The Safety and Immunogenicity of a TB Vaccine; MVA85A, in Healthy Volunteers Who Are Infected With HIV
Condition: Tuberculosis; HIV Infections
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 infected with HIV. In phase I studies, a single vaccination with MVA85A, when
      administered at a dose of 5 x 10^7pfu intradermally, has been shown to be safe in both
      mycobacterially naïve individuals, those previously vaccinated with BCG and latently infected
      individuals. Additionally, 5 x 10^7 pfu MVA containing HIV antigens administered twice, 4
      weeks apart, in HIV positive individuals, is safe. We will use 5 x 107 pfu MVA85A
      intradermally in this study. Subjects will be identified from HIV clinics in the Oxford
      Radcliffe Hospitals NHS Trust and also from Swindon and Marlborough NHS Trust and St. Mary's
      Hospital NHS Trust if our recruitment targets are not met.
    

Detailed description: 
      The need for new vaccine against tuberculosis 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 involve 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 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 (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 non- transformed 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 600
      healthy volunteers (adults and children) in Oxford and Africa (The Gambia and Kenya) without
      any serious adverse events (Adrian Hill, unpublished, 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 excellent and 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. To date these vaccines have been administered to over 600 people with no serious
      adverse events (Hill; personal communication) 40 HIV positive individuals treated with highly
      active anti-retroviral therapy (HAART) have been vaccinated with at least 5 x 107 PFU MVA
      containing HIV antigens with no serious adverse events (Dorrell, unpublished data; Cosma et
      al 2003; Harrer et al, 2005). 7 HIV positive individuals have been vaccinated with MVA
      containing malaria antigens with no serious adverse events and no significant or sustained
      rise in viral load (Bejon at al, CID 2006, in press).

      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, 2005).

      In rhesus macaques, this BCG prime-MVA85A and Fowlpox85A boost is more immunogenic than any
      of the vaccines alone, and is more protective than BCG alone (verrek et al, unpublished
      data).

      Clinical studies using MVA85A MVA85A (at a dose of 5 x 107pfu) has been administered to 48
      healthy volunteers in the UK, 21 healthy volunteers in The Gambia and 18 in South Africa,
      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, Nature Med,
      2004) and in The Gambia.

      There are two ongoing studies in Oxford. The first is a phase I trial of the safety and
      immunogenicity of MVA85A in individuals who are latently infected with M.tb. We have now
      vaccinated all 12 volunteers with no serious adverse events. The second is a dose selection
      study evaluating the safety and immunogenicity of 2 different doses of MVA85A (1x10^8 and
      1x10^7 pfu), in healthy adult volunteers who have previously been vaccinated with BCG. Here
      we have vaccinated 11 individuals with the higher dose (1x10^8) with no serious adverse
      events, the main side effect being a fever at 24-48 hours post-vaccination, which completely
      resolves over 24 hours. Results from the low dose arm will be collected over the next few
      months.
    

Intervention name(s): MVA85A (TB vaccine); MVA 85A
Intervention type(s): Biological; Biological
Intervention description(s): Intradermal vaccine; Intradermal vaccine
Other intervention name(s): TB vaccine; TB Vaccine; modified vaccinia virus Ankara
Intervention MeSH terms: Vaccines
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: TB; Tuberculosis; HIV; Vaccine; MVA85A; HIV Therapeutic Vaccine