Persistence and protective efficacy of a Mycobacterium tuberculosis auxotroph vaccine

New vaccines against tuberculosis are urgently required because of the impr essive incidence of this disease worldwide and the highly variable protecti ve efficacy of the current vaccine. The possibility of creating new live va ccines by the rational attenuation of strains from the Mycobacterium tuberc ulosis complex was investigated. Two auxotrophic mutants of M. tuberculosis and M. bovis BCG were constructed by disruption of one of their purine bio synthetic genes. These mutants appeared unable to multiply in vitro within mouse bone-marrow derived macrophages. They were also attenuated in vivo in the mouse and guinea pig animal models. In guinea pigs, the two mutants in duced strong delayed-type hypersensitivity response to purified protein der ivative. In a preliminary experiment, the two mutants were compared to the BCG vaccine for their protective efficacy in a challenge against aerosolize d virulent M. tuberculosis in the guinea pig model. Both mutants conferred some level of protection. These experiments demonstrate that the rational a ttenuation of M. tuberculosis could lead to the design of new candidate liv e vaccines against tuberculosis.