Grant: Project Grant

Tuberculosis (TB) is a leading infectious disease which caused 1.5 million deaths and 10.0 million active cases in 2020. BCG is the only approved TB vaccine but has limited efficacy. Despite achieving clinically significant protection in children, BCG has variable efficacy against pulmonary TB. More effective vaccines than BCG are required to stop transmission and reduce global TB burden. This is urgently needed given the increasing cases of drug-resistant TB. One reason fro the limited efficacy of BCG is that it cannot induce CD8 T cell response. We discovered that a lsr2 deletion mutant of Mycobacterium tuberculosis (Mtb) is able to induce both CD4 and CD8 T cell responses, and will likely to be more effective than BCG. In aim 1, we will evaluate the protective efficacy and safety of this vaccine candidate in animal models. Immune factors associated with Mtb infection outcomes are poorly understood. We discovered a T cell exhaustion phenotype mediated by CD39 expression in mice infected with Mtb, but not with BCG or the lsr2 mutant. We will determine the role of CD39 in Mtb infection and disease progression in mouse models of infection. We will test if pharmacological inhibition of CD39 will improve the performance of vaccination by live vaccines BCG and the lsr2 mutant, or a DNA vaccine. Our study will lead to the development of a new TB vaccine better than BCG, and novel vaccine combination (the use of CD39 inhibitors and vaccine) that can improve the performance of vaccines. These will have strong implications for clinical application especially for individuals who were previously infected with Mtb and consequently not amenable to BCG in the current vaccination program.