BNT162b2 vaccine induces divergent B cell responses to SARS-CoV-2 S1 and S2

The first ever US Food and Drug Administration-approved messenger RNA vaccines are highly protective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the contribution of each dose to the generation of antibodies against SARS-CoV-2 spike (S) protein and the degree of protection against novel variants warrant further study. Here, we investigated the B cell response to the BNT162b2 vaccine by integrating B cell repertoire analysis with single-cell transcriptomics pre- and post-vaccination. The first vaccine dose elicits a recall response of IgA plasmablasts targeting the S subunit S2. Three weeks after the first dose, we observed an influx of minimally mutated IgG memory B cells that targeted the receptor binding domain on the S subunit S1 and likely developed from the naive B cell pool. This response was strongly boosted by the second dose and delivers potently neutralizing antibodies against SARS-CoV-2 and several of its variants.