Tracking B cell responses to the SARS-CoV-2 mRNA-1273 vaccine

Protective immunity following vaccination is sustained by long-lived antibody-secreting cells and resting memory B cells (MBCs). Responses to two-dose SARS-CoV-2 mRNA-1273 vaccination are evaluated longitudinally by multimodal single-cell analysis in three infection-naïve individuals. Integrated surface protein, transcriptomics, and B cell receptor (BCR) repertoire analysis of sorted plasmablasts and spike⁺ (S-2P⁺) and S-2P^- B cells reveal clonal expansion and accumulating mutations among S-2P⁺ cells. These cells are enriched in a cluster of immunoglobulin G-expressing MBCs and evolve along a bifurcated trajectory rooted in CXCR3⁺ MBCs. One branch leads to CD11c⁺ atypical MBCs while the other develops from CD71⁺ activated precursors to resting MBCs, the dominant population at month 6. Among 12 evolving S-2P⁺ clones, several are populated with plasmablasts at early timepoints as well as CD71⁺ activated and resting MBCs at later timepoints, and display intra- and/or inter-cohort BCR convergence. These relationships suggest a coordinated and predictable evolution of SARS-CoV-2 vaccine-generated MBCs.