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Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Adimab, LLC, United States.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Zoonosis Unit, Department of Virology, Medical Faculty, University of Helsinki, Helsinki, Finland.ORCID iD: 0000-0001-6930-5230
Structural Virology Unit, Department of Virology, Institut Pasteur, Paris, France.
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2022 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 14, no 636, article id eabl5399Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Association for the Advancement of Science , 2022. Vol. 14, no 636, article id eabl5399
National Category
Microbiology in the medical area Infectious Medicine
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URN: urn:nbn:se:umu:diva-193408DOI: 10.1126/scitranslmed.abl5399ISI: 000772459100003PubMedID: 35294259Scopus ID: 2-s2.0-85126716233OAI: oai:DiVA.org:umu-193408DiVA, id: diva2:1648578
Funder
Swedish Research Council, 2020-06235Region Västerbotten, LL-579011Available from: 2022-03-31 Created: 2022-03-31 Last updated: 2023-09-05Bibliographically approved

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Tynell, JanneWigren, JuliaAhlm, ClasForsell, Mattias N. E.

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