Demographic and genetic factors shape the epitope specificity of the human antibody repertoire against viruses

Abstract Antibodies are central to immune defenses. Despite advances in understanding the mechanisms of antibody generation, a comprehensive model of how intrinsic and external factors shape human humoral responses to viruses has been lacking. Here we apply phage immunoprecipitation sequencing to investigate the effects of demographic factors—including 108 lifestyle and health-related variables—and genetic variation on antibody reactivity to over 97,000 viral peptides in 1,212 healthy adults. We demonstrate that age, sex and continent of birth extensively affect not only the viruses but also the specific viral epitopes targeted by the antibody repertoire. Notably, we find that antibodies against rapidly evolving epitopes of influenza A virus decrease with age, whereas immunoreactivity to conserved epitopes increases. Furthermore, we identify strong associations between antibodies against 34 viruses and genetic variants at HLA , FUT2 , IGH and IGK loci, some of which increase autoimmune disease risk. These findings offer a valuable resource for understanding the factors affecting antibody-mediated immunity, laying the groundwork for optimizing vaccine strategies.