Specific Immunotherapy for the Control of Hepatitis B Virus Multiplication

Key Learning Objectives

At the end of the session, the participants will be able to:

  • define the concept of “specific immunotherapy”
  • clearly delineate its potential side effects
  • update the literature on data obtained with current vaccines
  • define new strategies and, in particular, the concept of “DNA vaccination”
  • summarize the data available with DNA vaccines for HBV
  • evaluate the potentials and drawbacks of this approach

Abstract

Despite significant improvements, the treatment of chronic hepatitis due to HBV infection remains insufficient. Several lines of evidences suggest that tolerance to HBV might be, at least in part, abrogated by a specific immunotherapy. Thus, B lymphocytes of HBV chronic carriers have retained their capacity to synthetize anti-HBsAg antibodies. In addition, injection of HBsAg protein to HBV ­ expressing transgenic mice induces a significant reduction in HBV viremia and HBsAg titers, together with anti-HBs detection.

We have previously suggested in a pilot study that vaccination against HBV using a regular, PreS2/S or S-based vaccine, might abolish or significantly lower HBV multiplication in around 30% of patients with HBV-related chronic hepatitis. We will present recent results from a randomized prospective study which confirms the potential of this approach.

We have indeed comparatively evaluated the efficacy of six injections of the Genevac B (PreS2/S), the Recombivac (S). We were able to demonstrate that three injections of either PreS2/S or S-based vaccines were sufficient to abolish serum HBV DNA detection in 13/84 patients, compared to only 1/37 unvaccinated controls (p=0.04). In addition, anti-HBe seroconversion was only observed after 6-month follow-up in the vaccinated patients.

Finally we were able to demonstrate induction of a PreS/S specific T cell proliferation upon vaccination. Thus, collectively, these data pave the way for the use of immunotherapy for the treatment of HBV infection.

Still, the currently available recombinant vaccines show a too limited efficacy. These results therefore, stimulate the development of new approaches to achieve a more efficient and durable immunotherapy.

Beside the use of PreS1/S2/S-based vaccines which are now evaluated, DNA vaccination shows great promise and is currently being evaluated for HIV. DNA vaccination against HBV is based on the direct in vivo expression of HBsAg from a recombinant plasmid injected intramuscularly. Several studies, performed in mice and primates have demonstrated the capacity of such constructs to induce both humoral and cellular immune (in particular Th1) responses to the viral antigen. This efficacy is due to the neosynthesis of viral peptides from the injected plasmids. The production of anti-HBs has been shown to be stable after an 18 month follow-up and this humoral immune response does mimic that observed during natural infection. On the same line, injection of a 10 microgram dose of HBsAg encoding plasmid to BALB/c mice induces, for at least 12 weeks, a cytotoxic T cell response. Studies in ducks and woodchucks infected with the Hepadnaviruses DHBV and WHV, respectively, have confirmed the potential of this approach by showing protection against viral challenge and induction of specific neutralizing antibodies. Experiments performed in macaques have confirmed the possibility to induce a humoral and immune response to HBV and thus prompt clinical evaluation of this strategy.

There is so far no evidence for side-effects specific to this therapeutic approach and clinical studies are now initiated to thoroughly evaluate the actual clinical relevance of this elegant treatment option in humans.

Christian Bréchot, MD, PhD

Professor Cell Biology/Hepatology

References

  • Davis HL, McCluskie MJ, Gerin JL, Purcell RH. DNA vaccine for hepatitis B: evidence for immno-genicity in chimpanzees and comparison with other vaccines. Proc Natl Acad Sci USA 1996;93:7213-8.
  • Davis HL, Michel ML, Mancini M, Schleef M, Whalen RG. Direct gene transfer in skeletal muscle: plasmid DNA-based immunization against the hepatitis B virus surface antigen. Vaccine 1994;12:1503-9.
  • Geissler M, Tokushige K, Wakita T, Zurawski VR Jr, Wands JR. Differential cellular and humoral immune responses to HCV core and HBV envelope proteins after genetic immunizations using chimeric constructs. Vaccine 1998;16:857-67.
  • Le Borgne S. Mancini M, Le Grand R, Schleef M, Dormont D, Tiollais P, et al. In vivo induction of specific cytotoxic T lymphocytes in mice and rhesus macaques immunized with DNA vector encoding an HIV epitope fused with hepatitis B surface antigen. Virology 1998;240:304-15.
  • Mancini M, Hadchouel M, Davis HL, Whalen RG, Tiollias P, Michel ML. DNA-mediated immunization in a transgenic mouse model of the hepatitis B surface antigen chronic carrier state. Proc Natl Acad Sci USA 1996;93:12496-501

 

 

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