A Study of 2 Doses of a New TB Vaccine, MVA85A, in Healthy Volunteers Previously Vaccinated With BCG
Condition: Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 1

Summary: 
      The dose of recombinant MVA used in the TB trials to date is relatively low compared with
      other trials using recombinant MVAs which have used up to 2.5 x 108pfu (A Hill, personal
      communication). Having demonstrated safety and immunogenicity of 5 x 107pfu of MVA85A, we now
      need to perform a dose optimization study, prior to commencing larger scale Phase II and III
      studies in South Africa. We will vaccinate 12 volunteers with a dose half a log lower than
      the dose we are currently using, i.e. 107pfu MVA85A, and 12 volunteers with a dose half a log
      higher, i.e. 108pfu.
    

Detailed description: 
      MVA85A (at a dose of 5 x 107pfu) has been administered to 41 healthy volunteers in the UK and
      17 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, 2004). These volunteers are excluded if their Mantoux test is greater than 15
      millimeters. These studies are ongoing in The Gambia. The group we are currently recruiting
      for on this increasing mycobacterial spectrum are healthy volunteers who are latently
      infected with M.tb.

      Decision matrix for selecting MVA85A dose

        1. If reducing the dose of MVA85A results in reduced immunogenicity, we could use either
           the 5x107 or 108 dose, and would select the lower of these on the grounds of safety.

        2. If increasing the dose of MVA85A increases the incidence of side-effects, we could use
           either the 5x107 or 107 dose, and we would use the higher of these on the grounds of
           immunogenicity.

        3. If increasing the dose of MVA85A results in increased immunogenicity and no increase in
           side-effects, we could use either the 5x107 or 108 dose in subsequent trials

        4. If reducing the dose of MVA85A results in no reduction in immunogenicity we could use
           either the 107 or 5x107 dose in subsequent trials

        5. If all three doses are equally safe and immunogenic we will use either the low or 5x107
           dose.
    

Intervention name(s): MVA 85A
Intervention type(s): Biological
Intervention description(s): i.d. injection
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Tuberculosis; TB; MVA 85A; BCG