TY - JOUR
T1 - Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses
AU - Mittler, Eva
AU - Wec, Anna Z.
AU - Tynell, Janne
AU - Guardado-Calvo, Pablo
AU - Wigren-Byström, Julia
AU - Polanco, Laura C.
AU - O'Brien, Cecilia M.
AU - Slough, Megan M.
AU - Abelson, Dafna M.
AU - Serris, Alexandra
AU - Sakharkar, Mrunal
AU - Pehau-Arnaudet, Gerard
AU - Bakken, Russell R.
AU - Geoghegan, James C.
AU - Jangra, Rohit K.
AU - Keller, Markus
AU - Zeitlin, Larry
AU - Vapalahti, Olli
AU - Ulrich, Rainer G.
AU - Bornholdt, Zachary A.
AU - Ahlm, Clas
AU - Rey, Felix A.
AU - Dye, John M.
AU - Bradfute, Steven B.
AU - Strandin, Tomas
AU - Herbert, Andrew S.
AU - Forsell, Mattias N.E.
AU - Walker, Laura M.
AU - Chandran, Kartik
N1 - Publisher Copyright:
© 2022 The Authors.
PY - 2022/3/16
Y1 - 2022/3/16
N2 - 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.
AB - 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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U2 - 10.1126/scitranslmed.abl5399
DO - 10.1126/scitranslmed.abl5399
M3 - Article
C2 - 35294259
AN - SCOPUS:85126716233
SN - 1946-6234
VL - 14
JO - Science translational medicine
JF - Science translational medicine
IS - 636
M1 - abl5399
ER -