1. Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses
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Eva Mittler, Anna Z. Wec, Janne Tynell, Pablo Guardado-Calvo, Julia Wigren-Byström, Laura C. Polanco, Cecilia M. O’Brien, Megan M. Slough, Dafna M. Abelson, Alexandra Serris, Mrunal Sakharkar, Gerard Pehau-Arnaudet, Russell R. Bakken, James C. Geoghegan, Rohit K. Jangra, Markus Keller, Larry Zeitlin, Olli Vapalahti, Rainer G. Ulrich, Zachary A. Bornholdt, Clas Ahlm, Felix A. Rey, John M. Dye, Steven B. Bradfute, Tomas Strandin, Andrew S. Herbert, Mattias N. E. Forsell, Laura M. Walker, Kartik Chandran, Albert Einstein College of Medicine [New York], Adimab [Lebanon], Umeå University, Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Mapp Biopharmaceutical Inc., Institute of Novel and Emerging Infectious Diseases (INNT), Friedrich-Loeffler-Institut (FLI), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, The University of New Mexico [Albuquerque], This research was supported by NIAID of the NIH under award number U19AI142777 (Centers of Excellence in Translational Research) to K.C., L.M.W., J.M.D., Z.A.B., A.S.H., S.B.B., M.N.E.F., and L.Z. M.N.E.F. was supported by a Consolidator grant from the Swedish Science Council (#2020-06235). C.A. was supported by a Cutting Edge Research Grant from Region Västerbotten (VLL-579011). T.S. was supported by the Academy of Finland (#321809). P.G.-C. was supported by a grant of the National French Research Agency (ANR-18-CE11-0011). A.S. was supported by a fellowship of the French Foundation pour la Recherche Médicale (FRM, fellowship FDM20170638040). F.A.R. and P.G.-C. were supported by Labex IBEID (ANR-10-LABX-62-IBEID). R.G.U. was supported by the Bundesministerium für Bildung und Forschung (BMBF) within the Research Network Zoonotic Infectious Diseases (01KI1721A and 01KI2004A)., ANR-18-CE11-0011,LISEFU,Base structurale de la détection des lipides dans la fusion virale(2018), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
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Orthohantavirus ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,Hantavirus Infections ,virus diseases ,General Medicine ,Antibodies, Viral ,Antibodies, Neutralizing ,Puumala virus ,Article ,Epitopes ,Cricetinae ,Hemorrhagic Fever with Renal Syndrome ,Animals ,Humans ,Glycoproteins - Abstract
International audience; The rodent-borne hantavirus Puumala virus (PUUV) and related agents cause hemorrhagic fever with renal syndrome (HFRS) in humans. Other hantaviruses, including Andes virus (ANDV) and Sin Nombre virus, cause a distinct zoonotic disease, hantavirus cardiopulmonary syndrome (HCPS). Although these infections are severe and have substantial case fatality rates, no FDA-approved hantavirus countermeasures are available. Recent work suggests that monoclonal antibodies may have therapeutic utility. We describe here the isolation of human neutralizing antibodies (nAbs) against tetrameric Gn/Gc glycoprotein spikes from PUUV-experienced donors. We define a dominant class of nAbs recognizing the “capping loop” of Gn that masks the hydrophobic fusion loops in Gc. A subset of nAbs in this class, including ADI-42898, bound Gn/Gc complexes but not Gn alone, strongly suggesting that they recognize a quaternary epitope encompassing both Gn and Gc. ADI-42898 blocked the cell entry of seven HCPS- and HFRS-associated hantaviruses, and single doses of this nAb could protect Syrian hamsters and bank voles challenged with the highly virulent HCPS-causing ANDV and HFRS-causing PUUV, respectively. ADI-42898 is a promising candidate for clinical development as a countermeasure for both HCPS and HFRS, and its mode of Gn/Gc recognition informs the development of broadly protective hantavirus vaccines.
- Published
- 2022
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