Background/Purpose: Following Pfizer-BioNTech BNT162b2 vaccine authorization, Israel initiated a nationwide COVID-19 vaccination campaign. The vaccine caused a higher incidence of myocarditis in young males. Here, we investigated the potential genetic predisposition to post-vaccination myocarditis.

Methods: We retrospectively reviewed data obtained regarding all cases of myocarditis and categorized the information using the Brighton Collaboration definition. We analyzed the occurrence of myocarditis by computing the risk difference for the comparison of the incidence after the first and second vaccine doses (21 days apart); by calculating the standardized incidence ratio of the observed-to-expected incidence within 21 days after the first dose and 30 days after the second dose, independent of certainty of diagnosis; and by calculating the rate ratio 30 days after the second dose as compared with unvaccinated persons. Whole-exome sequencing (WES) was performed on 16 males, mean age 26.5 years (range 17−64), from three ethnic groups, who developed probable or definitive myocarditis following their second vaccination. Efferocytosis assay was performed using apoptotic cells and flow cytometry. 

Results: This was an active surveillance since all myocarditis cases were included. Among 304 persons with symptoms of myocarditis, 21 had received an alternative diagnosis. Of the remaining 283 cases, 142 occurred after receipt of the BNT162b2 vaccine; of these cases, 136 diagnoses were definitive or probable. The overall risk difference between the first and second doses was 1.76 per 100,000 persons, with the largest difference among male recipients between the ages of 16 and 19 years (difference, 13.73 per 100,000 persons). As compared with the expected incidence based on historical data, the standardized incidence ratio was 5.34  and was highest after the second dose in male recipients between the ages of 16 and 19 years (13.60). The rate ratio was again highest in male recipients between the ages of 16 and 19 years (8.96), with a ratio of 1 in 6637.

We found likely pathogenic mutations in 33%  of the patients in the CD36, KCNQ1, TNFRSF13B, MEFV, and VCL genes. Of these mutations, about 50% were variants located in scavenger receptor CD36, which is known to increase risk of cardiomyopathy, hyperlipidemia, and insulin resistance.

We tested the ability of mutated CD36 macrophages to express CD36 and other efferocytosis receptors, and clear apoptotic cells and fatty acids. CD36 expression was reduced to levels around 50%  of those in healthy donors, but no reduction in the expression of efferocytosis receptors TIM1, TIM4, SRB1, SIRPa, avb3, avb5, CD91, and Mertk, was seen.  The CD36 mutant significantly reduced macrophage efferocytosis by about 40−60%, with a notable 60−90% efferocytosis reduction by M1 macrophages, which are considered pro-inflammatory. 

Conclusion: Pfizer-BioNTech BNT162b2 vaccine causes myocarditis in young males. We identified CD36 pathogenic variants in 33% of well-characterized patients who developed myocarditis, and propose that these variants, along with increased susceptibility of young male adults, predispose to development of myocarditis via impaired resolution of inflammation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/myocarditis-following-pfizer-biontech-bnt162b2-vaccine-epidemiology-and-predisposition/