One-quarter of the global population is infected with Mycobacterium tuberculosis (Mtb), leading to tuberculosis (TB), which causes 1.5 million deaths annually. While largely eradicated in the global north, the disease remains a significant challenge globally.
Current Vaccine Limitations
The existing Bacillus Calmette-Guérin (BCG) vaccine, administered intradermally to children, is effective against disseminated TB in children but demonstrates declining effectiveness in adolescents and adults against pulmonary TB. This gap highlights the need for improved vaccination strategies. Associate Professor Andreas Kupz from James Cook University notes that the current BCG vaccine is not effective enough against adult pulmonary TB.
Advancing Vaccine Approaches
Researchers are exploring several avenues for a better TB vaccine, including entirely new vaccines (e.g., mRNA or protein-based) and improved delivery methods for existing vaccines. Associate Professor Kupz suggests that improving the BCG vaccine itself offers the most promising path, given its complex protein composition (approximately 4,000 proteins) compared to newer, simpler vaccine candidates.
Key Research Findings on Mucosal Delivery
Recent Australian research indicates that inhaling a more virulent version of the BCG vaccine activates progenitor cells within the lungs. This activation prompts T cells to differentiate and establish local residency, potentially leading to enhanced protection. This mechanism helps explain why mucosal delivery (directly into the lung) of modified BCG strains has shown superior protection in animal models compared to traditional intradermal vaccination.
Previous studies, including one published in Nature five years ago, demonstrated that intravenous administration of BCG in non-human primates provided significant protection against tuberculosis. While intravenous delivery is impractical for mass human vaccination, it underscored the importance of alternative delivery routes. Mucosal delivery in non-human primates and mice has also shown substantially better protection.
Transition to Human Trials and Global Impact
Associate Professor Kupz's team was among the first to link mucosal BCG delivery to the induction of tissue-residing T cells, highlighting its greater effectiveness a decade ago. Currently, clinical trials are underway at Oxford University to evaluate the safety, immunogenicity, and optimal dosage of licensed BCG delivered into human lungs.
The COVID-19 pandemic reversed a trend of declining TB deaths globally, particularly affecting lower and middle-income countries. TB is recognized as a disease exacerbated by poverty and vulnerability. In Australia, First Nations populations experience TB infection rates 5-6 times higher than the non-Indigenous population. Multi-drug resistant (MDR) TB is also increasing, with Papua New Guinea identified as a hotspot, posing a biosecurity risk to northern Australia due to cross-border movement.
Future Directions in TB Research
While the highly virulent RD1-containing BCG strain used in some studies is not yet safe for human use, researchers are developing modified BCG strains that offer improved immunity without increased virulence. Continued research and increased funding are essential to develop a safe and effective mucosal TB vaccine for global mass vaccination efforts.