Combination of DNA prime--adenovirus boost immunization with entecavir elicits sustained control of chronic hepatitis B in the woodchuck model

• Published in: PLoS pathogens 2013-06, Vol.9 (6), p.e1003391-e1003391
• Main Authors: Kosinska, Anna D, Zhang, Ejuan, Johrden, Lena, Liu, Jia, Seiz, Pia L, Zhang, Xiaoyong, Ma, Zhiyong, Kemper, Thekla, Fiedler, Melanie, Glebe, Dieter, Wildner, Oliver, Dittmer, Ulf, Lu, Mengji, Roggendorf, Michael
• Format: Article
• Language: English
• Subjects: Adenoviridae; Adenoviruses; Animals; Biology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA sequencing; Dosage and administration; Entecavir; Genetic aspects; Health aspects; Hepatitis; Hepatitis B; Hepatitis B Vaccines - genetics; Hepatitis B Vaccines - immunology; Hepatitis B Vaccines - pharmacology; Hepatitis B, Chronic - genetics; Hepatitis B, Chronic - immunology; Hepatitis B, Chronic - prevention & control; Host-parasite relationships; Humans; Hypotheses; Immunity, Cellular - drug effects; Immunity, Cellular - genetics; Immunity, Cellular - immunology; Immunization, Secondary; Liver cancer; Liver cirrhosis; Marmota; Medicine; Mice; Mice, Transgenic; Nucleotide sequencing; Physiological aspects; Prevention; T cell receptors; Vaccines; Vaccines, DNA - genetics; Vaccines, DNA - microbiology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003391

A potent therapeutic T-cell vaccine may be an alternative treatment of chronic hepatitis B virus (HBV) infection. Previously, we developed a DNA prime-adenovirus (AdV) boost vaccination protocol that could elicit strong and specific CD8+ T-cell responses to woodchuck hepatitis virus (WHV) core antigen (WHcAg) in mice. In the present study, we first examined whether this new prime-boost immunization could induce WHcAg-specific T-cell responses and effectively control WHV replication in the WHV-transgenic mouse model. Secondly, we evaluated the therapeutic effect of this new vaccination strategy in chronically WHV-infected woodchucks in combination with a potent antiviral treatment. Immunization of WHV-transgenic mice by DNA prime-AdV boost regimen elicited potent and functional WHcAg-specific CD8+ T-cell response that consequently resulted in the reduction of the WHV load below the detection limit in more than 70% of animals. The combination therapy of entecavir (ETV) treatment and DNA prime-AdV boost immunization in chronic WHV carriers resulted in WHsAg- and WHcAg-specific CD4+ and CD8+ T-cell responses, which were not detectable in ETV-only treated controls. Woodchucks receiving the combination therapy showed a prolonged suppression of WHV replication and lower WHsAg levels compared to controls. Moreover, two of four immunized carriers remained WHV negative after the end of ETV treatment and developed anti-WHs antibodies. These results demonstrate that the combined antiviral and vaccination approach efficiently elicited sustained immunological control of chronic hepadnaviral infection in woodchucks and may be a new promising therapeutic strategy in patients.