SARS-CoV-2 Omicron BA.1 breakthrough infection drives late remodeling of the memory B cell repertoire in vaccinated individuals.

How infection by a viral variant showing antigenic drift impacts a preformed mature human memory B cell (MBC) repertoire remains an open question. Here, we studied the MBC response up to 6 months after SARS-CoV-2 Omicron BA.1 breakthrough infection in individuals previously vaccinated with three doses of the COVID-19 mRNA vaccine. Longitudinal analysis, using single-cell multi-omics and functional analysis of monoclonal antibodies from RBD-specific MBCs, revealed that a BA.1 breakthrough infection mostly recruited pre-existing cross-reactive MBCs with limited de novo response against BA.1-restricted epitopes. Reorganization of clonal hierarchy and new rounds of germinal center reactions, however, combined to maintain diversity and induce progressive maturation of the MBC repertoire against common Hu-1 and BA.1, but not BA.5-restricted, SARS-CoV-2 Spike RBD epitopes. Such remodeling was further associated with a marked improvement in overall neutralizing breadth and potency. These findings have fundamental implications for the design of future vaccination booster strategies. ▪ • SARS-CoV-2 BA.1 breakthrough infection recalls cross-reactive RBD memory B cells (MBCs) • Recruitment of BA.1-restricted naive B cells to ASC and MBC-repertoires is limited • Longitudinal tracking reveals repertoire evolution up to 6 months post infection • Late remodeling is associated with improved MBC affinity and neutralization breadth How infection by a viral variant showing antigenic drift impacts a preformed mature human memory B cell (MBC) repertoire remains unclear. Sokal et al. show that SARS-CoV-2 Omicron BA.1 breakthrough infections induce late remodeling and maturation of the pre-existing memory B cell pool, with progressively improved MBC affinity and neutralization breadth but limited recruitment of BA.1-restricted naive B cells. [ABSTRACT FROM AUTHOR]