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 worldwi de. Apparently, the current BCG vaccine that has been used for 80 years, ha s failed to control the TB epidemic. Hunting for improved TB vaccine formul ations represents a daunting task to TB research community. Anti-TB host de fense requires T cell-mediated immunity and we are in desperate need of enh anced understanding of how to develop a new generation of TB vaccines that are able to provoke potent and long-lasting protective cell-mediated immuni ty, different from almost all of the vaccines currently in use. It is of im portance to successful TB vaccine development to identify the key cellular and molecular events governing the generation of anti-TB immunity, but unfo rtunately 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 an d an ever-intensifying effort is being made to develop various new formulat ions 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 ob stacles to successful development of TB vaccines. It also discusses about a ntigen presentation, activation of Th1 and Tc1 cells, anti-TB immune effect ers and the generation of memory T cells. The vaccine section describes fou r types of major TB vaccines under development: mycobacterial-, subunit-, p lasmid DNA- and viral-based vaccines. A special section is dedicated to the rationale and current design of cytokine-based adjuvant formulations for T B vaccines. We also take this opportunity to introduce our recent developme nt in cytokine transgene adjuvanted BCG vaccination and recombinant adenovi ral-based TB vaccines.