LAUSR

The long‐term health consequences of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection are still being understood. The molecular and phenotypic properties of SARS‐CoV‐2 antigen–specific T cells suggest a dysfunctional profile that persists in convalescence in those who were severely ill. By contrast, the antigen‐specific memory B‐cell (MBC) population has not yet been analyzed to the same degree, but phenotypic analysis suggests differences following recovery from mild or severe coronavirus disease 2019 (COVID‐19). Here, we performed single‐cell molecular analysis of the SARS‐CoV‐2 receptor‐binding domain (RBD)–specific MBC population in three patients after severe COVID‐19 and four patients after mild/moderate COVID‐19. We analyzed the transcriptomic and B‐cell receptor repertoire profiles at ~2 months and ~4 months after symptom onset. Transcriptomic analysis revealed a higher level of tumor necrosis factor‐alpha (TNF‐α) signaling via nuclear factor‐kappa B in the severe group, involving CD80, FOS, CD83 and TNFAIP3 genes that was maintained over time. We demonstrated the presence of two distinct activated MBCs subsets based on expression of CD80hiTNFAIP3hi and CD11chiCD95hi at the transcriptome level. Both groups revealed an increase in somatic hypermutation over time, indicating progressive evolution of humoral memory. This study revealed distinct molecular signatures of long‐term RBD‐specific MBCs in convalescence, indicating that the longevity of these cells may differ depending on acute COVID‐19 severity.