ABSTRACT
HLA molecules are key restrictive elements to present intracellular antigens for an effective T-cell response against SARS-CoV-2. HLA alleles vary with respect to their potential to present immunogenic viral epitopes and may therefore determine disease severity. Therefore, we set out to investigate the impact of individual HLA genotypes on the severity of SARS-CoV-2 infections. In August 2020 and July 2021, we performed cross-sectional studies among stem cell donors registered with DKMS in Germany. Volunteers registered for stem cell donation represent a comparable healthy subset of the working age population. Available genetic information was linked to self-reported COVID-19 outcome data. Multivariable regression models were fitted to determine the risk of contracting SARS-CoV-2, severe respiratory tract infection and respiratory hospitalization. More than 200,000 registered donors provided informed consent and participated in the study. Their age ranged from 18 to 61 years. Altogether 16,121 participants donors reported a history of COVID-19. Asymptomatic courses were reported by 1428 participants, mild/moderate symptoms by 10,353 participants, severe respiratory infections by 3913 not requiring hospitalization and respiratory hospitalizations by 427 patients. Notably, we did not observe a heterozygote advantage. The risk for severe infections was not statistically different among individuals with or without homozygosity at HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1. Of 84 HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles which were prevalent in more than 400 participants only the presence of HLA-B∗39:01 had significant impact on the risk for respiratory hospitalization (OR 2.23, p = 0.01) at a significance level of 1%. These findings suggest that the HLA genotype is no major factor determining COVID-19 severity. It is therefore possible that the relatively large viral genome of 29.8 kb encodes for abundant epitopes to mount T-cell responses not limited by the HLA genotype.