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]
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]
Eva Mittler
- Fonction : Auteur
- PersonId : 1202153
- ORCID : 0000-0002-5935-6314
Pablo Guardado-Calvo
- Fonction : Auteur
- PersonId : 745637
- IdHAL : pguardado
- ORCID : 0000-0001-7292-5270
Julia Wigren-Byström
- Fonction : Auteur
- PersonId : 1202156
- ORCID : 0000-0001-9131-5945
Cecilia O’brien
- Fonction : Auteur
- PersonId : 1202157
- ORCID : 0000-0001-7160-0220
Megan Slough
- Fonction : Auteur
- PersonId : 1202158
- ORCID : 0000-0003-3514-578X
Alexandra Serris
- Fonction : Auteur
- PersonId : 1202159
- ORCID : 0000-0002-7444-4662
Gerard Pehau-Arnaudet
- Fonction : Auteur
- PersonId : 777135
- ORCID : 0000-0001-6479-9470
Russell Bakken
- Fonction : Auteur
- PersonId : 1202161
- ORCID : 0000-0003-0419-4183
Rohit Jangra
- Fonction : Auteur
- PersonId : 811983
- ORCID : 0000-0002-3119-0869
Larry Zeitlin
- Fonction : Auteur
- PersonId : 1202162
- ORCID : 0000-0002-6857-1024
Olli Vapalahti
- Fonction : Auteur
- PersonId : 1202163
- ORCID : 0000-0003-2270-6824
Rainer Ulrich
- Fonction : Auteur
- PersonId : 1202164
- ORCID : 0000-0002-5620-1528
Zachary Bornholdt
- Fonction : Auteur
- PersonId : 1202165
- ORCID : 0000-0002-7557-9219
Felix Rey
- Fonction : Auteur
- PersonId : 804036
- ORCID : 0000-0002-9953-7988
- IdRef : 069298394
John Dye
- Fonction : Auteur
- PersonId : 1165084
- ORCID : 0000-0002-0883-5016
Steven Bradfute
- Fonction : Auteur
- PersonId : 1165058
- ORCID : 0000-0002-1985-751X
Tomas Strandin
- Fonction : Auteur
- PersonId : 1180869
- ORCID : 0000-0002-2454-7479
Kartik Chandran
- Fonction : Auteur
- PersonId : 771121
- ORCID : 0000-0003-0232-7077
Résumé
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.