Precursor Frequency and Affinity Determine B Cell Competitive Fitness in Germinal Centers, Tested with Germline Targeting HIV Vaccine Immunogens
Summary How 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 Abstract Figure. No Caption available. HighlightsPrecursor 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 weeks &NA; It 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.
Immunity