Drug Safety (2021) 44:1209–1214 https://doi.org/10.1007/s40264-021-01104-9 ORIGINAL RESEARCH ARTICLE Cumulative Adverse Event Reporting of Anaphylaxis After mRNA COVID‑19 Vaccine (Pfizer‑BioNTech) Injections in Japan: The First‑Month Report Toyotaka Iguchi1 · Hikari Umeda1 · Michie Kojima1 · Yuri Kanno1 · Yuta Tanaka1 · Natsumi Kinoshita1 · Daisaku Sato2 Accepted: 18 July 2021 / Published online: 4 August 2021 © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021 Abstract Introduction In mid-February, the nationwide immunization plan for the prevention of coronavirus disease 2019 (COVID- 19) started in Japan (at first primarily focused on health professionals) using an mRNA-based vaccine (Pfizer/BioNTech). During the phase-in period from February to March, attention was focused on post-vaccination anaphylaxis and anaphylactoid symptoms from the viewpoint of ensuring the safety of the vaccination program. Objective The aim of this report was to provide an update on the status of anaphylaxis and anaphylactoid symptoms occur- ring after vaccination for COVID-19, as reported under the Adverse Event Following Immunization (AEFI) reporting system in Japan. Methods The Pharmaceutical and Medical Devices Agency (PMDA) received AEFI reports from health professionals and manufacturers under the reporting system for AEFI after vaccination for COVID-19, which has been in operation since mid- February 2021. Reported AEFIs of anaphylaxis and anaphylactoid symptoms were assessed using the Brighton Collaboration Criteria to assess diagnostic certainty. Results 1-month since Japan started the vaccination program for COVID-19 in February 2021, 578,835 doses have been administered to health professionals, with the PMDA receiving 181 suspected event reports of anaphylaxis and anaphylac- toid symptoms. In 171 of these 181 cases, women developed these symptoms. Among 181 cases evaluated according to the Brighton Collaboration Criteria, 47 cases (26%) were classified as level 1–3 (reporting rate: 8.1/100,000 doses). Conclusion The results appear similar to reported AEFIs in foreign studies of coronavirus vaccine administration to health professionals, although the reporting rate was higher. Further work is needed to examine the causal relationship of anaphy- laxis reactions to coronavirus vaccine administration. Issues of multiple reporting and possible sex/age bias also remain to be analyzed. 1 Introduction On 14 February 2021, The Ministry of Health, Labour and Welfare (MHLW) granted Special Approval for Emergency for the first coronavirus vaccine—Comirnaty (Pfizer/BioN- Tech; hereinafter referred to as the ‘mRNA-based vaccine’) intramuscular injection—for the prevention of coronavirus * Daisaku Sato sato-daisaku@pmda.go.jp 1 Office of Pharmacovigilance II, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan 2 Center for Regulatory Science, Pharmaceuticals and Medical Devices Agency, Shin-Kasumigaseki Building, 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo 100-0013, Japan disease 2019 (COVID-19) in Japan. In mid-February, the nationwide immunization plan commenced, at first primar- ily focused on health professionals in the national hospi- tal group network and other front-line hospitals. The pro- gram was expanded to other health professionals, followed by elderly populations, in May 2021. During the phase-in period from February to March, health professionals who initially received the vaccination were closely monitored for adverse events (AEs). In particular, anaphylaxis and anaphylactoid symptoms that developed after vaccinations were of high interest in terms of determining the safety of the vaccination. The aim of this report was to update the status of ana- phylaxis and anaphylactoid symptoms reported under the Adverse Event Following Immunization (AEFI) reporting Vol.:(0123456789) 1210 Keypoints In Japan, 1 month after starting the vaccination program using the mRNA coronavirus disease 2019 (COVID-19) vaccine (Pfizer-BioNTech), 578,835 doses have been administered. We provide an update of reported adverse events following immunization (AEFIs), focusing on anaphylaxis. Forty-seven confirmed anaphylaxis cases were reported as AEFIs, corresponding to 8.1/100,000 doses. This is a higher rate than seen with conventional vaccines but is similar to rates reported in foreign studies of the corona- virus vaccine. system in Japan, in order to assess the need for further safety measures as the vaccination program is extended. 2 Methods [Adverse Events Following Immunization (AEFI) Reporting System] The Pharmaceutical and Medical Devices Agency (PMDA) is the operational body that, after vaccinations, receives AEFI reports from health professionals and manufacturers under the Immunization Act and the Pharmaceuticals and Medical Devices Act. Health professionals are obliged to report AEFIs when they encounter cases of AEs after vacci- nation, in accordance with these Acts. Anaphylaxis and ana- phylactoid symptoms were designated as serious AEFIs to be reported. AEFI reporting after vaccination for COVID-19 has been in operation since the emergency authorization in mid-February 2021. The number of administered doses was collected from the vaccination sites through the nationwide vaccine supply information network, the Vaccination Facili- tation System (V-SYS) [1], operated by the MHLW, which was used as the denominator for calculating the frequency of AEFI reporting. The reported AEFIs were assessed by PMDA/MHLW medical experts. The Brighton Collabora- tion Criteria were applied to classify event reports of sus- pected anaphylaxis and anaphylactoid symptoms according to diagnostic certainty (level 1 is the highest certainty and level 5 is the lowest) [2]. The widely used Brighton Collabo- ration Criteria were helpful in enabling comparison between different studies. T. Iguchi et al. For comparison, we also calculated the reporting ratio of anaphylaxis and anaphylactoid symptoms in the adult popu- lation (over 16 years of age) for influenza HA vaccines, from data in the PMDA’s AE reporting database (JADAR) during the 5 seasons from 2015 to 2019. The estimated total number of influenza HA vaccine doses over the five seasons was 262.48 million [3]. 3 Results (Suspected Anaphylaxis Reporting) As of 21 March 2021, 578,835 doses of the mRNA-based vaccine have been administered, and, to date, 733 (85 males [12%], 647 females [88%], 1 unknown [< 1%]) AEFIs have been reported from health care settings. Among these, there have been 181 (first dose: 177; second dose: 3; unknown: 1) suspected anaphylaxis reports [4], resulting in a report- ing rate of 31.3/100,000 doses. In 171 of 181 cases, women developed suspected anaphylaxis and anaphylactoid symp- toms. After 1 month of AEFI monitoring, the Committee on Drug Safety of the Pharmaceutical Affairs and Food Sani- tation Council and the Vaccine Adverse Reaction Review Committee (hereinafter referred to as the ‘Joint Committee’) of the MHLW evaluated these cases using the Brighton Col- laboration Criteria. Forty-seven of 181 (26%) cases reported by 21 March were evaluated as levels 1–3 cases (reporting rate: 8.1/100,000 doses) (Table 1). Thirty-five of the 47 cases (74%) had a history of allergic disease or allergic reactions to medicines and/or food. In 44 of 47 cases (94%), women developed anaphylaxis. The overall characteristics of reported anaphylaxis are summa- rized in Table 2. 4 Discussion In a summary of Yellow Card reporting of the coronavi- rus vaccine, the British Medicines and Healthcare Products Regulatory Agency (MHRA) reported 215 cases of anaphy- laxis and anaphylactoid symptoms after administration of 11.5 million vaccine doses (reporting rate: approximately 1.9/100,000 doses) [5]. The experience in the UK is based mainly on adenovirus vaccine, and care is needed in com- paring AEFIs of mRNA vaccines with those of adenovi- rus vaccines. Among mRNA vaccines, Shimabukuro et al. reported an anaphylaxis event rate of 0.47/100,000 doses for the Pfizer-BioNTech vaccine in the US, according to the Vaccine Adverse Event Reporting System (VAERS), during a 1-month period (14 December 2020–18 January 2021) [6]. Table 1 Confirmed anaphylaxis (Brighton level 1, 2 or 3) reaction reports after COVID-19 vaccination No. Age (years) Sex Lot no. Onset after vaccination (mins)b Background history of allergy Other possible cause Evaluation of the Brighton collaboration criteria Treatment Treatment outcome 1 36 F EP2163 5 Bronchial asthma Bronchial asthma – Urticaria Bronchial asthma, drug Food, allergic disease None Urticaria None Unknown Animals Food, drug – None None None 5 30 Immediately after vac- cination (1 min) 9 55 EP2163 10 Bronchial None asthma, ana- phylaxis EP2163 second 13 3 EP2163 Drug Urticaria None None EP9605 EP2163 EP2163 second 2 3 4 5 6 7 8 10 11 12 13 14 24 29 52 37 33 27 48 44 38 29 51 44 15 33 16 17 55 50 18 34 19 42 20 37 21 43 22 23 35 24 24 25 26 46 50 49 F F F F F F F F F F F F F F F F F F F F F F F F F EP2163 EP9605 EP2163 EP2163 EP9605 EP2163 EP9605 dose EP9605 EP9605 EP9605 EP9605 EP9605 EP9605 EP9605 EP9605 EP9605 EP9605 EP9605 EP9605 25 20 5 22 29 10 10 30 15 9 5 7 3 5 13 10 13 15 10 None Unknown None – – – – Bronchial None asthma, drug Food, drug None Allergic disease None None Food, pollen None Food, drug Unknown Food, drug None – Bronchial asthma, animals, house dust Food Urticaria Bronchial asthma Unknown None None None Unknown 1 1 2 3 2 2 2 2 2 2 2 3 2 2 2 2 2 2 3 2 2 2 2 2 1 1 1211 Adrenaline Corticosteroid SABA amino- phylline Adrenaline Adrenaline Corticosteroid Adrenaline Corticosteroid Anti-histaminic Adrenaline Adrenaline Adrenaline Corticosteroid Recovering Recovered Recovered Recovered Recovered Recovered Recovering Recovering Corticosteroid Anti-histaminic Recovered Recovering Recovering Recovering Corticosteroid Adrenaline Anti-histaminic Unspecified Recovered No information Recovering Recovered Adrenaline Corticosteroid Corticosteroid Anti-histaminic No information Recovered Adrenaline Corticosteroid Anti-histaminic Adrenaline Anti-histaminic Adrenaline Corticosteroid Anti-histaminic SABA Steroid Anti-histaminic Adrenaline Corticosteroid Anti-histaminic Recovering Recovering Corticosteroid Anti-histaminic Recovering Recovered Recovered Unrecovereda No information Corticosteroid Corticosteroid Adrenaline Corticosteroid Anti-histaminic Recovering Recovering Recovering Anaphylaxis Rate After the Pfizer-BioNTech Vaccination in Japan 1212 Table 1 (continued) No. Age (years) Sex Lot no. Onset after vaccination (mins)b Background history of allergy Other possible cause Evaluation of the Brighton collaboration criteria Treatment Treatment outcome 30 26 31 32 39 38 33 25 34 55 35 36 37 38 48 43 42 50 39 42 40 41 24 37 42 38 43 54 44 56 27 44 F EP9605 Food None 28 24 M EP9605 Food, pollen None 29 22 M EP9605 EP9605 480 Drug 10 10 15 5 7 15 50 30 5 10 20 20 230 40 60 10 5 20 EP2163 EP9605 EP9605 EP9605 EP9605 EP9605 EP9605 EP9605 EP2163 dose EP9605 EP9605 EP9605 F F F F F F F F F F F F F F F F M EP9605 F EP2163 second 30 2 2 3 2 2 3 2 1 2 2 2 3 2 1 2 2 2 2 1 2 3 2 – – – None None Drug Bronchial Menstruation None asthma, food, metal Chronic ton- silitis None – Drug, pollen None None Pollen Drug Drug, food, cosmet- ics, allergic disease Food, pollen Drug Bronchial asthma Unknown None None None None None Bronchial None asthma, drug Bronchial asthma None Bronchial None asthma, drug, pollen – Urticaria, food, Unknown None drug 45 41 EP9605 46 47 31 47 EP9605 EP2163 T. Iguchi et al. Recovered Recovering Recovering Corticosteroid Anti-histaminic Corticosteroid Anti-histaminic Corticosteroid Anti-histaminic Corticosteroid Anti-histaminic No information Recovering Recovered Corticosteroid Anti-histaminic Recovering Recovered Recovering Adrenaline Anti-histaminic Corticosteroid Anti-histaminic No information Recovered Recovered Adrenaline Corticosteroid Anti-histaminic Anti-histaminic Recovering Recovered Adrenaline Corticosteroid Adrenaline Recovering Unrecovereda Recovered Recovered Anti-histaminic Recovered Corticosteroid Anti-histaminic Adrenaline Corticosteroid SABA Adrenaline Anti-histaminic Corticosteroid Anti-histaminic Aminophylline Adrenaline Corticosteroid Anti-histaminic Anti-histaminic Recovered Anti-histaminic Recovered Recovering Recovering COVID-19 coronavirus disease 2019, F female, M male, SABA short-acting β-agonists a These cases were reported by 21 March 2021 and were evaluated for Brighton Collaboration Criteria by 25 March 2021 b Onset after vaccination’ includes estimates of elapsed time before onset for cases where the exact time was not recorded c The Brighton Collaboration Criteria are used to define the level of diagnostic certainty of reported cases of anaphylaxis and anaphylactoid symptoms, based on combinations of symptoms. Level 1 is the highest level of diagnostic certainty. Levels 4 and 5 do not meet the Brighton Collaboration Criteria definition of anaphylaxis d Most cases received treatments (adrenaline and/or corticosteroid and/or anti-histaminic drug) in a hospital after the onset of anaphylaxis, and had recovered or been recovering by the cut-off date Table 2 Characteristics of reported anaphylaxis (Brighton level 1, 2 or 3) after COVID-19 vaccination in Japan (14 February–21 March 2021) Characteristics No. of cases (%) [n = 47] Age, years [median (range)] Female sex Time to onset, min [median (range)] Symptom onset, min  ≤ 5  ≤ 30  > 30 Prior allergic history  Allergies and allergic reaction to food, drug, pollen, animals  Prior anaphylaxis Vaccine doses  First  Second Brighton level  1  2  3 Anaphylaxis reporting rate 41 (22–56) 44 (94) 10 (< 1–480) 30 (64) 41 (87) 6 (13) 34 (72) 1 (2) 45 2 7 (15) 33 (70) 7 (15) 8.1/100,000 1213 Blumenthal et al. demonstrated that Mass General Brigham employees who received their first dose of a COVID-19 vac- cine developed anaphylaxis at a rate of 25/100,000 doses [8]. There could also be other relevant factors, such as reporting bias, differences in the demography of the vaccinee popu- lation, etc. The possibility of anaphylaxis has been highly publicized in the context of the attention given to corona- virus vaccines by the media. We found that female cases accounted for 88% of the 733 AEFI reports, and the median age of cases reporting anaphylaxis AEFIs was 41 years, but these findings may simply reflect the demography of the vaccinee population. The MHLW has been warning health professionals to exercise caution in the case of vaccinees who have a previ- ous medical history of systemic allergic reactions, including anaphylaxis, allergy, or severe sensitivities to any vaccine, food, etc. [9]. When the vaccination program started, the joint committee of the MHLW recommended that for those who had encountered severe allergic symptoms in the past, including anaphylaxis, follow-up after vaccinations should be performed for 30 min, while for others, follow-up should be performed for at least 15 min [10]. Data are expressed as n (%) unless otherwise specified COVID-19 coronavirus disease 2019 5 Conclusion We have also reviewed the records of suspected anaphy- laxis and anaphylactoid symptoms reported in the past for comparable influenza HA vaccines. Over the last 5 seasons (2015–2019), the reported number of suspected anaphylaxis and allergy-related reactions was 56, corresponding to a rate of 0.02/100,000 doses, in the PMDA’s JADER database (electronic supplementary material). The most frequent rate of suspected anaphylaxis reporting for influenza HA vac- cine was 1.0/100,000 doses in the 2009 season (H1N1) [7]. Among 118 cases of suspected anaphylaxis, 55 (46.8%) were level 1–3 according to the Brighton Collaboration Criteria. In the 2009 H1N1 influenza vaccinations, the rate of female cases with suspected anaphylaxis was around 75% of the total, which is similar to the rate of development in women over the last 5 seasons of reporting after influenza vaccinations. Thus, the trend for a higher rate of reporting of anaphylaxis and anaphylactoid symptoms in women in the adult population after the influenza vaccination also appears to be the case for the COVID-19 vaccination in Japan. The current Japanese rate of anaphylaxis and anaphy- lactoid symptom reporting (8.1/100,000 doses) [level 1–3 according to the Brighton Collaboration Criteria] seems relatively high. Multiple factors may be potentially associ- ated with this high reporting rate. For example, the vaccinees were health professionals who were closely monitored and who were requested to report AEFIs. For comparison, One month after Japan started the vaccination program for COVID-19 in February 2021, 578,835 doses had been administered to health professionals. Among 181 AEFI cases of anaphylaxis and anaphylactoid symptoms evalu- ated according to the Brighton Collaboration criteria, 47 cases (26%) were classified as level 1–3 (reporting rate: 8.1/100,000 doses), which is similar to those AEFIs reported in foreign studies of coronavirus vaccine administration to health professionals, but higher than the rates reported for conventional scheduled vaccines. Further work is needed to examine the causal relationship of anaphylaxis reactions to administration of the coronavirus vaccine. Furthermore, the issues of multiple reporting and reporting sex/age bias also remain to be analyzed. In addi- tion, to date, only one type of coronavirus vaccine is avail- able in Japan, therefore the comparison of AEFI reporting rates among different types of coronavirus vaccines will be a challenge for the future. At this point, we are not able to conclude that the characteristics of AEFI reporting of the coronavirus vaccine are different from those of other vac- cines available on the market; however, they will be further assessed on the basis of the accumulation of AEFI reports in Japan and from the rest of the world. We need to continue close monitoring of the reporting trend of suspected anaphylaxis and anaphylactoid symptom cases after vaccinations, as the target populations of vacci- nation were shifted from health professionals to the elderly Anaphylaxis Rate After the Pfizer-BioNTech Vaccination in Japan 1214 T. Iguchi et al. population in May 2021. The PMDA, in collaboration with the MHLW, will be regularly publishing the cumulative results of event reporting. References Supplementary Information The online version contains supplemen- tary material available at https:// doi. org/ 10. 1007/ s40264- 021- 01104-9. Acknowledgements The opinions expressed in this article are those of the authors and do not necessarily reflect the official position of the PMDA. Declarations Funding No funding was received for this research. Conflict of Interest Toyotaka Iguchi, Hikari Umeda, Michie Kojima, Yuri Kanno, Yuta Tanaka, Natsumi Kinoshita, and Daisaku Sato de- clare no competing interests. Ethics Approval Not applicable (waived by the Ethics Committee of the PMDA). Consent to Participate Not applicable. All data are publicly available from the MHLW and PMDA websites. Consent for Publication Not applicable. All data are publicly available from the MHLW and PMDA websites. All authors approved publica- tion of this article. Availability of Data and Material Available from the MHLW and PMDA websites. Code Availability Not applicable. 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