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

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 Jr; 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

doi:10.1016/j.cell.2021.04.032

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

Cell. 2021 Jun 10;184(12):3205-3221.e24. doi: 10.1016/j.cell.2021.04.032. Epub 2021 Apr 24.

Authors

Johannes F Scheid¹, Christopher O Barnes², Basak Eraslan³, Andrew Hudak³, Jennifer R Keeffe², Lisa A Cosimi⁴, Eric M Brown⁵, Frauke Muecksch⁶, Yiska Weisblum⁶, Shuting Zhang³, Toni Delorey⁷, Ann E Woolley⁴, Fadi Ghantous⁸, Sung-Moo Park³, Devan Phillips⁷, Betsabeh Tusi³, Kathryn E Huey-Tubman², Alexander A Cohen², Priyanthi N P Gnanapragasam², Kara Rzasa³, Theodora Hatziioanno⁶, Michael A Durney³, Xiebin Gu³, Takuya Tada⁹, Nathaniel R Landau⁹, Anthony P West Jr², Orit Rozenblatt-Rosen⁷, Michael S Seaman⁸, Lindsey R Baden⁴, Daniel B Graham⁵, Jacques Deguine³, Paul D Bieniasz¹⁰, Aviv Regev¹¹, Deborah Hung¹², Pamela J Bjorkman¹³, Ramnik J Xavier¹⁴

Affiliations

¹ Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
² Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
³ Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
⁴ Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁵ Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁶ Laboratory of Molecular Virology, The Rockefeller University, New York, NY 10065, USA.
⁷ Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
⁹ Department of Microbiology, NYU Grossman School of Medicine, New York, NY 10016, USA.
¹⁰ Laboratory of Molecular Virology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
¹¹ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
¹² Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹³ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: bjorkman@caltech.edu.
¹⁴ Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

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.

Keywords: COVID-19; SARS-CoV cross-neutralization; cryo-electron microscopy; disordered CDRH3; memory B cells; monoclonal antibodies; single B cell genomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Monoclonal / chemistry
Antibodies, Monoclonal / immunology
Antibodies, Neutralizing / blood
Antibodies, Neutralizing / chemistry
Antibodies, Neutralizing / immunology*
Antibodies, Viral / blood
Antibodies, Viral / chemistry
Antibodies, Viral / immunology
Antigen-Antibody Complex / chemistry
Antigen-Antibody Complex / metabolism
Antigen-Antibody Reactions
B-Lymphocytes / cytology
B-Lymphocytes / metabolism*
B-Lymphocytes / virology
COVID-19 / pathology
COVID-19 / virology
Cryoelectron Microscopy
Crystallography, X-Ray
Gene Expression Profiling
Humans
Immunoglobulin A / immunology
Immunoglobulin Variable Region / chemistry
Immunoglobulin Variable Region / genetics
Protein Domains / immunology
Protein Multimerization
Protein Structure, Quaternary
SARS-CoV-2 / immunology*
SARS-CoV-2 / isolation & purification
SARS-CoV-2 / metabolism
Sequence Analysis, RNA
Spike Glycoprotein, Coronavirus / chemistry
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / immunology*
Spike Glycoprotein, Coronavirus / metabolism

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Antigen-Antibody Complex
Immunoglobulin A
Immunoglobulin Variable Region
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding