Grant: Operating Grant

Tuberculosis (TB) remains a major worldwide health problem, which causes ~2 million deaths and 10 million new infections annually. During recent years, the situation has worsened with the advent of M. tb/HIV coinfection and the emergence of multidrug-resistant and extensively drug-resistant TB. As such, effective approaches alternative to antibiotics are urgently needed for the control of TB. BCG, an attenuated live bacterium, is currently the only available vaccine against TB. However, BCG has a limited effect against pulmonary TB in adults and disconcerting safety record in immunocompromised individuals. During the past three-year granting period, my laboratory has made significant progress in understanding why current BCG vaccines do not provide optimal protections and we have identified several molecular factors that influence the vaccine properties of BCG, including safety, immunogenicity, and protective efficacy. Equipped with this knowledge, my current proposal aims to improve on BCG by several novel approaches. One approach is to genetically manipulate two regulatory proteins (PhoP, Lsr2) involved in the production of multiple antigens, allowing the modified BCG to have an improved immunogenicity hence protective efficacy. Another approach is to generate a recombinant BCG overproducing a key metabolic enzyme (GlnA1), allowing the BCG to grow better within host, thus providing a longer duration of protection. I describe in this proposal a number of experiments to test these different strategies. The outcome of our study will provide novel strategies for designing more effective and safe TB vaccines to replace BCG.