An epitope-enriched immunogen increases site targeting in germinal centers

Antibody immunodominance is the asymmetric elicitation of responses against protein antigens. For influenza hemagglutinin (HA), antibody responses often target variable regions on HA and do not provide lasting protection. Next-generation influenza vaccines should elicit antibodies targeting conserved regions such as the receptor binding site (RBS). Understanding how presenting an epitope on a rationally-designed immunogen influences immune responses could help achieve this goal. Here, we compared an engineered RBS-enriched immunogen and its non-enriched counterparts to characterize RBS-directed responses. We found that enriching the RBS-epitope on a single immunogen preferentially expands RBS-directed responses relative to a cocktail of the non-epitope-enriched immunogens. Single B cell analyses showed a genetically diverse RBS-directed population that structural characterization showed engagement of the RBS with canonical features shared with both its receptor and human broadly neutralizing antibodies. These data show how epitope-enriched immunogens can expand responses to a conserved viral site, while maintaining genetic and structural diversity. ### Competing Interest Statement T.M.C. and A.G.S. have filed a provisional patent application for the design of the HAtCh immunogen.