Study of a New MVA Vaccine for Hepatitis C Virus
Condition: Hepatitis C Infection
MeSH terms: Infections; Hepatitis A; Hepatitis C; Hepatitis
Study type: Interventional
Phase: Phase 1

Summary: 
      The study is aimed at assessing the safety of AdCh3NSmut and the new candidate vaccine
      MVA-NSmut when administered sequentially, or alone, to healthy volunteers and patients with
      hepatitis C virus infection The study also aims at assessing the cellular immune response
      generated by AdCh3NSmut and MVA-NSmut administered as mentioned above.
    

Detailed description: 
      The scientific rationale supporting this study can be summarised as follows: 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. Furthermore, mouse and other human models of persistent viral
      infection show that antigen load crucially determines the quality and quantity of the
      anti-viral T cell responses so generated [17-18]. This supports the case for the assessment
      of efficacy of T cell induction, a) in the setting of low viral loads following viral
      suppression with combination therapy, and b) in the setting of high viral loads. Since
      pre-existing anti-vector immunity to adenoviral vectors may limit vaccine efficacy, we have
      conducted a phase-I clinical trial in healthy human subjects using human (Ad6) and simian
      (AdCh3) adenoviral vectors found at low sero-prevalence in human populations, in a
      heterologous prime/boost regimen (study HCV001). The same vectors are also under
      investigation in HCV infected patients (HCV002). These vectors encode the HCV non-structural
      proteins with a genetically inactivated polymerase gene (NSmut). We have shown that both
      vectors are safe and highly immunogenic. In preclinical primate studies using identical
      vectors, heterologous boosting increased peak responses and long-term immunity. However, in
      humans it appears that, although HCV specific T-cell responses increase following boosting,
      the magnitude of this response is reduced compared to that observed during vaccine priming.
      This is probably due to the induction of cross-reactive immunity between the two vectors. In
      contrast, it has recently been shown that Modified Vaccinia Ankara (MVA) encoding the malaria
      antigen ME-TRAP very successfully boosts T-cell responses primed with a simian Adenovirus
      vector, inducing the highest level of CD4+ and CD8+ T-cell responses ever observed using a
      vectored vaccine and affording protection from malaria infection (A. Hill unpublished data).

      For these reasons we now wish to assess an MVA construct encoding HCV NS that will be
      combined with AdCh3NSmut (or AdCh3NSmut1) in a heterologous prime/boost vaccination regimen
      to assess the safety and immunogenicity of this strategy in healthy and HCV infected
      patients. This study will address the following questions: In healthy volunteers:

        1. Can vaccination with MVA-NSmut vector alone safely induce HCV specific T cell responses?

        2. Can vaccination using a heterologous prime/boost vaccination schedule with AdCh3NSmut
           and MVA-NSmut safely induce HCV specific T cell responses?

           In HCV infected patients can a heterologous prime/boost vaccination schedule using
           AdCh3NSmut and MVA-NSmut:

        3. Safely induce HCV specific T cell responses during pegylated-interferon and ribavirin
           (combination) therapy for HCV genotype-1 infection, after a significant decline in viral
           load, 14 weeks into therapy?

        4. Safely induce HCV specific T cell responses during combination therapy for HCV
           genotype-1 infection, 2 weeks into therapy?

        5. Safely induce HCV specific T cell responses in patients with chronic HCV (not receiving
           combination therapy) and a high viral load?

        6. Suppress viral load in patients with chronic HCV, not on treatment with IFN and
           Ribavirin? Since the effect of combination therapy on HCV specific T cells is currently
           debated (see below) we will compare the T cell responses generated by the therapeutic
           prime/boost vaccination schedule in this study, to a group of matched historical control
           patients treated with combination therapy in whom immunological assessment has been made
           in an identical way to that proposed in this study.
    

Intervention name(s): MVA-NSmut; AdCh3NSmut; AdCh3NSmut1
Intervention type(s): Biological; Biological; Biological
Intervention description(s): Genetic vaccine against Hepatitis C virus infection; genetic vaccine against Hepatitis virus infection; genetic vaccine against Hepatitis virus infection
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hepatitis C; vaccine; Adenovirus; MVA; chronic infection; interferon; ribavirin