title: Decreased Vector Gene Expression from E2b Gene-Deleted Adenovirus Serotype 5 Vaccines Intensifies Proinflammatory Immune Responses.
abstract: Recombinant adenovirus serotype 5 (Ad5) vectors are promising vaccine candidates due to their intrinsic immunogenicity and potent transgene expression; however, widespread preexisting Ad5 immunity has been considered a developmental impediment to the use of traditional, or conventional, E1 and E3 gene-deleted Ad5 (Ad5[E1-]) vaccines. Even in the presence of anti-Ad5 immunity, recent murine and human studies have confirmed E2b gene-deleted Ad5 (Ad5[E1-,E2b-]) vaccines to be highly efficacious inducers of transgene-specific memory responses and significantly less toxic options than Ad5[E1-] vaccines. While these findings have been substantially confirmed, the molecular mechanisms underlying the different reactions to these vaccine platforms are unknown. Using cultures of human peripheral blood mononuclear cells (hPBMCs) derived from multiple human donors, we found that Ad5[E1-,E2b-] vaccines trigger higher levels of hPBMC proinflammatory cytokine secretion than Ad5[E1-] vaccines. Interestingly, these responses were generated regardless of the donors' preexisting anti-Ad5 humoral and cell-mediated immune response status.In vitrohPBMC infection with the Ad5[E1-,E2b-] vaccine also provoked greater Th1-dominant gene responses yet smaller amounts of Ad-derived gene expression than Ad5[E1-] vaccines. These results suggest that Ad5[E1-,E2b-] vaccines, in contrast to Ad5[E1-] vaccines, do not promote activities that suppress innate immune signaling, thereby allowing for improved vaccine efficacy and a superior safety profile independently of previous Ad5 immunity.
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA.|College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Dionisia
authors.initials: D
authors.lastname: Quiroga
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Yasser A
authors.initials: YA
authors.lastname: Aldhamen
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Godbehere
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Harding
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA amalfit1@msu.edu.|College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D062705:Adenovirus Vaccines / Q000235:genetics / Q000276:immunology*; D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004337:Drug Carriers; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D065288:Serogroup; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology
chemical_list: D062705:Adenovirus Vaccines; D016207:Cytokines; D004337:Drug Carriers; D014614:Vaccines, Synthetic
keywords: adenoviruses; gene transfer; humoral immunity; immunization; innate immunity; tumor vaccines; vaccines; viral immunity