Discovery and characterization of a pan-betacoronavirus S2-binding antibody

Nicole V Johnson; Steven C Wall; Kevin J Kramer; Clinton M Holt; Sivakumar Periasamy; Simone I Richardson; Nelia P Manamela; Naveenchandra Suryadevara; Emanuele Andreano; Ida Paciello; Giulio Pierleoni; Giulia Piccini; Ying Huang; Pan Ge; James D Allen; Naoko Uno; Andrea R Shiakolas; Kelsey A Pilewski; Rachel S Nargi; Rachel E Sutton; Alexandria A Abu-Shmais; Robert Parks; Barton F Haynes; Robert H Carnahan; James E Crowe Jr; Emanuele Montomoli; Rino Rappuoli; Alexander Bukreyev; Ted M Ross; Giuseppe A Sautto; Jason S McLellan; Ivelin S Georgiev

doi:10.1016/j.str.2024.08.022

Discovery and characterization of a pan-betacoronavirus S2-binding antibody

Structure. 2024 Nov 7;32(11):1893-1909.e11. doi: 10.1016/j.str.2024.08.022. Epub 2024 Sep 25.

Authors

Nicole V Johnson¹, Steven C Wall², Kevin J Kramer², Clinton M Holt³, Sivakumar Periasamy⁴, Simone I Richardson⁵, Nelia P Manamela⁵, Naveenchandra Suryadevara⁶, Emanuele Andreano⁷, Ida Paciello⁷, Giulio Pierleoni⁷, Giulia Piccini⁸, Ying Huang⁹, Pan Ge¹⁰, James D Allen¹⁰, Naoko Uno¹¹, Andrea R Shiakolas², Kelsey A Pilewski², Rachel S Nargi⁶, Rachel E Sutton⁶, Alexandria A Abu-Shmais², Robert Parks¹², Barton F Haynes¹³, Robert H Carnahan¹⁴, James E Crowe Jr¹⁵, Emanuele Montomoli¹⁶, Rino Rappuoli¹⁷, Alexander Bukreyev⁴, Ted M Ross¹⁸, Giuseppe A Sautto¹⁹, Jason S McLellan²⁰, Ivelin S Georgiev²¹

Affiliations

¹ Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
² Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 73232, USA.
³ Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Program in Chemical and Physical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁴ Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA; Galveston National Laboratory, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
⁵ National Institute for Communicable Diseases of the National Health Laboratory Service, 2131 Johannesburg, South Africa; South African MRC Antibody Immunity Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa.
⁶ Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁷ Monoclonal Antibody Discovery (MAD) Lab, Fondazione Toscana Life Sciences, 53100 Siena, Italy.
⁸ VisMederi Research S.r.l., 53100 Siena, Italy.
⁹ Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL 34987, USA; Centers for Disease Control and Prevention, Atlanta, GA 30329, USA.
¹⁰ Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL 34987, USA.
¹¹ Department of Infection Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44196, USA; Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA.
¹² Duke Human Vaccine Institute, Duke University, Durham, NC 27710, USA.
¹³ Duke Human Vaccine Institute, Duke University, Durham, NC 27710, USA; Departments of Medicine and Immunology, Duke University, Durham, NC 27710, USA.
¹⁴ Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹⁵ Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 73232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹⁶ VisMederi Research S.r.l., 53100 Siena, Italy; VisMederi S.r.l, 53100 Siena, Italy; Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
¹⁷ Monoclonal Antibody Discovery (MAD) Lab, Fondazione Toscana Life Sciences, 53100 Siena, Italy; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy.
¹⁸ Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL 34987, USA; Department of Infection Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44196, USA; Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA; Department of Infectious Diseases, University of Georgia, Athens, GA 30602, USA.
¹⁹ Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL 34987, USA; Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA. Electronic address: [email protected].
²⁰ Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address: [email protected].
²¹ Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 73232, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Computer Science, Vanderbilt University, Nashville, TN 37232, USA; Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA; Program in Computational Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: [email protected].

PMID: 39326419
PMCID: PMC11560675 (available on 2025-11-07)
DOI: 10.1016/j.str.2024.08.022

Abstract

The continued emergence of deadly human coronaviruses from animal reservoirs highlights the need for pan-coronavirus interventions for effective pandemic preparedness. Here, using linking B cell receptor to antigen specificity through sequencing (LIBRA-seq), we report a panel of 50 coronavirus antibodies isolated from human B cells. Of these, 54043-5 was shown to bind the S2 subunit of spike proteins from alpha-, beta-, and deltacoronaviruses. A cryoelectron microscopy (cryo-EM) structure of 54043-5 bound to the prefusion S2 subunit of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike defined an epitope at the apex of S2 that is highly conserved among betacoronaviruses. Although non-neutralizing, 54043-5 induced Fc-dependent antiviral responses in vitro, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In murine SARS-CoV-2 challenge studies, protection against disease was observed after introduction of Leu234Ala, Leu235Ala, and Pro329Gly (LALA-PG) substitutions in the Fc region of 54043-5. Together, these data provide new insights into the protective mechanisms of non-neutralizing antibodies and define a broadly conserved epitope within the S2 subunit.

Keywords: LALA-PG; LIBRA-seq; S2 subunit; antibodies; betacoronaviruses; coronaviruses; cryo-EM; spike protein.

MeSH terms

Animals
Antibodies, Neutralizing / chemistry
Antibodies, Neutralizing / immunology
Antibodies, Neutralizing / metabolism
Antibodies, Viral* / chemistry
Antibodies, Viral* / immunology
Antibodies, Viral* / metabolism
Antibody-Dependent Cell Cytotoxicity
COVID-19* / immunology
COVID-19* / virology
Cryoelectron Microscopy*
Epitopes / chemistry
Epitopes / immunology
Humans
Mice
Models, Molecular
Protein Binding
SARS-CoV-2* / chemistry
SARS-CoV-2* / immunology
SARS-CoV-2* / metabolism
Spike Glycoprotein, Coronavirus* / chemistry
Spike Glycoprotein, Coronavirus* / immunology
Spike Glycoprotein, Coronavirus* / metabolism

Substances

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

Abstract

MeSH terms

Substances

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