Antibody responses against bacterial glycans affinity mature and diversify in germinal centers

Summary Anti-carbohydrate antibodies (Abs) play crucial roles in pathogen control, but their generation remains poorly understood. By studying responses to Streptococcus pyogenes in humans, we reveal that the glycan-targeted response shifts from IgM towards IgG and IgA memory with age and antigen exposure across blood, spleen, and tonsils. Both natural colonization and controlled human infection with S. pyogenes increased class-switched B cells, with evidence of within-clone switching. Glycan-specific B cells readily participated in germinal center (GC) responses and showed robust somatic hypermutation despite a molecular signature consistent with receiving reduced T cell help. We conclude that mucosal pathogen encounters elicit glycan responses that class-switch, evolve and diversify through the GC. These findings reveal how age and infection history can influence the quality, quantity, and isotype use of glycan-specific B cells, with implications for the design and schedule of glycan-containing vaccines. Competing Interest Statement A.C.S. co-chairs the Australian Strep A Vaccine Initiative (ASAVI) and the Strep A Vaccine Global Consortium (SAVAC). N.J.M. is co-leader of Rapua te mea ngaro ka tau, a New Zealand-based S. pyogenes vaccine initiative. H.R.F., D.L.H., J.O., and A.C.S. are Human Infection Challenge Network for Vaccine development (HIC-Vac) members. The remaining authors declare no competing interests.