Genetic variation in HLA, IGKV, and HHEX loci influences mRNA vaccine-induced humoral protection against COVID-19.

Humoral immune responses to COVID-19 vaccination vary widely across individuals, yet the genetic determinants of functional antibody protection beyond binding antibodies after two immunizations remain poorly understood. We performed genome-wide association studies on antigen-specific antibody concentrations and live-virus neutralization activities after two and three vaccine doses in two German cohorts of SARS-CoV-2 infection-naïve individuals (RisCoin study n = 2,877; KoCo19 study n = 1,654). We found the 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 neutralization, the HLA was additionally associated with a reduced incidence of breakthrough infection. We further replicated an association with antibody concentrations at the IGKV locus and discovered an association at the HHEX locus, implicating pathways linked to memory B-cell biology. Together, these findings reveal host genetic factors shaping neutralizing immunity and vaccine-induced protection against infection, with implications for personalized vaccination strategies.