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Transl. Med."],"published-print":{"date-parts":[[2026,8,12]]},"abstract":"<jats:p>The protective benefits of vaccination can critically depend on the durability of the corresponding immune response. However, the factors influencing vaccine durability are poorly understood. Here, we tested whether antigen avidity (i.e., cumulative multivalent binding strength) affected the durability, magnitude, and diversity of the humoral immune response in preclinical HIV vaccine models. We developed neoteric mosaic nanoparticle platforms to vary antigen avidity through precise modulation of its key constituents, epitope affinity and valency, while keeping other variables constant. High-valency immunogens elicited durable and clonally diverse memory B cell (MBC) responses that were detectable for more than 1 year postprime. Increased antigen valency also drove the formation and persistence of long-lived plasma cells (LLPCs) as well as epitope-specific serum antibody responses. This appeared to be due, in part, to more robust and durable germinal center (GC) reactions that were elicited by high-valency immunogens and were detectable for upward of 6 months postprime. High-valency antigens also promoted B cell responses in a clinically relevant homologous prime-boost regimen. The positive effects of antigen avidity in driving productive B cell responses were independent of antigen dose and adjuvant. However, when interclonal competition was suppressed, MBC, LLPC, and late GC responses to low-avidity immunogens were rescued. Affinity worked in concert with valency to drive the formation of MBC responses, with valency having strong influences. 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