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

Scheid, Johannes F. and Barnes, Christopher O. and Eraslan, Basak and Hudak, Andrew and Keeffe, Jennifer R. and Cosimi, Lisa A. and Brown, Eric M. and Muecksch, Frauke and Weisblum, Yiska and Zhang, Shuting and Delorey, Toni and Woolley, Ann E. and Ghantous, Fadi and Park, Sung-Moo and Phillips, Devan and Tusi, Betsabeh and Huey-Tubman, Kathryn E. and Cohen, Alexander A. and Gnanapragasam, Priyanthi N. P. and Rzasa, Kara and Hatziioannou, Theodora and Durney, Michael A. and Gu, Xiebin and Tada, Takuya and Landau, Nathaniel R. and West, Anthony P., Jr. and Rozenblatt-Rosen, Orit and Seaman, Michael S. and Baden, Lindsey R. and Graham, Daniel B. and Deguine, Jacques and Bieniasz, Paul D. and Regev, Aviv and Hung, Deborah and Bjorkman, Pamela J. and Xavier, Ramnik J. (2021) B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV. Cell, 184 (12). pp. 3205-3221. ISSN 0092-8674. PMCID PMC8064835. doi:10.1016/j.cell.2021.04.032.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Barnes, Christopher O.0000-0003-2754-5951
Eraslan, Basak0000-0003-3698-8279
Hudak, Andrew0000-0002-0241-2290
Keeffe, Jennifer R.0000-0002-5317-6398
Cosimi, Lisa A.0000-0002-5269-1881
Muecksch, Frauke0000-0002-0132-5101
Weisblum, Yiska0000-0002-9249-1745
Delorey, Toni0000-0001-6614-3803
Woolley, Ann E.0000-0002-2810-1618
Ghantous, Fadi0000-0002-6772-6901
Huey-Tubman, Kathryn E.0000-0002-4683-8138
Cohen, Alexander A.0000-0002-2818-656X
Rzasa, Kara0000-0002-5753-7517
Hatziioannou, Theodora0000-0002-7889-0766
Tada, Takuya0000-0003-0779-9954
Landau, Nathaniel R.0000-0002-9997-1004
Bieniasz, Paul D.0000-0002-2368-3719
Regev, Aviv0000-0003-3293-3158
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2021 Elsevier Inc. Received 18 December 2020, Revised 26 February 2021, Accepted 19 April 2021, Available online 24 April 2021. We thank all study participants who devoted time to our research and the clinical staff. We thank Heather Kang for editorial assistance with the manuscript and figures. We thank the Biogen, Broad Institute of MIT and Harvard, and Partners HealthCare COVID-19 biobank for support with patient samples. We thank members of the Bjorkman, Xavier, and Bieniasz laboratories for helpful discussions. We thank Liat Amir-Zilberstein and Novalia Pishesha for support with sample processing and Christy Lavine (BIDMC) for assistance with pseudovirus assays. We thank Harry Gristick (Caltech) for technical assistance with SPR binding experiments and Kawther Abu Elneel and Jenna Pfiffner-Borges for arranging and coordinating laboratory space during the COVID-19 pandemic. We thank Patricia Rogers and Natan Pirete (Broad Institute) for support with cell sorting, Reuben Ryan Cano (Broad Institute) for help with size exclusion chromatography, and the Nussenzweig laboratory (Rockefeller University) for providing plasmids for mAbs mGO53, JB40, and ED38. We thank Pauline Hoffman, Leesa Kakutani, Yu (Erica) Lee, Jost Vielmetter, and the Caltech Beckman Institute Protein Expression Center for expression and purification of antigens and support for automated assays and Drs. Songye Chen and Andrey Malyutin (Caltech) for maintaining electron microscopes. Cell sorting was performed at the Flow Cytometry Facility of the Broad Institute, sequencing of pre-constructed DNA libraries was performed at the Genomics Platform (Broad Institute), and electron microscopy was performed in the Caltech Beckman Institute Resource Center for Transmission Electron Microscopy. We thank the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support the Molecular Observatory (Dr. Jens Kaiser, director) and Drs. Silvia Russi, Aina Cohen, and Clyde Smith and the beamline staff at SSRL for data collection assistance. This work was supported by NIH (P01-AI138398-S1 and P50 8 P50 AI150464-13 to P.J.B.; DK43351 and U19 AI142784 to R.J.X.; and DA046100, AI122390, and AI120898 to N.R.L.), the Caltech Merkin Institute for Translational Research (to P.J.B.), George Mason University Fast Grant (to P.J.B.), the Manton Foundation (to R.J.X. and A.R.), the Center for Microbiome Informatics and Therapeutics (CMIT) at Massachusetts Institute of Technology (MIT) (to R.J.X.), and the Klarman Cell Observatory. Work at the Broad Institute was supported by a gift from an anonymous donor. C.O.B was supported by the Hanna Gray Fellowship Program from the Howard Hughes Medical Institute and the Postdoctoral Enrichment Program from the Burroughs Wellcome Fund. P.D.B. is a Howard Hughes Medical Institute Investigator. A.R. was a Howard Hughes Medical Institute Investigator while doing this research. T.T. was supported by the Vilcek/Goldfarb Fellowship Endowment Fund. Author contributions: J.F.S., C.O.B., B.E., D.G., P.J.B., J.D., A.R., D.H., and R.J.X. conceived the study and analyzed data. A.E.W., L.A.C., R.J.X., D.H., and J.D. established and orchestrated the patient cohort. J.F.S. established and performed cell staining and sorting, B.E. performed computational analysis with guidance from A.R. and B.E. J.F.S. analyzed repertoire and transcriptome data with guidance from A.R. J.F.S. and A.H. performed mAb cloning, production, purification, and binding characterization. C.O.B. performed protein characterization and crystallographic and cryo-EM studies and analyzed structures. T.D., D.P., O.R.-R., and A.R. developed and performed scRNA-seq library preparation and coordinated single-cell RNA-seq. J.F.S., E.B., S.P., and B.T. performed patient sample processing. K.H.T. purified proteins. J.R.K. and A.A.C. performed and analyzed ELISAs. J.R.K. performed SPR binding and polyreactivity assays. M.A.D. and X.G. assisted with size exclusion chromatography. P.N.G., F.M., Y.W., T.H., F.G., S.Z., D.H., M.S.S., and P.D.B. developed and performed in vitro neutralization assays. A.P.W. analyzed mAb sequences. T.T. and N.R.L. conceived and designed ACE2-CH3 protein purification. J.F.S., C.O.B., B.E., J.D., A.R., P.J.B., and R.J.X. wrote the paper with contributions from other authors. Declaration of interests: A provisional patent for the novel SARS-CoV-2 mAbs described in this study has been filed. The authors listed on that application are R.J.X., J.F.S., C.O.B., P.J.B., and B.E. The Broad Institute has filed multiple patents in the area of single cell RNA-seq on which A.R. and O.R.-R. are named inventors. Rockefeller University has applied for a patent relating to the replication competent VSV/SARS-CoV-2 chimeric virus on which Y.W., T.H., and P.D.B. are listed as inventors (US patent 63/036,124). R.J.X. is co-founder and equity holder of Jnana Therapeutics. R.J.X. and A.R. are co-founders and equity holders of Celsius Therapeutics. A.R. is an equity holder in Immunitas and was an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics, and Asimov. A.R. and O.R.-R. are employees of Genentech (member of the Roche Group) since August and October 2020, respectively. These companies did not provide support for this work.
Group:COVID-19, Richard N. Merkin Institute for Translational Research
Funding AgencyGrant Number
NIHP50 8 P50 AI150464-13
NIHU19 AI142784
Caltech Merkin Institute for Translational ResearchUNSPECIFIED
George Mason UniversityUNSPECIFIED
Manton FoundationUNSPECIFIED
Massachusetts Institute of Technology (MIT)UNSPECIFIED
Klarman Cell ObservatoryUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Vilcek/Goldfarb Fellowship Endowment FundUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Subject Keywords:single B cell genomics; COVID-19; monoclonal antibodies; SARS-CoV cross-neutralization; memory B cells; cryo-electron microscopy; disordered CDRH3
Issue or Number:12
PubMed Central ID:PMC8064835
Record Number:CaltechAUTHORS:20210429-090704273
Persistent URL:
Official Citation: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, B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV, Cell, Volume 184, Issue 12, 2021, Pages 3205-3221.e24, ISSN 0092-8674,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108862
Deposited By: Tony Diaz
Deposited On:29 Apr 2021 18:21
Last Modified:27 Aug 2021 16:31

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