Weidner, N. G.; Padilla, M. V.; Pruitt, L.; Cottrell, C. A.; Gonzales, K.; Kalyuzhniy, O.; Kubitz, M.; Alavi, N.; Phelps, N.; Weglarz, M.; Schief, W. R.; Abbott, R. K.

One challenge in vaccine development is designing immunogens that elicit durable immunity. We hypothesized that antigen avidity regulates the magnitude, diversity, and durability of the vaccine immune response. We tested this in multiple preclinical HIV vaccine models using a neoteric mosaic nanoparticle platform. This allowed us to precisely modulate antigen avidity by varying multivalency and affinity independently, whilst keeping other variables constant. Antigen avidity drove seeding, interclonal competition, and immunodominance within germinal centers. High-valency immunogens promoted durable germinal center, memory B cell, serum antibody, and long-lived plasma cell responses. Restricting interclonal competition rescued B cell responses to low-valency immunogens. B cell receptor sequencing revealed that antigen valency had minimal impact on individual somatic hypermutations but promoted clonal diversity. Affinity worked in concert with valency in driving productive B cell responses, with multivalency having dominant influences. The results underscore the importance of antigen avidity in driving durable and diverse vaccine responses.