Protein-prime/modified vaccinia virus Ankara vector-boost vaccination overcomes tolerance in high-antigenemic HBV-transgenic mice

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• 作者：Simone Backes^a ; ¹ ; ² ; Clemens J&auml ; ger^a ; ² ; Claudia J. Dembek^a ; ^b ; Anna D. Kosinska^a ; Tanja Bauer^a ; ^b ; Ann-Sophie Stephan^a ; Andris Di&scaron ; lers^c ; George Mutwiri^d ; ^e ; Dirk H. Busch^b ; ^f ; ^g ; Lorne A. Babiuk^h ; Georg Gasteiger^a ; ^g ; ¹ ; Ulrike Protzer^a ; ^b ; ^g ; ^{protzer@helmholtz-muenchen.de" class="auth_mail" title="E-mail the corresponding author} ; ^{protzer@tum.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Hepatitis B virus ; Therapeutic vaccination ; Tolerance ; Heterologous prime/boost strategy ; Recombinant MVA
• 刊名：Vaccine
• 出版年：2016
• 出版时间：10 February 2016
• 年：2016
• 卷：34
• 期：7
• 页码：923-932
• 全文大小：2006 K

文摘

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

spar0010">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

spar0015">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

spar0020">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.