Preclinical gene therapy tests against Tuberculosis which could shorten the duration of treatment, improve the treatment of latent infection and could be effective against MDR-TB

Abstract

Tuberculosis kills 3 million people every year. The disease is due to respiratory infection with Mycobacterium tuberculosis and the Wor1d Health Organization places its hope to bring tuberculosis under control on a combination of vaccination with bacillus Calmette-Guérin (BCG) to boost immunity and antibacterial drug treatment to directly kill the bacteria. Despite these efforts, there are still 10 million new cases and 3 million deaths world-wide every year, mainly in developing countries. The BCG vaccine is in widespread use against tuberculosis but has doubtful impact on the global position. It is a live vaccine, derived from M. bovis by virulence attenuation during prolonged cultivation of the bacteria in the laboratory. In ten randomized controlled trials of BCG vaccines carried out since 1930, the protective efficacy against tuberculosis has ranged from 0 to 80% in different populations. Thus, BCG is far from being an ideal vaccine against tuberculosis. Over the last few years, some of our experiments carried out at the Center for Tuberculosis Research -School of Medicine of Ribeirão Preto, University of São Paulo, in which mycobacterial antigens were presented to the immune system as if they were viral antigens (DNA vaccine) have had a significant impact on our understanding of protective immunity against tuberculosis. They have also markedly enhanced the prospects for new vaccines. Recently we now know that individual mycobacterial protein antigens expressed from DNA vaccine constructs can confer protection equal to that from live BCG vaccine in mice. A critical determinant of the outcome of immunization appears to be the degree to which antigen specific cytotoxic T cells are generated by the immune response. We have demonstrated that DNA vaccination is an effective way of establishing long lasting cytotoxic T cell memory and protection against tuberculosis. More recently, in the 15 July 1999 issue of Nature, we reported that the HSP65 DNA vaccine was also protective when applied therapeutically in two distinct models of persistent infection in mice. Thus, our new preclinical work show that DNA vaccines, initially designed to prevent infection, can have a dramatic therapeutic action too. In heavily infected mice, the immune response can be caused to switch from one that is relatively inefficient and gives bacterial stasis to one that kills the bacteria, simply by giving DNA vaccination and persistent bacteria can be eliminated... (AU)