Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause deadly disease

Panpan Zhou; Ge Song; Hejun Liu; Meng Yuan; Wan-Ting He; Nathan Beutler; Xueyong Zhu; Longping V Tse; David R Martinez; Alexandra Schäfer; Fabio Anzanello; Peter Yong; Linghang Peng; Katharina Dueker; Rami Musharrafieh; Sean Callaghan; Tazio Capozzola; Oliver Limbo; Mara Parren; Elijah Garcia; Stephen A Rawlings; Davey M Smith; David Nemazee; Joseph G Jardine; Yana Safonova; Bryan Briney; Thomas F Rogers; Ian A Wilson; Ralph S Baric; Lisa E Gralinski; Dennis R Burton; Raiees Andrabi

doi:10.1016/j.immuni.2023.02.005

Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause deadly disease

Immunity. 2023 Mar 14;56(3):669-686.e7. doi: 10.1016/j.immuni.2023.02.005. Epub 2023 Feb 16.

Authors

Panpan Zhou¹, Ge Song¹, Hejun Liu², Meng Yuan², Wan-Ting He¹, Nathan Beutler³, Xueyong Zhu², Longping V Tse⁴, David R Martinez⁴, Alexandra Schäfer⁴, Fabio Anzanello¹, Peter Yong¹, Linghang Peng³, Katharina Dueker¹, Rami Musharrafieh¹, Sean Callaghan¹, Tazio Capozzola¹, Oliver Limbo⁵, Mara Parren³, Elijah Garcia³, Stephen A Rawlings⁶, Davey M Smith⁶, David Nemazee³, Joseph G Jardine⁵, Yana Safonova⁷, Bryan Briney¹, Thomas F Rogers⁸, Ian A Wilson⁹, Ralph S Baric¹⁰, Lisa E Gralinski¹¹, Dennis R Burton¹², Raiees Andrabi¹³

Affiliations

¹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA.
² Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁶ Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
⁷ Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218, USA.
⁸ 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.
⁹ IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: wilson@scripps.edu.
¹⁰ Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Departments of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: rbaric@email.unc.edu.
¹¹ Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: lgralins@email.unc.edu.
¹² Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA. Electronic address: burton@scripps.edu.
¹³ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: andrabi@scripps.edu.

Abstract

Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and to more effectively respond to SARS-CoV-2 variants. The emergence of Omicron and subvariants of SARS-CoV-2 illustrates the limitations of solely targeting the receptor-binding domain (RBD) of the spike (S) protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors, which targets a conserved S2 region in the betacoronavirus spike fusion machinery. Select bnAbs showed broad in vivo protection against all three deadly betacoronaviruses, SARS-CoV-1, SARS-CoV-2, and MERS-CoV, which have spilled over into humans in the past two decades. Structural studies of these bnAbs delineated the molecular basis for their broad reactivity and revealed common antibody features targetable by broad vaccination strategies. These bnAbs provide new insights and opportunities for antibody-based interventions and for developing pan-betacoronavirus vaccines.

Keywords: COVID-19; S2 stem-helix site; SARS-CoV-2; SARS-CoV-2 variants of concern; broad coronavirus protection; broadly neutralizing antibodies; coronavirus spike; coronaviruses; pan-betacoronavirus vaccines.

Publication types

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

MeSH terms

Antibodies, Neutralizing
Antibodies, Viral
Broadly Neutralizing Antibodies
COVID-19*
Humans
SARS-CoV-2*

Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause deadly disease

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