Trends in Immunology
ReviewTB vaccines: progress and problems
Section snippets
The BCG vaccine
BCG was developed at the start of this century and is the most widely used vaccine in the world. It was developed by attenuation of M. bovis, which is closely related to M. tuberculosis (>90% DNA homology), and recent data indicate that a large number of mutations have taken place during the long in vitro propagation of this strain 5, 6. It is known that these mutations have resulted in the deletion of a great many open reading frames (ORFs; 16 deletions encoding 129 ORFs reported so far),
Characteristics of acquired cellular immunity to TB
The hallmark of cellular immunity to TB is the formation of granulomas in the lung with a centre of infected macrophages and a marginal zone containing lymphocytes (Fig. 1). Studies of TB infection in mice have demonstrated that immune mice are characterized by a highly accelerated recruitment of memory cells, formation of granulomas and control of bacterial multiplication 12. The acquired cellular immune response to M. tuberculosis is complex: CD4+ and CD8+ T cells, as well as unconventional T
Antigen discovery in the post-genomic era
The M. tuberculosis genome contains approximately 4000 different ORFs, which potentially encode the same number of proteins 4. The uncovering of the complete TB genome represents a major breakthrough in TB vaccine research and has been accompanied by considerable progress in antigen discovery. From a few defined proteins, recent progress in translating the genome information into proteins produced (the so-called proteome) has resulted in two-dimensional electrophoresis (2DE) maps comprising
Antigen selection and vaccine design for pre- and post-infection vaccines
Some of the most promising vaccine candidate antigens, antigen 85 A/B, ESAT-6 and heat shock protein 60 (HSP60) (Table 1), are strongly recognized, during the course of natural infection, in the same animal model in which they promote a protective immune response if administered as a pre-infection vaccine (Fig. 3a) 41. Furthermore, the same immunodominant antigens are recognized by TB patients and their healthy contacts 42. Therefore, there is no evidence to support the hypothesis that
Strategies for TB vaccine development
An ideal vaccine against TB would fulfil several theoretical requirements (Box 2). However, none of the vaccine technologies tested lives up to all of these ideal characteristics and, in a practical sense, candidates that fall short in one or more of these characteristics could still prove useful.
From challenge experiments in animals to clinical trials in humans
How to choose the most promising candidate vaccine to enter into clinical trials is a complicated but important question. Because there is still no good in vitro correlate of protective immunity (IFN-γ is the best but is far from sufficient), the best approach seems to be the evaluation of experimental vaccines in animal challenge studies. Currently, novel TB vaccines are tested in the mouse, guinea pig and, more recently, primate models of TB (68). Most vaccines are screened in the mouse model
Conclusion and perspectives
Recent years have witnessed several new scientific advances in our understanding of the immunological mechanisms and targets for a protective immune response against TB. Today, it is scientifically feasible to develop a novel TB vaccine and many groups have provided compelling evidence for the potential of novel vaccines using a variety of different strategies. However, our current knowledge of the complexity of this disease and its different manifestations in different populations have
Acknowledgements
I thank T.M. Doherty for helpful discussions and excellent drawings, A.W. Olsen, K. Weldingh and L. Holten-Andersen for critical reading of the manuscript, and S. Lomborg for expert secretarial assistance.
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