title: Type I IFN induced by adenovirus serotypes 28 and 35 has multiple effects on T cell immunogenicity.
abstract: Recombinant adenovirus (rAd) vectors are being investigated as vaccine delivery vehicles in preclinical and clinical studies. rAds constructed from different serotypes differ in receptor usage, tropism, and ability to activate cells, aspects of which likely contribute to their different immunogenicity profiles. In this study, we compared the infectivity and cell stimulatory capacity of recombinant adenovirus serotype 5 (rAd5), recombinant adenovirus serotype 28 (rAd28), and recombinant adenovirus serotype 35 (rAd35) in association with their respective immunogenicity profiles. We found that rAd28 and rAd35 infected and led to the in vitro maturation and activation of both human and mouse dendritic cells more efficiently compared with rAd5. In stark contrast to rAd5, rAd28 and rAd35 induced production of IFN-α and stimulated IFN-related intracellular pathways. However, the in vivo immunogenicity of rAd28 and rAd35 was significantly lower than that of rAd5. Deletion of IFN-α signaling during vaccination with rAd28 and rAd35 vectors increased the magnitude of the insert-specific T cell response to levels induced by vaccination with rAd5 vector. The negative impact of IFN-α signaling on the magnitude of the T cell response could be overcome by increasing the vaccine dose, which was also associated with greater polyfunctionality and a more favorable long-term memory phenotype of the CD8 T cell response in the presence of IFN-α signaling. Taken together, our results demonstrate that rAd-induced IFN-α production has multiple effects on T cell immunogenicity, the understanding of which should be considered in the design of rAd vaccine vectors.
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Johnson
authors.forename: Constantinos
authors.initials: C
authors.lastname: Petrovas
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Ross W B
authors.initials: RW
authors.lastname: Lindsay
authors.forename: Karin
authors.initials: K
authors.lastname: Loré
authors.forename: Jason G D
authors.initials: JG
authors.lastname: Gall
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: François
authors.initials: F
authors.lastname: Lefebvre
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cameron
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Elias
authors.initials: E
authors.lastname: Haddad
authors.forename: Rafick-Pierre
authors.initials: RP
authors.lastname: Sekaly
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005822:Genetic Vectors; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D013601:T-Lymphocytes / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D014614:Vaccines, Synthetic