New molecular basis of attenuation and immunogenicity of the tuberculosis vaccine candidate MTBVAC described
The tuberculosis vaccine candidate MTBVAC is the only vaccine in clinical trials based on an attenuated Mycobacterium tuberculosis strain of human origin. In various animal models, MTBVAC confers a similar attenuation and greater immunity than the current BCG vaccine against tuberculosis. BCG is a Mycobacterium bovis derivative, isolated from cows in the early twentieth century, which does not protect against respiratory forms of tuberculosis. MTBVAC is developed by TBVI’s research partner University of Zaragoza in collaboration with biopharmaceutical company Biofabri.
A publication in the journal PloS Pathogens discloses a new molecular basis to explain the good protection against tuberculosis conferred by MTBVAC. Protection is due to inactivation of the PhoP gene, essential to confer virulence in M. tuberculosis. The decline in virulence is due mainly to the lack of secretion of ESAT-6, the most important virulence factor in M. tuberculosis. In this publication it is described the mechanism by which PhoP regulates the secretion of ESAT-6 through interaction with EspR, which in turn regulates the operon espAC. The superior efficacy of MTBVAC can be explained by the lack of production of complex lipids regulated by PhoP that interfere with the immune response and especially for enhancing the antigenic properties of MTBVAC through Mcr7 an antisense RNA, regulating the TAT secretion system in M. tuberculosis. After silencing Mcr7 in MTBVAC, the vaccine increases the secretion of TAT substrates, which include the Ag85 family, considered to be the most important antigens of M. tuberculosis, thereby the vaccine MTBVAC increases exposure of these antigens to the immune system. The paper in PLoS Pathogens describes for the first time the role of a non-coding RNA in the genome of M. tuberculosis.
The work behind the publication was conduced by collaboration between the University of Zaragoza and French partners within the TBVI consortium and the group of the Polytechnic School of Lausanne (Switzerland). It was supported by EC FP7 funded project NEWTBVAC, the Spanish Ministry of Economy and Competitiveness and the Swiss National Science Foundation.