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.
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.
Capone
Stefania
S
Department of Cellular and Molecular Biology, IRBM P. Angeletti, via Pontina Km 30600, 00040 Rome, Italy.
Meola
Annalisa
A
Ercole
Bruno Bruni
BB
Vitelli
Alessandra
A
Pezzanera
Monica
M
Ruggeri
Lionello
L
Davies
Mary Ellen
ME
Tafi
Rosalba
R
Santini
Claudia
C
Luzzago
Alessandra
A
Fu
Tong-Ming
TM
Bett
Andrew
A
Colloca
Stefano
S
Cortese
Riccardo
R
Nicosia
Alfredo
A
Folgori
Antonella
A
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
D018937:Hepatitis C Antibodies; D018936:Hepatitis C Antigens; D019444:Vaccines, DNA; D014761:Viral Hepatitis Vaccines; D017361:Viral Nonstructural Proteins; D007371:Interferon-gamma