Journal of Travel Medicine, 2021, 1–3
https://doi.org/10.1093/jtm/taab090
Advance Access Publication Date: 14 June 2021
Research Letter

Research Letter

High anaphylaxis rates following vaccination with
the Pfizer BNT162b2 mRNA vaccine against COVID-19
in Japanese healthcare workers: a secondary analysis
of initial post-approval safety data
Takanao Hashimoto, PhD1,*, Akihiko Ozaki, MD, PhD2, Divya Bhandari, MHS3,
Toyoaki Sawano, MD4, Ranjit Sah, MD5 and Tetsuya Tanimoto, MD6

1Department of Pharmacy, Sendai City Medical Center, Sendai, Miyagi, Japan, 2Department of Breast Surgery, Jyoban
Hospital of Tokiwa Foundation, Iwaki, Fukushima 972-8322, Japan, 3Medical Governance Research Institute, Tokyo
108-0074, Japan, 4Department of Surgery, Jyoban Hospital of Tokiwa Foundation, Iwaki, Fukushima 972-8322, Japan,
5Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu 44600, Nepal and 6Internal Medicine, Navitas
Clinic Kawasaki, Kanagawa 210-0007, Japan

*To whom correspondence should be addressed. Takanao Hashimoto, PhD, Department of Pharmacy, Sendai City Medical Center, 5-22-1, Tsurugaya,
Miyagino-ku, Sendai, Miyagi 983-0824, Japan. Tel: +81-22-252-1111; Fax: +81-22-252-0454; Email: pharm.hashi@gmail.com

Submitted 12 April 2021; Revised 20 May 2021; Accepted 2 June 2021

Key words: BNT162b2 mRNA Covid-19 Vaccine, anaphylaxis, safety, Japan

To contain the coronavirus disease 2019 (COVID-19) pandemic,
vaccine development and rollout have progressed rapidly around
the world. After successful COVID-19 vaccine development,
following the past examples of vaccine-preventable diseases,1
nationwide vaccination programmes have been under way
swiftly on a global scale. The BNT162b2 mRNA COVID-19
vaccine (Comirnaty, Pfizer-BioNTech, USA) is one of the vaccines
granted earliest regulatory approval globally.2,3 In Japan, fast-
track approval was granted to the vaccine on 14 February
2021, with the scheduled provision of ∼140 million doses. The
vaccine was the sole approved product as of May 2021, and
the Japanese government set to prioritize vaccination in 4.84
million healthcare workers (HCWs) due to the sequential supply
of limited doses.

The first round of Japan’s vaccination programme against
COVID-19 was initiated at 100 medical institutions eligible
for priority vaccination for an estimated 40 000 HCWs from
17 February 2021.4 However, from early March 2021, the
vaccination programme was extended to additional 4.8 million
HCWs at other medical
institutions before disclosing the
initial safety data including anaphylaxis observed at preceding
institutions. As of 16 March 2021, >350 000 HCWs had
received the first dose of the vaccine, and >9000 HCWs
had received the second dose. Belatedly, on 12 March 2021,

the Ministry of Health, Labour, and Welfare (MHLW) dis-
closed preliminary data of serious adverse reactions to the
vaccine.

Therefore, using publicly available data by the MHLW, we
conducted a secondary analysis of initial post-approval safety
data concerning serious adverse reactions of anaphylaxis based
on the vaccination programme in Japanese HCWs. For the
diagnosis of anaphylaxis, each medical institution voluntarily
reported possible cases based on their own judgement. Subse-
quently, the expert committee of the MHLW evaluated them
based on the Brighton Collaboration case definition criteria
(hereafter Brighton criteria).5 Statistical analysis was not per-
formed due to the small number of subjects with anaphylaxis.
Ethical considerations were not applied to this study.

The data included 181 184 HCWs who received one or more
doses of vaccination by 11 March 2021.6 As shown in Table 1, 37
cases of anaphylaxis were observed, equating to 204.2 cases per
million doses administered. Among them, only 17 (45.9%) cases
were evaluated based on the Brighton criteria. Of which seven
(41.1%) cases met the Brighton criteria 1, 2 or 3, resulting in 38.6
cases per million doses administered. The mean age of 37 cases
was 40.4 years old, and a predominant cases were females (35,
94.5%). Twenty-one patients (56.8%) had a history of allergy
as shown in Table 1. Within 30 min of vaccination, 31 (83.8%)

© The Author(s) 2021. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions,
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2

Journal of Travel Medicine, 2021, Vol. 28, 7

Table 1. The Characteristics of anaphylaxis cases

Allergy histories

All N = 37

40.4 ∓ 11.0
[23–58]
35 (86.5)

9
3
12
7
6
18.2 ∓ 13.1

2
4
1
10
20

Female sex, N (%)
Time from vaccination to onset of anaphylaxis, min

Brighton Collaboration case definition criteria

Mean age [range]

0–5
6–10
11–20
21–30
31–
Mean (N = 36)a

1
2
3
4, 5
Unevaluated

Overall drugs and vaccines

Of these, influenza vaccine
Analgesics or NSAIDs
Antibacterial agents
Hepatitis vaccine
Contrast agents

Overall foods
Of these, egg

Animal (Cat)
Cosmetics

Crustaceans (shrimps, crabs, etc.)
Mackerel, buckwheat or wheat

No (N = 16)

39.4 ∓ 10.5

15 (93.8)

4
1
5
4
2
16.2 ∓ 10.5

2
3

3
8

Yes (N = 21)

41.2 ∓ 11.3

20 (95.2)

5
2
7
3
4
19.7 ∓ 14.5

1
1
7
12
Details of allergiesb
15
5
4
2
2
2
10
4
3
Each 1
2
4

Using data published by the Ministry of Health, Labour and Welfare as of 11 March 2021.5
All cases were the first dose of vaccination.
aOne person who took 145 min to develop anaphylaxis (no history of allergy) was considered an outlier affecting the mean and was excluded from this analysis.
bThe total does not necessarily add up to 21 because some patients have multiple allergy histories.

cases developed anaphylaxis. Those with allergic history had a
longer onset time and a larger standard deviation than those
without (19.7 ∓ 14.5 vs 16.2 ∓ 10.5 min). The outcomes were
reported as recovery or mild improvement in all cases.

In Japan, the estimated cases per million doses administered
were as high as 204.2 based on the spontaneous report, and
they were 38.6 even when limited to the cases evaluated as
level 1, 2 or 3 of the Brighton criteria. According to the US
CDC, among a total of 9 943 247 doses of the BNT162b2
mRNA vaccine administered from 14 December 2020 to 18
January 2021, the anaphylaxis cases per million doses admin-
istered were 4.7.3 The underlying reasons of such high inci-
dence of anaphylaxis in Japan are unknown, but the presence
of polyethylene glycol (PEG) additive,7 which is also used in
many cosmetic and pharmaceutical products is considered to be
one of the reasons for inducing anaphylaxis by the BNT162b2
mRNA vaccine. Of the 37 HCWs who developed anaphylaxis,
57% had some history of allergy, and four patients had a
history of cosmetics allergy, suggesting the potential involvement
of PEG.

for adverse reactions is already in place, but the information on
the safety of the BNT162b2 mRNA vaccine after approval is
still limited. We found that the MHLW had not fully evaluated
vaccine anaphylaxis at the early phase of the vaccination pro-
gramme, and it is understandable that the Japanese government
tried to make up the delayed vaccine rollout compared with other
high-income countries under the uncontrolled spread of COVID-
19 in the country. However, precautious measures should be
paid to vaccine hesitancy prevailing in Japan, as illustrated in
the past human papillomavirus vaccine controversy.8 One of
the first medical institutions that joined the vaccination pro-
gramme is planning to conduct a safety survey (COV-Safe) using
a social networking service for HCWs, and some hospitals have
started their safety verification efforts.9 Also, the US CDC3
and the European Medicines Agency10 continue to monitor
and publicize the safety of coronavirus vaccines on an ongoing
basis. In order to promote the vaccination programme, further
effort should be directed domestically and internationally to
ensure the safety of vaccines with prompt evaluation and timely
publication.

In Japan, based on ‘Immunization Act and the Pharmaceuti-
cals and Medical Devices Act’, a spontaneous reporting system

There are several

limitations. First, the data about ana-
phylaxis were based on spontaneous reports without exact

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Journal of Travel Medicine, 2021, Vol. 28, 7

3

definition from medical institutions, and some reported cases
were not evaluated by the MHLW using the Brighton criteria.
This might have led to over or underestimation of the effect.
Second, although the high proportion of women experiencing
adverse reactions is consistent with previous studies,3 a factor
of gender bias is possible because all participants were HCWs.
Third, we could not perform joint research with the MHLW
using raw data, and our study included the publicly available
data only, preventing us from conducting in-depth exploration
of subject.

In conclusion, this study suggests that the incidence of ana-
phylaxis by the BNT162b2 mRNA vaccine may be higher in cer-
tain populations, such as the Japanese. Further safety studies that
take into account ethnicity and race are necessary. Further global
efforts should be directed to ensure the safety of vaccines with
prompt evaluation and timely publication to promote effective
vaccination programmes.

Authors’ contributions

Takanao Hashimoto wrote the manuscript. All authors critically
revised the manuscript, agree to be fully accountable for ensuring
the integrity and accuracy of the work, and approved the final
manuscript.

Funding

None declared.

Conflicts of interest

Dr Ozaki reports personal fees from Medical Network Systems,
MNES Inc. outside the submitted work. Dr Tanimoto reports
personal fees from Medical Network Systems, MNES Inc., and
Bionics co. ltd, outside the submitted work.

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