Human Vaccines & Immunotherapeutics
ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/khvi20
Safety and reactogenicity of the BNT162b2
COVID-19 vaccine: Development, post-marketing
surveillance, and real-world data
Frank van den Ouweland, Nicola Charpentier, Özlem Türeci, Ruben Rizzi,
Federico J. Mensa, Claudia Lindemann & Shanti Pather
To cite this article: Frank van den Ouweland, Nicola Charpentier, Özlem Türeci, Ruben Rizzi,
Federico J. Mensa, Claudia Lindemann & Shanti Pather (2024) Safety and reactogenicity of the
BNT162b2 COVID-19 vaccine: Development, post-marketing surveillance, and real-world data,
Human Vaccines & Immunotherapeutics, 20:1, 2315659, DOI: 10.1080/21645515.2024.2315659
To link to this article: https://doi.org/10.1080/21645515.2024.2315659
© 2024 The Author(s). Published with
license by Taylor & Francis Group, LLC.
Published online: 26 Feb 2024.
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HUMAN VACCINES & IMMUNOTHERAPEUTICS
2024, VOL. 20, NO. 1, 2315659
https://doi.org/10.1080/21645515.2024.2315659
REVIEW ARTICLE
Safety and reactogenicity of the BNT162b2 COVID-19 vaccine: Development,
post-marketing surveillance, and real-world data
Frank van den Ouwelanda, Nicola Charpentierb, Özlem Türecic, Ruben Rizzid, Federico J. Mensae, Claudia Lindemannf,
and Shanti Patherg
a
Medical Safety and Pharmacovigilance, BioNTech, Mainz, Germany; bRisk Management, BioNTech, Mainz, Germany; cBioNTech, Mainz, Germany;
Global Regulatory Affairs, BioNTech, Germany, Germany; eClinical Development, Infectious Diseases, BioNTech, Mainz, Germany; fNon-Clinical Safety,
BioNTech, Mainz, Germany; gGlobal Medical Affairs, BioNTech, Mainz, Germany
d
ABSTRACT
ARTICLE HISTORY
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to urgent
actions by innovators, vaccine developers, regulators, and other stakeholders to ensure public access to
protective vaccines while maintaining regulatory agency standards. Although development timelines for
vaccines against SARS-CoV-2 were much quicker than standard vaccine development timelines, regula­
tory requirements for efficacy and safety evaluations, including the volume and quality of data collected,
were upheld. Rolling review processes supported by sponsors and regulatory authorities enabled rapid
assessment of clinical data as well as emergency use authorization. Post-authorization and pharmacov­
igilance activities enabled the quantity and breadth of post-marketing safety information to quickly
exceed that generated from clinical trials. This paper reviews safety and reactogenicity data for the
BNT162 vaccine candidates, including BNT162b2 (Comirnaty, Pfizer/BioNTech COVID-19 vaccine) and
bivalent variant-adapted BNT162b2 vaccines, from preclinical studies, clinical trials, post-marketing
surveillance, and real-world studies, including an unprecedentedly large body of independent evidence.
Received 6 November 2023
Revised 19 January 2024
Accepted 3 February 2024
Introduction
Following the emergence of severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2), an urgent need to develop vac­
cines to counter the rapidly spreading pandemic was quickly
recognized. While maintaining rigorous clinical trial stan­
dards, multiple stakeholders collaborated to expedite vaccine
development, authorization, and roll-out.1
Vaccine clinical development timelines were compressed
through leverage of existing research on previous coronavirus
outbreaks, the utilization of novel vaccine technologies with
shorter design-to-production times, increased funding and
collaboration, at-risk investment in commercial production
from manufacturers prior to approval, and the use of accel­
erated regulatory procedures and expedited review
timelines.1–3 In addition, high infection rates and participant
willingness to take part in clinical trials led to more rapid
enrollment and study completion, when compared with stan­
dard vaccine development timelines. Pre-existing manufac­
turing processes for messenger RNA (mRNA) vaccines
enabled rapid production and scale-up.1 Subsequently, devel­
opment and commercialization timelines were much shorter
compared with other vaccines, such as influenza, while every
step of the pathway required for regulatory approval was
fulfilled (Figure 1).2
The clinical development programs for coronavirus disease
2019 (COVID-19) vaccines, such as BNT162b2, the focus of
this review, generated a large amount of safety data. The initial
CONTACT Shanti Pather
Shanti.Pather@biontech.de
KEYWORDS
SARS-CoV-2; safety;
reactogenicity; vaccine
development; postmarketing surveillance; realworld studies
approvals were based on compelling efficacy and short-term
safety data (up to 2 months follow-up post-primary schedule
for BNT162b2, in line with regulatory guidance).5 Variations
of these approvals to include a booster dose were based on 2.6
months follow-up post-BNT162b2 booster.6 After authoriza­
tion, vaccine manufacturers continued clinical trials and col­
laborated with regulatory authorities and other organizations
for post-marketing pharmacovigilance activities to monitor
longer-term safety. The quantity and breadth of this postauthorization safety data quickly surpassed that generated
from clinical trials. This was supported by real-world data
from countries initiating mass vaccination programs,1 as well
as independent clinical and real-world trials in special popula­
tions and with different vaccination regimens, which con­
firmed the safety profile observed in clinical trials, allowed
analysis of real-world practice patterns, and created an unpre­
cedented level of transparency.7
The ongoing emergence of new variants of SARS-CoV-2
has led to further generation of safety data for mRNA vaccines,
as booster doses and variant-adapted bivalent vaccines have
been developed and brought to the market. Here, we review
safety and reactogenicity data for the BNT162 mRNA vaccine
candidates, including BNT162b2 (Comirnaty, Pfizer/
BioNTech), from preclinical studies, clinical trials, postmarketing surveillance, and real-world studies, as well as
from studies of booster doses and variant-adapted BNT162b2
vaccines.
An der Goldgrube 12, Mainz 55131, Germany.
© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits
unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the
posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
2
F. VAN DEN OUWELAND ET AL.
Figure 1. Accelerated timelines for the development and approval of COVID-19 vaccines.1,2,4 COVID-19, coronavirus disease 2019.
Methods
A literature search was performed in Medline (PubMed) and
pre-print servers medRxiv and bioRxiv for English-language
articles. No additional inclusion or exclusion criteria were
applied. Additional references were obtained by searching
citation lists of retrieved articles, and the authors identified
further appropriate references for inclusion based on expert
knowledge. Other sources of information included pharma­
ceutical company press releases and public health websites.
Systematic search methodology was not used.
The initial formal literature search, comprising terms such
as BNT162b2, SARS-CoV-2, adverse event (AE), AE following
immunization, and AE of special interest (AESI; including
itemized terms such as ‘myocarditis’, ‘Bell’s Palsy’, ‘syncope’,
etc.), was performed on October 05, 2023. After the date of the
initial search, owing to the fast-moving nature of the field,
additional targeted follow-up searches were performed
throughout manuscript development, from first draft to
finalization.
Results
Clinical development of BNT162b2 vaccines
Clinical development of BNT162 vaccines was carried out in
line with regulatory agency standards and applicable
guidelines.5,8,9 Although timelines were compressed because
of the public health emergency, the overall clinical develop­
ment process used was the same as that used for the develop­
ment and approval of other vaccines in terms of trials
performed and data collected (Figure 1).10 Expectations for
safety evaluations, including the volume and quality of data
collected, were the same for vaccines developed in accelerated
and non-emergency pre-approval environments.7
Both the European Medicines Agency (EMA) and the
United States Food and Drug Administration (FDA) devoted
extra resources to support the rapid development and author­
ization of vaccines.7 The FDA EUA pathway enabled the pub­
lic to access COVID-19 vaccines in the emergency pandemic
setting quickly while requiring manufacturers to supply addi­
tional vaccine data from clinical settings for rigorous review.7
Similarly, the EMA expedited its evidence appraisal process
through rolling review stages,3,11 which allowed regulators to
receive and review the data as soon as they became available.
Regular dialogue between manufacturers, regulatory authori­
ties, and other stakeholders was essential in expediting time­
lines while adhering to the development process. Increased
familiarity with the data, and preplanned opportunities for
sponsor/regulator discussions, enabled regulators to provide
expedited assessments of marketing authorization
applications.3 Conditional marketing authorization for
BNT162b2 was first granted by the European Commission
on December 21, 2020.12
Vaccine development was also able to be expedited by
building upon experience gained from development of severe
acute respiratory syndrome coronavirus (SARS-CoV) and
Middle East respiratory syndrome coronavirus (MERS-CoV)
vaccines,13 and because developers had clinical, regulatory,
and manufacturing experience with mRNA formats and lipid
nanoparticle (LNP)-based formulations.14,15 In accordance
with guidance issued in early 2020, led by the International
Coalition of Medicines Regulatory Authorities (ICMRA), wellcharacterized toxicology data could be leveraged across closely
related vaccines using the same platform technology (e.g.,
same RNA formats and LNPs).16 Therefore, a platform-based
toxicology program could be conducted to explore diverse
combinations of mRNA chemistries and formats with different
receptor-binding domain (RBD) or full-length SARS-CoV-2
HUMAN VACCINES & IMMUNOTHERAPEUTICS
spike antigen designs in conjunction with the selected LNP
formulation.
Highly reproducible preclinical data were obtained from
BNT162 vaccine candidates across independent toxicological
evaluations in animal models.17 These efforts established an
early platform toxicology profile that enabled rapid initiation
of a first-in-human clinical trial investigating several of these
vaccine candidates (Figure 1).17 Early stage clinical trials used
sentinel cohorts and dose escalation to optimize enrollment
rate and monitor safety, with stopping rules in place in the
event of safety issues.18 An independent data monitoring
committee reviewed safety data from clinical trials to deter­
mine whether any changes to planned doses should be made,
and any treatment group should be terminated early.18
Double-blind study designs allowed for true assessment of
safety events, and the large numbers of subjects enabled robust
assessment of AEs. For example, clinical evaluation of
BNT162b2 vaccines in approximately 20,000 vaccinated parti­
cipants enabled the detection of events with an incidence of > 1
event in 1,000 vaccinated individuals.19 Key safety and reacto­
genicity data from BNT162 preclinical and clinical trials are
described below.
Preclinical studies of original BNT162 candidate vaccines
Preclinical assessment of BNT162 candidate vaccines was per­
formed in rats, mice, and monkeys. BNT162 vaccine candi­
dates coding for the RBD of the spike glycoprotein (S protein)
have vaccine identifier names that end in “−1, −3,” whereas
those coding for the full-length S protein have vaccine identi­
fier names that end in “−2” (Table 1).15 The preceding letter
refers to distinct RNA platforms differing in chemistry or
format used to construct the vaccine (a = unmodified uridinecontaining RNA [uRNA]; b = pseudouridine-modified RNA
[modRNA]; c = self-amplifying RNA [saRNA]).15,20 All var­
iants were formulated with the same lipid formulation.
3
Five vaccine candidates were evaluated in preclinical
repeat-dose toxicity studies in Wistar Han rats: four encoded
different sequence variants on the RBD of the S protein
(BNT162a1, BNT162b1, BNT162b3 and BNT162c1), and one
encoded the full-length S protein in its pre-fusion conforma­
tion (BNT162b2, with sequence variants V8 and V9;
Table 1A).17 Each candidate vaccine was tolerated without
evidence of systemic toxicity at all doses evaluated, and vac­
cine-related findings for all candidates were similar. Clinical
signs, including swelling at the injection site and increases in
white blood cells, were as expected and consistent with vaccine
administration and immune response; all effects were
reversible.17 There were no effects of BNT162b2 on fertility
parameters or fetal development.21,22 The BNT162b1 and
BNT162b2 vaccine candidates were also evaluated in mice
and rhesus macaques (Table 1A).23
Early clinical trials of original BNT162 vaccines
Clinical dose-evaluation studies were performed to select the
vaccine candidate with an optimal safety, reactogenicity, and
immunogenicity profile.24,25
In an initial Phase I/II dose-escalation study conducted in
Germany in adults 18–85 years of age (NCT04380701), four
BNT162 vaccine candidates were evaluated: BNT162a1,
BNT162b1, BNT162b2, and BNT162c2 (Table 1).26,27
Injection-site reactions within 7 days of administration were
mainly injection-site pain and tenderness, and the severity of
reported reactions was mostly mild or moderate, with an
occasional severe (Grade 3) event. The incidence of reacto­
genicity events was dose-dependent. All AEs resolved sponta­
neously. No serious AEs were reported, and no withdrawals
due to AEs were observed for any dose.27,28
A Phase I, randomized, placebo-controlled, dose-escalation
trial in the United States in adults 18–55 years and 65–85 years
of age evaluated BNT162b1 and BNT162b2 (NCT04368728).29
Table 1. BNT162 vaccine candidates evaluated in (A) preclinical trials and (B) early clinical trials.
BNT162 vaccine
candidate
(product code)†
Platform
(A) Preclinical trials17,23
BNT162a1
uRNA
BNT162b1
modRNA
BNT162b2
modRNA
Wild type
Wild type
Wild type
BNT162b3
BNT162c1
Wild type
Wild type
modRNA
saRNA
SARS-CoV-2
variant†
(B) Early clinical trials26–30,32,105
BNT162a1
uRNA
Wild type
BNT162b1
modRNA
Wild type
†
Encoded antigen
Evaluation
SARS-CoV-2 RBD, a secreted variant
SARS-CoV-2 RBD, a secreted variant
Full-length SARS-CoV-2 S protein bearing mutations preserving
neutralization-sensitive sites,§ a secreted variant
SARS-CoV-2 RBD, a membrane-bound variant
SARS-CoV-2 RBD, a secreted variant
Rats‡
Rats, mice, rhesus macaques
Rats, mice, rhesus macaques
SARS-CoV-2 RBD, a secreted variant
SARS-CoV-2 RBD, a secreted variant
Germany, NCT04380701
Germany, USA, China
NCT04380701
NCT04368728
NCT04523571
Germany, USA, Brazil, Argentina,
Turkey, Germany
NCT04380701
NCT04368728
Germany
NCT04380701
BNT162b2
modRNA
Wild type
Full-length SARS-CoV-2 S protein bearing mutations preserving
neutralization-sensitive sites, a secreted variant
BNT162c2
saRNA
Wild type
Full-length SARS-CoV-2 S protein, a secreted variant
Rats‡
Rats‡
Wild type refers to the USA-WA1/2020 strain. ‡Data on file. §Two sequence variants, V8 and V9, were evaluated in preclinical studies; V9 was included in the final
approved vaccine. modRNA, modified RNA; RBD, Receptor-Binding Domain; S protein, spike protein; saRNA, self-amplifying RNA; SARS-CoV-2, Severe Acute
Respiratory Syndrome Coronavirus 2; uRNA, uridine RNA.
4
F. VAN DEN OUWELAND ET AL.
The most common local reaction within 7 days after receipt of
BNT162b1 and BNT162b2 was injection-site pain; this was
more frequent after the second dose.29,30 Most local reactions
and systemic events resolved by day 7.29,30 No participant who
received either candidate reported a Grade 4 reactogenicity
event, and there were no serious AEs.29 Systemic reactogeni­
city events were milder with BNT162b2 than with BNT162b1,
and fewer recipients of BNT162b2 reported using antipyretic
or pain medication, while the neutralizing antibody profiles of
the vaccines were similar. BNT162b2, which encodes the fulllength SARS-CoV-2 S protein, was selected for further devel­
opment. The 30 μg dose was selected as the preferred dose
level,29 driven by neutralizing antibody response and tolerabil­
ity data across all subgroups by age and sex.
Similar safety and reactogenicity profiles were also observed
for BNT162b1 in Chinese adults and for BNT162b2 in
Japanese adults in Phase I and Phase I/II clinical trials
(NCT04523571 and NCT04588480, respectively).31,32
Phase II/III clinical trials of original BNT162b2
The pivotal Phase II/III clinical trial of BNT162b2
(NCT04368728) was a continuation of the Phase I trial in the
United States, expanded to a global scope. This trial rando­
mized 43,548 participants ≥16 years of age to receive two doses
of 30 μg BNT162b2 or placebo, and included participants from
130 sites in the United States, Argentina, Brazil, South Africa,
Germany, and Turkey.19 The overall safety population
included 18,860 participants who received BNT162b2. In
total, 58% were 16–55 years of age and 42% were >55 years of
age.19
The prescribing information for BNT162b2 presents early
reactivity data from the trial among 5,807 participants 16–55
years of age (2,682 randomized to BNT162b2 and 2,684
randomized to placebo; data cutoff March 13, 2021)
(Table 2).33 In this dataset, the majority of local reactions
after dose 2 were mild, with a mean duration of <3 days.33 In
a larger reactogenicity subset (N = 8,183), the most commonly
reported local reaction was injection-site pain within 7 days of
dose 1 administration, occurring in 83% and 71% of
BNT162b2-vaccinated participants 16–55 years of age and
>55 years of age, respectively. The proportion of participants
vaccinated with BNT162b2 reporting local reactions within 7
days of administration was lower after the second dose (78%
and 66%, respectively).19 No participant reported a Grade 4
local reaction.
Systemic events were more frequent after the second dose
and in younger (16–55 years of age) versus older (≥55 years of
age) participants.19 In total, ≤2% of participants vaccinated
with BNT162b2 reported solicited systemic events graded as
severe within 7 days of administration, with the exception of
fatigue, which occurred in 3.8% of participants after dose 2.19
Two participants vaccinated with BNT162b2 reported
a temperature of ≥40°C within 7 days of administration, as
did two participants in the placebo group.19 Overall, reacto­
genicity events were transient and resolved within 1–2 days
after onset.19 The reactogenicity profile of a larger subgroup of
participants, including the initial 8,183 participants plus
another 1,656 enrolled after the initial data cutoff, remained
consistent with the earlier datasets.34
Among 43,252 participants with variable follow-up time for
AEs, lymphadenopathy was reported by 64 (0.3%) BNT162b2
recipients and six (<0.1%) placebo recipients. This generally
resolved within 10 days and was likely a result of a robust
vaccine-elicited immune response in the BNT162b2
recipients.19 Participants were followed for serious AEs up to
6 months after dose 2. Four serious AEs considered to be
related to vaccination were reported by recipients of
Table 2. Frequency and percentages of participants with solicited local reactions, by maximum severity,
within 7 days after each dose – participants 16–55 years of age – reactogenicity subset.†,33.
Redness‖
Any (>2.0 cm)
Mild
Moderate
Severe
BNT162b2
Dose 1
N‡ = 2,899
n§ (%)
Placebo
Dose 1
N‡ = 2,908
n§ (%)
BNT162b2
Dose 2
N‡ = 2,682
n§ (%)
Placebo
Dose 2
N‡ = 2,684
n§ (%)
156 (5.4)
113 (3.9)
36 (1.2)
7 (0.2)
28 (1.0)
19 (0.7)
6 (0.2)
3 (0.1)
151 (5.6)
90 (3.4)
50 (1.9)
11 (0.4)
18 (0.7)
12 (0.4)
6 (0.2)
0
16 (0.6)
6 (0.2)
8 (0.3)
2 (0.1)
183 (6.8)
110 (4.1)
66 (2.5)
7 (0.3)
5 (0.2)
3 (0.1)
2 (0.1)
0
414 (14.2)
391 (13.4)
20 (0.7)
3 (0.1)
2,101 (78.3)
1,274 (47.5)
788 (29.4)
39 (1.5)
312 (11.6)
284 (10.6)
28 (1.0)
0
Swelling‖
Any (>2.0 cm)
184 (6.3)
Mild
124 (4.3)
Moderate
54 (1.9)
Severe
6 (0.2)
Pain at the injection site¶
Any
2,426 (83.7)
Mild
1,464 (50.5)
Moderate
923 (31.8)
Severe
39 (1.3)
Reactions were collected in the electronic diary (e-diary) from day 1 to day 7 after vaccination. No Grade 4
solicited local reactions were reported in participants 16–55 years of age. †Randomized participants in the
safety analysis population who received at least one dose of the study intervention. Participants with chronic,
stable human immunodeficiency virus (HIV) infection were excluded. ‡N = number of participants reporting at
least one yes or no response for the specified reaction after the specified dose. The N for each reaction was the
same; therefore, this information was included in the column header. §N = number of participants with the
specified reaction. ‖Mild: > 2.0 to ≤ 5.0 cm; moderate: > 5.0 to ≤ 10.0 cm; severe: > 10.0 cm. ¶Mild: does not
interfere with activity; moderate: interferes with activity; severe: prevents daily activity.
HUMAN VACCINES & IMMUNOTHERAPEUTICS
BNT162b2; these were shoulder injury, right axillary lympha­
denopathy, paroxysmal ventricular arrhythmia, and right leg
paresthesia. No deaths were considered to be related to the
vaccine, and few patients had AEs that led to trial
withdrawal.19,34
After authorization of BNT162b2, participants were
given the option to learn their trial assignment, and
those receiving placebo were offered BNT162b2 in the
context of the pandemic.34 To ensure long-term followup of both BNT162b2 and placebo recipients, participants
continued to be followed after unblinding. No safety sig­
nals were observed during the extended follow-up
period.34
BNT162b2 has also been evaluated in a Phase II trial in
960 Chinese adults 18–85 years of age, in which 720 indi­
viduals received BNT162b2 (NCT04649021). The reacto­
genicity and safety profile of BNT162b2 in this
population was consistent with that of the global Phase
II/III trial.35
Pediatric development
Following authorization of the BNT162b2 vaccine for adult
populations, a clinical trial was performed in participants 6
months–11 years of age to assess pediatric age-related doses
of BNT162b2. In the Phase I portion, the cohort of children
5–11 years of age received two doses of BNT162b2 10 μg, 20
μg, or 30 μg (NCT04816643). Owing to a higher frequency
of fever with the higher doses, and because the neutralizing
antibody profiles of the 10 μg and 20 μg doses were similar,
the 10 μg dose was selected for further assessment in the
Phase II/III portion.36 In the cohort of children 6 months–4
years of age, participants received either 10 μg or 3 μg
BNT162b2. Owing to a higher frequency and greater severity
of reactogenicity to the 10 μg dose versus the 3 μg dose, and
similar neutralizing antibody profiles across dose levels to
that observed in older age groups, the 3 μg dose was selected
for further assessment.37
The pivotal Phase II/III clinical trial of BNT162b2
(NCT04368728) also included a cohort of 2,260 participants
12–15 years of age, of whom 1,131 received BNT162b2.
Solicited local and systemic events were generally mild or
moderate in severity and were reported at a similar frequency
to participants 16–25 years of age. One participant discontin­
ued the study due to a vaccine-related event of temperature ≥
40°C after dose 1. Lymphadenopathy was reported by nine
(0.8%) recipients of BNT162b2. Up to 1 month after dose 2,
no vaccine-related serious AEs and no deaths had been
reported.38 Of the 1,131 participants who received
BNT162b2, 786 were followed for ≥4 months after the second
dose, with the overall safety profile remaining similar to that
seen in participants ≥16 years of age.21
In the Phase II/III portion of the clinical trial in children
<12 years of age (NCT04816643), 1,517 children 5–11 years of
age were randomized to receive 10 μg BNT162b2. Local reac­
tions were generally mild to moderate in intensity and lasted
1–2 days. Consistent with the trial in adults, injection-site pain
was the most common local reaction, and fatigue and head­
ache were the most common solicited systemic reactions. One
5
recipient of BNT162b2 reported a temperature of ≥ 40°C after
the second dose, which resolved with antipyretics.36 After
a median follow-up time of 2.3 months after the second dose
(95% of BNT162b2 recipients had a follow-up of ≥2 months),
no vaccine-related serious AEs, AEs leading to withdrawal, or
deaths had been reported.36 Safety evaluation in this study is
ongoing.21
In a cohort of 3,013 children 6 months–4 years of age who
received BNT162b2, most local and systemic reactions were
mild to moderate in intensity and no Grade 4 local reactions
were reported. The frequency of AEs was similar in BNT162b2
and placebo recipients, few participants were withdrawn due
to AEs, and no deaths occurred.37
Booster doses
The safety and reactogenicity of third and fourth doses of
BNT162b2 were assessed in participants from the pivotal
Phase II/III clinical trials. In 5,081 participants who received
a third dose of BNT162b2, reactogenicity was similar to that
observed after the second dose. With a median of 2.5 months
of follow-up from dose 3, the safety profile of the vaccine was
consistent with earlier trials, and no new safety signals were
identified. Three participants who received BNT162b2 experi­
enced serious AEs that were considered to be related to the
vaccine; these were tachycardia in one participant and
increased hepatic enzyme levels in two participants.39
A subset of 306 participants 18–55 years of age were followed
for a median of 8.3 months post-booster dose, with 301 fol­
lowed for ≥6 months. The overall safety profile of the booster
dose remained consistent with that seen after two doses.21
In the trial in children <12 years of age, 401 participants 5–
11 years of age received a third dose at least 5 months (range 5–
9 months) after completing the primary series. With a median
follow-up time of 1.3 months, the overall safety profile was
similar to that seen after the primary course.21 In 570 infants
6–23 months of age with a median of 1.3 months of follow-up
after dose 3, and 886 children 2–4 years of age with 1.4 months
of follow-up after dose 3, reactogenicity after dose 3 was con­
sistent with the known safety profile of BNT162b2.21
In adults 18–55 years of age (N = 325) and >55 years of age
(N = 305) who received a fourth dose of BNT162b2, the safety
profile was similar to that observed after dose 3, after a median
of 1.4 and 1.7 months follow-up post-dose 4, respectively.21
Because these studies enrolled participants from the previous
trials who consented to further study, results may be subject to
selection bias.
Overall, the clinical development program for BNT162b2
included the largest pivotal registrational COVID-19 vaccine
trial conducted to date and evaluated more than 44,000 parti­
cipants >12 years of age from around the world (Table 3).19,38
These findings were supported by further study in different
world regions31,35 and Phase II/III trials in children >6 months
of age.21,36,37
Variant-adapted vaccines
The emergence of SARS-CoV-2 variants became apparent
shortly after the first COVID-19 vaccines were deployed,
Finland, Poland, Spain,
United States
Brazil, Finland, Poland,
Spain, United States
II/III
United States
II/III
NCT04816643 I/II
II/III
NCT04368728 I
Recipients (N,† age)
N = 16
5–11 years
31.3% male, 68.8% White,
18.8% Black or African
American, 12.5% Asian
N = 16
6 months to <2 years
62.5% male, 87.5% White,
6.3% Asian
N = 16
2–4 years
56.3% male, 75.0% White,
6.3% Asian
N = 1,518
5–11 years
52.6% male, 79.3% White,
5.9% Black, 5.9% Asian
N = 1,178
6 months to <2 years
50.0% male, 78.3% White,
3.6% Black, 7.7% Asian
N = 1,835
2–4 years
49.1% male, 80.1% White,
5.1% Black, 6.9% Asian
N = 12
18–55 years
66.7% male, 100% Caucasian
United States
N = 12
18–55 years
50% male, 83% White,
17% Asian
N = 12
65–85 years
33% male, 83% White,
17% Asian
Argentina, Brazil,
N = 21720
Germany, South Africa, ≥16 years
Turkey, United States
51.1% male, 82.9% White,
9.2% Black or African
American, 4.2% Asian
N = 1,131
12–15 years
50.1% male, 85.9% White,
4.6% Black or African
American, 6.4% Asian
Trial
Phase
Location
Original vaccine primary series
NCT04380701 I/II
Germany
Publication
Two doses
3 μg
Two doses 10 μg
Two doses
3 μg
Two doses 10 μg
● Most reactogenicity events were mild to moderate, no Grade 4 local reactions
● Few participants withdrawn due to AEs
● No deaths occurred
follow-up of 2.3 months after dose 2 (95% with ≥2 months follow-up)
(Continued)
Munoz et al.37
● Local and systemic reactions generally mild to moderate
Walter et al.36
● Severe reactions: injection-site pain 0.6%, fatigue 0.9%, headache 0.3%
● No vaccine-related serious AEs, AEs leading to withdrawal, or deaths with median
● Local and systemic reactions generally mild to moderate
Munoz et al.37
Local and systemic reactions generally mild to moderate, resolved within 1–2 days
Frenck et al.38
Severe injection-site pain in 1.5%, one discontinuation due to temperature ≥40°C
EMA SmPC21
Lymphadenopathy in 0.8%
No serious AEs related to vaccine
In 786 participants with ≥4 months follow-up after dose 2, the safety profile remained
similar to that in ≥16 years of age after
● Most local reactions mild to moderate, all transient
Walter et al.36
Two doses 30 μg
●
●
●
●
●
● No Grade 4 local reactions; most local events resolved within 1–2 days
Polack et al.19
● Severe systemic events in ≤2% except fatigue (3.8%) within 7 days after dose 2
Thomas et al.34
● Four related serious AEs and no vaccine-related deaths with up to 6 months follow-up
Local reactions mostly mild to moderate in intensity, occasionally severe (Grade 3)
Sahin et al.28
All AEs resolved spontaneously and were managed with simple measures
No serious AEs or withdrawals due to related AEs
Most common local reaction was injection-site pain, more frequent after dose 2
Walsh et al.29
No Grade 4 reactogenicity events
Related AEs reported by 25% of participants 18–55 years of age and 0% participants
65–85 years of age
● No serious AEs
●
●
●
●
●
●
Reactogenicity/safety
Two doses 30 μg
Two doses 30 μg
Two doses 30 μg
Doses
Table 3. Safety data for approved BNT162b2 doses from clinical trials. Data for approved formulation and doses included only.
6
F. VAN DEN OUWELAND ET AL.
China
NCT04649021 II
Location
N = 97
20–64 years
51.5% male, 100% Asian
N = 22
65–85 years
40.9% male, 100% Asian
N = 720
18–85 years
51.5% male, 100% Chinese
(Han ethnicity)
Recipients (N,† age)
N = 412
≥12 years
41.3% male, 79.1% White,
12.6% Black, 5.3% Asian
N = 74
≥18 years
N = 305
>55 years
53.1% male, 89.8% White,
4.3% Black, 5.2% Asian
N = 305
>55 years
N = 325
18–55 years
N = 401
5–11 years
N = 1,456
6 months to 4 years
Doses
Fourth to seventh dose
30 μg
Fourth dose
30 μg
Fourth dose
30 μg
Fourth dose
30 μg
Fourth dose
30 μg
Third dose
10 μg
Third dose
3 μg (any primary course
dose)
Third dose
30 μg
Two doses 30 μg
Two doses 30 μg
†
Total N randomized to BNT162b2 at dose shown.
AE, adverse event; EMA, European Medicines Agency; SmPC, Summary of Product Characteristics.
XBB.1.5 variant-adapted vaccine
NCT05997290 II/III
United States
Original/Omicron BA.4–5 variant-adapted vaccine
NCT05472038 II/III
United States
Original/Omicron BA.1 variant-adapted vaccine
NCT04955626 III
United States
Not stated
Not stated
Not stated
III
NCT04816643 II/III
Not stated
III
Original vaccine booster doses
NCT04955626 II/III
Brazil, South Africa, United N = 5,081
States
≥16 years
48.4% male, 78.7% White,
9.3% Black, 5.7% Asian
Japan
Phase
NCT04588480 I/II
Trial
Table 3. (Continued).
Most reactogenicity events mild to moderate
No Grade 4 reactogenicity events
No new adverse reactions identified
No vaccine-related serious AEs, AEs leading to withdrawal, or deaths
●
●
●
●
After 1 month follow-up, most reactogenicity events mild to moderate
AEs infrequent (7.5% in the total population); none led to study withdrawal
No myocarditis or pericarditis reports
No new safety signals
● Safety profile similar to that of the original vaccine
●
●
●
●
children 2–4 years of age with 1.4 months follow-up after dose 3, reactogenicity
after dose 3 was consistent with the known safety profile of BNT162b2
Gayed et al.42
BioNTech41
Winokur et al.40
● In 570 infants 6–23 months of age with median 1.3 months follow-up, and 886 EMA SmPC21
similar to that seen after the primary course
● With median follow-up time of 1.3 months after dose 3, overall safety profile was EMA SmPC21
known safety profile of BNT162b2
● With median follow-up of 1.4 months after dose 4, reactogenicity was consistent with EMA SmPC21
seen after dose 3
● With median follow-up of 1.7 months after dose 4, the safety profile was similar to that EMA SmPC21
identified
● Three vaccine-related serious AEs
● Subset of 306 participants followed for median 8.3 months, no new safety signals
consistent with primary series
● Reactogenicity after dose 3 similar to that after dose 2
Moreira et al.39
● With median follow-up of 2.5 months after dose 3, the safety profile remained EMA SmPC21
Hui et al.35
● Most reactogenicity events mild to moderate and transient
● No vaccine-related serious AEs or deaths
Publication
Haranaka
et al.31
Reactogenicity/safety
● Most common local reaction: injection-site pain
● Reactogenicity events mild to moderate and generally transient
● No serious/life-threatening AEs and no deaths
HUMAN VACCINES & IMMUNOTHERAPEUTICS
7
8
F. VAN DEN OUWELAND ET AL.
Table 4. Surveillance systems.
Passive surveillance systems
Purpose Collect spontaneous AE reports
Example CDC VAERS in the United States and the EMA
EudraVigilance system in the European
Union57,61,62
Active surveillance systems
Collect all reports of pre-specified AEs from
a representative population, such as a sentinel
site
United States VSD and BEST61,62
Other
Track post-marketing surveillance AEs
Collaborate with academic and nongovernment healthcare systems
CISA and the CBER61,62
WHO VigiBase captures reports from
national centers from over 130
countries63
AE, Adverse Event; BEST, Biologics Effectiveness and Safety; CBER, Center for Biologics Evaluation and Research; CDC, United States Centers for Disease Control and
Prevention; CISA, CDC Clinical Immunization Safety Assessment; EMA, European Medicines Agency; VAERS, Vaccine Adverse Event Reporting System; VSD, Vaccine
Safety Datalink; WHO, World Health Organization.
prompting developers to evaluate updated vaccine candidates.
When the Omicron BA.1 variant of SARS-CoV-2 and its sub­
sequent lineages emerged, BioNTech/Pfizer pursued the devel­
opment of several variant-adapted vaccines, including
a monovalent BA.1 vaccine candidate, a bivalent vaccine can­
didate targeting both the original wild-type virus and BA.1,
and a bivalent vaccine targeting the original wild-type virus
and BA.4/BA.5.40
In view of the public health urgency for protection against
Omicron subvariants, the bivalent vaccines encoding the
Original/Omicron BA.1 and Original/Omicron BA.4/5
spike proteins were approved by regulators in different
regions. These approvals were based on clinical trials con­
ducted with BA.1 vaccine candidates (monovalent and biva­
lent, at different dose levels) demonstrating significant
increases in neutralizing antibody titers,40 as well as precli­
nical immunogenicity data, and were supported by the
extensive and robust safety database for the original
BNT162b2 vaccine and the clinical data generated across
multiple variant-adapted vaccine candidates encoding earlier
SARS-CoV-2 variants.43 In parallel, clinical trials were
initiated to further evaluate the safety and reactogenicity of
these vaccines.
In a Phase III clinical trial, adults >55 years of age who had
previously received three doses of the original BNT162b2
vaccine were randomized to receive either bivalent Original/
Omicron BA.1 BNT162b2 vaccine or original BNT162b2
(NCT04955626) (Table 3). In total, 306 participants were ran­
domized to receive a 30 μg dose and 316 received a 60 μg dose
of bivalent vaccine.40 The bivalent Original/Omicron BA.1
BNT162b2 vaccine had a similar local reaction and systemic
event profile to the original BNT162b2 vaccine.21,40 Most
reactogenicity events were mild to moderate in intensity and
no Grade 4 reactogenicity events were reported. Injection-site
pain and fatigue were the most common local and systemic
reactogenicity events, respectively. In participants >55 years of
age, mild-to-moderate injection-site pain, fatigue, and muscle
pain were more common with the 60 μg dose than with the 30
μg dose of bivalent vaccine.44 No serious AEs were considered
related to the bivalent vaccine, and there were no AEs leading
to withdrawal or deaths.40 No new safety signals were
detected.21
The 30 μg bivalent Original/Omicron BA.4–5 vaccine was
assessed in a Phase II/III trial in adults 18–55 years of age and
>55 years of age who had previously received three doses of the
original BNT162b2 vaccine (NCT05472038).45 Early clinical
safety data from 7 and 30 days post-vaccination indicate that
the bivalent Original/Omicron BA.4–5 BNT162b2 vaccine is
well tolerated, with a safety profile similar to that of the
original vaccine.41,45
Continued evolution of SARS-CoV-2 led to recommenda­
tions from the WHO Technical Advisory Group on COVID19 Vaccine Composition (TAG-CO-VAC) to include
a component of an XBB.1 descendant sub-lineage of SARSCoV-2 in COVID-19 vaccines for fall 2023.46 Following con­
sistent guidance issued by the EMA/European Centre for
Disease Control and Prevention,47 and by the FDA,48
BioNTech and Pfizer developed a monovalent XBB.1.5 vaccine
that has received regulatory approvals in various countries.49,50
1-month safety follow-up from an ongoing Phase II/III study
of this vaccine in participants ≥12 years of age (NCT05997290)
did not detect any new safety signals. Local reactions and
systemic events were mostly mild to moderate in severity,
AEs were infrequent (7.5% of the total population), and no
AEs led to study withdrawal.42
Post-marketing surveillance and real-world data
In both the United States and European Union, postauthorization safety monitoring and risk minimization proce­
dures were put in place following BNT162b2 commercializa­
tion. International Risk Management Plans (RMPs), or
comprehensive documents summarizing the vaccine safety
profile and measures taken to further investigate and mitigate
risks, were submitted alongside dossiers for marketing
authorization.51 Post-authorization commitments included in
the European Union RMP included studies to assess the risk of
vaccine-associated enhanced disease, impacts on special popu­
lations (including pregnant/breastfeeding women and those
with compromised immune systems or comorbidities), and
the potential for interactions between vaccines, as well as
studies to obtain longer-term safety data.52 After FDA
approval following a period of EUA, additional postmarketing studies to assess the risk of myocarditis and peri­
carditis were required. A registry to evaluate pregnancy and
infant outcomes was also established.53 In the European
Union, the EMA Pharmacovigilance Risk Assessment
Committee published regular safety update reports based on
data from the marketing authorization holder and data
reported by either patients or healthcare providers to
EudraVigilance.12,54
Post-marketing safety reporting for COVID-19 vaccines
has been extremely robust compared with other vaccines.
COVID-19 vaccine safety surveillance in the United States
has been described as the most intensive in the country’s
history.55 During the peak of the pandemic, manufacturers of
HUMAN VACCINES & IMMUNOTHERAPEUTICS
COVID-19 vaccines were required to submit monthly safety
reports to the EMA.56 These safety updates subsequently
reduced in frequency and were eventually discontinued when
the EMA concluded that the safety profile of the vaccines had
been well established.56,57 Monthly safety reports continue to
be submitted to the FDA.58 Marketing authorization holders
are legally obliged to set up and maintain database systems for
authorized products to receive, record, and analyze safety data
and signals from spontaneous reporting.59
Post-authorization, the safety of BNT162b2 and other
COVID-19 vaccines has been monitored through both passive
and active surveillance systems.60 Together, these surveillance
systems (Table 4) capture safety data from an extensive and
heterogenous global population. In European Union/
European Economic Area countries alone, as of June 16,
2023, almost 535 million doses of original BNT162b2 and
32 million doses of bivalent BNT162b2 have been
administered.64 In the United States, as of May 10, 2023,
more than 360 million and 36 million doses, respectively,
have been administered.65
When rare events are detected by a safety monitoring sys­
tem, manufacturers, as well as regulatory bodies such as the
FDA and EMA, review the signals. This is done, for example,
by comparing rates in vaccinated and unvaccinated people,
comparing rates in an early reporting period with a later inter­
val when more data have been collected, and comparing with
data from other surveillance systems, databases, and published
literature. If an event is determined as likely to be associated
with vaccination, regulatory agencies may then request
changes to vaccine recommendations or product information.
Monitoring and analysis of the event will continue in order to
detect any changes to a signal, until the event is closed.55,57
Implementation of mass vaccination programs also enables
real-world studies of vaccine safety in vaccinated populations.
These studies can complement post-marketing surveillance by
providing additional data on safety signals. They may also
provide estimates on more common events, such as reacto­
genicity, in different populations from those enrolled in the
clinical trials. For COVID-19 vaccines, real-world studies had
an important impact on post-authorization regulatory agency
and government decision-making due to their unprecedented
number, early conduct, and rapid publication.
Selected AESIs reported with BNT162b2 vaccination
AESIs are pre-identified and pre-defined serious or nonserious AEs of scientific and medical interest for which
ongoing monitoring, further investigation, and/or rapid com­
munication by the sponsor to the regulator or other stake­
holders may be appropriate.66,67 AESIs are usually identified
through active vaccine safety surveillance systems.67 Prior to
vaccine use in the community, AESIs are identified based on
known occurrence patterns in the population and their poten­
tial to be associated with one or more vaccine platforms.67 AE
case definitions are developed by the Brighton Collaboration,
which also maintains a list of vaccine platform-related
AESIs.11,67,68 AESIs that have been reported following
BNT162b2 vaccination include Bell’s palsy, and myocarditis
and pericarditis.
Facial paralysis and swelling, bell’s palsy
Acute peripheral facial paralysis, or Bell’s palsy, is a rare event
associated with BNT162b2 vaccination, occurring in ≥1 in
10,000 to <1 in 1,000 recipients (Table 5).21 This rare event
was initially detected during clinical trials,21 and cases have
since been observed post-BNT162b2 administration during
mass vaccination campaigns,69,70 although a causal association
between these events and BNT162b2 vaccination has not been
clearly demonstrated.71,72 In case – control studies in
Hong Kong and Israel, rates of facial nerve palsy/Bell’s palsy
reported after COVID-19 vaccination were similar to back­
ground rates recorded during years prior to the emergence of
COVID-19.71,73
Facial nerve palsy has been described as an AE following
administration of other vaccines, including influenza, varicella,
human papillomavirus, diphtheria – tetanus – pertussis, and
meningococcal vaccines.74 Causality is not confirmed, with the
exception of an intranasal influenza vaccine containing
Escherichia coli heat-labile toxin as an adjuvant, leading to
the hypothesis that this toxin or the route of administration
may be a cause.72,75 BNT162b2 does not include this toxin and
uses a different mechanism to stimulate an immune
response.71
Myocarditis and pericarditis
Myocarditis/pericarditis is a very rare AE that has been
observed after administration of COVID-19 mRNA vaccines
(Table 5).76 Owing to its rarity, this event was not detected in
clinical trials, but was reported post-authorization.21
Myocarditis and pericarditis are considered important identi­
fied risks for COVID-19 mRNA vaccines, including original
BNT162b2 vaccine and variant-adapted vaccines, and are
included and described accordingly in the European Union
RMP and aggregate safety reports. The frequency varies
Table 5. Frequency of selected adverse events and AESIs following BNT162b2 vaccination in individuals ≥12 years
of age based on clinical trials and post-authorization experience21.
Adverse event/AESI
Acute peripheral facial paralysis (Bell’s palsy)
Myocarditis/pericarditis
Hypersensitivity reactions
Heavy menstrual bleeding
Anaphylaxis†
†
9
Frequency
Rare (≥ 1/10,000 to < 1/1,000)
Very rare (< 1/10,000)
Uncommon (≥ 1/1,000 to < 1/100)
Not known (cannot be estimated from available data)
Not known (cannot be estimated from available data)
Appropriate medical treatment and supervision should always be readily available in case of an anaphylactic
reaction following administration of the vaccine. Close observation for at least 15 minutes is recommended
following vaccination. No further dose of the vaccine should be given to those who have experienced
anaphylaxis after a prior dose.21 AESI, adverse event of special interest.
10
F. VAN DEN OUWELAND ET AL.
depending on the mRNA vaccine used.77 After BNT162b2
vaccination, myocarditis has occurred in <1 in 10,000
recipients.21
Myocarditis has been reported within a few days of vacci­
nation, usually within 14 days. It is more frequently observed
after the second dose than the first dose of the vaccine, and its
incidence is highest in young men.21 A large European phar­
macoepidemiologic study estimated that the excess risk of
myocarditis over the 7 days post-dose 2 was 0.265 (95% con­
fidence interval [CI]: 0.255–0.275) extra cases per 10,000 for
men 12–29 years of age, compared with unexposed persons.
Another similar study estimated an excess of 0.56 extra cases
per 10,000 during the 28 days post-dose 2 in men 16–24 years
of age.21 In the United States, the estimated incidence of
myocarditis during the 7 days post-dose 2 of any COVID-19
mRNA vaccine based on cases reported to the United States
Centers for Disease Control and Prevention (CDC) Vaccine
Adverse Event Reporting System (VAERS) was 40.6 cases
per million doses in men 12–29 years of age and 2.4 per million
in those ≥30 years of age; corresponding rates for women were
4.2 and 1.0 per million, respectively.76 Estimates from
a systematic literature review reported a range of 50–139 and
28–147 cases per million in young men 12–17 years of age and
18–29 years of age, respectively, after COVID-19 mRNA
vaccination.77
The clinical course and prognosis of post-vaccination myo­
carditis is comparable with myocarditis of other causes.54 In
fact, the available literature supports that COVID-19 vaccineassociated myocarditis has a milder presentation, higher recov­
ery rate, and lower mortality compared with myocarditis of
other causes (Table 6).78–82 In the few cases observed, the
severity of myocarditis and pericarditis following BNT162b2
vaccination varied; most patients responded well to medications
and rest, with prompt improvement of symptoms. Preliminary
United States CDC surveys conducted ≥90 days post-diagnosis
showed that most patients fully recovered.83 Data from the
United States CDC, VAERS, and a European observational
study suggest that SARS-CoV-2 infection-related myocarditis
occurs in 15–400 people per 10,000 infected.84–87 Based on
a study evaluating magnetic resonance imaging from the
University of Toronto and a systematic literature review, the
patterns of myocardial injury with vaccine‐associated myocar­
ditis are similar to those seen with idiopathic or viral myocardi­
tis, such as that induced by COVID-19.81,82 Immunopathology
data from the United States suggest that myocarditis postvaccination might be driven by elevation of circulating inflam­
matory cytokines and corresponding lymphocytes, with no evi­
dence of cardiac-targeted autoantibodies, hypersensitivity, or
hyperimmune humoral mechanisms.88
Other select AEs following BNT162b2 immunization
Hypersensitivity
Hypersensitivity to BNT162b2 has been reported, with symp­
toms such as rash and pruritus occurring in ≥1 in 1,000 to <1
in 100 recipients ≥12 years of age (Table 5).21 Allergic reac­
tions may be due to active ingredients or excipients used in the
vaccine formulation.89 The incidence of anaphylaxis (severe,
life-threatening allergic reaction) is low and, thus, difficult to
estimate from available data.21
After administration of 1,893,360 first doses of
BNT162b2, 21 cases meeting Brighton Collaboration cri­
teria for anaphylaxis were identified in the CDC’s VAERS,
corresponding to a rate of 11.1 cases per million doses.90
A later report after 9,943,247 doses of BNT162b2 estimated
a rate of 4.7 cases of anaphylaxis per million doses
administered.91 In total, 77% of individuals had a past
history of allergic reaction, and 34% had a past history of
anaphylaxis.91
Although anaphylaxis was one of the first safety signals to
be detected with BNT162b2 during post-marketing surveil­
lance, with progressive exposure, it became apparent that the
cumulative number of cases was very small.12 Late hypersen­
sitivity reactions (appearing or lasting >24 h after vaccina­
tion) linked with prior exposure to hyaluronic acid
dermatological fillers have been reported in a study in
Israel, but these did not prevent individuals from receiving
subsequent doses of the vaccine.92
Anxiety-related reactions
Anxiety-related reactions, such as syncope, dizziness, palpita­
tions, increases in heart rate, alterations in blood pressure,
paresthesia, hypoesthesia, and sweating, may occur after
BNT162b2 vaccination. These are not AEs caused by the
vaccine formulation, but are rather due to stress and anxiety
associated with the vaccination process itself.21 These stressrelated reactions are temporary and will resolve on their own.
Individuals suffering from anxiety should bring symptoms to
the attention of the vaccination provider for evaluation.
Precautions should be taken to avoid injury from fainting.21
Heavy menstrual bleeding
Heavy menstrual bleeding (defined as increased volume or dura­
tion that interferes with quality of life) has been reported after
BNT162b2 administration.21,93,94 The incidence of this event is
unknown (Table 5), and based on evidence from nearly 9,000
cases from clinical trials, observational studies, post-marketing
surveillance activities, and spontaneous reports, most cases have
appeared to be non-serious and temporary in nature.94
A small number of cases involving positive re-challenge
suggested a possible causal relationship.94 COVID-19 vaccina­
tion is a powerful immune stimulant; thus, it could be
hypothesized that the sensitive immune system of the endo­
metrium is briefly modified by vaccination, potentially leading
to menstrual disorders.95 However, other studies have failed to
detect an association between change in menses cycle length
and COVID-19 vaccination.96 Menstrual disorders can occur
for a wide range of reasons, including some underlying med­
ical conditions.94 There is no evidence to suggest that men­
strual changes occurring after BNT162b2 vaccination have any
impact on fertility.94
Comparison with other prophylactic vaccines
An analysis of the WHO international database, VigiBase,
comparing the incidence of AEs following COVID-19 mRNA
vaccination with that of approved influenza vaccines, showed
that serious cardiovascular events were more prevalent with
Nationwide register data
7,292 patients with new onset myocarditis (530 associated with mRNA
vaccination, 109 associated with COVID-19, 6,653 with conventional
myocarditis), within a population of 23 million individuals
Population
1,612 cases of myocarditis, within a population of 32 million 12–50 years of
age (21.2 million received first and 19.3 million received second doses of
BNT162b2; 2.86 million received first and 2.58 million received second
doses of mRNA-1273)
Self-controlled case series 2,861 cases of myocarditis, within a population of 42,842,345 people
receiving at least one dose of COVID-19 vaccine
Design
Matched case – control
study
CI, confidence interval; COVID-19, coronavirus disease 2019; mRNA, messenger RNA; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Denmark, Finland,
Norway, and
Sweden
Husby et al.
202380
Location
England
France
Patone et al.
202279
Publication
Le Vu et al.
202278
Table 6. Key studies comparing post-vaccination myocarditis with myocarditis from other causes including COVID-19.
Outcomes
●
●
●
●
tion, and death was observed in patients with post-mRNA vaccination
myocarditis than in unvaccinated patients with myocarditis from any
cause
Risk of myocarditis was increased in the 1 to 28 days after a first, second,
and booster dose of BNT162b2 (1.52 [95% CI 1.24–1.85], 1.57 [95% CI
1.28–1.92], and 1.72 [95% CI 1.33–2.22]) but was lower than the risks
after a positive SARS-CoV-2 test before or after vaccination (11.14 [95%
CI 8.64–14.36] and 5.97 [95% CI 4.54–7.87])
At 90 days follow-up, relative risk of heart failure was higher for
myocarditis associated with COVID-19 than for myocarditis associated
with vaccination (1.48 [95% CI 0.86–2.54] and 0.56 [95% CI 0.37–0.85]
versus conventional myocarditis)
At 90 days follow-up, relative risk of death was higher for myocarditis
associated with COVID-19 than for myocarditis associated with vacci­
nation (2.35 [95% CI 1.06–5.19] and 0.48 [95% CI 0.21–1.09] versus
conventional myocarditis)
Among patients 12–39 years of age with no predisposing comorbidities,
the relative risk of heart failure or death was markedly higher for
myocarditis associated with COVID-19 disease than for myocarditis
associated with vaccination (relative risk 5.78 [95% CI 1.84–18.20])
● A lower frequency of intensive care unit admission, mechanical ventila­
HUMAN VACCINES & IMMUNOTHERAPEUTICS
11
12
F. VAN DEN OUWELAND ET AL.
the COVID-19 vaccines, while influenza vaccines were more
frequently associated with neurological AEs.97 Overall, the risk
of serious events with the COVID-19 mRNA vaccines was
lower than that of the influenza vaccines. Similarly, in
a study evaluating AEs in children <5 years of age in
Germany, symptoms following BNT162b2 vaccination were
generally comparable to those following non-SARS-CoV-2
vaccines including influenza, meningococcal, measles –
mumps – rubella, tetanus – diphtheria – pertussis, hepatitis
A/B, and human papillomavirus vaccines.98
Discussion
The overall experience accrued over time on the safety and
reactogenicity of BNT162b2 is extensive, robust, and compre­
hensive, and it has confirmed the initial safety profile observed
in clinical trials, demonstrating that the vaccine is well toler­
ated. Most adverse reactions are transient, can be managed
with medications, or can be reduced through preventive mea­
sures. The BNT162 original and variant-adapted vaccines have
been well tolerated, and their safety and reactogenicity profiles
have remained consistent throughout the clinical development
process, which included the largest pivotal registrational
COVID-19 vaccine trial conducted to date.
Occurrences of suspected AEs following vaccination should
be interpreted in the context of overall numbers of doses
administered and background rates of events. Serious AEs
potentially related to vaccination are very rare21,99; therefore,
vaccination should be encouraged, as it provides protection
against a potentially deadly illness. Although the benefit – risk
profile of BNT162b2 varies by age and sex, the prevention of
hospitalization, severe disease, and death outweighs the risk of
AEs after vaccination in the populations for which vaccination
is recommended. Vaccine-associated myocarditis/pericarditis
is a rare adverse reaction identified for COVID-19 vaccines. As
the risk of myocarditis/pericarditis resulting from COVID-19
disease is higher than the risk of myocarditis/pericarditis asso­
ciated with vaccination,100 and as the benefits of prevented
COVID-19 cases and related severe outcomes outweigh the
risks of myocarditis and pericarditis after receipt of mRNA
COVID-19 vaccines, the overall benefit – risk profile of
BNT162b2 is positive.83,101 It has been estimated that
COVID-19 vaccines saved 19.8 million lives during the
first year of rollout alone.102
Vaccine developers continue to collaborate with regulatory
authorities for ongoing safety surveillance of COVID-19 vac­
cines as a key priority, while variant-adapted vaccines are
rolled out.49,50,103,104 Ongoing collection of safety data for the
XBB.1.5 monovalent vaccine, as well as any future variantadapted vaccines, will continue.105
In summary, the BNT162b2 vaccines have undergone thor­
ough and extensive safety testing and monitoring, consistently
demonstrating a favorable safety profile. Although no longer
considered a public health emergency, COVID-19 continues to
pose a threat to public health. Vaccines are critical for disease
prevention and have been an essential tool in the management
of the COVID-19 pandemic. Annual immunization against
SARS-CoV-2 may be an option for the future. Education for
healthcare providers and the general public regarding the
safety of BNT162b2 and other COVID-19 vaccines are essen­
tial to ensure the success of vaccination programs.
Acknowledgments
Medical writing support, including assisting authors with the develop­
ment of the outline and initial draft and incorporation of comments was
provided by Rachel Wright, PhD, and Helene Wellington, MS, and
editorial support was provided by Ian Norton, PhD, all of Scion,
London, UK, supported by BioNTech SE according to Good Publication
Practice guidelines (Link).
Disclosure statement
ÖT is a management board member and employee at BioNTech SE
(Mainz, Germany) and co-founder of the company. FvO, NC, FJM, CL,
SP, and RR are employees at BioNTech SE. ÖT is an inventor on patents
and patent applications related to RNA technology and COVID-19 vac­
cines. SP, RR, CL and ÖT have securities from BioNTech SE.
Funding
The work was supported by the BioNTech .
Author contributions
All authors contributed to the manuscript conception, writing, and review
process, and approved the final version for submission.
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