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The emergence of the Omicron variant marked a major antigenic shift from previous SARS-CoV-2 variants. While the emergence of new variants of concern was associated with loss of protection from infection, protection from serious disease was maintained. What was less clear was whether this protection was associated with expansion, affinity maturation of pre-existing cross-reactive B cells, or de novo generation of variant-specific B cells. To define the cross-reactivity of memory B cell populations generated through infection and/or vaccination with pre-Omicron variant spike, we utilised archived samples from healthcare workers enrolled in the extensively monitored Panther study cohort. Using samples collected from Omicron-naïve individuals approximately three months (106 days) after a third BNT162b2 vaccine dose, we analyzed the spike-specific B cell repertoire via multiparameter flow cytometry and B cell receptor (BCR) sequencing.

Reactivity to both Lineage A and Omicron spike proteins was higher for serum IgG than IgA, and serum neutralisation potency was significantly reduced against pseudoviruses bearing the Omicron spike compared to those with Lineage A spike. The frequency of Omicron-reactive IgA+ B cells was markedly lower than that of Lineage A-reactive cells, whereas Omicron-reactive IgG+ memory B cells were more frequent. These responses were predominantly localized to classical memory and double-negative (DN) B cell subsets. BCR sequencing of donors unexposed to Omicron confirmed that Omicron-binding clones were class-switched and somatically mutated, indicating they originated from pre-existing memory B cells primed by vaccination or infection.

Our findings demonstrate that memory B cells generated through infection and/or immunisation with pre-Omicron variants were primed for broad antigenic recognition despite Omicron’s extensive genetic divergence. However, the diminished IgA+ B cell frequency suggests a weakened mucosal antibody defence, potentially explaining the continued susceptibility to infection despite preserved protection from severe disease.