B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV

Scheid, Johannes F.; Barnes, Christopher O.; Eraslan, Basak; Hudak, Andrew; Keeffe, Jennifer R.; Cosimi, Lisa A.; Brown, Eric M.; Muecksch, Frauke; Weisblum, Yiska; Zhang, Shuting; Delorey, Toni; Woolley, Ann E.; Ghantous, Fadi; Park, Sung-Moo; Phillips, Devan; Tusi, Betsabeh; Huey-Tubman, Kathryn E.; Cohen, Alexander A.; Gnanapragasam, Priyanthi N.P.; Rzasa, Kara; Hatziioanno, Theodora; Durney, Michael A.; Gu, Xiebin; Tada, Takuya; Landau, Nathaniel R.; West, Anthony P.; Rozenblatt-Rosen, Orit; Seaman, Michael S.; Baden, Lindsey R.; Graham, Daniel B.; Deguine, Jacques; Bieniasz, Paul D.; Regev, Aviv; Hung, Deborah; Bjorkman, Pamela J.; Xavier, Ramnik J.

Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract SARS-CoV-2 and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA-seq and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses.