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The development of safe and effective vaccines against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was a major turning point in the fight against the Coronavirus 2019 (COVID-19) pandemic. However, pharmacovigilance has revealed a small but significant incidence of cardiac inflammation manifesting clinically as myocarditis or pericarditis, particularly in younger vaccine recipients. The incidence is the highest among men under age 40 within a week of receiving the second dose of the mRNA vaccine. In this review, we summarise the evidence for, and guidelines in relation to, SARS-CoV2 vaccine-related myocarditis.

Vaccine-related myocarditis is recognized as a rare but important complication, especially after mass-scale mRNA COVID-19 vaccination. Knowledge regarding how to minimize the risk is limited. As NK cells can mediate acute myocarditis after mRNA COVID-19 vaccination and vitamin D may inhibit NK cells via cytokine modulation, we hypothesize that the myocarditis side effect is related to a hypovitaminosis D - mRNA vaccine - hypercytokinemia - NK cell axis, which is amendable to clinical intervention. Biochemical, immunophenotypic and genotyping assays were performed to examine vitamin D status and immune profiles in 60 patients who had BNT162b2 vaccine-related acute myocarditis. A high incidence of hypovitaminosis D (73.3%) was observed in these individuals with vaccine-related myocarditis, particularly in those presented with chest pain or intensive care unit (ICU) admission. Moreover, vitamin D level was negatively associated with peak serum cardiac troponin T level during vaccine-related myocarditis. Genotypically, the (vitamin D binding protein) rs4588T allele which encoded the isoform of vitamin D binding protein was a risk allele, whereas the isoform was protective. Mechanistically, hypovitaminosis D was associated with higher levels of cytokines pivotal for natural killer (NK) cells (particularly interleukin-1β (IL-1β), IL-12, Interferon-γ (IFN-γ), and IL-8) and higher percentage of CD69+ NK cells in blood, which in turn correlated with chest pain presentation. These data support the hypothesis that vitamin D plays a crucial role in mitigating mRNA vaccine-related myocarditis by modulating proinflammatory cytokine milieu and subsequent unfavorable NK cell activation, laying a groundwork for preventive and treatment strategies.