SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses.

Turner, Jackson S; O'Halloran, Jane A; Kalaidina, Elizaveta; Kim, Wooseob; Schmitz, Aaron J; Zhou, Julian Q; Lei, Tingting; Thapa, Mahima; Chen, Rita E; Case, James Brett; Amanat, Fatima; Rauseo, Adriana M; Haile, Alem; Xie, Xuping; Klebert, Michael K; Suessen, Teresa; Middleton, William D; Shi, Pei-Yong; Krammer, Florian; Teefey, Sharlene A; Diamond, Michael S; Presti, Rachel M; Ellebedy, Ali H

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA)-based vaccines are ~95% effective in preventing coronavirus disease 20191-5. The dynamics of antibody secreting plasmablasts (PBs) and germinal centre (GC) B cells induced by these vaccines in humans remain unclear. We examined antigen-specific B cell responses in peripheral blood (n=41) and draining lymph nodes (LNs) in 14 individuals who received two doses of BNT162b2, an mRNA-based vaccine encoding full-length SARS-CoV-2 spike (S) gene1. Circulating IgG- and IgA-secreting PBs targeting the S protein peaked one week after the second immunization then declined, becoming undetectable three weeks later. These PB responses preceded maximal levels of serum anti-S binding and neutralizing antibodies to an early circulating SARS-CoV-2 strain as well as emerging variants, especially in individuals previously infected with SARS-CoV-2, who produced the most robust serologic responses. By examining fine needle aspirates (FNAs) of draining axillary LNs, we identified GC B cells that bound S protein in all participants sampled after primary immunization. Remarkably, high frequencies of S-binding GC B cells and PBs were sustained in these draining LNs for at least twelve weeks after the booster immunization. S-binding GC B cell-derived monoclonal antibodies predominantly targeted the receptor binding domain of the S protein, with fewer clones binding to the N-terminal domain or to epitopes shared with the S proteins of the human betacoronaviruses OC43 and HKU1. The latter cross-reactive B cell clones had higher levels of somatic hypermutation compared to those that only recognized SARS-CoV-2 S protein, suggesting a memory B cell origin. Our studies demonstrate that SARS-CoV-2 mRNA-based vaccination of humans induces a persistent GC B cell response, enabling the generation of robust humoral immunity.