2. Academic Validation
  3. Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses

Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses

  • Sci Transl Med. 2022 Mar 16;14(636):eabl5399. doi: 10.1126/scitranslmed.abl5399.
Eva Mittler 1,  Anna Z Wec 2,  Janne Tynell 3 4,  Pablo Guardado-Calvo 5,  Julia Wigren-Byström 3,  Laura C Polanco 1,  Cecilia M O'Brien 6 7,  Megan M Slough 1,  Dafna M Abelson 8,  Alexandra Serris 5,  Mrunal Sakharkar 2,  Gerard Pehau-Arnaudet 5,  Russell R Bakken 6,  James C Geoghegan 2,  Rohit K Jangra 1,  Markus Keller 9,  Larry Zeitlin 8,  Olli Vapalahti 4 10,  Rainer G Ulrich 9 11,  Zachary A Bornholdt 8,  Clas Ahlm 3,  Felix A Rey 5,  John M Dye 6,  Steven B Bradfute 12,  Tomas Strandin 4,  Andrew S Herbert 6 7,  Mattias N E Forsell 3,  Laura M Walker 2 13,  Kartik Chandran 1
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 2 Adimab, LLC, Lebanon, NH 03766, USA.
  • 3 Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
  • 4 Zoonosis Unit, Department of Virology, Medical Faculty, University of Helsinki, Helsinki, Finland.
  • 5 Structural Virology Unit, Department of Virology, Institut Pasteur, Paris 75724, France.
  • 6 U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA.
  • 7 The Geneva Foundation, Tacoma, WA 98402, USA.
  • 8 Mapp Biopharmaceutical Inc., San Diego, CA 92121, USA.
  • 9 Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, 17493 Greifswald-Insel Riems, Germany.
  • 10 Veterinary Biosciences, Veterinary Faculty, University of Helsinki, Helsinki, Finland.
  • 11 Deutsches Zentrum für Infektionsforschung, Partner site Hamburg-Lübeck- Borstel-Riems, Greifswald-Insel Riems, Germany.
  • 12 Center for Global Health, Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.
  • 13 Adagio Therapeutics Inc., Waltham, MA 02451, USA.
PMID: 35294259 DOI: 10.1126/scitranslmed.abl5399
Abstract

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.

Figures
Products