The data presented here and elsewhere (Huygen et al 1996) demonstrate Ag85A DNA vaccination against tuberculosis in animal models. DNA encoding hsp65 and the 38kDa antigen of M. tuberculosis have also been shown to confer protection (Tascon et al 1996, Zhu et al 1997). These data suggest that there may be several protective antigens in M. tuberculosis and that a combination of DNA
plasmids encoding discrete antigens should be investigated. But which antigens? There are likely to be several thousand proteins expressed by M. tuberculosis, thereby greatly complicating the determination of those that are protective against disease. One potential means of identifying these proteins is by taking advantage of the DNA vaccine technology itself. Johnston and colleagues recently showed that pools of many thousand different plasmids each containing a fragment of the genome of a pathogen (in this case Mycoplasmapulmonis) could be used to vaccinate and protect mice from challenge (Barry et al 1995). By extension, if these libraries could be successively fractionated to yield the protective plasmids in the mixture, then the protective antigens they encode could be identified. Alternatively, one could take a more directed approach by using open reading frames, as identified using nucleotide sequence information, to test a much more defined set of plasmids. If one wanted to target specific types of M. tuberculosis antigens to be tested in this way, high on the list would be those proteins secreted from mycobacteria. These could be identified using bioinformatics by the presence of recognizable signal sequences or functionally using genetic approaches (Lim et al 1995).
In summary, DNA vaccination can be used to express mycobacterial antigens in situ, to induce immune responses relevant to protection from mycobacterial disease (i.e. Th1 cells and CTLs) and to confer protection in animal models of tuberculosis. The next step in tuberculosis vaccine development lies in the identification of the protective antigens of M. tuberculosis, a process which may be aided by the DNA vaccine technology itself. As a result, a combination of DNA plasmids encoding these antigens can be tested for its potential as an improved tuberculosis vaccine.
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