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

Immunogens that elicit broadly neutralizing antibodies targeting the conserved receptor-binding site (RBS) on influenza hemagglutinin may serve as candidates for a universal influenza vaccine. Here, we develop a computational model to interrogate antibody evolution by affinity maturation after immunization with two types of immunogens: a heterotrimeric chimerahemagglutinin that is enriched for the RBS epitope relative to other B cell epitopes and a cocktail composed of three non-epitope-enriched homotrimers of the mono-mers that comprise the chimera. Experiments in mice find that the chimera 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 helper T cells and requires T cell-mediated selection of germinal center B cells to be a stringent constraint. Our results shed light on antibody evolution and highlight how immunogen design and T cells modulate vaccination outcomes.

Automated summary

By using a computational model, this study investigates antibody evolution through affinity maturation after immunization with two types of immunogens (a heterotrimeric chimerahemagglutinin enriched for the receptor-binding site epitope and a cocktail of non-epitope-enriched homotrimers). Experiments in mice demonstrate that the chimerahemagglutinin is more effective in eliciting receptor-binding site-specific antibodies compared to the cocktail. The results highlight the interplay between B cells, antigens, and diverse helper T cells in antibody evolution and emphasize the importance of immunogen design and T cell modulation in vaccination outcomes.