Differential protective efficacy of DNA vaccines expressing secreted proteins of Mycobacterium tuberculosis

The development of more-effective antituberculosis vaccines would assist in the control of the global problem of infection with Mycobacterium tubercul osis. One recently devised vaccination strategy is immunization with DNA pl asmids encoding individual microbial genes. Using the genes for the M. tube rculosis secreted proteins MPT64 (23 kDa), Ag85B (30 kDa), and ESAT-6 (6 kD a) as candidate antigens, DNA vaccines were prepared and tested for immunog enicity and protective efficacy in a murine model of aerosolized tuberculos is (TB). Intramuscular immunization with DNA-64 or DNA-85B resulted in the activation of CD4(+) T cells, which produce gamma interferon (IFN-gamma), a nd high titers of specific immunoglobulin G antibodies. Further, DNA-64 ind uced major histocompatibility complex class I-restricted CD8(+) cytotoxic T cells. The addition of a eukaryotic leader sequence to mpt64 did not signi ficantly increase the T-cell or antibody response. Each of the three DNA ve ctors stimulated a significant reduction in the level of dt tuberculosis in fection in the lungs of mice challenged 4 weeks after immunization, but not to the levels resulting after immunization,vith Mycobacterium bovis BCG. T he vaccines showed a consistent hierarchy of protection, with the most effe ctive being Ag85B, followed by ESAT-6 and then MPT64. Coimmunization with t he three vectors resulted in a greater degree of protection than that induc ed by any single vector. This protective efficacy was associated with the e mergence of IFN-gamma-secreting T cells earlier than in infected animals im munized with a control vector. The efficacy of these DNA vaccines suggests that multisubunit vaccination may contribute to future vaccine strategies a gainst TB.