title: A novel adenovirus type 6 (Ad6)-based hepatitis C virus vector that overcomes preexisting anti-ad5 immunity and induces potent and broad cellular immune responses in rhesus macaques.
abstract: Success in resolving hepatitis C virus (HCV) infection has been correlated to vigorous, multispecific, and sustained CD8(+) T-cell response in humans and chimpanzees. The efficacy of inducing T-cell-mediated immunity by recombinant serotype 5 adenovirus vector has been proven in many animal models of infectious diseases, but its immunogenicity can be negatively influenced by preexisting immunity against the vector itself. To evaluate the less prevalent adenovirus serotype 6 (Ad6) as an alternative vector for and HCV vaccine development, we have generated serotype 5 and 6 adenoviral vectors directing expression of the nonstructural region of HCV (MRKAd5-NSmut and MRKAd6-NSmut). Immunogenicity studies in mice showed that the two vectors induced comparable T-cell responses but that only MRKAd6-NSmut was not suppressed in the presence of anti-Ad5 immunity. In contrast, preexisting anti-Ad5 immunity dramatically blunted the immunogenicity of the serotype 5-based HCV vector. Furthermore, MRKAd6-NSmut showed equivalent potency, breadth, and longevity of HCV-specific T-cell responses in rhesus macaques as the corresponding Ad5-based vector over a wide range of doses and was capable of boosting DNA-primed animals even if administered at low doses. These data support the use of the MRKAd6-NSmut for anti-HCV immunotherapy and, more generally, for the Ad6 serotype as a better genetic vaccine vehicle than Ad5.
authors.affiliation: Department of Cellular and Molecular Biology, IRBM P. Angeletti, via Pontina Km 30600, 00040 Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Capone
authors.forename: Annalisa
authors.initials: A
authors.lastname: Meola
authors.forename: Bruno Bruni
authors.initials: BB
authors.lastname: Ercole
authors.forename: Alessandra
authors.initials: A
authors.lastname: Vitelli
authors.forename: Monica
authors.initials: M
authors.lastname: Pezzanera
authors.forename: Lionello
authors.initials: L
authors.lastname: Ruggeri
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Davies
authors.forename: Rosalba
authors.initials: R
authors.lastname: Tafi
authors.forename: Claudia
authors.initials: C
authors.lastname: Santini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Luzzago
authors.forename: Tong-Ming
authors.initials: TM
authors.lastname: Fu
authors.forename: Andrew
authors.initials: A
authors.lastname: Bett
authors.forename: Stefano
authors.initials: S
authors.lastname: Colloca
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cortese
authors.forename: Alfredo
authors.initials: A
authors.lastname: Nicosia
authors.forename: Antonella
authors.initials: A
authors.lastname: Folgori
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D003429:Cross Reactions; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D005822:Genetic Vectors; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000517:prevention & control; D018937:Hepatitis C Antibodies; D018936:Hepatitis C Antigens / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular; D007117:Immunization, Secondary; D007371:Interferon-gamma / Q000032:analysis; D008253:Macaca mulatta; D051379:Mice; D009500:Neutralization Tests; D011995:Recombination, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology; D014761:Viral Hepatitis Vaccines / Q000008:administration & dosage / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D018937:Hepatitis C Antibodies; D018936:Hepatitis C Antigens; D019444:Vaccines, DNA; D014761:Viral Hepatitis Vaccines; D017361:Viral Nonstructural Proteins; D007371:Interferon-gamma