The protective role of vitamin D in BNT162b2 vaccine-related acute myocarditis

Abstract

Introduction: 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.

Methods: 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.

Results: 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 GC (vitamin D binding protein) rs4588T allele which encoded the GC2 isoform of vitamin D binding protein was a risk allele, whereas the GC1S 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.

Conclusion: 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.

Keywords: BNT162b2 vaccine-related myocarditis; hypercytokinemia; hyperinflammation; mRNA COVID-19 vaccines; natural killer cell; vitamin D; vitamin D deficiency; vitamin D genetics.

Figure 1

Assessment of vitamin D status and serum levels related to cardiac complications in BNT162b2 vaccine-related myocarditis. (A) Prevalence (%) of vitamin D deficiency, insufficiency, and sufficiency 60 BNT162b2 vaccine-related myocarditis patients. (B) Comparative analysis of circulating 25(OH)D levels between 9 acute and convalescent paired patient samples. Blue and red dotted lines represent the cutoffs for vitamin D insufficiency and deficiency, respectively. *p<0.05. (C) Spearman’s correlation analysis between 25(OH)D levels and presented symptoms in vaccinated myocarditis patients. *p<0.05. (D) Comparative analysis of 25(OH)D levels between (i) patients presenting with or without chest pain and (ii) those admitted to the ICU or not. *p<0.05. (E)(i) Comparative analysis of serum cTnT levels between vitamin D deficient/insufficient and sufficient patients. **p<0.01. (ii) Spearman’s analysis between cTnT levels and 25(OH)D levels among patients. The red dotted line represents the cutoff between vitamin D deficiency/insufficiency and sufficiency (50 nmol/L). The green box highlights patients with relatively higher cTnT levels. *p<0.05.

Figure 2

Correlation and qualitative comparison of activation subsets of NK cells and monocytes in BNT162b2 vaccine-related myocarditis patients with different vitamin D status. (A) Association of measured frequencies of activation subsets of NK cells and monocytes with the occurrence of the initial presented symptoms in BNT162b2 vaccine-related myocarditis patients. **p<0.01. (B) Comparative analysis of CD69+ NK cell and HLA-DR+ monocyte subsets between (i,iii) patients presenting with or without chest pain and (ii,iv) those admitted to the ICU or not. **p<0.01. (C) Qualitative comparison of activation frequency of (i) NK cell and (ii) monocyte subsets in vitamin D deficient/insufficient patients, and vitamin D sufficient patients. Data are presented as mean ± SD and analyzed using a two-sided Student’s t-test. **p<0.01. (D) Spearman’s correlation analysis of activated subset frequencies of (i) NK cells and (ii) monocytes plotted against 25(OH)D levels in BNT162b2 vaccine-related myocarditis patients. The best-fit trendline is shown. *p<0.05.