Atypical and non-classical CD45RB memory B cells are the majority of circulating SARS-CoV-2 specific B cells following mRNA vaccination or COVID-19.

Resting memory B cells can be divided into classical or atypical groups, but the heterogenous marker expression on activated memory B cells makes similar classification difficult. Here, by longitudinal analysis of mass cytometry and CITE-seq data from cohorts with COVID-19, bacterial sepsis, or BNT162b2 mRNA vaccine, we observe that resting B cell memory consist of classical CD45RB memory and CD45RB memory, of which the latter contains of two distinct groups of CD11c atypical and CD23 non-classical memory cells. CD45RB levels remain stable in these cells after activation, thereby enabling the tracking of activated B cells and plasmablasts derived from either CD45RB or CD45RB memory B cells. Moreover, in both COVID-19 patients and mRNA vaccination, CD45RB B cells formed the majority of SARS-CoV2 specific memory B cells and correlated with serum antibodies, while CD45RB memory are activated by bacterial sepsis. Our results thus identify that stably expressed CD45RB levels can be exploited to trace resting memory B cells and their activated progeny, and suggest that atypical and non-classical CD45RB memory B cells contribute to SARS-CoV-2 infection and vaccination.