Vasileiou E, Simpson CR, Shi T, et al.
Interim findings from first-dose mass COVID-19 vaccination roll-out and CO-VID-19 hospital admissions in Scotland:
a national prospective cohort study. Lan-cet 2021; 397: 1646-57.
19.Haynes BF, Corey L, Fernandes P, et
al. Prospects for a safe COVID-19 vaccine. Sci Transl Med 2020; 12(568): eabe0948.
20. Walsh EE, Frenck RW Jr, Falsey AR, et
al. Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N Engl J Med 2020; 383: 2439-50.
21.S a h i n U , M u i k A , V o g l e r I , e t a l .
BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in hu-
mans. Nature 2021; 595: 572-7.
22. Goel RR, Apostolidis SA, Painter MM,
et al. Distinct antibody and memory B cell responses in SARS-CoV-2 naïve and recov-ered individuals following mRNA vacci-nation. Sci Immunol2021; 6 (58): eabi6950.
23.Knudson CJ, Alves-Peixoto P, Mura-
matsu H, et al. Lipid-nanoparticle-encap-sulated mRNA vaccines induce protective memory CD8 T cells against a lethal viral
infection. Mol Ther 2021 May 14 (Epub ahead of print).
24. Tauzin A, Nayrac M, Benlarbi M, et al.
A single BNT162b2 mRNA dose elicits an-
tibodies with Fc-mediated effector func-tions and boost pre-existing humoral and T cell responses. March 18, 2021 (https://
www . biorxiv . org/ content/ 10 . 1101/ 2021 . 03
. 18 . 435972v1). preprint.
25.Gallagher KME, Leick MB, Larson
RC, et al. SARS-CoV-2 T-cell immunity to
variants of concern following vaccination. May 3, 2021 (https://www . biorxiv . org/
content/ 10 . 1101/ 2021 . 05 . 03 . 442455v1).
preprint.
26.Painter MM, Mathew D, Goel RR, et
al. Rapid induction of antigen-specific
CD4+ T cells guides coordinated humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination. April 22, 2021 (https://www . biorxiv . org/ content/ 10 . 1101/
2021 . 04 . 21 . 440862v1). preprint.
27.Centers for Disease Control and Pre-
vention. SARS-CoV-2 variant classifica-
tions and definitions. 2021 (https://www
. cdc . gov/ coronavirus/ 2019 - ncov/ cases
- updates/ variant - surveillance/ variant - info
. html#print).
28. Xie X, Liu Y, Liu J, et al. Neutralization
of SARS-CoV-2 spike 69/70 deletion,
E484K and N501Y variants by BNT162b2 vaccine-elicited sera. Nat Med 2021; 27:
620-1.
29. Zou J, Xie X, Fontes-Garfias CR, et al.
The effect of SARS-CoV-2 D614G muta-tion on BNT162b2 vaccine-elicited neu-tralization. NPJ Vaccines 2021; 6: 44.
30. Muik A, Wallisch A-K, Sänger B, et al.
Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine-elicited human sera. Science 2021; 371:
1152-3.
31.Liu Y, Liu J, Xia H, et al. BNT162b2-
elicited neutralization against new SARS-CoV-2 spike variants. N Engl J Med 2021; 385: 472-4.
32.Liu J, Liu Y, Xia H, et al. BNT162b2-
elicited neutralization of B.1.617 and other SARS-CoV-2 variants. Nature 2021 June 10 (Epub ahead of print).
33.Dagan N , Barda N , K epten E, et al.
BNT162b2 mRNA Covid-19 vaccine in a na-
tionwide mass vaccination setting. N Engl J Med 2021; 384: 1412-23.
34.Tande AJ, Pollock BD, Shah ND, et al.
Impact of the COVID-19 vaccine on asymp-tomatic infection among patients under-
going pre-procedural COVID-19 molecu-lar screening. Clin Infect Dis 2021 March 10 (Epub ahead of print).
Copyright © 2021 Massachusetts Medical Society.
The New England Journal of Medicine
. Copyright © 2021 Massachusetts Medical Society. All rights reserved. 090177e19814de9d\Final\Final On: 16-Se p-2021 13:02 (GMT )
Page 74
FDA-CBER-2022-5812-0228202
CorrespondenceThe new england journal of medicine
n engl j med nejm.org 1SARS-CoV-2 Neutralization with BNT162b2 Vaccine Dose 3
To the Editor: We conducted a global, random-
ized, placebo-con
trolled, phase 1–2–3 pivotal
trial in which two 30-μg doses of BNT162b2
(Pfizer–BioNTech) were administered 21 days apart (ClinicalTrials.gov number, NCT04368728). These doses of vaccine had mainly low-grade side effects and provided 95% efficacy against coronavirus disease 2019 (Covid-19) from 7 days to approximately 2 months after dose 2.
1 Effi-
cacy waned to 84% between 4 and approximate-ly 6 months after dose 2.
2 Since vaccine authori-
zation, viral variants have replaced the original strain, with the highly transmissible B.1.617.2 (delta) variant currently dominant.
3 Although the
effectiveness of the vaccine against severe dis-ease, hospitalization, and death remains high, waning immunity and viral diversification create a possible need for a third vaccine dose.
Therefore, we administered a third 30-μg
BNT162b2 dose 7.9 to 8.8 months after dose 2 to 11 participants 18 to 55 years of age and to 12 participants 65 to 85 years of age from U.S. sites in the phase 1 part of the ongoing pivotal trial (additional details of the trial are provided in Table S1 and text within the Supplementary Ap-pendix, as well as in the trial protocol, both of which are available with the full text of this let-ter at NEJM.org). Local reactions and systemic events after dose 3 were predominantly mild to moderate and were similar to those after dose 2 (Figs. S1 and S2). No unsolicited adverse events were reported in the month after dose 3.
We determined 50% serum neutralization ti-
ters against wild-type (USA-WA1/2020) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a recombinant beta variant strain (i.e., the beta variant spike gene on wild-type genetic background), as described previously.
4
Serum specimens were obtained before dose 1, at 7 days and 1 month after dose 2, and before and 7 days and 1 month after dose 3 (Fig. 1A). These data supported four key conclusions. First, during the approximately 8 months from 7 days after dose 2 to before dose 3, SARS-CoV- 2 neu-tralization geometric mean titers (GMTs) in this subgroup of participants from phase 1 of the trial declined far more rapidly than vaccine ef-ficacy declined in participants in the phase 2–3 pivotal trial.
2 Second, by 1 month after dose 3,
neutralization GMTs against wild-type virus in-creased to more than 5 times as high (in 18-to-55-year-olds) and to more than 7 times as high (in 65-to-85-year-olds) as the GMTs 1 month after dose 2. Third, neutralization GMTs against the beta variant increased more after dose 3 than
Figure 1 (next page). Neutralizing Responses after Two
and Three Doses of B
NT162b2.
The 50% neutralization titers against a wild-type tar-
get strain (USA-WA1/2020) and against B.1.351 (beta) lineage and B.1.617.2 (delta) lineage target strains are shown for both age groups. Geometric mean titers from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plaque-reduction neutralization testing are shown for serum specimens obtained at the time points shown on the x axes from participants in the dose 3 immunogenicity population (11 participants in the 18-to-55-year age group and 12 participants in the 65-to-85-year age group). I bars indicate 95% confi-dence intervals. Neutralization titers against wild-typevirus were determined twice (once together with titersagainst each variant), and each titer against wild-typevirus is reported separately with the correspondingvariant titer. Differences among the determinations ofthe neutralization titer against wild-type virus repre-sent experimental variation on repeat testing. Valuesabove the error bars are geometric mean titers. Datapoints shown on the bar graph represent individual50% neutralization titers. Individual titers for all par-ticipants are shown for all time points except for be-fore dose 1, when all values were below the lower limitof quantitation (LLOQ) of 20; results below the LLOQwere set to 0.5 times the LLOQ. Geometric mean ra-tios (GMRs) of the titers against the variants and wild-type virus are shown below the graph. In Panel A, thegeometric mean fold rises (GMFRs) in titers againstthe wild-type strain from before dose 3 to 1 month af-ter dose 3 were 25.7 (95% confidence interval [CI],12.4 to 53.3) for younger adults and 49.4 (95% CI,29.2 to 83.3) for older adults. The corresponding GM-FRs against the beta variant were 38.7 (95% CI, 19.8 to75.5) and 78.3 (95% CI, 40.7 to 150.6), respectively.
The New England Journal of Medicine
090177e1983233ce\Final\Final On: 30-Sep-2021 11:30 (GMT)
Page 75
FDA-CBER-2022-5812-0228203
The new england journal of medicine
n engl j med nejm.org 2did GMTs against wild-type virus, to more than
15 times as high (in younger adults) and more than 20 times as high (in older adults) as those after dose 2, reducing the gap between neutral-ization of wild-type virus and the beta variant. Fourth, neutralization GMTs decreased from 7 days to 1 month after dose 2 but increased from 7 days to 1 month after dose 3. A similar pattern of broader neutralization (i.e., against variant strains) and higher GMTs after dose 3 was seen in assays of neutralization GMTs against recom-binant virus with delta variant spike protein on 50% Serum Neutralization Titer104
103
102
101
Before
Dose 17 Days
after
Dose 218–55 Yr of Age
(11 participants)65–85 Yr of Age
(12 participants)
1 Mo
after
Dose 2Before
Dose 37 Days
after
Dose 31 Mo
after
Dose 3
BNeutralization of Wild-Type Virus and the Delta VariantANeutralization of Wild-Type Virus and the Beta Variant
1.00
(1.00–1.00)0.30
(0.20–0.45)0.27
(0.18–0.39)0.48
(0.36–0.66)0.69
(0.52–0.91)0.73
(0.52–1.02)Before
Dose 17 Days
after
Dose 27 Days
after
Dose 31 Mo
after
Dose 3
1.00
(1.00–1.00)0.27
(0.16–0.45)0.29
(0.17–0.49)0.49
(0.34–0.69)0.67
(0.53–0.84)0.77
(0.51–1.16)GMRbeta:wild type
(95% CI)Wild type B.1.351 (beta) LLOQ50% Serum Neutralization Titer105
104
103
102
10118–55 Yr of Age
(11 participants)65–85 Yr of Age
(12 participants)
1 Mo after Dose 2 1 Mo after Dose 3
0.78
(0.63–0.96)0.85
(0.71–1.03)0.63
(0.46–0.86)0.92
(0.71–1.18)GMRdelta:wild type
(95% CI)Wild type B.1.617.2 (delta) LLOQ497
150
1 Mo
after
Dose 2Before
Dose 3204113188792032
1567
387
103
408376261538
14715462119
12021754
10 10 10 10
3102411321 1546
1 Mo after Dose 2 1 Mo after Dose 31613 1479
196
123
The New England Journal of Medicine
.
..
_
090177e1983233ce\Final\Final On: 30-Sep-2021 11:30 (GMT)
Page 76
FDA-CBER-2022-5812-0228204
Correspondence
n engl j med nejm.org 3a wild-type genetic background: the geometric
mean ratio of neutralization GMTs (delta variant to wild type) 1 mon
…[truncated]