Primary Outcome Measures:
- The occurence and severity of local side-effects
The occurence and severity of systemic side-effects [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
Secondary Outcome Measures:
- The induction of T cell responses (as measured by an interferon-gamma Elispot assay).
Other exploratory cellular immunology assays will be performed as such assays are developed. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
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:
- BCG alone
- MVA85A alone
- 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.