Deep repertoire mining uncovers ultra-broad coronavirus neutralizing antibodies targeting multiple spike epitopes

Jonathan Hurtado; Thomas F Rogers; David B Jaffe; Bruce A Adams; Sandhya Bangaru; Elijah Garcia; Tazio Capozzola; Terrence Messmer; Pragati Sharma; Ge Song; Nathan Beutler; Wanting He; Katharina Dueker; Rami Musharrafieh; Sarah Burbach; Alina Truong; Michael J T Stubbington; Dennis R Burton; Raiees Andrabi; Andrew B Ward; Wyatt J McDonnell; Bryan Briney

doi:10.1016/j.celrep.2024.114307

Deep repertoire mining uncovers ultra-broad coronavirus neutralizing antibodies targeting multiple spike epitopes

Cell Rep. 2024 Jun 25;43(6):114307. doi: 10.1016/j.celrep.2024.114307. Epub 2024 Jun 5.

Authors

Jonathan Hurtado¹, Thomas F Rogers², David B Jaffe³, Bruce A Adams³, Sandhya Bangaru⁴, Elijah Garcia⁵, Tazio Capozzola¹, Terrence Messmer¹, Pragati Sharma¹, Ge Song¹, Nathan Beutler⁵, Wanting He¹, Katharina Dueker¹, Rami Musharrafieh¹, Sarah Burbach¹, Alina Truong¹, Michael J T Stubbington³, Dennis R Burton⁶, Raiees Andrabi¹, Andrew B Ward⁷, Wyatt J McDonnell⁸, Bryan Briney⁹

Affiliations

¹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for Viral Systems Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Scripps Center for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA 92037, USA.
² Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
³ 10x Genomics, Inc., 6230 Stoneridge Mall Road, Pleasanton, CA 94588, USA.
⁴ Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA.
⁵ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁶ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Scripps Center for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of MGH, Harvard and MIT, Cambridge, MA 02139, USA.
⁷ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Scripps Center for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁸ 10x Genomics, Inc., 6230 Stoneridge Mall Road, Pleasanton, CA 94588, USA. Electronic address: [email protected].
⁹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for Viral Systems Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Scripps Center for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA 92037, USA; Multi-Omics Vaccine Evaluation Consortium, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].

Abstract

The development of vaccines and therapeutics that are broadly effective against known and emergent coronaviruses is an urgent priority. We screened the circulating B cell repertoires of COVID-19 survivors and vaccinees to isolate over 9,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific monoclonal antibodies (mAbs), providing an expansive view of the SARS-CoV-2-specific Ab repertoire. Among the recovered antibodies was TXG-0078, an N-terminal domain (NTD)-specific neutralizing mAb that recognizes diverse alpha- and beta-coronaviruses. TXG-0078 achieves its exceptional binding breadth while utilizing the same VH1-24 variable gene signature and heavy-chain-dominant binding pattern seen in other NTD-supersite-specific neutralizing Abs with much narrower specificity. We also report CC24.2, a pan-sarbecovirus neutralizing antibody that targets a unique receptor-binding domain (RBD) epitope and shows similar neutralization potency against all tested SARS-CoV-2 variants, including BQ.1.1 and XBB.1.5. A cocktail of TXG-0078 and CC24.2 shows protection in vivo, suggesting their potential use in variant-resistant therapeutic Ab cocktails and as templates for pan-coronavirus vaccine design.

Keywords: CP: Immunology; CP: Microbiology.

MeSH terms

Animals
Antibodies, Monoclonal / immunology
Antibodies, Neutralizing* / immunology
Antibodies, Viral* / immunology
Betacoronavirus / immunology
COVID-19* / immunology
COVID-19* / virology
Epitopes* / immunology
Humans
Mice
SARS-CoV-2* / immunology
Spike Glycoprotein, Coronavirus* / immunology

Substances

Spike Glycoprotein, Coronavirus
Antibodies, Neutralizing
Epitopes
Antibodies, Viral
Antibodies, Monoclonal
spike protein, SARS-CoV-2

Supplementary concepts

SARS-CoV-2 variants