Author(s): David N McMurray [[dagger]] 1 , Lan H Ly 2
Traditional roadblocks to effective TB control (e.g., lack of attention to the disease, lack of resources, antiquated diagnostic tests, lack of patient compliance with therapy and a huge reservoir of persistently infected individuals) have been compounded by the terrible synergy between TB and HIV, and the development of almost untreatable multi- and extensively drug-resistant strains of Mycobacterium tuberculosis  . Case-finding and chemotherapy employing the Directly Observed Treatment, Short-course strategy, and several promising new TB drugs currently in the pipeline, will undoubtedly continue to have a significant impact on TB incidence [2,3] . However, it is clear that an effective vaccine is essential if TB is to be controlled as rapidly as possible [4-6] . The urgency to license a new TB vaccine has driven a worldwide effort over the past 20 years involving basic scientists, public and private funding agencies, regulatory bodies, and disease control experts in high-burden countries  . That effort has been shaped at various stages by several paradigms that reflected the current understanding of the type of vaccine that would be needed, the manner in which vaccines should be evaluated for efficacy in animal models, the process by which preclinical development of vaccines would occur, the design of clinical trials, and the public and private organizations that would participate in the process. Almost without exception, those paradigms have shifted as the understanding of vaccine-induced protection has improved, an appreciation for the biological relevance of certain animal models of TB has grown, new strategies for organizing and funding preclinical development and human trials have emerged, and the realities of testing and using TB vaccines in diverse high-burden populations have become apparent.
Variety is the spice of life
In general, the induction of protective cell-mediated immunity is much more challenging than inducing a protective antibody response, a fact which has complicated the search for a better TB vaccine. The current vaccine, bacillus Calmette-Guérin (BCG), is a living, attenuated strain (actually several different strains) of Mycobacterium bovis , which has served as a model for new TB vaccines and a gold standard for their evaluation in animal models  . BCG has many characteristics that recommend it as a platform for new TB vaccines, and several of the promising new vaccines utilize recombinant BCG strains overexpressing the genes for several mycobacterial antigens [9,10] . However, the fact that BCG does not seem to protect against adult pulmonary TB in some high-burden settings has stimulated the search for other types of TB vaccines. The traditional approach of using purified components of the bacterium together with an effective adjuvant has been modernized by cloning the genes for target antigens and either expressing those genes in an expression vector (e.g., vaccinia virus and adenovirus) or using the DNA directly [11,12] . In fact, the variety of TB vaccine types that have been taken into the clinic in the past few years is impressive and reflects the realization that the unknown factors that impair BCG efficacy may also render less effective...