Genetic variation in HLA, IGKV and HHEX loci influence mRNA vaccine-induced long-lasting humoral protection against COVID-19

There is a notable variability in the humoral response mounted across individuals after COVID-19 vaccination. A growing number of studies link genetic factors to antigen-specific antibody levels after the first two immunizations. However, knowledge on the potential influence of genetics on the neutralizing activity of vaccine-induced antibodies and the humoral immune response to the third immunization is limited. Here, we performed genome-wide association studies on antigen-specific antibody concentrations and live-virus neutralization activities after two and three doses of COVID-19 vaccines across two German cohorts of SARS-CoV-2 infection-naive individuals (RisCoin study n=2877; KoCo19 study n=1654). We found the Human leukocyte antigen (HLA) locus to be associated with differential live-virus neutralizing and anti-SARS-CoV-2 spike antibodies after both the second and third vaccinations. Consistent with its effect on third-dose neutralizing antibodies the HLA locus was further associated with a lower incidence of breakthrough infections, indicating sustained protection. We confirmed the association of the Immunoglobulin kappa variable cluster (IGKV) with antibody concentrations after two vaccinations and discovered a novel association in the Hematopoietically expressed homeobox (HHEX) locus. Studying HLA, IGKV, and HHEX may clarify mechanisms of variable humoral immunity and contribute towards personalized vaccination strategies.