title: Pre- and post-exposure safety and efficacy of attenuated rabies virus vaccines are enhanced by their expression of IFNγ.
abstract: Consistent with evidence of a strong correlation between interferon gamma (IFNγ) production and rabies virus (RABV) clearance from the CNS, we recently demonstrated that engineering a pathogenic RABV to express IFNγ highly attenuates the virus. Reasoning that IFNγ expression by RABV vaccines would enhance their safety and efficacy, we reverse-engineered two proven vaccine vectors, GAS and GASGAS, to express murine IFNγ. Mortality and morbidity were monitored during suckling mice infection, immunize/challenge experiments and mixed intracranial infections. We demonstrate that GASγ and GASγGAS are significantly attenuated in suckling mice compared to the GASGAS vaccine. GASγ better protects mice from lethal DRV4 RABV infection in both pre- and post-exposure experiments compared to GASGAS. Finally, GASγGAS reduces post-infection neurological sequelae, compared to control, during mixed intracranial infection with DRV4. These data show IFNγ expression by a vaccine vector can enhance its safety while increasing its efficacy as pre- and post-exposure treatment.
authors.affiliation: Department of Cancer Biology, 1020 Locust St., Jefferson Alumni Hall, Room 454, Philadelphia, PA 19107, USA; Center for Neurovirology 1020 Locust St., Jefferson Alumni Hall, Room 454, Philadelphia, PA 19107, USA.
authors.forename: Darryll A
authors.initials: DA
authors.lastname: Barkhouse
authors.affiliation: Center for Neurovirology 1020 Locust St., Jefferson Alumni Hall, Room 454, Philadelphia, PA 19107, USA; Department of Microbiology and Immunology 1020 Locust St., Jefferson Alumni Hall, Room 465, Philadelphia, PA 19107, USA.
authors.forename: Milosz
authors.initials: M
authors.lastname: Faber
authors.affiliation: Department of Cancer Biology, 1020 Locust St., Jefferson Alumni Hall, Room 454, Philadelphia, PA 19107, USA; Department of Neurological Surgery, 1020 Locust St., Jefferson Alumni Hall, Room 454, Philadelphia, PA 19107, USA; Center for Neurovirology 1020 Locust St., Jefferson Alumni Hall, Room 454, Philadelphia, PA 19107, USA. Electronic address: douglas.hooper@jefferson.edu.
authors.forename: D Craig
authors.initials: DC
authors.lastname: Hooper
mesh_terms: D000818:Animals; D000833:Animals, Suckling; D002460:Cell Line; D005260:Female; D015870:Gene Expression; D005818:Genetic Engineering; D016679:Genome, Viral; D007371:Interferon-gamma / Q000235:genetics*; D051379:Mice; D009154:Mutation; D011818:Rabies / Q000276:immunology / Q000517:prevention & control / Q000628:therapy; D011819:Rabies Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D011820:Rabies virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D011994:Recombinant Proteins / Q000235:genetics; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014774:Virulence / Q000235:genetics / Q000276:immunology
chemical_list: D011819:Rabies Vaccines; D011994:Recombinant Proteins; D014613:Vaccines, Attenuated; D007371:Interferon-gamma
keywords: CNS; Interferon gamma; Post-exposure treatment; Rabies; Vaccine