Antibodies from primary humoral responses modulate the recruitment of naive B cells during secondary responses

Vaccines generate high-affinity antibodies by recruiting antigen-specific B cells to germinal centers (GCs), but the mechanisms governing the recruitment to GCs on secondary challenges remain unclear. Here, using preclinical SARS-CoV and HIV mouse models, we demonstrated that the antibodies elicited during primary humoral responses shaped the naive B cell recruitment to GCs during secondary exposures. The antibodies from primary responses could either enhance or, conversely, restrict the GC participation of naive B cells: broad-binding, low-affinity, and low-titer antibodies enhanced recruitment, whereas, by contrast, the high titers of high-affinity, mono-epitope-specific antibodies attenuated cognate naive B cell recruitment. Thus, the directionality and intensity of that effect was determined by antibody concentration, affinity, and epitope specificity. Circulating antibodies can, therefore, be important determinants of antigen immunogenicity. Future vaccines may need to overcome—or could, alternatively, leverage—the effects of circulating primary antibodies on subsequent naive B cell recruitment. [Display omitted] •Circulating antibodies affect the recruitment of naive B cells to germinal centers (GCs)•Broad, low-affinity responses enhance naive B cells in GCs on secondary challenge•High-titer, high-affinity, epitope-focused antibodies block cognate naive B cells•Blocking can be overcome by the administration of excess antigen Using preclinical models for HIV and SARS-CoV, Tas et al. show that circulating antibodies from primary responses affect which naive B cells participate in germinal centers after secondary challenges. The directionality and intensity of this influence is determined by the epitope specificity of the primary response and by the affinity and concentration of the circulating antibody.