title: Protein-prime/modified vaccinia virus Ankara vector-boost vaccination overcomes tolerance in high-antigenemic HBV-transgenic mice.
abstract: BACKGROUND
  Therapeutic vaccination is a novel treatment approach for chronic hepatitis B, but only had limited success so far. We hypothesized that optimized vaccination schemes have increased immunogenicity, and aimed at increasing therapeutic hepatitis B vaccine efficacy.
  
  
  METHODS
  Modified Vaccinia virus Ankara (MVA) expressing hepatitis B virus (HBV) antigens was used to boost protein-prime vaccinations in wildtype and HBV-transgenic (HBVtg) mice.
  
  
  RESULTS
  Protein-prime/MVA-boost vaccination was able to overcome HBV-specific tolerance in HBVtg mice with low and medium but not with high antigenemia. HBV-specific antibody titers, CD8+ T-cell frequencies and polyfunctionality inversely correlated with HBV antigen levels. However, optimization of the adjuvant formulation, increasing the level of antigen expression and utilization of HBsAg of heterologous subtype induced HBV-specific CD8+ and CD4+ T-cells and neutralizing antibodies even in high-antigenemic HBVtg mice.
  
  
  CONCLUSIONS
  Our results indicate that high HBV antigen levels limit the immunological responsiveness to therapeutic vaccination but optimization of the vaccine formulation can overcome tolerance even in the presence of high antigenemia. These findings have important implications for the development of future therapeutic hepatitis B vaccination strategies and potentially also for the stratification of chronic hepatitis B patients for therapeutic vaccination.
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Trogerstr. 30, 81675 Munich, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Backes
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Trogerstr. 30, 81675 Munich, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Jäger
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Trogerstr. 30, 81675 Munich, Germany; German Center for Infection Research (DZIF), Munich Site, 81675 Munich, Germany.
authors.forename: Claudia J
authors.initials: CJ
authors.lastname: Dembek
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Trogerstr. 30, 81675 Munich, Germany.
authors.forename: Anna D
authors.initials: AD
authors.lastname: Kosinska
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Trogerstr. 30, 81675 Munich, Germany; German Center for Infection Research (DZIF), Munich Site, 81675 Munich, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Bauer
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Trogerstr. 30, 81675 Munich, Germany.
authors.forename: Ann-Sophie
authors.initials: AS
authors.lastname: Stephan
authors.affiliation: Biomedical Research and Study Centre, University of Latvia, 1 Ratsupites Street, LV-1067 Riga, Latvia.
authors.forename: Andris
authors.initials: A
authors.lastname: Dišlers
authors.affiliation: Vaccinology and Immunotherapeutics, School of Public Health, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E3; Vaccine and Infectious Disease Organization-International Vaccine Centre, University of Saskatchewan, 120 Veterinary Road, Saskatoon, SK, Canada S7N 5E3.
authors.forename: George
authors.initials: G
authors.lastname: Mutwiri
authors.affiliation: German Center for Infection Research (DZIF), Munich Site, 81675 Munich, Germany; Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität München, Trogerstr. 30, 81675 Munich, Germany; Clinical Cooperation Group Antigen Specific Immunotherapy and Immune Monitoring, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.affiliation: University of Alberta, 3-7 University Hall, Edmonton, AB, Canada T6G 2J9.
authors.forename: Lorne A
authors.initials: LA
authors.lastname: Babiuk
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Trogerstr. 30, 81675 Munich, Germany; Clinical Cooperation Group Antigen Specific Immunotherapy and Immune Monitoring, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Gasteiger
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Trogerstr. 30, 81675 Munich, Germany; German Center for Infection Research (DZIF), Munich Site, 81675 Munich, Germany; Clinical Cooperation Group Antigen Specific Immunotherapy and Immune Monitoring, Helmholtz Zentrum München, Munich, Germany. Electronic address: protzer@helmholtz-muenchen.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Protzer
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006509:Hepatitis B / Q000517:prevention & control*; D006510:Hepatitis B Antibodies / Q000097:blood; D006512:Hepatitis B Core Antigens / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000097:blood / Q000276:immunology; D017325:Hepatitis B Vaccines / Q000276:immunology*; D006513:Hepatitis B e Antigens / Q000097:blood; D007108:Immune Tolerance; D007117:Immunization, Secondary; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009500:Neutralization Tests; D014616:Vaccinia virus
chemical_list: D057134:Antibodies, Neutralizing; D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D006513:Hepatitis B e Antigens
keywords: Hepatitis B virus; Heterologous prime/boost strategy; Recombinant MVA; Therapeutic vaccination; Tolerance