Study of the Safety and Immunogenicity of Bacille Calmette Guerin (BCG) Vaccine
Condition: TB
Study type: Interventional
Phase: Phase 1

Summary: 
      Tuberculosis (TB) kills about three million people annually. It is estimated that one third
      of the world's population are latently infected with Mycobacterium tuberculosis (M.tb).
      Multi-drug resistant strains of M.tb, and co-infection with M.tb and HIV present major new
      challenges. The currently available vaccine, M. bovis BCG, is largely ineffective at
      protecting against adult pulmonary disease in endemic areas and it is widely agreed that a
      new more effective tuberculosis vaccine is a major global public health priority1. However,
      it may be unethical and impractical to test and deploy a vaccine strategy that does not
      include BCG, as BCG does confer worthwhile protection against TB meningitis and leprosy. An
      immunisation strategy that includes BCG is also attractive because the populations in which
      this vaccine candidate will need to be tested will already have been immunised with BCG.

      M.tb is an intracellular organism. CD4+ Th1-type cellular responses are essential for
      protection and there is increasing evidence from animal and human studies that CD8+ T cells
      also play a protective role2. However, it has generally been difficult to induce strong
      cellular immune responses in humans using subunit vaccines. DNA vaccines induce both CD4+ and
      CD8+ T cells and thus offer a potential new approach to a TB vaccine. DNA vaccines encoding
      various antigens from M. tuberculosis have been evaluated in the murine model, and to date no
      DNA vaccine alone has been shown to be superior to BCG.

      A heterologous prime-boost immunisation strategy involves giving two different vaccines, each
      encoding the same antigen, several weeks apart. Such regimes are extremely effective at
      inducing a cellular immune response. Using a DNA- prime/MVA-boost immunisation strategy
      induces high levels of CD8+ T cells in animal models of malaria and HIV5, and high levels of
      both CD4+ and CD8+ T cells in animal models of TB. BCG immunisation alone induces only CD4+ T
      cells in mice. A prime-boost strategy using BCG as the prime and a recombinant MVA encoding
      an antigen from M.tb that is also present in BCG (antigen 85A: 'MVA85A') as the boost,
      induces much higher levels of CD4+ T cells than BCG or MVA85A alone. In addition, this regime
      generates specific CD8+ T cells that are undetectable following immunisation with BCG alone.
    

Detailed description: 
      Recombinant viruses as vaccines.

      Recombinant viruses used alone have for some years represented a promising vaccine delivery
      system, particularly for inducing cellular immune responses8. The recombinant virus encodes
      the immunising protein or peptide. Immunisation by a recombinant virus vaccine occurs when
      host cells take up and express the inoculated attenuated virus encoding a protective antigen.
      The expressed protein often has the native conformation, glycosylation, and other
      post-translational modifications that occur during natural infection. Recombinant viral
      vaccines may elicit both antibody and cytotoxic T-lymphocyte responses, which persist without
      further immunisations.

      Many viruses have been investigated as potential recombinant vaccines. The successful
      worldwide eradication of smallpox via vaccination with live vaccinia virus highlighted
      vaccinia as a candidate for recombinant use. The recognition in recent years that
      non-replicating strains of poxvirus such as MVA and avipox vectors can be more immunogenic
      than traditional replicating vaccinia strains has enhanced the attractiveness of this
      approach. MVA (modified vaccinia virus Ankara) is a strain of vaccinia virus which has been
      passaged more than 570 times though avian cells, is replication incompetent in human cell
      lines and has a good safety record. It has been administered to more than 120,000 vaccinees
      as part of the smallpox eradication programme, with no adverse effects, despite the
      deliberate vaccination of high risk groups. This safety in man is consistent with the
      avirulence of MVA in animal models. MVA has six major genomic deletions compared to the
      parental genome severely compromising its ability to replicate in mammalian cells. Viral
      replication is blocked late during infection of cells but importantly viral and recombinant
      protein synthesis is unimpaired even during this abortive infection. Replication-deficient
      recombinant MVA has been seen as an exceptionally safe viral vector. When tested in animal
      model studies recombinant MVAs have been shown to be avirulent, yet protectively immunogenic
      as vaccines against viral diseases and cancer. The most useful data on the safety and
      efficacy of various doses of a recombinant MVA vaccine comes from clinical trial data with a
      recombinant MVA expressing a number of CTL epitopes from Plasmodium falciparum
      pre-erythrocytic antigens fused to a complete pre-erythrocytic stage antigen, Thrombospondin
      Related Adhesion Protein (TRAP). These trials have given a total of 169 immunisations with
      this recombinant MVA, to 49 UK vaccinees 38 Gambian vaccines (20 of whom were children aged
      1-5). 6 doses of 1 x 10^7 pfu, 139 doses of 5 x 10^7 pfu, 6 doses of 1 x 10^8 pfu and 18
      doses of 2.5 x 10^8 pfu have been administered, all without serious adverse effects.

      Recombinant MVA encoding antigen 85A

      Secreted antigens from M. tuberculosis are released from actively metabolising bacteria, and
      are important targets in protective immunity. Antigen 85A is a major secreted antigen from M.
      tuberculosis which forms part of the antigen 85 complex (A, B and C). This complex
      constitutes a major portion of the secreted proteins of both M.tb and BCG. It is involved in
      fibronectin binding within the cell wall and has mycolyltransferase activity.

      MVA85A induces both a CD4+ and a CD8+ epitope when used to immunise mice. When mice are
      primed with BCG and then given MVA85A as a boost, the levels of CD4+ and CD8+ T cells induced
      are higher than with either BCG or MVA85A alone.

      We are evaluating the safety and immunogenicity of the following 3 groups:

        1. BCG alone

        2. MVA85A alone

        3. BCG prime-MVA85A boost

      BCG-BCG provides a control group for BCG-MVA85A. Many countries have a tradition of repeated
      BCG vaccination and the criteria for revaccination differ between countries.
    

Intervention name(s): BCG
Intervention type(s): Biological
Intervention description(s): intradermal injection of 0.1ml BCG over the deltoid muscle
Other intervention name(s): Bacille Calmette-Guerin
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: TB; Tuberculosis; MVA85A; Vaccine; BCG