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Journal of Virology, October 2005, p. 12807-12817, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.12807-12817.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Low-Dose Adenovirus Vaccine Encoding Chimeric Hepatitis B Virus Surface Antigen-Human Papillomavirus Type 16 E7 Proteins Induces Enhanced E7-Specific Antibody and Cytotoxic T-Cell Responses

Gentherapie von Tumoren, Deutsches Krebsforschungszentum (DKFZ), and Institut für Angewandte Tumorbiologie, Ruprecht-Karls Universität, Im Neuenheimer Feld 280/220, D-69120 Heidelberg, Germany,¹ Molekulare Immunologie, DKFZ, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany,² Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, 1230 York Avenue, New York 10021, New York,³ Laboratory of Animal Resources, European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69012 Heidelberg, Germany,⁴ Angewandte Tumorvirologie, DKFZ, Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany⁵

Received 23 February 2005/ Accepted 19 July 2005

Induction of effective immune responses may help prevent cancer progression. Tumor-specific antigens, such as those of human papillomaviruses involved in cervical cancer, are targets with limited intrinsic immunogenicity. Here we show that immunization with low doses (10⁶ infectious units/dose) of a recombinant human adenovirus type 5 encoding a fusion of the E7 oncoprotein of human papillomavirus type 16 to the carboxyl terminus of the surface antigen of hepatitis B virus (HBsAg) induces remarkable E7-specific humoral and cellular immune responses. The HBsAg/E7 fusion protein assembled efficiently into virus-like particles, which stimulated antibody responses against both carrier and foreign antigens, and evoked antigen-specific kill of an indicator cell population in vivo. Antibody and T-cell responses were significantly higher than those induced by a control adenovirus vector expressing wild-type E7. Such responses were not affected by preexisting immunity against either HBsAg or adenovirus. These data demonstrate that the presence of E7 on HBsAg particles does not interfere with particle secretion, as it occurs with bigger proteins fused to the C terminus of HBsAg, and results in enhancement of CD8⁺-mediated T-cell responses to E7. Thus, fusion to HBsAg is a convenient strategy for developing cervical cancer therapeutic vaccines, since it enhances the immunogenicity of E7 while turning it into an innocuous secreted fusion protein.