After the U.S. Food and Drug Administration’s (US FDA) authorization of the BNT162b2 messenger RNA (mRNA) vaccine (Pfizer–BioNTech) against coronavirus disease 2019 (COVID-19) for emergency use, Israel commenced a national vaccination campaign on December 20, 2020. This campaign comprised a two-dose regimen, with the second dose of the vaccine to be administered after 21 days.
Initially, passive surveillance––21 days after the first vaccine dose and 30 days after the second dose—was conducted, and the data was reported to Israel’s Ministry of Health. Active surveillance was initiated in February 2021, heeding the reports of myocarditis – by collating all hospital reports of myocarditis since December 2020, regardless of the vaccination status. This surveillance data is likely to include all myocarditis cases since individuals with suspected myocarditis are usually hospitalized in Israel.
Aim of the Study
A new study, published in the New England Journal of Medicine, aimed to present clinical, epidemiological, and follow-up findings of myocarditis cases diagnosed in temporal proximity to COVID-19 vaccination and explore the possibility of a causal relationship between the two.
Sources of Data and Case definition
The data for this study was obtained from medical records, including clinical and laboratory records and discharge summaries of presumptive cases of myocarditis, from December 2021 to May 2021.
The codes used for myocarditis were 422.0-9x and 429.0x as per the International Classification of Diseases – 9th Revision (ICD-9). The case definition and classification of myocarditis was as per classification of the Brighton Collaboration (Pandemic Emergency Response Process), which was even compared to the classification issued by the Centers for Disease Control and Prevention (CDC) for adverse effects post smallpox vaccination.
The cases were categorized into five types – definitive, probable, possible, having insufficient data or having an alternative diagnosis. These excluded cases that were only diagnosed as pericarditis. The diagnosis of myocarditis was verified via retrospective review of data. Pfizer–BioNTech did not in any capacity have a role in the collection, analysis, or reporting of this data.
Data were categorized according to age groups and analyzed separately for males and females. To assess the incidence of myocarditis among the vaccine recipients the risk differences, observed-to-expected ratios, and rate-ratios, between vaccinated and unvaccinated individuals, were calculated.
The findings revealed that the risk of myocarditis in vaccinated individuals was more than twice (approximately 1 per 26,000 males and 1 per 218,000 females) compared to that in unvaccinated individuals—with young male recipients having the highest association within the first week after the second vaccine dose.
Approximately 1 out of 6,637 males and 1 among 99,853 females between 16 and 19 years of age were identified as definite or probable cases of myocarditis. No instances of myocarditis were seen in the phase 3 trial, possibly due to the small sample size of 15,000 male and female recipients.
The rate-ratio for the comparison of the incidence of myocarditis among vaccinated and unvaccinated persons was 2.35, according to the Brighton Collaboration classification and after adjustment for age and sex.
Symptoms of myocarditis mostly developed within a few days after the second dose of the vaccine. As the number of newly vaccinated individuals decreased over time, the incidence of myocarditis also declined, suggesting a possible causal relationship.
The mechanism of vaccine-induced myocarditis remains obscure. It was speculated to be imposed by the active component of the vaccine – the mRNA sequence that codes for the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or by the immune response post-vaccination.
A significant limitation of this study was that the rate ratios were calculated individually in the vaccinated group instead of through aggregated data in the unvaccinated group.
Acquisition bias could exist as the diagnosis of myocarditis was not validated by myocardial biopsy, and clinical assessors were aware of the vaccination status.
There is a possibility of misclassification during surveillance which could have resulted in under-diagnosis or over-diagnosis of myocarditis.
The standardized incidence ratios relied upon data from the Israeli National Hospital Discharge Database from 2017 through 2019. The viral circulation and myocarditis reporting are not comparable.
Comparison with other studies
The rates of myocarditis in this study can be compared with those in the Clalit Health Services database in the study by Witberg et al. The Witberg study reported a lower incidence of myocarditis—owing to a variation in the study design—possibly depicted due to a shorter follow-up of vaccine recipients post the second dose.
This study concurred with the study by Barda et al., which also reported that myocarditis was more common after SARS-CoV-2 infection than after vaccination.
The results suggested that the incidence of myocarditis was still low after two doses of the BNT162b2 mRNA vaccine; nevertheless, the incidence was higher compared to that in unvaccinated individuals and historical controls.
The risk of myocarditis was notably higher after the second dose and more so in young male recipients.