Study of a Novel Therapeutic Vaccine Against Hepatitis C Using Ad6NSmut and MVA-NSmut in Chronically Infected Patients
Condition: Hepatitis C
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to determine whether administration of recombinant IMPs Ad6NSmut
      and MVA-NSmut (experimental vaccines for hepatitis C) in HCV chronically infected patients in
      combination with the standard Interferon/ribavirin therapy is safe and induces an
      immunological response.
    

Detailed description: 
      An effective antiviral T cell response can mediate HCV viral control and induce the
      spontaneous resolution of HCV during primary infection. This observation strongly supports
      the case for the development of T cell induction strategies as a potential therapy for HCV. A
      hallmark of persistent HCV infection, when viral loads are high, is a weak and narrowly
      focused HCV specific T cell response, whereas in resolved infection with undetectable viral
      loads robust T cell responses are detected. A very potent immunization strategy might
      overcome this problem and induce a strong and diversified cell mediated immune response
      against HCV.

      The rationale of using HCV vaccine in combination with PEG-IFN/RBV is supported both, by in
      vitro models and by mathematical models of HCV dynamics under antiviral therapy. Studies of
      viral dynamics suggested that HCV RNA kinetics result from the sum of two major actions or
      phases: inhibition of viral production and reduction of infected cells number. The
      mathematical model, relying on both HCV-RNA and alanine aminotransferase (ALT) measures after
      PEG-IFN/RBV therapy, suggests that the elimination of infected cells by the immune system
      could play a major role in sustaining viral reduction. This view is in accordance with the
      results of a recent study showing that IFN-γ, one of the cytokines secreted by CTLs
      (Cytotoxic T Lymphocyte) and NK (Natural Killer) cells, is able to inhibit HCV genomic and
      subgenomic replication in an "in vitro" model. In the mathematical description the parameter
      that represents the putative "non lytic" control of HCV replication during antiviral therapy
      is φ, resulting from the difference π-δ0, where π and δ0 are the time constant of the second
      phase decay of viraemia and of the infected cells, respectively. Interestingly, the median
      value of parameter φ, which is inversely related to the half-life of HCV-RNA molecules in the
      infected cells after phase 1, was significantly higher in sustained responders than in
      transient responders and non responders (NR). In addition, whereas the baseline HCV-RNA
      production was comparable in all patients regardless of their outcome, the median value of
      the residual HCV-RNA production during therapy was significantly higher in NR than in
      responders. This data support the hypothesis that to reach a sustained response and an
      efficacious control of the infection, the elimination of the infected cells is more relevant
      than a strong inhibition of viral production. All the above considerations support the
      hypothesis that vaccination might be a new therapeutic opportunity to a cohort of consecutive
      HCV genotype 1a and 1b infected patients who failed to respond to PEG-IFN/RBV therapy.
      Therefore a potent induction of T cell responses in chronically infected patients might be
      used in combination with the current antiviral therapy in order to achieve sustained response
      in previously partial responders or relapsers.
    

Intervention name(s): Ad6NSmut, MVA-NSmut
Intervention type(s): Biological
Intervention description(s): 2 doses Ad6NSmut at week 0 and 4, then 2 doses of MVA-NSmut at weeks 8 and 12. PEG-IFN/RBV therapy starts at week 10 after first vaccination
Other intervention name(s): Ad6NSmut; MVA-NSmut
Intervention MeSH terms: Cloricromen
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hepatitis; Hepatitis C; HCV; vaccine; adenovirus; MVA; T cells; ELISpot