01 DNA immunisation for HBV infections

M.L. Michel.UREG/INSERM U163 Institut Pasteur, Paris, France

Chronic liver disease and hepatocellular carcinoma associated with chronic hepatitis B virus (HBV) infection are among the most serious human health problems in highly endemic regions. Current therapeutic approaches to control chronic hepatitis such as interferon-alpha and lamivudine are unsatisfactory. Vaccination would be the therapeutic procedure with the lowest cost and the potentially greatest benefit. The immunogenicity of selected HBV envelope or capsid based vaccine formulations for the induction or the broadening of T and B cell responses, deficient in HBV chronic carriers, are currently under study in animal models and in clinical trials.

DNA based or genetic vaccination is an efficient new technique to stimulate specific immune responses after in vivo delivery of bacterial plasmids encoding antigens. Systemic immunisation of mice by intramuscular injection of plasmid DNA expressing HBV envelope proteins and HBV surface antigen (HBsAg) induces rapid, strong and sustained humoral and cell-mediated immune responses. Antibodies, which are initially of the IgM then IgG isotype (predominantly IgG2a), recognise several of the B cell epitopes present on the S, preS2, or preS1 domains of the envelope proteins. High titres of anti-HBs are present by 4–8 weeks and persist for at least 17 months after a single DNA injection, although they can be boosted ten-fold by a second injection of DNA, or somewhat less, by injection of a recombinant HBsAg protein. A strong cellular immune response is induced by the DNA based immunisation with high level of CTL and CTL precursors being detected by one week and being maintained for several months. DNA vaccine also acts as its own adjuvant owing to the presence of bacterial immunostimulatory CpG motifs. Such sequences present in the plasmid backbone promote a Th1 like pattern of cytokine production dominated by IL-12 and IFN-γ with little secretion …