Investigation of the role ofvaccine induced Th17 and regulatory T cells in protection from tuberculosis disease. (360G-Wellcome-086338_Z_08_A)

1) To investigate the impact of TB and HIV infection on the establishment of Th1, Th17 and T regulatory T cell responses in humans vaccinated with the virally vectored TB vaccine, MVA85A. 2) To investigate Th17 and regulatory T cell induction in mice vaccinated with BCG and MVA85A and to determine the role of these cells in protection against an M. tuberculosis aerosol challenge. 3) To investigate the effects of ATP and apyrase inhibitors as vaccine adjuvants for promoting Th17 immune responses and enhancing protection against an M. tuberculosis aerosol challenge. 4) To investigate the induction of C039+ Treg during infection with multidrug-resistant strains of M. tuberculosis. As substantial clinical efficacy has yet to be demonstrated with any T cell-inducing vaccine, we must question whether we truly understand what is required for a protective T cellular immune response. In the last decade a number of new vaccines for tuberculosis (TB) have entered early phase clinical trials and 2009 saw the start of the first efficacy trial of a new TB vaccine. Vaccine candidates are selected on the basis of safety, efficacy in small animals and the ability of the vaccine to induce the secretion of IFN-y by antigen-specific CD4+ and CD8+ T cells (Von Eschen 2009, Holt 2008, Aagaard 2009). Although IFN-y alone is not sufficient for protection, in the absence of a better biomarker, IFN-y production remains the primary gauge of vaccine-induced immune responses in both animals and humans (Hanekom 2008). CD4+ T cells can differentiate into diverse effector cell subsets upon antigenic stimulation and the classical Th1ffh2 paradigm has now been expanded to include Th17, Th22, Th9 and T regulatory (Treg) cells. The role of these different cell subsets in TB remains unclear and even less is known about the contribution of these sub sets to a vaccine induced protective immune response. Cooper et al. (2007) have recently identified vaccine-induced Th17 cells as potentially important in mice and have hypothesised a role for them in recruiting Th1 cells to the lungs. In contrast to Th1 and Th17 cells, regulatory T cells act to suppress T cell responses and are thereby thought to prevent pathology from chronic or excessive immune responses (ltoh 1999; Sakaguchi 2000). Understanding the balance between these different CD4+ T cell subsets will increase our understanding of the protective immune response to TB and aid in the development of better vaccines and vaccination strategies. Using BCG and a novel viral vector vaccine for TB (MVA85A) I have the opportunity to investigate vaccine-induced Th17, Th22 and regulatory T cell responses in vaccinated humans and mice. Using an M. tb aerosol challenge model I will be able to determine the role of MVA85A vaccine-induced Th17 and T regulatory cells in protection from disease.