Germinal center-mediated broadening of B cell responses to SARS-CoV-2 booster immunization

Germinal centers (GC) are key sites for antibody diversification and affinity maturation. SARS-CoV-2 mRNA vaccines elicit robust GC B cell responses in humans, but how these influence the breadth of immunity against viral variants remains unclear. We analyzed GC B cell responses in nine healthy adults following mRNA booster immunization. We show that 77.8% of the B cell clones in the GC expressed representative monoclonal antibodies (mAbs) recognizing the spike protein, with 37.8% of these targeting the receptor-binding domain (RBD). One RBD-targeting mAb, mAb-52, neutralized all tested SARS-CoV-2 strains, including the recent XEC variant. mAb-52 utilized the IGHV3-66 public clonotype, protected hamsters challenged against the EG.5.1 variant, and targeted the class I/II RBD epitope, closely mimicking the binding footprint of ACE2. Its broad reactivity was driven by extensive somatic hypermutation, underscoring the critical role of GC reactions in shaping cross-variant B cell immunity following SARS-CoV-2 booster vaccination.