TB Vaccines: The (Human) Challenge Ahead

Tuberculosis (TB) remains a global health threat, with 8.6 million new cases and 1.3 million deaths (including 0.3 million in HIV-positive people) in 2012 [1]. An estimated one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb) [2]. TB is one of the leading causes of death by an infectious disease worldwide, second only to HIV (1.6 million deaths in 2012), and the increase in drug resistant strains of Mtb is alarming [1,3]. An effective vaccine to prevent infection and/or pulmonary TB disease is desperately needed. However, there are several hurdles that have made TB vaccine research and development painfully slow, including the slow growth rate of Mtb, the lack of a predictive animal model, and the lack of an immune correlate [3]. In addition, animal challenge models are very expensive due to the requirement of an ABSL-3 facility, and clinical efficacy studies are long and require large numbers of patients. Funding continues to be an issue in the TB vaccine field (Figure 1) [1,4-6], particularly given the difficulties and the expense of preclinical and clinical studies. New tools are needed to evaluate candidate vaccines that produce a more rapid and accurate assessment of the potential for vaccine efficacy and, therefore, help to increase the speed, and reduce the cost, of vaccine candidate selection. Given the absence of an immune correlate, functional assays that can assess the ability of a vaccine to inhibit mycobacterial growth are needed to give some measure of assurance of the efficacy of a vaccine candidate. There has been some progress in this area, such as the mycobacterial growth inhibition assay (MGIA), which is currently being developed by a consortium of international scientists and organizations. The MGIA has the potential to be a surrogate for protection and may lead to the identification of immune correlates [7,8]. However, it remains to be seen whether this in vitro assay correlates with any type of protection in humans. Malaria vaccine development has experienced similar challenges to the TB vaccine field given the lack of an immune correlate [9,10]. While smaller clinical trials can assess the safety and immunogenicity of a vaccine, large and expensive efficacy studies generally ar