title: A West Nile virus recombinant protein vaccine that coactivates innate and adaptive immunity.
abstract: A chimeric protein West Nile virus (WNV) vaccine capable of delivering both innate and adaptive immune signals was designed by fusing a modified version of bacterial flagellin (STF2 Delta ) to the EIII domain of the WNV envelope protein. This fusion protein stimulated interleukin-8 production in a Toll-like receptor (TLR)-5-dependent fashion, confirming appropriate in vitro TLR5 bioactivity, and also retained critical WNV-E-specific conformation-dependent neutralizing epitopes as measured by enzyme-linked immunosorbent assay. When administered without adjuvant to C3H/HeN mice, the fusion protein elicited a strong WNV-E-specific immunoglobulin G antibody response that neutralized viral infectivity and conferred protection against a lethal WNV challenge. This potent EIII-specific immune response requires a direct linkage of EIII to STF2 Delta , given that a simple mixture of the 2 components failed to induce an antibody response or to provide protection against virus challenge. The presence of a functional TLR5 gene in vivo is also required--TLR5-deficient mice elicited only a minimal antigen-specific response. These results confirm that vaccines designed to coordinately regulate the innate and adaptive immune responses can induce protective immune responses without the need for potentially toxic adjuvants. They also support the further development of an effective WNV vaccine and novel monovalent and multivalent vaccines for related flaviviruses.
authors.affiliation: VaxInnate Corporation, New Haven, CT 06511, USA. wmcdonald@vaxinnate.com
authors.forename: William F
authors.initials: WF
authors.lastname: McDonald
authors.forename: James W
authors.initials: JW
authors.lastname: Huleatt
authors.forename: Harald G
authors.initials: HG
authors.lastname: Foellmer
authors.forename: Duane
authors.initials: D
authors.lastname: Hewitt
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Priyanka
authors.initials: P
authors.lastname: Desai
authors.forename: Albert
authors.initials: A
authors.lastname: Price
authors.forename: Andrea
authors.initials: A
authors.lastname: Jacobs
authors.forename: Virginia N
authors.initials: VN
authors.lastname: Takahashi
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Valerian
authors.initials: V
authors.lastname: Nakaar
authors.forename: Lena
authors.initials: L
authors.lastname: Alexopoulou
authors.forename: Erol
authors.initials: E
authors.lastname: Fikrig
authors.forename: T J
authors.initials: TJ
authors.lastname: Powell
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D000918:Antibody Specificity; D002460:Cell Line; D005408:Flagellin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007111:Immunity, Cellular; D007113:Immunity, Innate; D051379:Mice; D008809:Mice, Inbred C3H; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D012486:Salmonella typhimurium / Q000235:genetics / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010948:Viral Plaque Assay; D014901:West Nile Fever / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D053060:West Nile Virus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D014902:West Nile virus / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D011993:Recombinant Fusion Proteins; D051198:Toll-Like Receptor 5; D014759:Viral Envelope Proteins; D053060:West Nile Virus Vaccines; D005408:Flagellin