title: Combination of DNA prime--adenovirus boost immunization with entecavir elicits sustained control of chronic hepatitis B in the woodchuck model.
abstract: 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.
authors.affiliation: Institute of Virology, University Hospital of Essen, Essen, Germany.
authors.forename: Anna D
authors.initials: AD
authors.lastname: Kosinska
authors.forename: Ejuan
authors.initials: E
authors.lastname: Zhang
authors.forename: Lena
authors.initials: L
authors.lastname: Johrden
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Pia L
authors.initials: PL
authors.lastname: Seiz
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Ma
authors.forename: Thekla
authors.initials: T
authors.lastname: Kemper
authors.forename: Melanie
authors.initials: M
authors.lastname: Fiedler
authors.forename: Dieter
authors.initials: D
authors.lastname: Glebe
authors.forename: Oliver
authors.initials: O
authors.lastname: Wildner
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
authors.forename: Michael
authors.initials: M
authors.lastname: Roggendorf
mesh_terms: D000256:Adenoviridae; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D017325:Hepatitis B Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D007117:Immunization, Secondary; D008392:Marmota; D051379:Mice; D008822:Mice, Transgenic; D019444:Vaccines, DNA / Q000235:genetics / Q000382:microbiology*
chemical_list: D017325:Hepatitis B Vaccines; D019444:Vaccines, DNA