The hunt for new tuberculosis vaccines: anti-TB immunity and rational design of vaccines.

Tuberculosis (TB) remains to be a leading infectious cause of death worldwide. Apparently, the current BCG vaccine that has been used for 80 years, has failed to control the TB epidemic. Hunting for improved TB vaccine formulations represents a daunting task to TB research community. Anti-TB host defense requires T cell-mediated immunity and we are in desperate need of enhanced understanding of how to develop a new generation of TB vaccines that are able to provoke potent and long-lasting protective cell-mediated immunity, different from almost all of the vaccines currently in use. It is of importance to successful TB vaccine development to identify the key cellular and molecular events governing the generation of anti-TB immunity, but unfortunately little has been understood as to why 90% of infected humans never develop active TB. However, waiting would not help us to win the battle and an ever-intensifying effort is being made to develop various new formulations according to the immunology that we have been learning, in large part, from experimental models. This review article attempts to unite the current understanding of anti-TB immunity with the rational design of anti-TB vaccines. It examines what may have confounded the immunogenicity of current BCG vaccine and the major obstacles to successful development of TB vaccines. It also discusses about antigen presentation, activation of Th1 and Tc1 cells, anti-TB immune effectors and the generation of memory T cells. The vaccine section describes four types of major TB vaccines under development: mycobacterial-, subunit-, plasmid DNA- and viral-based vaccines. A special section is dedicated to the rationale and current design of cytokine-based adjuvant formulations for TB vaccines. We also take this opportunity to introduce our recent development in cytokine transgene adjuvanted BCG vaccination and recombinant adenoviral-based TB vaccines.