title: A recombinant novirhabdovirus presenting at the surface the E Glycoprotein from West Nile Virus (WNV) is immunogenic and provides partial protection against lethal WNV challenge in BALB/c mice.
abstract: West Nile Virus (WNV) is a zoonotic mosquito-transmitted flavivirus that can infect and cause disease in mammals including humans. Our study aimed at developing a WNV vectored vaccine based on a fish Novirhabdovirus, the Viral Hemorrhagic Septicemia virus (VHSV). VHSV replicates at temperatures lower than 20°C and is naturally inactivated at higher temperatures. A reverse genetics system has recently been developed in our laboratory for VHSV allowing the addition of genes in the viral genome and the recovery of the respective recombinant viruses (rVHSV). In this study, we have generated rVHSV vectors bearing the complete WNV envelope gene (EWNV) (rVHSV-EWNV) or fragments encoding E subdomains (either domain III alone or domain III fused to domain II) (rVHSV-DIIIWNV and rVHSV-DII-DIIIWNV, respectively) in the VHSV genome between the N and P cistrons. With the objective to enhance the targeting of the EWNV protein or EWNV-derived domains to the surface of VHSV virions, Novirhadovirus G-derived signal peptide and transmembrane domain (SPG and TMG) were fused to EWNV at its amino and carboxy termini, respectively. By Western-blot analysis, electron microscopy observations or inoculation experiments in mice, we demonstrated that both the EWNV and the DIIIWNV could be expressed at the viral surface of rVHSV upon addition of SPG. Every constructs expressing EWNV fused to SPG protected 40 to 50% of BALB/cJ mice against WNV lethal challenge and specifically rVHSV-SPGEWNV induced a neutralizing antibody response that correlated with protection. Surprisingly, rVHSV expressing EWNV-derived domain III or II and III were unable to protect mice against WNV challenge, although these domains were highly incorporated in the virion and expressed at the viral surface. In this study we demonstrated that a heterologous glycoprotein and non membrane-anchored protein, can be efficiently expressed at the surface of rVHSV making this approach attractive to develop new vaccines against various pathogens.
authors.affiliation: UR0892 Unité de Virologie et Immunologie Moléculaires, INRA, CRJ, Jouy en Josas, France.
authors.forename: Angella
authors.initials: A
authors.lastname: Nzonza
authors.affiliation: UMR 1161 Virologie, INRA, ANSES, UPEC ENVA, Maisons-Alfort, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lecollinet
authors.affiliation: UR1196 Unité Génomique et Physiologie de la Lactation, Plateau de Microscopie Électronique, INRA, CRJ, Jouy-en-Josas, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Chat
authors.affiliation: UMR 1161 Virologie, INRA, ANSES, UPEC ENVA, Maisons-Alfort, France.
authors.forename: Steeve
authors.initials: S
authors.lastname: Lowenski
authors.affiliation: UR0892 Unité de Virologie et Immunologie Moléculaires, INRA, CRJ, Jouy en Josas, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Mérour
authors.affiliation: UR0892 Unité de Virologie et Immunologie Moléculaires, INRA, CRJ, Jouy en Josas, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Biacchesi
authors.affiliation: UR0892 Unité de Virologie et Immunologie Moléculaires, INRA, CRJ, Jouy en Josas, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Brémont
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000276:immunology; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000276:immunology; D017951:Antigen Presentation; D002460:Cell Line; D004274:DNA, Recombinant / Q000235:genetics*; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D029141:Novirhabdovirus / Q000235:genetics* / Q000276:immunology*; D017434:Protein Structure, Tertiary; D018418:Th2 Cells / Q000276:immunology; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D014902:West Nile virus / Q000276:immunology / Q000502:physiology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D004274:DNA, Recombinant; D014759:Viral Envelope Proteins