Combination of DNA Prime – Adenovirus Boost Immunization with Entecavir Elicits Sustained Control of Chronic Hepatitis B in the Woodchuck Model

PLoS Pathogens

Jia Liu¹  Thekla Kemper²  Xiaoyong Zhang³  Ulf Dittmer³  Pia L. Seiz⁴  Dieter Glebe⁴  Melanie Fiedler⁴  Oliver Wildner⁴  Anna D. Kosinska⁴  Zhiyong Ma⁴  Ejuan Zhang⁴  Michael Roggendorf⁴  Mengji Lu⁵  Lena Johrden⁶ 

[1] Department of Molecular and Medical Virology, Institute of Microbiology and Hygiene, Ruhr-University Bochum, Bochum, Germany;Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China;Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, Justus-Liebig University, Giessen, Germany;Institute of Virology, University Hospital of Essen, Essen, Germany;Paul-Ehrlich-Institut, Division of Medical Biotechnology, Langen, Germany;Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People's Republic of China

关键词: T cells;    Cytotoxic T cells;    Vaccination;    immunization;    Immune response;    Mouse models;    Antibodies;    DNA replication;    Vaccines;   

DOI  :  10.1371/journal.ppat.1003391

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY