title: The human immune response to Dengue virus is dominated by highly cross-reactive antibodies endowed with neutralizing and enhancing activity.
abstract: Antibodies protect against homologous Dengue virus (DENV) infection but can precipitate severe dengue by promoting heterotypic virus entry via Fcγ receptors (FcγR). We immortalized memory B cells from individuals after primary or secondary infection and analyzed anti-DENV monoclonal antibodies (mAbs) thus generated. MAbs to envelope (E) protein domain III (DIII) were either serotype specific or cross-reactive and potently neutralized DENV infection. DI/DII- or viral membrane protein prM-reactive mAbs neutralized poorly and showed broad cross-reactivity with the four DENV serotypes. All mAbs enhanced infection at subneutralizing concentrations. Three mAbs targeting distinct epitopes on the four DENV serotypes and engineered to prevent FcγR binding did not enhance infection and neutralized DENV in vitro and in vivo as postexposure therapy in a mouse model of lethal DENV infection. Our findings reveal an unexpected degree of cross-reactivity in human antibodies against DENV and illustrate the potential for an antibody-based therapy to control severe dengue.
authors.affiliation: Institute for Research in Biomedicine, Bellinzona 6500, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Beltramello
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Williams
authors.forename: Cameron P
authors.initials: CP
authors.lastname: Simmons
authors.forename: Annalisa
authors.initials: A
authors.lastname: Macagno
authors.forename: Luca
authors.initials: L
authors.lastname: Simonelli
authors.forename: Nguyen Than Ha
authors.initials: NT
authors.lastname: Quyen
authors.forename: Soila
authors.initials: S
authors.lastname: Sukupolvi-Petty
authors.forename: Erika
authors.initials: E
authors.lastname: Navarro-Sanchez
authors.forename: Paul R
authors.initials: PR
authors.lastname: Young
authors.forename: Aravinda M
authors.initials: AM
authors.lastname: de Silva
authors.forename: Félix A
authors.initials: FA
authors.lastname: Rey
authors.forename: Luca
authors.initials: L
authors.lastname: Varani
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Whitehead
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Eva
authors.initials: E
authors.lastname: Harris
authors.forename: Antonio
authors.initials: A
authors.lastname: Lanzavecchia
authors.forename: Federica
authors.initials: F
authors.lastname: Sallusto
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D019067:Antibody-Dependent Enhancement; D001402:B-Lymphocytes / Q000276:immunology; D015153:Blotting, Western; D003429:Cross Reactions; D003715:Dengue / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D009500:Neutralization Tests; D017452:Receptors, IgG / Q000276:immunology; D012703:Serotyping; D014759:Viral Envelope Proteins / Q000276:immunology*; D017361:Viral Nonstructural Proteins
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C051821:E-glycoprotein, Dengue virus type 2; D017452:Receptors, IgG; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins