Protective efficacy of an attenuated Mtb Delta LprG vaccine in mice

Author summary Many successful vaccines are based on attenuated human pathogens. The only licensed tuberculosis vaccine, BCG, is based on an attenuated version of live whole cell Mycobacterium bovis, the causative agent of tuberculosis (TB) in cattle. Advantages to using attenuated pathogens as vaccines include a broad antigen composition including proteins, lipids, carbohydrates and other molecules that can induce durable immune responses sometimes lasting decades. Here we test an attenuated Mycobacterium tuberculosis (Mtb), the causative agent of human TB, that lacks a key virulence factor as an alternative whole cell vaccine in mice. Attenuated Mtb lacking a key virulence protein, LprG, is immunogenic and protects mice against Mtb challenge. The LprG whole cell vaccine is protective in mice that develop lung pathology more similar to what is described in human TB and the LprG vaccine induces a key cytokine, IL-17, thought to be important for vaccine protection, in the peripheral blood early after vaccination. Together these data support the continued development of attenuated TB as a potential vaccine candidate. Furthermore our data suggests that serum IL-17 should be explored as potential biomarker for vaccine efficacy in preclinical animal models. Bacille Calmette-Guerin (BCG), an attenuated whole cell vaccine based on Mycobacterium bovis, is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), but its efficacy is suboptimal and it fails to protect against pulmonary tuberculosis. We previously reported that Mtb lacking the virulence genes lprG and rv1410c (Delta LprG) was highly attenuated in immune deficient mice. In this study, we show that attenuated Delta LprG Mtb protects C57BL/6J, Balb/cJ, and C3HeB/FeJ mice against Mtb challenge and is as attenuated as BCG in SCID mice. In C3HeB/FeJ mice, Delta LprG vaccination resulted in innate peripheral cytokine production and induced high polyclonal PPD-specific cytokine-secreting CD4(+) T lymphocytes in peripheral blood. The Delta LprG vaccine afforded protective efficacy in the lungs of C3H/FeJ mice following both H37Rv and Erdman aerosolized Mtb challenges. Vaccine efficacy correlated with antigen-specific PD-1-negative CD4(+) T lymphocytes as well as with serum IL-17 levels after vaccination. We hypothesize that induction of Th17 cells in lung is critical for vaccine protection, and we show a serum cytokine biomarker for IL-17 shortly after vaccination may predict protective efficacy.