CW Leung

Tuberculosis currently causes 3 million deaths a year. It is the leading cause of death from a single infectious disease. About one-third of the world's population might be infected with Mycobactenum tuberculosis. An additional 8 million new victims occur each year, 95% of whom are in developing countries. Tuberculosis will continue to claim more than 30 million lives in the coming decade unless immediate action is taken to prevent and control its transmission. The emergence of multidrug-resistant tubercle bacilli and their deadly link with AIDS globally have made tuberculosis prevention, instead of chemotherapy, the more realistic and cost-effective means of controlling this pandemic scourge.

BCG vaccine is the most widely used vaccine in the world. It is usually recommended in populations with an annual incidence of tuberculosis exceeding 1%. Since its introduction in 1928, BCG has appeared to reduce the risk of serious disseminated disease and dreadful complications of primary tuberculosis in children. However, the protective mechanisms of BCG are not fully understood. Its efficacy around the world is very variable and has remained controversial.^1,2 The protective efficacy of BCG as demonstrated by prospective controlled studies has ranged from 0% to 80%, with a tendency towards higher efficacy in non-endemic industrialized countries where background sensitization to non-tuberculous environmental mycobacteria are less common. This heterogeneity might be explained by latitude difference or vaccine strain variability, among other postulations. There exists an urgent need to define protective immunity critically. The spectacular failure of the existing BCG vaccine in recent tuberculosis control trials has prompted a search for potential replacements and evaluation of alternative vaccines against tuberculosis. New advances in molecular genetics may generate innovative approaches to improve BCG vaccine or develop novel interventions to replace BCG altogether.

Identification of "virulence determinants" and "protective epitopes" are crucial to successful engineering of vaccines against tuberculosis. The ideal vaccine will need to protect against all forms of the disease, including primary tuberculosis, reactivation and exogenous reinfection, as well as wide strain variations in M. tuberculosis. The antigen(s) administered must initiate, promote and sustain cell-mediated immunity with potential for "memory" and "cytotoxicity". Such a vaccine has yet to be developed as we lack understanding about immunity in tuberculosis, and what antigenic components might trigger it.³

There is evidence that the "protective" antigens of mycobacteria are to be found amongst those common to the genus. If cross-protection of antigenic determinants is the case, attempting to develop second generation vaccines by genetic manipulation of tubercle bacilli only will seem both unnecessary and illogical. Furthermore, the lack of efficacy of BCG in countries where individuals are usually highly sensitized by environmental mycobacteria and already tuberculin positive before vaccination suggested the need for a vaccine based on a mycobacterial species totally devoid of the species-specific epitopes of the tubercle bacilli. Thus, the ideal vaccine might be derived from certain species of non-pathogenic mycobacteria which are rapidly eliminated from the body after eliciting the desired cellular immune reactions against protective antigens. Attenuated "benign" strains of M. tuberculosis, M. bovis and atypical mycobacteria like M. vaccae and M. microti are attractive live vaccine alternatives if they can be proved to confer cross-immunity against tuberculosis. In fact, immunizing with a preparation of dead or inactivated bacilli could well be another viable option as mycobacteria have well known powerful adjuvant effects in promoting immunogenicity. It is not necessary for the immunogen(s) to persist in tissues as the immune responses induced would be repeatedly boosted by day to day contact with many environmental mycobacteria. The immunotherapeutic property of M. vaccae has been further investigated to establish its potential as a vaccine against tuberculosis in close contacts of tuberculous patients. A killed vaccine based on M. vaccae, if shown to be effective in all environments, in those already infected with tubercle bacilli and in uninfected individuals, could become a substitute to BCG. Mutants of M. tuberculosis or BCG which lack one or more enzymes essential for growth have been studied. Such auxotrophic vaccines should be safe even in H1V-infected individuals.³

Many people discard the possibility that there could be an alternative to BCG as an effective vaccine against tuberculosis. This preconception stems from the unfounded belief that any vaccine strain that is effective against tuberculosis must be a living close relative of its virulent counterpart and capable of inducing a "limited tuberculous infection" without causing disease. This dogma has now been challenged subsequent to recent advances in the understanding of the mycobacteriology and immunology of tuberculosis. Subunit vaccines are attractive considerations in this regard and might well prove to be superior to conventional whole cell preparations in terms of immunogenicity, safety and tolerability. Candidate components for subunit vaccines might include protective protein antigens of the tubercle bacillus which are cytoplasmic, cell membrane associated, cell wall associated or secreted (e.g. heat shock proteins). With recombinant DNA technology, attenuated pox virus (vaccinia or avipoxviruses) or Salmonella can be used as vectors to express and deliver the protective antigens of M. tuberculosis.³ Studies on novel approaches like nucleic acid vaccines, with naked DNA encoding mycobacterial antigens, are already underway.⁴ All need to be further evaluated outside of animal studies in large-scale clinical trials before their ultimate utility can be clearly defined.

As there is no surrogate marker for rapidly indicating protective immunity, it is difficult to monitor the success of any alternative vaccination strategy. If the development of tuberculosis or the lack of it is taken as an outcome measure, it may take decades before any valid conclusion regarding the efficacy and duration of immunoprotection can be drawn from vaccine trials.

Development of an effective vaccine and new potent drugs may help circumvent problems of increased transmission and infection with multidrug-resistant M. tuberculosis in the era of AIDS. However, without expeditious actions, concerted efforts and government funding, two decades can easily pass before either is available and affordable in developing countries, which harbour the largest number of infected individuals.

References

1. Colditz GA, Brewer TF, Berkey CS, et al. Efficacy of BCG vaccine in the prevention of tuberculosis: Meta-analysis of the published literature. JAMA 1994;271:698-702.

2. Rodrigues LA, Diwan VK, Wheeler JG. Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: A meta-analysis. Int J Epidemiol 1993;22:1154-8.

3. Rom WN. Prospects for a tuberculosis vaccine. In: Rom WN, Garay SM, editors. Tuberculosis. Boston: Little, Brown and Company 1996:905-10.

4. Lowrie DB, Tascon RE, Silva CL. Vaccination against tuberculosis. Int Arch Allergy Immunol 1995;108:309-12.