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

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 is lacking. Here, we apply PhIP-Seq to investigate the effects of demographic and genetic factors on antibody reactivity to more than 97,000 viral peptides in 1,212 healthy adults. We demonstrate that age, sex, and continent of birth extensively influence the viruses and viral epitopes targeted by the human antibody repertoire. Among 108 lifestyle and health-related variables, smoking exerts the strongest, yet reversible, impact on antibody profiles, primarily against rhinoviruses. Additionally, we identify strong associations between antibodies against 34 viruses and genetic variants at HLA, FUT2, IGH, and IGK genes, 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.