title: Type I Interferons are essential for the efficacy of replicase-based DNA vaccines.
abstract: The immunogenicity and efficacy of nucleic acid vaccines can be greatly enhanced when antigen production is under the control of an alphaviral replicase enzyme. However, replicase-mediated mRNA overproduction does not necessarily result in enhanced antigen level. Instead, the strong adaptive immune response of alphavirus replicon-based vectors is due to their production of double-stranded RNA (dsRNA) intermediates, which trigger innate immunity. Because viral infections are known to trigger innate immune responses that lead to the rapid production of Type I Interferons (IFNs), namely IFN-alpha and IFN-beta, we investigated the role of Type I IFNs in the enhanced immunogenicity of replicase-based DNA vaccines. In vitro, cells transfected with replicase-based plasmids produce significantly more Type I IFNs than cells transfected with a conventional DNA plasmid. In vivo, replicase-based DNA vaccines yield stronger humoral responses in the absence of Type I IFN signaling but the lack of this signaling pathway in IFN-alphabeta receptor-/- (knockout) mice abolishes T cell mediated efficacy against tumors of both conventional and alphavirus replicase-based DNA vaccines. Moreover, the co-delivery of an IFNalpha-encoding plasmid significantly improved the efficacy of a weakly immunogenic conventional plasmid. These results suggest a central role for Type I IFNs in the mechanism of replicase-based DNA vaccines and indicate that vaccines can be enhanced by enabling their capacity to triggering innate anti-viral defense pathways.
authors.affiliation: Clinical Research Center, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. wolfgang_leitner@nih.gov
authors.forename: Wolfgang W
authors.initials: WW
authors.lastname: Leitner
authors.forename: Elke S
authors.initials: ES
authors.lastname: Bergmann-Leitner
authors.forename: Leroy N
authors.initials: LN
authors.lastname: Hwang
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000524:Alphavirus / Q000201:enzymology*; D000818:Animals; D007114:Immunization; D007370:Interferon Type I / Q000502:physiology*; D008546:Melanoma, Experimental / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000235:genetics* / Q000276:immunology; D010957:Plasmids; D012093:Replicon; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D008562:Membrane Glycoproteins; D019444:Vaccines, DNA; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse