Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody

  • Sci Transl Med. 2023 Jun 14;15(700):eadg1855. doi: 10.1126/scitranslmed.adg1855.
Eva Mittler  1 ,  Alexandra Serris  2 ,  Emma S Esterman  3 ,  Catalina Florez  4  5 ,  Laura C Polanco  1 ,  Cecilia M O'Brien  4  5 ,  Megan M Slough  1 ,  Janne Tynell  6  7 ,  Remigius Gröning  6 ,  Yan Sun  8 ,  Dafna M Abelson  9 ,  Anna Z Wec  3 ,  Denise Haslwanter  1 ,  Markus Keller  10 ,  Chunyan Ye  11 ,  Russel R Bakken  4 ,  Rohit K Jangra  1 ,  John M Dye  4 ,  Clas Ahlm  6 ,  C Garrett Rappazzo  3 ,  Rainer G Ulrich  10  12 ,  Larry Zeitlin  9 ,  James C Geoghegan  3 ,  Steven B Bradfute  11 ,  Simone Sidoli  8 ,  Mattias N E Forsell  6 ,  Tomas Strandin  7 ,  Felix A Rey  2 ,  Andrew S Herbert  4 ,  Laura M Walker  3 ,  Kartik Chandran  1 ,  Pablo Guardado-Calvo  2
Affiliations
  • 1. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 2. Institut Pasteur, Université Paris Cité, CNRS UMR3569, Structural Virology Unit, F-75015 Paris, France.
  • 3. Adimab LLC, Lebanon, NH 03766, USA.
  • 4. U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.
  • 5. The Geneva Foundation, Tacoma, WA 98402, USA.
  • 6. Department of Clinical Microbiology, Umeå University, 90187 Umeå, Sweden.
  • 7. Zoonosis Unit, Department of Virology, Medical Faculty, University of Helsinki, 00290 Helsinki, Finland.
  • 8. Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 9. Mapp Biopharmaceutical Inc., San Diego, CA 92121, USA.
  • 10. Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, 17493 Greifswald-Insel Riems, Germany.
  • 11. Center for Global Health, Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.
  • 12. Partner site: Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), 17493 Greifswald-Insel Riems, Germany.
PMID: 37315110 DOI: 10.1126/scitranslmed.adg1855
Abstract

Emerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus-experienced human donor. Here, we report its structure bound to its target, the Gn/Gc glycoprotein heterodimer comprising the viral fusion complex. The structure explains the broad activity of the nAb: It recognizes conserved Gc fusion loop sequences and the main chain of variable Gn sequences, thereby straddling the Gn/Gc heterodimer and locking it in its prefusion conformation. We show that the nAb's accelerated dissociation from the divergent Andes virus Gn/Gc at endosomal acidic pH limits its potency against this highly lethal virus and correct this liability by engineering an optimized variant that sets a benchmark as a candidate pan-hantavirus therapeutic.

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