Grant: Project Grant

Tuberculosis (TB) remains one of the top 10 causes of death worldwide. In 2015, there were an estimated 1.4 million TB deaths, and an additional 0.4 million deaths resulting from TB disease among people living with HIV, 480,000 new cases of multidrug-resistant TB (MDR-TB) were reported, and cases of extensively drug-resistant TB (XDR-TB) were detected in 105 countries. Because of these situations, effective vaccines are urgently needed. BCG, an attenuated live bacterium, is the only available vaccine against TB. Over 90% of children worldwide are vaccinated with BCG and >120 million doses of BCG are administered annually, making it the world's most widely used vaccine. However, BCG is not an ideal vaccine and has a limited effect against pulmonary TB in adolescents and adults. We have recently identified several molecular factors that affect the vaccine properties (safety and effectiveness) of BCG. Based on these findings, I have developed two strategies to construct new TB vaccines to replace BCG. Firstly, we have constructed a novel recombinant BCG by genetically manipulating regulatory proteins PhoP-PhoR to enhance the immunogenicity and protective efficacy of BCG. Secondly, we have constructed an attenuated live vaccine strain of M. tb (lsr2 deletion mutant), which has the ability to induce macrophage apoptosis and promote antigen presentation. We have made substantial and promising progress on each of this strategy. I describe in this proposal a number of experiments to complete the studies of our promising lead candidates. The outcome of our study will provide more effective TB vaccines to replace BCG, which will help to end the TB epidemic.