Mechanisms that promote the evolution of cross-reactive antibodies upon vaccination with designed influenza immunogens

SUMMARY Immunogens that elicit broadly neutralizing antibodies targeting the conserved receptor-binding site (RBS) on influenza hemagglutinin (HA) may serve as a universal influenza vaccine candidate. Here, we developed a computational model to interrogate antibody evolution by affinity maturation after immunization with two types of immunogens: a chimeric heterotrimeric ‘HAtCh’ antigen that is enriched for the RBS epitope relative to other B cell epitopes, and a cocktail composed of three non-epitope-enriched homotrimeric antigens that comprise the HAtCh. Experiments in mice (Caradonna et al.) find that the chimeric antigen outperforms the cocktail for eliciting RBS-directed antibodies. We show that this result follows from an interplay between how B cells engage these antigens and interact with diverse T helper cells, and requires T cell-mediated selection of germinal center B cells to be a stringent constraint. Our results shed new light on antibody evolution, and highlight how immunogen design and T cells modulate vaccination outcomes.