The 100-Year Struggle: The Search for a New Vaccine for Tuberculosis

Abstract

Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (Mtb), is the infectious disease that causes the most deaths worldwide today. The only clinically-approved vaccine available for TB is the Bacillus Calmette-Guérin (BCG) vaccine, which was developed in 1921 and is widely thought to be ineffective against the main cause of the global TB burden: adult pulmonary TB. Therefore, the objective of this thesis is to investigate causes for the failure of BCG, and to evaluate current efforts to develop a new TB vaccine. As a foundation for this investigation, I first review the current understanding of the Mtb organism’s structure, genome, and phylogeny. While research has elucidated certain aspects of Mtb that are important for pathogenesis, like the PE/PPE family of proteins which may be a source of antigenic variation, there are several areas that need further research, such as how Mtb strains differ in clinical phenotype. Next, I investigate current knowledge of the BCG vaccine. The BCG vaccine is immunogenic and induces Mtb-specific Interferon-gamma, T-cell, and antibody responses. However, it is largely ineffective in protecting against pulmonary TB and may be unsafe for immunocompromised individuals. In addition, there are still significant gaps in our understanding about different BCG strains. Third, I evaluate current TB vaccine candidates, which can largely be categorized as BCG replacement and BCG booster vaccines. New vaccines have been specifically designed to mitigate the limitations of the original BCG vaccine that have been revealed by molecular biological research. Several vaccines are in clinical trials, and have been demonstrated to be immunogenic and safe in humans. In conclusion, I propose that the story of TB vaccine development is a prime case study for the importance of molecular biology in fighting a global infectious disease epidemic, and offer future directions for research towards this aim.