Memory B cells dominate the early antibody-secreting cell response to SARS-CoV-2 mRNA vaccination in naïve individuals independently of their antibody affinity

Abstract

Memory B cells (MBCs) formed over the individual’s lifetime constitute nearly half of the adult peripheral blood B cell repertoire in humans. To assess their response to novel antigens, we tracked the origin and followed the differentiation paths of MBCs in the early anti-S response to mRNA vaccination in SARS-CoV-2-naïve individuals on single-cell and monoclonal antibody level. Newly generated and pre-existing MBCs differed in their differentiation paths despite similar levels of SARS-CoV-2 and common corona virus S-reactivity. Pre-existing highly mutated MBCs showed no signs of germinal center re-entry and rapidly developed into mature antibody secreting cells (ASCs). In contrast, newly generated MBCs derived from naïve precursors showed strong signs of antibody affinity maturation before differentiating into ASCs. Thus, although pre-existing human MBCs have an intrinsic propensity to differentiate into ASCs, the quality of the anti-S antibody and MBC response improved through the clonal selection and affinity maturation of naïve precursors.HighlightsmRNA vaccination of SARS-CoV-2 naïve individuals recruits naïve and pre-existing MBCs with similar levels of S-reactivity into the responseS-reactive naïve but not pre-existing MBCs undergo affinity maturationS-reactive pre-existing MBCs dominate the early ASC response independent of their antigen affinityHigh-affinity S-reactive MBCs and ASCs develop over time and originate from affinity matured naïve precursors