Simone Backes1, Clemens Jäger1, Claudia J Dembek2, Anna D Kosinska1, Tanja Bauer2, Ann-Sophie Stephan1, Andris Dišlers3, George Mutwiri4, Dirk H Busch5, Lorne A Babiuk6, Georg Gasteiger7, Ulrike Protzer8. 1. Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Trogerstr. 30, 81675 Munich, Germany. 2. 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. 3. Biomedical Research and Study Centre, University of Latvia, 1 Ratsupites Street, LV-1067 Riga, Latvia. 4. 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. 5. 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. 6. University of Alberta, 3-7 University Hall, Edmonton, AB, Canada T6G 2J9. 7. 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. 8. 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.
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.
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 Bpatients for therapeutic vaccination.
Authors: Sheila F Lumley; Anna L McNaughton; Paul Klenerman; Katrina A Lythgoe; Philippa C Matthews Journal: Front Immunol Date: 2018-07-16 Impact factor: 7.561
Authors: Timur O Yarovinsky; Stephen W Mason; Manisha Menon; Marie M Krady; Maria Haslip; Bhaskara R Madina; Xianyong Ma; Safiehkhatoon Moshkani; Carolina Chiale; Anasuya Chattopadhyay Pal; Bijan Almassian; John K Rose; Michael D Robek; Valerian Nakaar Journal: iScience Date: 2019-10-24