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Journal of Virology, February 2006, p. 1688-1699, Vol. 80, No. 4
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.4.1688-1699.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Stefania Capone,1 Annalisa Meola,1 Bruno Bruni Ercole,1 Alessandra Vitelli,1 Monica Pezzanera,1 Lionello Ruggeri,1 Mary Ellen Davies,2 Rosalba Tafi,1 Claudia Santini,1 Alessandra Luzzago,1 Tong-Ming Fu,2 Andrew Bett,2 Stefano Colloca,1 Riccardo Cortese,1 Alfredo Nicosia,1 and Antonella Folgori1*

Istituto di Ricerche di Biologia Molecolare "P. Angeletti," Pomezia, Rome, Italy,1 Merck Research Laboratories, West Point, Pennsylvania2

Received 12 October 2005/ Accepted 7 November 2005

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.

* Corresponding author. Mailing address: Department of Cellular and Molecular Biology, IRBM "P. Angeletti," via Pontina Km 30600, 00040 Rome, Italy. Phone: 39 06 91093292. Fax: 39 06 91093225. E-mail: antonella_folgori{at}merck.com.

Journal of Virology, February 2006, p. 1688-1699, Vol. 80, No. 4
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.4.1688-1699.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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