SARS‐CoV‐2 mRNA Vaccination Leads to Transient Humoral and B Cell Bystander Responses in Adults

After antigen encounter, long-lived antibody-secreting cells (ASC) secrete high-affinity circulating antibodies. In addition, memory B cells (MBC) are quickly reactivated upon antigen re-exposure and predominantly generate shorter-lived ASCs. Studies have suggested that MBC can differentiate into ASCs without recognizing their cognate antigen, a process known as "bystander activation". This antigen-independent reactivation of MBC could help maintain circulating antibody levels, thereby protecting against future infections. To elucidate whether SARS-CoV-2 mRNA vaccination leads to bystander activation of B cells, the dynamics of antibody concentrations against six pathogen-specific antigens not encountered during the sampling period were analyzed over time. Deep profiling of antigen-specific B cell responses was simultaneously performed using multiparameter high-dimensional spectral flow cytometry. Antibody concentrations against tetanus toxoid (TT), respiratory syncytial virus (RSV), and influenza hemagglutinin (HA) unexpectedly increased 6 weeks after the first SARS-CoV-2 vaccination. Deep profiling of B cell differentiation stages demonstrated a short-term increase in influenza-specific IgG+ DN3 B cells, RSV-specific IgG+ CD11c+ activated B cells, and TT-specific IgG+ MBC following vaccination. In this study, we demonstrated at both the antibody and cellular levels that SARS-CoV-2 mRNA vaccination transiently activates distinct early activated B cell compartments directed against influenza HA, RSV, and TT.