title: Engineered alphavirus replicon vaccines based on known attenuated viral mutants show limited effects on immunogenicity.
abstract: The immunogenicity of alphavirus replicon vaccines is determined by many factors including the level of antigen expression and induction of innate immune responses. Characterized attenuated alphavirus mutants contain changes to the genomic 5' UTR and mutations that result in altered non-structural protein cleavage timing leading to altered levels of antigen expression and interferon (IFN) induction. In an attempt to create more potent replicon vaccines, we engineered a panel of Venezuelan equine encephalitis-Sindbis virus chimeric replicons that contained these attenuating mutations. Modified replicons were ranked for antigen expression and IFN induction levels in cell culture and then evaluated in mice. The results of these studies showed that differences in antigen production and IFN induction in vitro did not correlate with large changes in immunogenicity in vivo. These findings indicate that the complex interactions between innate immune response and the replicon's ability to express antigen complicate rational design of more potent alphavirus replicons.
authors.affiliation: Novartis Vaccines and Diagnostics Inc., 350 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors.forename: Giulietta
authors.initials: G
authors.lastname: Maruggi
authors.forename: Christine A
authors.initials: CA
authors.lastname: Shaw
authors.forename: Gillis R
authors.initials: GR
authors.lastname: Otten
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mason
authors.forename: Clayton W
authors.initials: CW
authors.lastname: Beard
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D000941:Antigens / Q000096:biosynthesis / Q000276:immunology; D004337:Drug Carriers; D004666:Encephalitis Virus, Venezuelan Equine / Q000235:genetics*; D020869:Gene Expression Profiling; D005822:Genetic Vectors; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012845:Sindbis Virus / Q000235:genetics*; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D020121:5' Untranslated Regions; D000941:Antigens; D004337:Drug Carriers; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; D007371:Interferon-gamma
keywords: 5′ UTR; Alphavirus replicon vaccine; Antigen expression; Attenuating mutation; Interferon induction; Secondary structure