Integrating host genetics with the antibody response to viral infections may aid our
understanding of inter-individual differences in immune response and disease outcomes. The antibody response to viral peptides was characterized using VirScan which allows for high- throughput antibody profiling of viral epitopes. We study the genetics of the antibody response to 52 Epstein-Barr Virus (EBV) and 52 Human Adenovirus (HAdv) prevalent peptides in a cohort of 625 unrelated participants of European and African ancestry and an independent cohort of 494 twins from UK. We identified 4 epitopes of EBV that were heritably targeted, and at least two EBNA-2 binding specificities that were associated with variants in the MHC class-II locus. Similarly, we identified genetic associations in the HLA Class-II genes with the long-term antibody response to protein peptides in the core proteins V, VII and minor capsid protein VIII of HAdv. Furthermore, we performed an in-silico finemapping of these HLA-associated regions and identified the specific classical alleles and amino acids in the DQB1 and DRB1 genes implicated in the long-term antibody response to the EBNA-2 and the minor capsid protein VIII of HAdv. This demonstrates that specific amino acid variation in the HLA-class II influence the long-term viral antibody response in an epitope specific manner
