Systems-Scale Structural Modeling Reveals the Germline Architecture of Immunodominance

The adaptive immune system generates diverse antibodies to protect against infection, yet responses often focus on a limited number of antigenic sites, a phenomenon called immunodominance. Using the SARS-CoV-2 receptor-binding domain as a model, this study combines large-scale antibody sequencing, deep mutational scanning, and AlphaFold 3 structural modeling to investigate the basis of immunodominant epitope selection. The results show that germline-encoded antibody features are a primary driver of immunodominance. Specifically, 76% of RBD-targeting antibodies display conserved gene segment usage and/or germline-encoded HCDR3 motifs. Structural analyses identified recurrent germline-encoded residues within these regions that interact with immunodominant epitopes, and mutating these residues eliminated binding. Mutations in SARS-CoV-2 variants frequently disrupt these interactions and are associated with immune escape; other mutations enable germline-mediated recognition and generate new immunodominant epitopes. These findings indicate that innate features, rather than diverse somatic mutations, determine binding specificity for the large majority of the antibody response and underlie antibody immunodominance.