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

Eva Mittler (1) , Anna Wec (2) , Janne Tynell (3) , Pablo Guardado-Calvo (4) , Julia Wigren-Byström (3) , Laura Polanco (1) , Cecilia O’brien (5) , Megan Slough (1) , Dafna Abelson (6) , Alexandra Serris (4) , Mrunal Sakharkar (2) , Gerard Pehau-Arnaudet (4) , Russell Bakken (5) , James Geoghegan (2) , Rohit Jangra (1) , Markus Keller (7) , Larry Zeitlin (6) , Olli Vapalahti (8) , Rainer Ulrich (7) , Zachary Bornholdt (6) , Clas Ahlm (3) , Felix Rey (4) , John Dye (5) , Steven Bradfute (9) , Tomas Strandin (8) , Andrew Herbert (5) , Mattias Forsell (3) , Laura Walker (2) , Kartik Chandran (1)

1 Albert Einstein College of Medicine [New York]
2 Adimab [Lebanon]
3 Umeå University
4 Virologie Structurale - Structural Virology
5 USAMRIID - U.S. Army Medical Research Institute of Infectious Diseases
6 Mapp Biopharmaceutical Inc.
7 INNT - Institute of Novel and Emerging Infectious Diseases
8 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
9 The University of New Mexico [Albuquerque]

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.

Domains: Life Sciences [q-bio]; Biochemistry, Molecular Biology; Structural Biology [q-bio.BM]

Eva Mittler, Anna Wec, Janne Tynell, Pablo Guardado-Calvo, Julia Wigren-Byström, et al.. Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses. Science Translational Medicine, 2022, 14 (636), ⟨10.1126/scitranslmed.abl5399⟩. ⟨pasteur-03902510⟩