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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., Competing Interests: Declaration of interests Outside of the submitted work, M. Mahévas received research funds from GSK and personal fees from LFB and Amgen. J.-C.W. received consulting fees from Institut Mérieux. P.B. received consulting fees from Regeneron Pharmaceuticals., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The SARS-CoV-2 Omicron variant can escape neutralization by vaccine-elicited and convalescent antibodies. Memory B cells (MBCs) represent another layer of protection against SARS-CoV-2, as they persist after infection and vaccination and improve their affinity. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant remains unclear. We assessed the affinity and neutralization potency against the Omicron variant of several hundred naturally expressed MBC-derived monoclonal IgG antibodies from vaccinated COVID-19-recovered and -naive individuals. Compared with other variants of concern, Omicron evaded recognition by a larger proportion of MBC-derived antibodies, with only 30% retaining high affinity against the Omicron RBD, and the reduction in neutralization potency was even more pronounced. Nonetheless, neutralizing MBC clones could be found in all the analyzed individuals. Therefore, despite the strong immune escape potential of the Omicron variant, these results suggest that the MBC repertoire generated by mRNA vaccines still provides some protection against the Omicron variant in vaccinated individuals., Competing Interests: Declaration of interests Outside of the submitted work, M. Mahévas received research funds from GSK and personal fees from LFB and Amgen. J.-C.W. received consulting fees from Institut Mérieux. P.B. received consulting fees from Regeneron Pharmaceuticals. J.-M.P. received personal fees from Abbvie, Gilead, Merck, and Siemens Healthcare. F.A.R. is a member of the board of MELETIOS Therapeutics and of the Scientific Advisory Board of eureKARE., (Copyright © 2022. Published by Elsevier Inc.)