SARS-CoV-2 RBD-specific atypical memory B cells exhibit effector memory-like features in multi-dose mRNA vaccination

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Abstract Memory B cell is a heterogenous population and such heterogeneity is a focus of active investigation. How distinct subsets of memory B cells respond to repeated novel antigen challenges such as SARS-CoV-2 in human remains a subject of vigorous research. We employed fluorochrome-conjugated streptavidin tetramers bound with RBD of wild-type and omicron variant (B.1.1.529), respectively, to sort RBD-specific B cells and performed CITE-seq to investigate detailed dynamics of transcriptomes, surface phenotyes and clonality in healthy mRNA vaccination cohort. PBMC samples of 8 BNT162b2 vaccine recipients from 7 consecutive timepoints, before and after each dose of 3-times vaccination, were analyzed. We found pulsating, yet with increasing trend, frequency of atypical memory B cells among tetramer-binding B cells after each dose of vaccine. SCENIC analysis of tetramer-binding memory B cells to find subset-specific regulatory gene networks revealed atypical memory B cells have distinct regulons of genes related to activation such as receptor clustering, signaling and calcium-dependent activation compared with classical memory B cells and found only one shared clone between atypical and classical tetramer-binding memory B cells, suggesting infrequent interconversion between the two subsets. Furthermore, in-vitro polyclonal stimulation of atypical memory B cells showed higher frequency of antibody-secreting cells (ASC) and pre-plasmablasts in flow cytometry and wild-type RBD-specific ASCs in IgG ELISPOT assay, compared with classical memory B cells. These findings highlight effector memory-like features of atypical memory B cells in viral antigen challenge and a potential target of future vaccine design.

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