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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.

Summary As SARS-CoV-2 infections and death counts continue to rise, it remains unclear why some individuals recover from infection whereas others rapidly progress and die. While the immunological mechanisms that underlie different clinical trajectories remain poorly defined, pathogen-specific antibodies often point to immunological mechanisms of protection. Here, we profiled SARS-CoV-2–specific humoral responses on a cohort of 22 hospitalized individuals. Despite inter-individual heterogeneity, distinct antibody signatures resolved individuals with different outcomes. While no differences in SARS-CoV-2-specific IgG levels were observed, spike–specific humoral responses were enriched among convalescent individuals, whereas functional antibody responses to the nucleocapsid were elevated in deceased individuals. Furthermore, this enriched immunodominant S-specific antibody profile in convalescents was confirmed in a larger validation cohort. These results demonstrate that early antigen-specific and qualitative features of SARS-CoV-2-specific antibodies, point to differences in disease trajectory, highlighting the potential importance of functional antigen-specific humoral immunity to guide patient care and vaccine development., Graphical Abstract, Highlights • Limited early differences across groups were observed in titers and neutralization • Five antibody features collectively could differentiate convalescents and deceased • A shift in the balance of spike versus nucleocapsid immunity separated the groups • Spike-specific phagocytic and complement fixing activity was enriched in convalescents, Although most SARS-CoV-2 infected individuals experience mild disease, a significant fraction of individuals become severely infected. Early biomarkers that predict outcome are urgently needed. Atyeo et al demonstrate that distinct acute SARS-CoV-2 humoral immune responses exist across severely ill individuals that ultimately convalesce or pass away.

Germinal center (GC) B cells evolve towards increased affinity by a Darwinian process that has been studied primarily in genetically restricted, hapten-specific responses. We explored the population dynamics of genetically diverse GC responses to two complex antigens – Bacillus anthracis protective antigen and influenza hemagglutinin – in which B cells competed both intra- and interclonally for distinct epitopes. Preferred VH rearrangements among antigen-binding, naïve B cells were similarly abundant in early GCs but, unlike responses to haptens, clonal diversity increased in GC B cells as early “winners” were replaced by rarer, high-affinity clones. Despite affinity maturation, inter- and intraclonal avidities varied greatly, and half of GC B cells did not bind the immunogen but nonetheless exhibited biased VH use, V(D)J mutation, and clonal expansion comparable to antigen-binding cells. GC reactions to complex antigens permit a range of specificities and affinities, with potential advantages for broad protection.