title: High-avidity and potently neutralizing cross-reactive human monoclonal antibodies derived from secondary dengue virus infection.
abstract: The envelope (E) protein of dengue virus (DENV) is the major target of neutralizing antibodies (Abs) and vaccine development. Previous studies of human dengue-immune sera reported that a significant proportion of anti-E Abs, known as group-reactive (GR) Abs, were cross-reactive to all four DENV serotypes and to one or more other flaviviruses. Based on studies of mouse anti-E monoclonal antibodies (MAbs), GR MAbs were nonneutralizing or weakly neutralizing compared with type-specific MAbs; a GR response was thus not regarded as important for vaccine strategy. We investigated the epitopes, binding avidities, and neutralization potencies of 32 human GR anti-E MAbs. In addition to fusion loop (FL) residues in E protein domain II, human GR MAbs recognized an epitope involving both FL and bc loop residues in domain II. The neutralization potencies and binding avidities of GR MAbs derived from secondary DENV infection were stronger than those derived from primary infection. GR MAbs derived from primary DENV infection primarily blocked attachment, whereas those derived from secondary infection blocked DENV postattachment. Analysis of the repertoire of anti-E MAbs derived from patients with primary DENV infection revealed that the majority were GR, low-avidity, and weakly neutralizing MAbs, whereas those from secondary infection were primarily GR, high-avidity, and potently neutralizing MAbs. Our findings suggest that the weakly neutralizing GR anti-E Abs generated from primary DENV infection become potently neutralizing MAbs against the four serotypes after secondary infection. The observation that the dengue immune status of the host affects the quality of the cross-reactive Abs generated has implications for new strategies for DENV vaccination.
authors.affiliation: Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA.
authors.forename: Wen-Yang
authors.initials: WY
authors.lastname: Tsai
authors.forename: Chih-Yun
authors.initials: CY
authors.lastname: Lai
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Wu
authors.forename: Hong-En
authors.initials: HE
authors.lastname: Lin
authors.forename: Carolyn
authors.initials: C
authors.lastname: Edwards
authors.forename: Amonrat
authors.initials: A
authors.lastname: Jumnainsong
authors.forename: Srisakul
authors.initials: S
authors.lastname: Kliks
authors.forename: Scott
authors.initials: S
authors.lastname: Halstead
authors.forename: Juthathip
authors.initials: J
authors.lastname: Mongkolsapaya
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Screaton
authors.forename: Wei-Kung
authors.initials: WK
authors.lastname: Wang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D003429:Cross Reactions; D003715:Dengue / Q000276:immunology* / Q000821:virology; D003716:Dengue Virus / Q000145:classification / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D014759:Viral Envelope Proteins
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