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SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study

BMJ 2021; 375 doi: https://doi.org/10.1136/bmj-2021-068665 (Published 16 December 2021) Cite this as: BMJ 2021;375:e068665

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Myocarditis after vaccination against covid-19

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The risk of vaccination may be higher by considering “healthy vaccinee effect”

Dear Editor
Husby et al reported that adjusted hazard ratio (aHR) of myocarditis/myopericarditis within 14- day was 1.89(95%CI:1.23-2.90) with BNT162b2 and 5.46(2.97-10.07) with mRNA-1273[1]. We point out that the risk of vaccination may be higher by considering “healthy vaccinee effect” [2,3]. This effect can be estimated by Husby’s own data and may be greater based on other data.

1) One of their data is the low aHR of cardiac arrest or death within 28 days after vaccination (0.51 with BNT162b2 and 0.41 with mRNA-1273). Husby mentioned the fact that SARS-CoV-2 vaccines were rarely given to people with an acute or terminal illness as a likely explanation for low aHRs. This explanation is exactly “healthy vaccinee effect” [2,3].

2) Another is the low aHR of myocarditis/myopericarditis at 29 days or more: 0.47(0.28-0.79) with BNT162B2 and 0.57(0.20-1.66) with mRNA-1273. Husby denied a systemic bias, due to inconsistency of risk pattern. However, the point aHR (0.57) for mRNA-1273 is consistent with that of BNT162B2(0.47) and of cardiac arrest or death. This is another example.
The ratio of aHR of 14-day risk window to aHR of 29-days or more was 4.02(2.05-7.88) with BNT162B2 and 9.58(2.82-32.50) with mRNA-1273 by Kollassa’s method [4].

3) The same phenomena are observed by analysing several data [5,6]. One is the analysis of non-COVID-19 death using the UK statistics [7]. Monthly non-COVID-19 mortality rate (MR) from January to December, 2021 in unvaccinated were constantly higher than expected MR for 2021 supposing that there was no COVID-19 epidemic in England and Wales (eMR2021: 932.1/100,000 person years). The mortality rate ratio (MRR) to eMR2021 was 1.4 in January and averaged 1.8 over 2021.
On the other hand, non-COVID-19 MRR, 21 days or more after second dose in January was 0.15 to eMR2021 and 0.11(0.08-0.14) to MR of unvaccinated.
Healthy vaccinee effect by SARS-CoV-2 vaccination expressed as MRR in ever vaccinated to eMR2021 at the day of vaccination was estimated approximately at 0.10 to 0.24 by applying the following results [5,6].

4) According to the analysis [6] using the Dagan’s data [8], daily odds ratio (OR) of asymptomatic SARS-CoV-2 infection and symptomatic COVID-19 of vaccinated to unvaccinated is the least at the vaccinated day (day1): OR was 0.62(0.47-0.82) for asymptomatic infection, and 0.40(0.31-0.51) for symptomatic COVID-19. Vaccine does not work to reduce incidence of COVID-19 at the vaccinated day. Hence this low OR is the result of “healthy vaccinee effect”. Thereafter OR increased as days passed over 1 to 2 weeks possibly due to adverse effects of the vaccine. It seems that the severer the symptoms, the higher this tendency. For example, for symptomatic COVID-19, the ratio of OR on day1(0.40) to OR during day8-14(1.02) is 0.39(0.30-0.50). For hospitalised COVID-19, the ratio of ORs (day1-3/day8-14=0.12/0.68) was 0.17(0.04-0.78).
In addition, OR on day1 decreased as the symptom became severer: OR for asymptomatic, symptomatic, hospitalised, severe and death from COVID-19 were estimated approximately at 0.62, 0.40, 0.27, 0.18 and 0.13, respectively [6].

5) According to Hippisley-Cox’s data [9], incidence rate ratios of common venous and arterial thromboembolic events were the lowest on the day of vaccination without exception: 0.29 to 0.46.
If these were applied, the risk of myocarditis/myopericarditis with SARS-CoV-2 vaccine may be greater.

6) A reliable MRR of cardiac arrest or death on the day of vaccination in the Husby’s study can be calculated, because the number of events within 28 days after BNT162B2 is enough: total number is 4438 (more than 150 events/day).

Healthy vaccinee effect should be assessed by calculating the risk on the vaccination day to know more accurate harm and effectiveness of SARS-CoV-2 vaccine.

References
1. Husby A, Hansen JV, Fosbol E, et al. SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study. BMJ 2021; 375: e068665. doi: 10.1136/bmj-2021-068665
2. Fine PEM, Chen RT. Confounding in Studies of Adverse Reactions to Vaccines. Am J Epidemiol 1992; 136(2):121-35. doi: 10.1093/oxfordjournals.aje.a116479
3. Jackson LA, Jackson ML, Nelson JC, et al. Evidence of bias in estimates of influenza vaccine effectiveness in seniors. Int J Epidemiol 2006; 35(2):337-44. doi: 10.1093/ije/dyi274
4. Kolassa S. Calculate 95% CI for ratio of odds ratio.
https://stats.stackexchange.com/questions/471805/calculate-95-ci-for-rat...
5. Med Check editorial team. Non-COVID-19-related deaths were reduced in the vaccinated population Robust evidence for healthy vaccinee effect. Med Check 2022; 8(24r): 24-32.
https://www.npojip.org/english/MedCheck/Med%20Check%20Tip-24-2022-9-25.pdf (Accessed 26 September 2022)
6. Med Check editorial team. Why does vaccine look effective? Another evidence of healthy vaccinee effect. Med Check 2022; 8(24): 34-38. Available at:
https://www.npojip.org/english/MedCheck/Med%20Check%20Tip-24-2022-9-25.pdf
(Accessed 26 September 2022)
7. Office for National Statistics, Dataset. Deaths by vaccination status, England. Deaths occurring between 1 January 2021 and 31 December 2021 edition of this dataset. Available at: https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarri... (Accessed 13 September 2022)
8. Dagan N, Barda N, Kepten E et al. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. NEJM. 2021 Apr 15;384(15):1412-1423. doi:10.1056/NEJMoa2101765. PMID: 33626250
9. Hippisley-Cox J, Patone M, Mei XW et al Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study. BMJ. 2021 Aug 26;374: n1931. doi: 10.1136/bmj.n1931.PMID: 34446426

Competing interests: No competing interests

27 September 2022
Rokuro Hama
Medical Doctor
Sintaroo Watanabe Medical Doctor Japan Marine United Corporation, Kure Shipyard, Kure, Japan
NPO Japan Institute of Pharmacovigilance
#602 Katsuyama 2-14-8, Tennoji-ku, Osaka 543-0043 Japan