Progress in tuberculosis vaccine development Sven Baumann, Ali Nasser Eddine and Stefan HE Kaufmann The first tuberculosis vaccine candidates have reached clinical testing. Novel subunit vaccine candidates aimed at boosting previous BCG-prime vaccination and novel viable attenuated vaccine candidates aimed at substituting BCG have both completed the preclinical stage. Despite these achievements, rational vaccine design against tuberculosis has not come to an end. Novel findings in basic immunology and microbiology will advance further improvements in vaccine development. These include the potential role of crosspriming to induce more potent T-cell responses, the role of memory T cells and regulatory T cells in sustaining or curtailing optimal immune responses, respectively, as well as the involvement of cytokines in T-cell migration to nonimmunologic tissue sites and in the generation of memory. Knowledge about basic mechanisms underlying optimum protection will not only have a direct impact on future vaccine design against tuberculosis but also help in the formulation of a set of biomarkers with predictive value for vaccine efficacy assessment. Addresses Max Planck Institute for Infection Biology, Department of Immunology, Schumannstrasse 21-22, 10117 Berlin, Germany Corresponding author: Kaufmann, Stefan HE (kaufmann@mpiib-berlin.mpg.de) Current Opinion in Immunology 2006, 18:438–448 This review comes from a themed issue on Host–pathogen interactions Edited by Stefan HE Kaufmann and Bruce D Walker Available online 13th June 2006 0952-7915/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2006.05.016 Introduction Tuberculosis vaccine development has reached a new stage. In the past few years, several vaccine candidates have entered clinical trials and several more are going to follow soon. Tuberculosis is a major health threat causing nine million new cases and two million deaths annually (Global tuberculosis control — surveillance, planning, financing, WHO report 2006; http://www.who.int/tb/pub- lications/global_report/en/index.html). It is caused by the intracellular bacterium Mycobacterium tuberculosis, which has developed sophisticated strategies to persist inside macrophages even when they are fully activated. T lymphocytes are critical for both protection against and pathology of tuberculosis. Current evidence suggests that T lymphocytes contribute to protection in at least three ways: first, CD4 + T cells restricted by gene products of the major histocompatibility complex (MHC) class II play a major role; second, MHC class I-restricted CD8 + T cells contribute to protection, notably in later phases of the infectious process; and third, g/d T cells and CD1- restricted T cells with specificity for nonproteinaceous antigens are of additional value [1]. Generally, contribution of antibodies to protection is considered minimal. Accord- ingly, current vaccination strategies against tuberculosis are focused on activation of a potent T-cell response. A large number of the world’s inhabitants are latently infected with M. tuberculosis without signs of clinical disease, which has been estimated to be as high as two billion individuals. Although these latently infected healthy individuals represent a significant target popula- tion for tuberculosis vaccines, current vaccine candidates are aimed at protecting naı¨ve individuals. Future work will be needed to determine whether vaccines, which are given pre-exposure with M. tuberculosis, can also be con- sidered for post-exposure vaccination. Although a tuber- culosis vaccine is already available, termed bacille Calmette Gue ´ rin (BCG), general agreement exists that better vaccines are needed. The 100 million BCG vacci- nations given to children every year will have prevented 30 000 cases of tuberculosis meningitis in infants during their first five years of life and an additional 11 000 cases of disseminated or miliary tuberculosis [2]. However, BCG fails to prevent pulmonary tuberculosis in adults. New tuberculosis vaccine candidates comprise both sub- unit adjuvant formulations and improved live recombi- nant (r) strains of the current vaccine BCG. With tuberculosis vaccine development leaving the pre- clinical stage and moving forward into clinical trials, is it still possible to exploit the most recent immunological findings for further vaccine improvement? Because vac- cine efficacy testing of tuberculosis vaccine candidates is a long-lasting endeavor, which requires decades rather than years, it is important to find ways to introduce novel findings that could improve vaccine candidates whilst they are tested in the field. This can be achieved by an iterative and reciprocal approach. In this way, findings obtained in the wet lab, which promise further improve- ment of vaccine candidates, could be integrated into ongoing clinical trials. Reciprocally, immunological find- ings, such as biomarkers indicating protective immunity that are newly identified in clinical trials, should be contested in experimental animal models to validate their potential role in protective immunity. Thus, a merger of hypothesis-driven experimental research and clinical trials can provide new opportunities that could accelerate Current Opinion in Immunology 2006, 18:438–448 www.sciencedirect.com