@article{1216271ea6984acca9fd09037603d3b8,
title = "Isolation of a Potently Neutralizing and Protective Human Monoclonal Antibody Targeting Yellow Fever Virus",
abstract = "Yellow fever virus (YFV) causes sporadic outbreaks of infection in South America and sub-Saharan Africa. While live-attenuated yellow fever virus vaccines based on three substrains of 17D are considered some of the most effective vaccines in use, problems with production and distribution have created large populations of unvaccinated, vulnerable individuals in areas of endemicity. To date, specific antiviral therapeutics have not been licensed for human use against YFV or any other related flavivirus. Recent advances in monoclonal antibody (mAb) technology have allowed the identification of numerous candidate therapeutics targeting highly pathogenic viruses, including many flaviviruses. Here, we sought to identify a highly neutralizing antibody targeting the YFV envelope (E) protein as a therapeutic candidate. We used human B cell hybridoma technology to isolate mAbs from circulating memory B cells from human YFV vaccine recipients. These antibodies bound to recombinant YFV E protein and recognized at least five major antigenic sites on E. Two mAbs (designated YFV-136 and YFV-121) recognized a shared antigenic site and neutralized the YFV-17D vaccine strain in vitro. YFV-136 also potently inhibited infection by multiple wild-type YFV strains, in part, at a postattachment step in the virus replication cycle. YFV-136 showed therapeutic protection in two animal models of YFV challenge, including hamsters and immunocompromised mice engrafted with human hepatocytes. These studies define features of the antigenic landscape of the YFV E protein recognized by the human B cell response and identify a therapeutic antibody candidate that inhibits infection and disease caused by highly virulent strains of YFV.",
keywords = "KEYWORDS monoclonal antibodies, mouse model, neutralization, vaccine, yellow fever virus",
author = "Doyle, {Michael P.} and Genualdi, {Joseph R.} and Bailey, {Adam L.} and Nurgun Kose and Christopher Gainza and Jessica Rodriguez and Reeder, {Kristen M.} and Nelson, {Christopher A.} and Jethva, {Prashant N.} and Sutton, {Rachel E.} and Bombardi, {Robin G.} and Gross, {Michael L.} and Julander, {Justin G.} and Fremont, {Daved H.} and Diamond, {Michael S.} and Crowe, {James E.}",
note = "Funding Information: The work of M.P.D. was supported by NIH fellowship grant F31 AI152332. J.E.C. is a recipient of the Future Insight Prize from Merck KGaA, which supported this work with a grant. The project described was also supported by grant R01 AI073755 (M.S.D., D.H.F., and J.E.C.), and the mass spectrometry was supported by grant R24 GM136766. Vanderbilt University Medical Center has used the nonclinical and preclinical services program offered by the Division of Microbiology and Infectious Diseases (DMID) of the National Institute of Allergy and Infectious Diseases (NIAID). The YFV Jimenez strain in vitro and hamster studies were provided under contract number HHSN272201700041I Task Order A11 for the in vivo study and contract number 75N93019D00021 Task Order B05 for the in vitro studies. Protein production was supported by NIAID contract number HHSN272201700060C (D.H.F.). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIAID or NIH. Funding Information: Editor Steven J. Projan Copyright {\textcopyright} 2022 Doyle et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Address correspondence to James E. Crowe, Jr, james.crowe@vumc.org. *Present address: Adam L. Bailey, Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA. The authors declare a conflict of interest. M.L.G. is an unpaid member of the scientific advisory boards of Protein Metrics and GenNext. M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, and Carnival Corporation and on the scientific advisory boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. J.E.C. has served as a consultant for Luna Innovations, Merck, GlaxoSmithKline, is a member of the scientific advisory board of Meissa Vaccines and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received unrelated sponsored research agreements from IDBiologics, AstraZeneca and Takeda. This article is a direct contribution from James E. Crowe, a Fellow of the American Academy of Microbiology, who arranged for and secured reviews by Alan Barrett, University of Texas Medical Branch, and Bill Messer, Oregon Health & Science University. Received 22 February 2022 Accepted 7 March 2022 Published 14 April 2022 Publisher Copyright: {\textcopyright} 2022 American Society for Microbiology. All rights reserved.",
year = "2022",
month = jun,
doi = "10.1128/mbio.00512-22",
language = "English",
volume = "13",
journal = "mBio",
issn = "2161-2129",
number = "3",
}