key: cord-0949266-1z0xlyvt
authors: Saita, Mizue; Yan, Yan; Ito, Kanami; Sasano, Hiroshi; Seyama, Kuniaki; Naito, Toshio
title: Reactogenicity following two doses of the BNT162b2 mRNA COVID-19 vaccine: real-world evidence from healthcare workers in Japan
date: 2021-09-16
journal: J Infect Chemother
DOI: 10.1016/j.jiac.2021.09.009
sha: 10f19dcfabeca35ce40a9fc037cd19f8544d44d3
doc_id: 949266
cord_uid: 1z0xlyvt

As the first authorized COVID-19 vaccine in Japan, the BNT162b2 mRNA COVID-19 vaccine is utilized for mass vaccination. Although efficacy has been proved, real-world evidence on reactogenicity in Japanese personnel is needed to prepare the public. Healthcare workers in a large academic hospital in Japan received two doses of the Pfizer-BioNTech vaccine from March 17 to May 19, 2021. Online questionnaires were distributed to registered recipients following each dose, from day 0 through day 8. Primary outcomes are the frequency of reactogenicity including local and systemic reactions. Length of absence from work was also analyzed. Most recipients self-reported reactogenicity after the first dose (97.3%; n=3,254; mean age [36.4]) and after the second dose (97.2%; n=3,165; mean age [36.5]). Systemic reactions following the second dose were substantially higher than the first dose, especially for fever (OR, 27.38; 95% CI, [22.00-34.06]; p<0.001), chills (OR, 16.49; 95% CI, [13.53-20.11]; p<0.001), joint pain (OR, 8.49; 95% CI, [7.21-9.99]; p<0.001), fatigue (OR, 7.18; 95% CI, [6.43-8.02]; p<0.001) and headache (OR, 5.43; 95% CI, [4.80-6.14]; p<0.001). Reactogenicity was more commonly seen in young, female groups. 19.3% of participants took days off from work after the second dose (2.2% after the first dose), with 4.7% absent for more than two days. Although most participants reported reactogenicity, severe cases were limited. This study provides real-world evidence for the general population and organizations to prepare for BNT162b2 mRNA COVID-19 vaccination in Japan and other countries in the region.

Since the outbreak of the coronavirus pandemic, Japan's citizens have practiced strict personal hygiene including masks and hand-washing. Japan has declared a nationwide State of Emergency twice since the outbreak, with 10 prefectures currently under a third round as of June 18, 2021. Nonetheless, the disease continues to spread in the country.

Vaccination is expected to be a critical step in fighting the disease. Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine (thereafter: Pfizer-BioNTech COVID-19 vaccine) was the first to be authorized for emergency use by the Ministry of Health, Labor and Welfare of Japan on February 14, 2021. 1 However, due to the high awareness of reactogenicity following vaccines such as Human Papillomavirus (HPV) vaccines in the past, the Japanese people are cautious about COVID-19 vaccination. 2 Vaccine safety has been shown to be important to the Japanese public.

High efficacy of the Pfizer-BioNTech COVID-19 vaccine (95%) was observed in clinical trials and supported in real world vaccination efforts. [3] [4] [5] However, previous studies showed reactogenicity following Pfizer-BioNTech COVID-19 vaccines. 3,6-8 Severe allergic reactions after receiving this mRNA-based vaccine were reported as well. 9 Because the frequency and degrees of reactogenicity may vary depending on ethnicity and region, assessment of the adverse reactions is an important step toward preparation of Japan's general population to receive the vaccine. Reactogenicity reflecting differences in age groups and gender is informative, as well as to provide data to organizations anticipating possible absences from work following each worker's dose of the vaccine.

Healthcare workers in a large academic hospital (1,051 beds) voluntarily registered to receive COVID-19 vaccines from March 17 to April 23 for the first dose, and April 7 to May 19 for the second dose. Pfizer-BioNTech COVID-19 vaccines were administered. According to a previous study targeting the healthcare workers in the same hospital in the summer of 2020, J o u r n a l P r e -p r o o f 0.34% (n=4,147) were found to have antibody evidence of previous SARS-CoV-2 infection. 10 A healthcare questionnaire was distributed prior to the vaccination. 11 Those with medicine/food allergies, previous experience of spasm, or anaphylaxis following vaccination, were asked to remain for 30 minutes in the vaccination setting.

An online questionnaire survey was conducted with approval of the institutional review board of this academic hospital. (No. 2021055) . Questionnaires were distributed to registered vaccine recipients from Day 0 to Day 8 after each dose. Reactogenicity was divided into two groups: injection site reactions such as pain, swelling, burning sensation, redness, induration, and itching; systemic reactions such as fatigue, myalgia (muscle ache), headache, fever (self-reported; ≧37.5℃), chills, joint pain, and nasal discharge. Anaphylaxis cases were asked to be self-reported, then confirmed by researchers' review of patient treatment records, and subsequently recorded based on Brighton Collaboration's definitions. 12 Consequences of reactogenicity such as any work absences were asked to be self-reported as well.

Primary outcomes are the frequencies of reactogenicity after the first and second dose.

Multivariate analysis was performed to assess differences in reactogenicity by sex, age and between the two doses. In addition, the average length of absence from work due to adverse reactions was assessed. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 27 (IBM Japan). Two-sided p-values less than 0.05 were considered statistically significant.

3,381 healthcare workers received the first dose of the Pfizer-BioNTech vaccine from reaction (75.1% after dose 1; 86.8% after dose 2) during the days 0 to 8 after vaccination.

Regarding adverse reactions after the first dose, pain at the injection site was most commonly reported as a local reaction (89.4%). Approximately 30% self-reported swelling and a burning sensation. For systemic reactions, muscle ache was the top self-reported reaction (65.5%), followed by fatigue (27.7%), headache (14.2%), joint pain (6.1%), chills (3.7%) and fever (2.9%). Regarding adverse reactions after the second dose, pain (87.3%) remained as the top local reaction, but the overall frequency of systemic reactions was higher than after the first dose, especially for fatigue (72.8%), muscle pain (64.3%), headache (45.7%), fever (42.8%), chills (37.3%) and joint pain (34.5%). (Supplementary, Figure 1) Multivariate analysis was performed to assess the differences in reactogenicity by sex and age, for the first dose and the second dose. (Table 2 ) Women were found to have higher rates of reactogenicity in all items, compared to men. Additionally, those with older age tended to have lower rates of reactogenicity. Comparing reactogenicity following the doses, the rates following the second dose were higher, especially for fever (OR, 27.38 Figure 1 . Compared to the first dose, healthcare worker participants had substantially higher rates of fever after the second dose, especially for age groups ≦29 years (53.5%). Among participants who reported fever following the second dose, more than 40% reported fever of 38.0℃ or higher in age groups under 60 years old, with the percentage slightly higher among younger groups. (Figure 1) Due to adverse reactions including fever, fatigue, headache, and chills, 610 (19.3%) participating healthcare workers took at least one day off from work after the second dose, compared to 71 (2.2%) after the first dose. (Table 1) J o u r n a l P r e -p r o o f One case of anaphylaxis was reported by a woman (32 years old) immediately after receiving the first dose; flushing in the face, itching on the abdominal area, vomiting, and cough were reported; adrenaline injection was administered. No abnormal vital signs were found.

Another case of anaphylaxis was reported by a woman (38 years old) 5 minutes after receiving the second dose. Abnormalities on throat and cough were reported; adrenaline injection was administered. Pharyngeal edema was not found with fiberscope examination. No abnormal vital signs were reported.

This study showed a sample of real-world adverse reactions following Pfizer-BioNTech COVID-19 vaccines among healthcare workers in a large academic hospital in Tokyo, Japan. Most recipients self-reported reactogenicity (including injection site or systemic reactions) after the first dose (97.3%), as well as after the second dose (97.2%). The rate of reactogenicity was higher compared to the findings from Korean studies with 80.1% (n=277) after the first dose and 89.1% (n=265) after the second dose. 6,7 These adverse reactions were more commonly seen in female younger participants, which is consistent with the findings of the reports from Korea. 6 Compared to the US study, we found even higher rates of these systemic reactions in our healthcare workers in Japan: fatigue (72.8% vs 47.8%), muscle ache (64.3% vs 36.8%), and fever (42.8% vs 21.5%). 8 The large-scale US study also revealed that local and systemic reactions were less commonly reported by participants 65 years and older compared with those J o u r n a l P r e -p r o o f younger than 65 years, which is consistent with our findings. Regarding gender differences, no detailed information was available in the US study, but a UK study reported that reactogenicity was higher among women, consistent with the findings of our study. 13 Anaphylaxis was confirmed in one participant after the first dose (0.031%) and one participant after the second dose (0.031%). Both confirmed anaphylaxis cases were Brighton Collaboration level 3; no level 1 or 2 cases were reported in this academic hospital. According Although most healthcare worker participants in this Japanese academic hospital selfreported local or systemic reactions following each dose of Pfizer-BioNTech vaccine, severe cases were limited. 19.3% of the participants self-reported absence from work after receiving the second dose, but they typically took 1 day off (14.6%), with less than 5.0% needing to take more than 2 days from work. This study has several limitations worth addressing. First, this questionnaire survey was self-administered online. Although all the participants were healthcare workers, perception regarding adverse reactions may vary, resulting in under-reporting or over-reporting. Second, this study was conducted in a single hospital, which may not fully represent the large number of healthcare workers in Japan.

In conclusion, most healthcare workers reported reactogenicity in this Japanese hospital. The rates of fatigue, headache, fever, chills, and joint pain were greatly increased following the second dose. Higher incidence of adverse reactions was found in women and younger ages. Although adverse reactions were commonly reported, severe cases were limited.

Our findings provide real-world evidence on the frequency of reactogenicity after receiving the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine in Japan, helping clinicians and the general population set realistic expectations for postvaccination adverse reactions in Japan and other countries in the region. Figure 1 : Figure 1 -a: Incidence of fever following 1 st dose by age groups Figure 1 -b: Incidence of fever following 2 nd dose by age groups Notes:

1. Fever is defined as ≧37.5ºC with 2 categories: low-grade fever (≧37.5ºC, but <38.0ºC) and high-grade fever (≧38.0ºC).

2. Percentages of fever incidence by age groups are calculated by numbers of fever incidence of each group as percentage of total number of participating healthcare workers in the associated age groups.

J o u r n a l P r e -p r o o f Figure 1 -a: Incidence of fever following 1 st dose by age groups Figure 1 -b: Incidence of fever following 2 nd dose by age groups 

English version of pre-vaccination screening questionnaire for COVID-19 vaccine

Anaphylaxis: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data

Real-world data shows increased reactogenicity in adults heterologous compared to homologous prime-boost COVID-19 vaccination

Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine -United States

Acute allergic reactions to mRNA COVID-19 vaccines

We thank healthcare workers in Juntendo University Hospital, Tokyo, Japan for their participation. We thank Kristin Thurlby, assistant professor in the Department of Science, Johnson County Community College, Kansas, USA, for her editorial support.

The authors declare no conflicts of interests. 

GLAY, a music group, contributed financially to this study. The group plays no role in data interpretation and manuscript preparation.