Safety and Immunogenicity of MVA85A in Volunteers Latently Infected With TB.
Condition: Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 1

Summary: 
      This study is designed to evaluate the safety of MVA85A in healthy volunteers in the UK who
      are latently infected with M.tb. A single vaccination with MVA85A, when administeredat a dose
      of 5 x 107pfu intradermally, is safe in both mycobacterially naïve individuals and those
      previously vaccinated with BCG. We will use the same vaccination regime in this study.
      Subjects will be defined as being latently infected if they have a positive elispot response
      to ESAT6 or CFP10. Subjects will be identified from TB contact clinics.
    

Detailed description: 
      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) (Dye,
      1999). These latently infected individuals are at risk of reactivation of infection, should
      they become immunosuppressed. Worldwide, coinfection with HIV is the commonest cause of
      immunosuppression and increases the chances of reactivation from a 10% lifetime risk to a 10%
      annual risk (Corbett, 1996). 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
      priority (Colditz, 1994). 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. Given the high prevalence of infection with M.tb, a vaccine
      that could be administered to latently infected individuals and eradicate latent infection
      would have an enormous impact on the mortality and morbidity from TB.

      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 role (Flynn, 2001). However, it has generally been difficult to induce
      strong cellular immune responses in humans using subunit vaccines. DNA vaccines, recombinant
      viral vectors and protein/adjuvant combinations all induce both CD4+ and CD8+ T cells,
      however none of these antigen delivery systems induce high levels of antigen specific T
      cells, when used alone. Heterologous prime-boost immunisation strategies involves giving two
      different vaccines, each encoding the same antigen, several weeks apart. Using a DNA
      prime-recombinant modified vaccinia virus Ankara (MVA) boost induces higher levels of antigen
      specific CD4+ and CD8+ T cells than using homologous boosting with the same vector in a
      number of different disease models (Schneider, 1998; McShane, 2001). Given the protective
      efficacy of BCG in childhood, ideally BCG would be the priming immunisation in such a
      prime-boost strategy. In order to do this, we have focused on antigen 85A as a candidate
      antigen.

      Antigen 85A is highly conserved amongst all mycobacterial species and is present in all
      strains of BCG. 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. Antigen 85A is immunodominant in murine and human
      studies and is protective in small animals (Huygen, 1996). Recombinant modified vaccinia
      virus Ankara (rMVA). 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
      nonreplicating 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 (Stickl, 1974; Mahnel, 1994). 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 (Meher, 1991). No replication has been documented in nontransformed 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. The viral
      genome has been proven to be stable through a large series of passages in chicken embryo
      fibroblasts. 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. Recent
      studies in severely immuno-suppressed macaques have supported the view that MVA should be
      safe in immuno-compromised humans (Akira, 2001; Stittelaar, 2001). There is now safety data
      from a number of recombinant MVAs that are currently in Phase I/II trials in both the UK and
      Africa. 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). To date MVA ME-TRAP has been
      administered to over 250 healthy volunteers in Oxford and The Gambia without any serious
      adverse events (Adrian Hill, personal communication). Volunteers have received one to three
      doses of from 3 to 15 x 107 pfu per dose of intra-dermal vaccine at three-week intervals. All
      subjects have temporary local redness with typically a 5mm central red area with a paler pink
      surrounding area that ranges in size from about 1 -7cm in diameter and peaks at 48 hours post
      vaccination. At seven days post vaccination generally only the central red area remains. This
      fades over the next few weeks and is usually not apparent at 2 months after vaccination. The
      emerging safety profile of recombinant MVA vaccine is supported by data from clinical studies
      of three other MVA recombinants made in Oxford and currently in clinical studies using MVAs
      for HIV, HBV and melanoma. Recombinant MVA encoding antigen 85A 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, and this regime is more protective than either vaccine alone
      (Goonetilleke et al, 2003). In the more sensitive guinea pig model, guinea pigs vaccinated
      with BCG, and then MVA85A, and then a second viral vector, fowlpox expressing antigen 85A,
      6/6 guinea pigs are alive at the end of the experiment, compared with 2/6 guinea pigs
      vaccinated with BCG alone, and 0/6 control animals (Williams et al, submitted). In rhesus
      macaques, this BCG prime-MVA85A and Fowlpox85A boost is more immunogenic than any of the
      vaccines alone. Clinical studies using MVA85A MVA85A (at a dose of 5 x 107pfu) has been
      administered to 40 healthy volunteers in the UK and 15 healthy volunteers in The Gambia, with
      no serious adverse events. We have designed our Phase I studies to allow for a vaccination of
      volunteer groups sequentially with a step-wise increase in mycobacterial exposure, in order
      to minimize the possibility of a Koch reaction. A Koch reaction describes the development of
      immunopathology in a person or animal with tuberculosis, when an exaggerated immune response
      to M.tb is stimulated. It was described in patients with TB disease when Koch performed his
      original studies employing mycobacteria as a type of therapeutic vaccination. It has now been
      demonstrated in the mouse model of therapeutic vaccination (Taylor, 2003). Available animal
      data suggest that these reactions do not occur in mice latently infected with M.tb,
      suggesting that such reactions may correlate with high bacterial load and that the Koch
      phenomenon may not pose a problem for vaccination of healthy albeit latently infected humans.
      We started these studies in healthy volunteers who were as mycobacterially naïve as possible.
      They were skin test negative and Elispot negative for PPD, ESAT 6 and CFP10, and had not had
      previously been vaccinated with BCG. We have now completed studies in the UK vaccinating
      volunteers previously vaccinated with BCG (McShane, submitted). These volunteers are excluded
      if their Heaf test is greater than grade II. These studies are ongoing in The Gambia. The
      next group we then plan to vaccinate on this increasing mycobacterial spectrum are healthy
      volunteers who are latently infected with M.tb. Rationale This study is designed to evaluate
      the safety of MVA85A in healthy volunteers in the UK who are latently infected with M.tb. A
      single vaccination with MVA85A, when administered at a dose of 5 x 107pfu intradermally, is
      safe in both mycobacterially naïve individuals and those previously vaccinated with BCG. We
      will use the same vaccination regime in this study. Subjects will be defined as being
      latently infected if they have a positive elispot response to ESAT6 or CFP10. Subjects will
      be identified from TB contact clinics.
    

Intervention name(s): MVA 85A
Intervention type(s): Biological
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Tuberculosis; Latent; TB; Vaccine; MVA 85A