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

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

Cell (2021-05-21)
Johannes F Scheid, Christopher O Barnes, Basak Eraslan, Andrew Hudak, Jennifer R Keeffe, Lisa A Cosimi, Eric M Brown, Frauke Muecksch, Yiska Weisblum, Shuting Zhang, Toni Delorey, Ann E Woolley, Fadi Ghantous, Sung-Moo Park, Devan Phillips, Betsabeh Tusi, Kathryn E Huey-Tubman, Alexander A Cohen, Priyanthi N P Gnanapragasam, Kara Rzasa, Theodora Hatziioanno, Michael A Durney, Xiebin Gu, Takuya Tada, Nathaniel R Landau, Anthony P West, Orit Rozenblatt-Rosen, Michael S Seaman, Lindsey R Baden, Daniel B Graham, Jacques Deguine, Paul D Bieniasz, Aviv Regev, Deborah Hung, Pamela J Bjorkman, Ramnik J Xavier
PMID34015271
ABSTRACT

Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (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.