Precursor Frequency and Affinity Determine B Cell Competitive Fitness in Germinal Centers, Tested with Germline-Targeting HIV Vaccine Immunogens

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SummaryHow precursor frequencies and antigen affinities impact interclonal B cell competition is a particularly relevant issue for candidate germline-targeting HIV vaccine designs because of the in vivo rarity of naive B cells that recognize broadly neutralizing epitopes. Knowing the frequencies and affinities of HIV-specific VRC01-class naive human B cells, we transferred B cells with germline VRC01 B cell receptors into congenic recipients to elucidate the roles of precursor frequency, antigen affinity, and avidity on B cell responses following immunization. All three factors were interdependently limiting for competitive success of VRC01-class B cells. In physiological high-affinity conditions using a multivalent immunogen, rare VRC01-class B cells successfully competed in germinal centers (GC), underwent extensive somatic hypermutation, and differentiated into memory B cells. The data reveal dominant influences of precursor frequency, affinity, and avidity for interclonal GC competition and indicate that germline-targeting immunogens can overcome these challenges with high-affinity multimeric designs.Graphical AbstractHighlightsPrecursor frequency and affinity limit VRC01-class B cell fitness upon immunizationFrequency and affinity constraints can be modulated by immunogen multivalencyPhysiologically rare VRC01-class precursor B cells can successfully compete in GCsInterclonal competition in germinal centers can resolve within 2–3 weeksIt is not clear how precursor frequencies and antigen affinities impact interclonal B cell competition. Abbott et al. show these parameters interdependently limit germinal center B cell fitness. When these variables are matched to the human physiological range, HIV bnAb precursor B cells compete in germinal centers, undergo extensive mutation, and form memory.

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