Tuberculosis vaccines - rethinking the current paradigm

The vaccine discovery paradigm in tuberculosis (TB) has been to mimic the natural immune response to infection. With an emphasis on interferon (IFN)-gamma as the main protective cytokine, researchers have selected dominant antigens and administered them in delivery systems to promote strong T helper (Th)1 responses. However, the Bacillus Calmette-Guerin (BCG) vaccine is a strong inducer of Th1 cells, yet has limited protection in adults, and further boosting by the Modified-Vaccinia-Ankara (MVA)85A vaccine failed to enhance efficacy in a clinical trial. We review the current understanding of host-pathogen interactions in TB infection and propose that rather than boosting Th1 responses, we should focus on understanding protective immune responses that are lacking or insufficiently promoted by BCG that can intervene at critical stages of the TB life cycle.