A Phase II Study Evaluating the Safety and Immunogenicity of a New TB Vaccine, MVA85A, in Healthy Children and Infants After BCG Vaccination at Birth

M.tb is an intracellular organism and protective immunity is dependent on an intact cellular immune system. Both Class II-restricted CD4+ and Class I-restricted CD8+ T lymphocytes are important for protection. Gamma delta cells and non-classically restricted T cells such as CD1-restricted T cells may also play a protective role but knowledge of how to induce these to protective levels by vaccination is very limited. Although several vaccine delivery systems are capable of inducing T cells, e.g. protein/adjuvant combinations, DNA vaccines and recombinant viral vectors, when used alone these delivery systems induce only low-level responses. Heterologous prime-boost immunisation strategies involve immunizing with 2 two different vaccines, each expressing the same antigen, several weeks apart. These strategies induce higher levels of CD4+ and CD8+ T cells than homologous boosting in animal models of malaria, HIV and TB.

Recombinant modified vaccinia virus Ankara expressing antigen 85A (MVA85A). When used in heterologous prime-boost strategies, some viral vectors are very good at boosting previously primed T cell responses, particularly recombinant adenoviral constructs and recombinant pox viruses. Modified vaccinia virus Ankara (MVA) is an attenuated strain of vaccinia virus that has been passaged more than 500 times through chick embryo fibroblasts and as a consequence has lost both host range genes and cytokine receptor genes. MVA has an excellent safety record, as it was used to vaccinate more than 120,000 people at the end of the smallpox eradication campaign, with no serious adverse events. In humans, several hundred HIV negative volunteers have now been immunized with recombinant MVAs expressing a number of different antigens, with no serious adverse events. A recombinant MVA expressing an antigen from Plasmodium falciparum has been demonstrated to boost CD4+ and CD8+ T cells in humans. Recombinant MVAs are now in clinical trials for several infectious diseases including HIV, hepatitis B and malaria. Importantly, for a new TB vaccine, the safety of MVA as a viral vector has now been demonstrated in HIV positive patients.

Including BCG in such heterologous prime-boost regimes allows for the beneficial effects of BCG to be retained. We have developed an immunisation strategy using BCG as the priming immunisation and a recombinant MVA (rMVA) as the boost. The antigen selected for inclusion in the rMVA must be present in all strains of BCG. We have selected Antigen 85A, which forms part of the immunodominant antigen 85 complex. Although there are numerous candidate antigens for use in a TB vaccine, antigen 85A has long been considered a leading choice. It is a major target antigen recognised by T cells from infected individuals and it is protective as a DNA vaccine in small animals. Importantly, for use in BCG prime-MVA boost regimes, it is highly conserved amongst all mycobacterial species and is present in all strains of BCG. In small animals it is a major target of the immune responses induced by BCG and in humans HLA-A2 restricted CD8 T cells have been found in a high proportion of BCG-immunised individuals. Antigen 85A is an enzyme, mycolyl transferase, which is involved in cell wall biosynthesis.

Pre-clinical data Using this BCG prime-MVA85A boost in BALB/c mice induces higher levels of both antigen specific interferon-gamma (IFN-γ) secreting CD4 T and CD8+ T cells and higher levels of protection than after BCG alone. This regime has now been further evaluated in the more sensitive guinea pig aerosol challenge model with very encouraging results. Guinea pigs vaccinated with BCG, followed by MVA85A, and then further boosted with a second recombinant viral vector, fowlpox, expressing antigen 85A (FP85A) showed significantly greater protection against challenge than guinea pigs vaccinated with BCG alone. This regime is also immunogenic and protective in rhesus macaques

Clinical studies The safety and immunogenicity of this BCG prime-MVA85A boost vaccination strategy has now been evaluated in a series of small-scale Phase I studies in the UK. MVA85A was the first candidate TB vaccine in clinical trials anywhere in the world in September 2002, and is currently the only one in clinical trials in Africa . The main immunological read-out used in these clinical trials is the ex-vivo IFN-γ Elispot assay, which is used to assess specific T cell responses to tuberculin PPD, antigen 85 complex and pools of overlapping peptides spanning the length of antigen 85A. The best immunological correlate of protection in murine and human TB is the secretion of IFN-γ from sensitised T cells.