Safety, Immunogenicity, and Impact of MVA85A, on the Immunogenicity of the EPI Vaccines
Condition: TB
Study type: Interventional
Phase: Phase 1

Summary: 
      This study is preliminary to proving that this vaccine could protect against tuberculosis in
      humans. Although there is no proven data to show that infants will benefit directly from
      participation in this study by being protected against TB, MVA85A protection of mice, guinea
      pigs and monkeys against tuberculosis is encouraging. It is hoped that the information gained
      from this study will contribute to the development of a safe and effective TB vaccine for HIV
      negative and positive individuals. Participants in this study will benefit by having
      information about their general health status, and the rigorous follow up visit that could
      enhance early detection and management of medical conditions that might arise in the course
      of the study.
    

Detailed description: 
      Over the last 3 years Phase I studies with MVA85A allowed for sequential vaccination of
      volunteer groups with a step-wise increase in mycobacterial exposure, to minimize the
      possibility of a Koch reaction. Trials were also conducted sequentially in the UK and The
      Gambia, as there is a greater degree of exposure to both environmental mycobacteria and M.tb
      in The Gambia. 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 has
      now been demonstrated in the mouse model of therapeutic vaccination (Taylor et al, 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 (Taylor et al, 2003).

      In the UK, 14 mycobacterially and BCG naïve, healthy volunteers were vaccinated twice with 5
      x 107pfu MVA85A, administered intradermally at 3 week intervals. MVA85A was found to be safe
      and well tolerated. A single vaccination with MVA85A induced remarkably high levels of
      specific effector T cell responses 1 week after vaccination (mean γ IFN Elispot response to
      PPD was 460 spots per million PBMC). MVA85A was also safe in 17 volunteers vaccinated with
      BCG in the previous 0.5-37 years. The safety profile of MVA85A in these 17 volunteers was the
      same as in the BCG naïve group. Interestingly, these 17 volunteers showed even higher peak
      levels of antigen specific T cells (mean response to PPD was 917 spots per million PBMC) 1
      week post-vaccination than those immunized with MVA85A alone. Perhaps more importantly for
      the induction of T cell memory, these volunteers who were previously BCG vaccinated
      maintained significantly higher levels of antigen specific T cells after MVA85A for up to 24
      weeks after vaccination, when compared to those volunteers vaccinated with either BCG or
      MVA85A alone (McShane et al, 2004). The next trial in the UK looked at the boosting efficacy
      of MVA85A when administered one month after BCG vaccination. 10 healthy, BCG naïve volunteers
      were vaccinated with BCG and one month later were boosted with MVA85A. Safety and boosting
      efficacy was comparable to the previous trial where the interval between BCG and MVA85A was
      0.5-37 years.

      2.3.2 Gambian studies Following the success of the trials with MVA85A in the UK, a
      collaboration with the MRC unit in The Gambia was initiated. MVA85A was first evaluated in
      Phase I clinical trials in BCG naïve subjects (n = 11) and subsequently in BCG primed
      subjects (n=10). In these studies the safety and immunogenicity profile is comparable to that
      seen in the UK studies. In both the UK and The Gambian studies, MVA85A induces 5-10 fold
      higher immune responses than any other recombinant MVA in clinical trials. The most likely
      explanation for this is that the volunteers have some weak pre-existing anti-mycobacterial
      immunity induced by exposure to environmental mycobacteria, and this is being boosted by
      vaccination with MVA85A. When MVA85A is administered to BCG naïve subjects in the Gambia, the
      magnitude and kinetics of response resemble the BCG primed group in the UK, a finding that is
      likely to represent a greater degree of environmental priming in tropical climates.

      Taken together, over 600 people, including HIV positive and over 250 Gambian adults and
      children, have now been immunised with various recombinant MVA investigational vaccines
      including constructs expressing malaria, HIV, hepatitis B and melanoma antigens without
      significant adverse reactions (Hill, unpublished data). Furthermore, 190 children aged 1-5
      years were vaccinated with a recombinant MVA expressing a malarial antigen in 2006, with no
      vaccine related SAEs (Hill, personal communication). This safety data now allows for
      progression to testing MVA85A in a phase II study in infants who have been vaccinated with
      BCG, in a Gambian population which may include low numbers of latently M.tb infected and HIV
      positive children.

      It is important to test the safety, immunogenicity, and possible interference (detrimental,
      none or beneficial) with other EPI vaccines of the MVA85A vaccine in such a group, which is
      one of the potential target populations for a large-scale efficacy study. Also the effects of
      simultaneous EPI vaccine administration on the immunogenicity of MVA85A need to be evaluated.
    

Intervention name(s): MVA 85A
Intervention type(s): Biological
Intervention description(s): intradermal vaccine
Other intervention name(s): TB vaccine; modified vaccinia virus Ankara
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: TB; Tuberculosis; Infants; EPI