BNT162b2 Vaccine Induces Divergent B cell responses to SARS-CoV-2 S1 and S2

The first ever messenger RNA (mRNA) vaccines received emergency approvals in December 2020 and are highly protective against SARS-CoV-21–3. 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, including delta, warrant further study. Here, we investigated the B cell response to the BNT162b2 vaccine by integrating repertoire analysis with single-cell transcriptomics of B cells from serial blood collections pre- and post-vaccination. The first vaccine dose elicits highly mutated IgA+ plasmablasts against the S protein subunit S2 at day 7, suggestive of recall of a memory B cell response generated by prior infections with heterologous coronaviruses. On day 21, we observed minimally-mutated IgG+ activated switched memory B cells targeting the receptor binding domain (RBD) of the S protein, likely representing a primary response derived from na?ve B cells. The B cell response against RBD is specifically boosted by the second vaccine dose, and encodes antibodies that potently neutralize SARS-CoV-2 pseudovirus and partially neutralize novel variants, including delta. These results demonstrate that the first vaccine dose activates a non-neutralizing recall response predominantly targeting S2, while the second vaccine dose is vital to boosting neutralizing anti-S1 RBD B cell responses.