SARS-CoV-2 Infection or COVID-19 mRNA Vaccination Elicit Similar Spike-Reactive Memory B Cell Responses in Naïve Individuals

Background: The COVID-19 pandemic provided a unique opportunity to evaluate how the human immune system responded to a novel pathogen, and to determine whether immune responses initiated through natural infection differ from those elicited by vaccination against the same antigen. Here, we provide a comprehensive analysis of SARS-CoV-2 Spike (S-antigen)-reactive memory B cells (Bmem) elicited in previously immunologically naïve subjects following their first infection with the original Wuhan-Hu-1 (WH1)-like strain, or their initial COVD-19 mRNA prime-boost regimen encoding the same WH1-S-antigen. In particular, we tested the hypothesis that the primary encounter of SARS-CoV-2 S-antigen in lung mucosal tissues during infection vs. intramuscular COVID-19 mRNA injection would elicit different Bmem responses. Methods: Cryopreserved peripheral blood mononuclear cell (PBMC) samples collected following primary infection with the WH1 strain or completion of the initial prime-boost vaccination regimen were tested in ImmunoSpot® assays to assess the frequency, Ig class/subclass usage, and cross-reactivity of the S-antigen-reactive Bmem compartment; pre-pandemic blood draws served as naïve controls. Results: The Bmem repertoires generated post-infection vs. post-vaccination were found to be quite similar, but with some subtle differences. In both cases, the prevalent induction of IgG1-expressing Bmem in similar frequencies was seen, ~30% of which targeted the receptor binding domain (RBD) of the WH1-S-antigen. Also, the extent of cross-reactivity with the future Omicron (BA.1) RBD was found to be similar for both cohorts. However, IgA+ Bmem were preferentially induced after infection, while IgG4+ Bmem were detected only after vaccination. Conclusions: Bmem elicited in naïve human subjects following SARS-CoV-2 infection or after WH1-S-antigen encoding mRNA vaccination were only subtly different. Our findings serve to illustrate the usefulness and feasibility of performing comprehensive monitoring of antigen-specific B cell memory in larger cohorts using the ImmunoSpot® technique.