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
  • 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.

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