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

Hing Wai Tsang ^1,2* Gilbert T Chua ¹ Keith Tsz Suen Tung ¹ Rosa Wong ³ Sabrina Tsao ¹ Joshua Sung Chih Wong ⁴ Joanna Yuet Ling Tung ⁵ Janette Siu Yin Kwok ⁶ Jason C. Yam ⁷ Godfrey Chi-Fung Chan ⁸ Kelvin To ⁹ Ian Chi Kei Wong ^10,11,12 Wing Hang Leung ¹ Mike Yat Wah Kwan ¹ Patrick Ip ^1*

• ¹ Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR China
• ² The University of Hong Kong, Pokfulam, Hong Kong, SAR China
• ³ Department of Special Education and Counselling, The Education University of Hong Kong, Tai Po, Hong Kong, SAR China
• ⁴ Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, Hong Kong, SAR China
• ⁵ Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong, Hong Kong, SAR China
• ⁶ Department of Pathology, Queen Mary Hospital, Hong Kong, Hong Kong, SAR China
• ⁷ Department of Ophthalmology and Visual Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong Region, China
• ⁸ Paediatric Haematology & Oncology Centre, Hong Kong Sanatorium & Hospital, Hong Kong, Hong Kong, SAR China
• ⁹ Department of Microbiology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR China
• ¹⁰ Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR China
• ¹¹ School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Taipa, Macau Region, China
• ¹² Aston Pharmacy School, School of Life & Health Sciences, Aston University, Birmingham, West Midlands, United Kingdom

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-1 (IL-1), IL-12, Interferon-IFN-, 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.