HLA binding-groove motifs are associated with myocarditis induction after Pfizer-BioNTech BNT162b2 vaccination

ABSTRACT

We found a higher incidence of myocarditis in young males who had received Pfizer-BioNTech BNT162b2 vaccinations as compared with historical controls and unvaccinated individuals. The analyses focused on risk following the first and second vaccine in adults and adolescents, as well as risk in adults following the third (booster) vaccine. Males, mainly aged 12-30 years, were found to be at higher risk. However, the question remains what causes lead one specific young male, but not another, to develop post-vaccination myocarditis. The HLA molecule is known to play an important role in infectious and auto-inflammatory diseases. We hypothesized that differences in HLA alleles could lead to either protection or susceptibility to vaccination-induced myocarditis. On this basis, HLA typing was performed using next-generation sequencing technology for the HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 loci, in 21 wellcharacterized patients who developed myocarditis after the second Pfizer BNT162b2 vaccination. The HLA genotypes were compared with high-resolution HLA data of 272 healthy controls from the Hadassah Bone Marrow registry samples, who are representative of HLA frequencies in the Israeli population. Our findings demonstrated that in HLA class II, DRB1*1401 (19.04% vs. 5.3%, Pcorr = 0.028, OR = 4.17), HLA-DQB1*0503 (19.04% vs. 6.06%, Pcorr = 0.034, OR = 3.64) and DRB1*1503 (7.14% vs. 0.0%, Pcorr = 0.003, OR = 41.76) were significantly associated with disease susceptibility. We further discovered susceptibility motifs in the HLA-DR peptidebinding grooves His60 (Pcorr0.01, OR = 3.52) and Arg70 (Pcorr = 0.0047, OR = 3.43). Our findings suggest that immunogenetic fingerprints in HLA peptide-binding grooves may have changed the binding affinity of different peptides derived from the Pfizer-BioNTech BNT162b2 vaccination, and induced myocarditis.