New tuberculosis vaccines based on attenuated strains of the Mycobacteriumtuberculosis complex

The world urgently needs a better tuberculosis vaccine. Bacille Calmette-Gu erin (BCG), an attenuated strain of Mycobacterium bovis, has been very wide ly used as a vaccine for many years but has had no major effect on reducing the incidence of tuberculosis. A number of alternative living and non-livi ng vaccines are being investigated. Live vaccine candidates include genetic ally modified forms of BCG, genetically attenuated strains of the Mycobacte rium tuberculosis complex and genetically engineered vaccinia virus and Sal monella strains. Non-living vaccine candidates include killed mycobacterial species, protein subunits and DNA vaccines. One requirement for acceptance of any new vaccine will be a favourable comparison of the protection it in duces relative to BCG in a range of animal models, some of which may need f urther development. Molecular genetic techniques are now available that ena ble production of live attenuated strains of the M. tuberculosis complex wi th vaccine potential. In the first of two broadly different approaches that are being used, large numbers of mutants are produced by transposon mutage nesis or illegitimate recombination and are screened for properties that co rrelate with attenuation. In the second approach, putative genes that may b e required for virulence are identified and subsequently inactivated by all elic exchange. In both approaches, mutants that are attenuated need to be i dentified and subsequently tested for their vaccine efficacy in animal mode ls. Many mutants of the M. tuberculosis complex have now been produced and the vaccine properties of a substantial number will be assessed in the next 3 years.