AB0061 PATHOGENIC VARIANTS OF SCAVENGER RECEPTOR CD36 LEAD TO DECREASED EFFEROCYTOSIS AND PREDISPOSE TO MYOCARDITIS FOLLOWING VACCINATION WITH PFIZER-BioNTech BNT162b2 AGAINST CORONAVIRUS INFECTION (COVID-19)
Authors: D. Mevorach
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> 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. <h3>Objectives:</h3> To explore the potential genetic predisposition to mRNA post-vaccination myocarditis. <h3>Methods:</h3> 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[1] following their second vaccination. Efferocytosis assay was performed using apoptotic cells and flow cytometry. We isolated PBMCs from 3/4 patients representing all four mutations. Monocytes were differentiated to M0/M1/M2 macrophages, stained for efferocytosis receptors, and evaluated for efferocytosis. <h3>Results:</h3> We found likely pathogenic mutations in 50% (8/16) of the patients in the <i>CD36, KCNQ1, TNFRSF13B, MEFV,</i> and <i>VCL</i> genes. Of these mutations, 4/8 were variants located in scavenger receptor <i>CD36</i>, which is known to increase risk of cardiomyopathy, hyperlipidemia, and insulin resistance. We tested the ability of mutated <i>CD36</i> 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. Thus, all CD36 variants were found pathogenic and led to a significant decrease in efferocytosis. Together this suggests that mRNA and/or lipid nanoparticles induce activation and maturation of antigen-presenting cells at the injection site, leading to myocardium inflammation with altered resolution of inflammation in predisposed individuals. <h3>Conclusion:</h3> We identified CD36 pathogenic variants in 25% of well-characterized patients who developed post Pfizer-BioNTech BNT162b2 vaccination-related myocarditis, and propose that these variants, along with increased susceptibility of young male adults, predispose to development of myocarditis. <h3>REFERENCES:</h3> [1] Mevorach D, et al. Myocarditis after BNT162b2 mRNA vaccine against Covid-19 in Israel. N Engl J Med. 2021; 385:2140-2149. doi: 10.1056/NEJMoa2109730. [2] Mevorach D, et al. Myocarditis after BNT162b2 Vaccination in Israeli Adolescents. N Engl J Med. 2022 Mar 10;386(10):998-999..PMID: 35081295. [3] Myocarditis After BNT162b2 COVID-19 Third Booster Vaccine in Israel. Mevorach D et al. Circulation. 2022; PMID: 36067275. <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> Dror Mevorach Enlivex Therapeutics, Merck Serono, Enlivex Therapeutics, Enlivex Therapeutics.