Immunization with mosaic nanoparticles reveals that antigen avidity shapes the clonal hierarchy of the B cell response

Vaccination with real-world complex antigens often elicits a hierarchical immune response to different epitopes. This immunodominance is a major obstacle in vaccine design because nonprotective epitopes often divert the immune response away from protective epitopes. We posited that B cell epitope avidity (i.e., total multivalent binding strength) is a key regulator of immunodominance hierarchy by modulating both germinal center (GC) seeding and B cell competitive fitness in GCs. To test these hypotheses, we used two sets of mosaic nanoparticle immunogens to precisely modulate epitope avidity by varying the valency and affinity components independently while keeping nanoparticle size and helper T cell epitopes constant. We evaluated these immunogens in three HIV vaccine models that use humanized mice to recapitulate physiological precursor frequencies and affinities. Increased epitope avidity drove seeding of GCs, as well as B cell competitive fitness and immunodominance hierarchies in GCs. B cell receptor sequencing revealed that epitope valency had negligible impact on total somatic hypermutations but collectively promoted clonal diversity and affinity maturation in GCs. Restricting interclonal competition rescued early GC B cell responses to low-valency immunogens. Epitope valency and affinity worked in combination to promote GC B cell competitive fitness, although valency had prominent influences. Furthermore, both valency and affinity regulated the early extrafollicular (EF) plasma cell response in a manner dependent on interclonal competition. The data highlight the critical importance of relative epitope avidity in shaping the competitive immunodominance landscape in GC and EF responses. This should be considered when designing next-generation nanoparticle vaccines.