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Title: Potent neutralizing human monoclonal antibodies preferentially target mature dengue virus particles: Implication for novel strategy for dengue vaccine
Authors: Wen Yang Tsai
Hui Ling Chen
Jih Jin Tsai
Wanwisa Dejnirattisai
Amonrat Jumnainsong
Juthathip Mongkolsapaya
Gavin Screaton
James E. Crowe
Wei Kung Wang
Kaohsiung Medical University Chung-Ho Memorial Hospital
Vanderbilt University Medical Center
University of Oxford
Khon Kaen University
Kaohsiung Medical University
Faculty of Medicine, Siriraj Hospital, Mahidol University
Nuffield Department of Clinical Medicine
University of Hawaii at Manoa John A. Burns School of Medicine
Keywords: Agricultural and Biological Sciences;Immunology and Microbiology
Issue Date: 1-Jan-2018
Citation: Journal of Virology. Vol.92, No.23 (2018)
Abstract: Copyright © 2018 American Society for Microbiology. All Rights Reserved. The four serotypes of dengue virus (DENV) cause the most important mosquito-borne viral disease in humans. The envelope (E) protein is the major target of neutralizing antibodies and contains 3 domains (domain I [DI], DII, and DIII). Recent studies reported that human monoclonal antibodies (MAbs) recognizing DIII, the D1/DII hinge, the E-dimer epitope, or a quaternary epitope involving DI/DII/DIII are more potently neutralizing than those recognizing the fusion loop (FL) of DII. Due to inefficient cleavage of the premembrane protein, DENV suspensions consist of a mixture of mature, immature, and partially immature particles. We investigated the neutralization and binding of 22 human MAbs to DENV serotype 1 (DENV1) virions with differential maturation status. Compared with FL MAbs, DIII, DI/DII hinge, and E-dimer epitope MAbs showed higher maximum binding and avidity to mature particles relative to immature particles; this feature may contribute to the strong neutralizing potency of such MAbs. FL-specific MAbs required 57 to 87% occupancy on mature particles to achieve half-maximal neutralization (NT 50 ), whereas the potently neutralizing MAbs achieved NT 50 states at 20 to 38% occupancy. Analysis of the MAb repertoire and polyclonal sera from patients with primary DENV1 infection supports the immunodominance of cross-reactive anti-E antibodies over type-specific antibodies. After depletion with viral particles from a heterologous DENV serotype, the type-specific neutralizing antibodies remained and showed binding features shared by potent neutralizing MAbs. Taken together, these findings suggest that the use of homogeneous mature DENV particles as an immunogen may induce more potent neutralizing antibodies against DENV than the use of immature or mixed particles.
ISSN: 10985514
Appears in Collections:Scopus 2018

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