Mycobacterium tuberculosis Δlsr2 Vaccine Enhances Protection Against Tuberculosis

Tuberculosis (TB) has been a leading cause of death from a single infectious agent for decades. Bacille Calmette-Guerin (BCG) remains both the primary TB vaccine strategy and the oldest vaccine in circulation, with severe limitations in adult populations. Recently, live attenuated vaccine strategies, or generating safe strains of Mycobacterium tuberculosis (Mtb) through genetic engineering, have shown considerable promise. We previously developed an attenuated strain of Mtb lacking the nucleoid-associated protein Lsr2 ({Delta}lsr2) which is also phthiocerol dimycocerosates (PDIM) deficient and induces an immune response that represents an intermediate stage between the parental Mtb strain and BCG. In this study we examined the immune response of {Delta}lsr2 vaccinated mice in comparison to BCG and found a substantially stronger CD4 and CD8 T cell responses from {Delta}lsr2 vaccinated mice. Complementary, we conducted Mtb protection studies in {Delta}lsr2 and BCG vaccinated mice and guinea pigs, where we found that {Delta}lsr2 provided superior protection in both animals. This improved protection is shown with reduced bacterial burden and improved organ pathology in the lungs and spleen. Taken together, our work shows {Delta}lsr2 serves as a promising vaccine candidate for continued preclinical development.