SARS-CoV-2-specific atypical memory B cells induced by mRNA vaccine exhibit robust effector functions

Atypical memory B cell is an ill-defined memory B cell subset found expanded in many chronic inflammatory diseases. Exact roles and functions of this subset against cognate antigen exposures remain elusive. We employed streptavidin tetramers bound with RBD of Wuhan-Hu-1 and B.1.1.529, respectively, to sort RBD-specific B cells and performed CITE-seq to investigate detailed transcriptome, surface phenotypes and BCR properties in mRNA vaccination cohort. PBMC samples of BNT162b2 vaccine recipients were analyzed. Increasing frequency of atypical memory B cells among RBD-specific B cells after each dose of vaccine was observed. GSEA of RBD-specific atypical memory B cells compared with classical memory B cells showed significant enrichment of gene sets related to immune effector functions. In addition, comparable increase of heavy chain somatic hypermutation by repeated vaccinations was also observed in RBD-specific atypical memory B cells suggesting robust affinity maturation. In corroboration with these findings, 48 hours of in-vitro polyclonal stimulation of atypical memory B cells yielded higher frequency of antibody secreting cells (ASC) in flow cytometry, Wuhan-Hu-1 RBD-specific ASCs in IgG ELISPOT assay compared with classical memory B cells, and 11 days of stimulation yielded comparable neutralizing antibody secretion against Wuhan-Hu-1 RBD. These findings highlight effector memory features of atypical memory B cells and as a potential target of future vaccine design.