Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses

Jacob C Milligan; Carl W Davis; Xiaoying Yu; Philipp A Ilinykh; Kai Huang; Peter J Halfmann; Robert W Cross; Viktoriya Borisevich; Krystle N Agans; Joan B Geisbert; Chakravarthy Chennareddy; Arthur J Goff; Ashley E Piper; Sean Hui; Kelly C L Shaffer; Tierra Buck; Megan L Heinrich; Luis M Branco; Ian Crozier; Michael R Holbrook; Jens H Kuhn; Yoshihiro Kawaoka; Pamela J Glass; Alexander Bukreyev; Thomas W Geisbert; Gabriella Worwa; Rafi Ahmed; Erica Ollmann Saphire

doi:10.1016/j.cell.2022.02.023

Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses

Cell. 2022 Mar 17;185(6):995-1007.e18. doi: 10.1016/j.cell.2022.02.023.

Authors

Jacob C Milligan¹, Carl W Davis², Xiaoying Yu³, Philipp A Ilinykh⁴, Kai Huang⁴, Peter J Halfmann⁵, Robert W Cross⁶, Viktoriya Borisevich⁶, Krystle N Agans⁶, Joan B Geisbert⁶, Chakravarthy Chennareddy², Arthur J Goff⁷, Ashley E Piper⁷, Sean Hui¹, Kelly C L Shaffer¹, Tierra Buck¹, Megan L Heinrich⁸, Luis M Branco⁸, Ian Crozier⁹, Michael R Holbrook¹⁰, Jens H Kuhn¹⁰, Yoshihiro Kawaoka¹¹, Pamela J Glass⁷, Alexander Bukreyev¹², Thomas W Geisbert⁶, Gabriella Worwa¹³, Rafi Ahmed¹⁴, Erica Ollmann Saphire¹⁵

Affiliations

¹ Center for Infectious Disease and Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
² Emory Vaccine Center and Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA.
³ Center for Infectious Disease and Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, Galveston, TX, 77550, USA.
⁵ Division of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA.
⁶ Galveston National Laboratory, Galveston, TX, 77550, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
⁷ Virology Division, United States Army Research Institute for Infectious Disease, Fort Detrick, Frederick, MD 21702, USA.
⁸ Zalgen Labs, Germantown, MD 20876, USA.
⁹ Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
¹⁰ Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD 21702, USA.
¹¹ Division of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA; Department of Microbiology and Immunology, Division of Virology, Institute of Medical Science, Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
¹² Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Galveston National Laboratory, Galveston, TX, 77550, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
¹³ Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, MD 21702, USA. Electronic address: gabriella.worwa@nih.gov.
¹⁴ Emory Vaccine Center and Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA. Electronic address: rahmed@emory.edu.
¹⁵ Center for Infectious Disease and Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: erica@lji.org.

Abstract

Several ebolaviruses cause outbreaks of severe disease. Vaccines and monoclonal antibody cocktails are available to treat Ebola virus (EBOV) infections, but not Sudan virus (SUDV) or other ebolaviruses. Current cocktails contain antibodies that cross-react with the secreted soluble glycoprotein (sGP) that absorbs virus-neutralizing antibodies. By sorting memory B cells from EBOV infection survivors, we isolated two broadly reactive anti-GP monoclonal antibodies, 1C3 and 1C11, that potently neutralize, protect rodents from disease, and lack sGP cross-reactivity. Both antibodies recognize quaternary epitopes in trimeric ebolavirus GP. 1C11 bridges adjacent protomers via the fusion loop. 1C3 has a tripartite epitope in the center of the trimer apex. One 1C3 antigen-binding fragment anchors simultaneously to the three receptor-binding sites in the GP trimer, and separate 1C3 paratope regions interact differently with identical residues on the three protomers. A cocktail of both antibodies completely protected nonhuman primates from EBOV and SUDV infections, indicating their potential clinical value.

Keywords: Bundibugyo virus; Ebola virus; Sudan virus; antibody therapeutic; cryo-EM; ebolavirus; medical countermeasure; monoclonal antibody; nonhuman primate.

Publication types

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

MeSH terms

Animals
Antibodies, Neutralizing*
Antibodies, Viral*
Ebolavirus*
Epitopes
Glycoproteins / chemistry
Hemorrhagic Fever, Ebola*
Protein Subunits

Substances

Antibodies, Neutralizing
Antibodies, Viral
Epitopes
Glycoproteins
Protein Subunits

Abstract

Publication types

MeSH terms

Substances

Grants and funding