Understanding why people get TB by instilling live mycobacteria into the human lung
Tuberculosis (TB) remains a major global health threat with ~1.5 million deaths annually. Global elimination of TB is hampered by the lack of an effective vaccine. BCG is currently the only licenced TB vaccine but its efficacy is limited especially in adults. The lack of an effective vaccine is largely hindered by our incomplete understanding of TB immuno-pathogenesis, which comes primarily from animal models and in vitro studies using cells from the blood compartment. Subsequently, we still don’t fully understand why some people get TB and others don’t despite extensive exposure, and correlates of immunity are poorly defined. Another unmet need is the lack of clarity about the optimal route for TB vaccine administration. A pragmatic method to prioritize the most promising vaccine candidates (out of ~20 in the pipeline) is urgently needed as the existing approach, involving trials on hundreds of patients, is prolonged (~10-15-year development trajectory) and extremely expensive (~US$1 billion per candidate).
The Centre for Lung Infection and Immunity recently completed the TB-HART study, which evaluated the safety, feasibility and immunogenicity of BCG and PPD administered directly into the human lung. Our initial findings were recently published in the American Journal of Respiratory and Critical Care Medicine (manuscript entitled “A Human Lung Challenge model to evaluate the safety and immunogenicity of PPD and BCG”). This ‘first-in-man study’ demonstrates that bronchoscopic instillation of live BCG and PPD into the lungs of healthy participants, along a gradient of TB susceptibility, is safe and feasible when performed in a TB endemic setting. Several concentrations of BCG and PPD were evaluated to identify the lowest safe and immunogenic dose. These data demonstrate that a lung-orientated mycobacterial human infection model can provide a solid foundation for the advancement of several lines of research including (i) the study TB immunopathogenesis, (ii) identification of biosignatures of TB risk, (iii) development of better models to evaluate vaccine efficacy, and (iv) optimising the route of vaccine delivery (respiratory tract versus intradermal).