title: Optimization of vaccine responses with an E1, E2b and E3-deleted Ad5 vector circumvents pre-existing anti-vector immunity.
abstract: Recombinant serotype 5 adenovirus (Ad5) vectors lacking E1 expression induce robust immune responses against encoded transgenes in pre-clinical models, but have muted responses in human trials because of widespread pre-existing anti-adenovirus immunity. Attempts to circumvent Ad5-specific immunity by using alternative serotypes or modifying capsid components have not yielded profound clinical improvement. To address this issue, we explored a novel alternative strategy, specifically reducing the expression of structural Ad5 genes by creating E1 and E2b deleted recombinant Ad5 vectors. Our data show that [E1-, E2b-]vectors retaining the Ad5 serotype are potent immunogens in pre-clinical models despite the presence of significant Ad5-specific immunity, in contrast to [E1-] vectors. These pre-clinical studies with E1 and E2b-deleted recombinant Ad5 vectors suggest that anti-Ad immunity will no longer be a limiting factor, and that clinical trials to evaluate their performance are warranted.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: T
authors.initials: T
authors.lastname: Osada
authors.forename: X Y
authors.initials: XY
authors.lastname: Yang
authors.forename: Z C
authors.initials: ZC
authors.lastname: Hartman
authors.forename: O
authors.initials: O
authors.lastname: Glass
authors.forename: B L
authors.initials: BL
authors.lastname: Hodges
authors.forename: D
authors.initials: D
authors.lastname: Niedzwiecki
authors.forename: M A
authors.initials: MA
authors.lastname: Morse
authors.forename: H K
authors.initials: HK
authors.lastname: Lyerly
authors.forename: A
authors.initials: A
authors.lastname: Amalfitano
authors.forename: T M
authors.initials: TM
authors.lastname: Clay
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D017498:Adenovirus E1 Proteins / Q000235:genetics* / Q000276:immunology; D017502:Adenovirus E2 Proteins / Q000235:genetics* / Q000276:immunology; D017503:Adenovirus E3 Proteins / Q000235:genetics* / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D017353:Gene Deletion; D005822:Genetic Vectors / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D017498:Adenovirus E1 Proteins; D017502:Adenovirus E2 Proteins; D017503:Adenovirus E3 Proteins; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen