Therapeutic vaccination of chronic hepatitis B patients with virus suppression by antiviral therapy: A randomized, controlled study of co-administration of HBsAg/AS02 candidate vaccine and lamivudine

Vandepapelière, Pierre; Lau, George; Leroux‐Roels, Geert; Horsmans, Yves; Gane, Edward; Tawandee, Tawesak; Merican, M. I.; Win, Khin Maung; Trépo, Christian; Cooksley, Graham; Wettendorff, Martine; Ferrari, Carlo

doi:10.1016/j.vaccine.2007.09.072

Cited by 162 publications

(122 citation statements)

References 57 publications

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“…On one hand, combining HBsAg vaccine with an immunostimulator, such as CpG, exhibited improved efficacy to break HBV tolerance via Th1-biased mechanisms (14). On the other hand, combining HBsAg vaccine with an antiviral agent, including lamivudine, was favored in other trials, because HBV-specific T cell hyporesponsiveness during CHB infection always correlated with high viral load (15). However, neither approach was completely effective in the clinic, suggesting the possibility that an agent possessing both immunostimulatory and antiviral effects could optimize vaccination therapy in combination with a vaccine.…”

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confidence: 99%

IL-12–Based Vaccination Therapy Reverses Liver-Induced Systemic Tolerance in a Mouse Model of Hepatitis B Virus Carrier

Zeng

Kong

et al. 2013

The Journal of Immunology

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Liver-induced systemic immune tolerance that occurs during chronic hepadnavirus infection is the biggest obstacle for effective viral clearance. Immunotherapeutic reversal of this tolerance is a promising strategy in the clinic but remains to be explored. In this study, using a hepatitis B virus (HBV)-carrier mouse model, we report that IL-12–based vaccination therapy can efficiently reverse systemic tolerance toward HBV. HBV-carrier mice lost responsiveness to hepatitis B surface Ag (HBsAg) vaccination, and IL-12 alone could not reverse this liver-induced immune tolerance. However, after IL-12–based vaccination therapy, the majority of treated mice became HBsAg− in serum; hepatitis B core Ag was also undetectable in hepatocytes. HBV clearance was dependent on HBsAg vaccine-induced anti-HBV immunity. Further results showed that IL-12–based vaccination therapy strongly enhanced hepatic HBV-specific CD8+ T cell responses, including proliferation and IFN-γ secretion. Systemic HBV-specific CD4+ T cell responses were also restored in HBV-carrier mice, leading to the arousal of HBsAg-specific follicular Th–germinal center B cell responses and anti–hepatitis B surface Ag Ab production. Recovery of HBsAg-specific responses also correlated with both reduced CD4+Foxp3+ regulatory T cell frequency and an enhanced capacity of effector T cells to overcome inhibition by regulatory T cells. In conclusion, IL-12–based vaccination therapy may reverse liver-induced immune tolerance toward HBV by restoring systemic HBV-specific CD4+ T cell responses, eliciting robust hepatic HBV-specific CD8+ T cell responses, and facilitating the generation of HBsAg-specific humoral immunity; thus, this therapy may become a viable approach to treating patients with chronic hepatitis B.

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confidence: 99%

IL-12–Based Vaccination Therapy Reverses Liver-Induced Systemic Tolerance in a Mouse Model of Hepatitis B Virus Carrier

Zeng

Kong

et al. 2013

The Journal of Immunology

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“…Therapy with interferon or nucleoside/tide analogs is not satisfactory due to the low responder rate and resistance development (16,18,20,33). To date, immunotherapy against chronic hepatitis B has not yet achieved satisfactory results (7,14,17,31,32,41,44). Given the crucial role of cytotoxic T lymphocytes in the control of HBV infections, new therapeutic vaccines with the ability to stimulate vigorous, broad HBV-specific cytotoxic T lymphocyte responses are needed (3,11,26,38,39).…”

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confidence: 99%

Combination of an Antiviral Drug and Immunomodulation against Hepadnaviral Infection in the Woodchuck Model

Yao

et al. 2008

J Virol

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Approximately 400 million people worldwide are chronically infected with hepatitis B virus (HBV). Therapy with interferon or nucleoside/tide analogs is not satisfactory due to the low responder rate and resistance development (16,18,20,33). To date, immunotherapy against chronic hepatitis B has not yet achieved satisfactory results (7,14,17,31,32,41,44). Given the crucial role of cytotoxic T lymphocytes in the control of HBV infections, new therapeutic vaccines with the ability to stimulate vigorous, broad HBV-specific cytotoxic T lymphocyte responses are needed (3,11,26,38,39).Several studies of therapeutic vaccinations have been carried out in the woodchuck model (reviewed in references 24, 25, 34, and 35) and demonstrated collectively that B-or T-cell responses to viral antigens could be induced in chronic woodchuck hepatitis virus (WHV) carriers (12,13,23,30). Yet, none of these studies have demonstrated the capability of vaccines to suppress viral replication. Here, we carried out a proof-of-principle experiment using DNA vaccines alone and DNA vaccines combined with immune complexes (IC) in the woodchuck model. IC of HBsAg and anti-HBs have been tested in patients and in transgenic mice (42,43,45,46). IC are more efficiently taken up by antigen-presenting cells than free antigens, leading to an improved presentation to T cells. DNA vaccines are potent inducers of T-cell responses. They could stimulate HBV-specific immune responses in humans and prevent hepadnaviral infections in the animal model (21,22,37). In addition, woodchucks were pretreated with lamivudine, a potent antiviral drug against HBV with the ability to enhance T-cell responses in chronically HBV-infected patients (1, 2).A total of 10 chronically WHV-infected woodchucks (from Northeastern Wildlife, Ithaca, NY) were first treated with 15 mg of lamivudine daily and randomly divided into three groups: the control group (n ϭ 2), a group vaccinated with WHV surface antigen (WHsAg)-IC and DNA (n ϭ 4), and a group vaccinated with DNA (n ϭ 4). The immunization schedule is presented in Fig. 1.The DNA vaccines consisted of an equimolar mixture of three plasmids, pWHsIm, pWHcIm, and pWIFN, expressing WHsAg, WHV core antigen (WHcAg), and woodchuck gamma interferon, respectively, as described previously (21, 37). To produce IC for woodchucks, antibodies to WHs (antiWHs) and WHsAg were titrated by the checkerboard method to determine the stoichiometry of the antigen and antibodies. The appropriate concentration of WHsAg was chosen and incubated with antibodies at 37°C for 30 min and then incubated overnight at 4°C, resulting in a preparation with a final concentration of 80 g WHsAg/ml in complex with anti-WHs. The vaccine consisted of 20 g WHsAg-IC and 250 g plasmid pWHsIm DNA per 0.5-ml dose. The DNA vaccines and IC-DNA vaccines were administered by intramuscular injections (21,22).The following parameters were determined by the indicated methods: serum WHV DNA concentrations as genome equivalents (GE) by real-time PCR with the LightCycler DNA Master S...

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“…The patients who received the combination therapy showed a greater reduction in HBV DNA than those who received IFN--2b monotherapy. Vandepapelière et al, 2007; In HBeAg-positive CHB patients, the combination with lamivudune and vaccine on the base of surface antigen with adjuvant did not improve the HBe seroconversion rate in comparison with lamivudine therapy alone. Senturk et al, 2009; CHB patients who were treated with lamivudine and vaccine on the base of surface antigen showed sustained negativity of HBV DNA in 1/4 of the treated patients.…”

Section: Immunotherapy For Viral Hepatitismentioning

confidence: 92%

Immunopathogenesis and Immunotherapy for Viral Hepatitis

Shimizu¹

2011

Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics

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Therapeutic vaccination of chronic hepatitis B patients with virus suppression by antiviral therapy: A randomized, controlled study of co-administration of HBsAg/AS02 candidate vaccine and lamivudine

Cited by 162 publications

References 57 publications

IL-12–Based Vaccination Therapy Reverses Liver-Induced Systemic Tolerance in a Mouse Model of Hepatitis B Virus Carrier

IL-12–Based Vaccination Therapy Reverses Liver-Induced Systemic Tolerance in a Mouse Model of Hepatitis B Virus Carrier

Combination of an Antiviral Drug and Immunomodulation against Hepadnaviral Infection in the Woodchuck Model

Immunopathogenesis and Immunotherapy for Viral Hepatitis

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