Efficacy and Safety of Dual-plasmid Hepatitis B Virus DNA Vaccine in Chronic Hepatitis B Patients

Overview

In order to study the immunotherapeutic effects of electroporation (EP)-mediated dual-plasmids Hepatitis B Virus DNA vaccine, the investigators plan to conduct a double-blind, randomized, placebo-controlled trial, approved by Chinese State Food and Drug Administration with written informed consent from each chronic hepatitis B (CHB) patients with baseline ALT more than 2 times the ULN, for whom antiviral treatment is indicated and who were under the simultaneous lamivudine (LAM) chemotherapy.

Hepatitis B virus (HBV) affects approximately more than 350 million people worldwide, leading to a wide spectrum of clinical manifestations ranging from an asymptomatic carrier state to self-limited acute infection or fulminant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma and poses a serious public health problem in endemic counties like China. Current available therapeutic remedies such as interferons and nucleotide/nucleoside analogues are far from satisfactory, for their therapeutic efficacies are limited by the high economic cost with the less tolerable adverse effects or the lack of viral eradicative effect for its long term control of the virus in most of the patients. Viral persistence has been associated with a defect in the development of HBV-specific cellular immunity. Strategies to boost or to broaden the weak virus-specific T-cell response of patients with chronic hepatitis B have been proposed as a means of curing this persistent infection. HBV envelope- and nucleocapsid-based vaccines, new formulations for recombinant vaccines and DNA-based vaccines are currently being assessed in clinical trials, among which DNA vaccine represents a promising immunotherapeutic approach that can induce T-cell mediated antigen specific immunity, owing to its de novo intracellular antigenic protein expression and synthesis. In clinical trials, although HBV DNA vaccination developed protective antibody responses and antigen-specific CD8 T cells in healthy hepatitis-naive human volunteers, the detectable HBV-specific IFN-γ secreting T cells and decreased serum HBV DNA levels only in some chronic HBV carriers vaccinated with HBV PreS2/S DNA vaccine were limited. One resolution for the main obstacles of the new technique development is to enhance the transfection efficiency of plasmids into host cells; the other is to improve the immunogenicity of DNA vaccine by driving the naïve T cell responses towards the Th1 profile. To tackle the first problem of low transfection rate of DNA vaccine, the investigators had applied the in vivo electroporation (EP) for potency enhancement of HBV DNA vaccine, which dramatically improved the host cell transfection of the plasmids and enabled the DNA vaccine the investigators prepared to elicit both humoral and cellular immune responses in the large body weight animals like rabbit and nonhuman primates. In order to achieve the second goal of immunogenicity improvement of HBV DNA vaccine for its therapeutic usage, the investigators had designed and constructed the Th1 type cytokines (interleukin-2 and interferon-γ) fusion protein expression gene plasmids (pFP), in attempt to direct Th1 bias in favor of cellular immunity augment when being used in combination with HBV DNA vaccine. Both tactics in the form of the dual-plasmids DNA vaccination mediated by EP have been investigated to be safe and efficient to improve the transfection and enhance the immunogenicity of DNA vaccine to the host in both animal models and in phase I,II trials of healthy volunteers and CHB patients. In order to study the immunotherapeutic effects of EP-mediated dual-plasmids HBV DNA vaccine, the investigators plan to conduct a clinical trial, approved by Chinese State Food and Drug Administration (license number: 2006L03542) with written informed consent from each patient. The trial is a double-blind, randomized, placebo-controlled one in CHB patients with baseline ALT more than 2 times the ULN, for whom antiviral treatment is indicated and who were under the simultaneous lamivudine (LAM) chemotherapy.

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