Evaluation of host and mycobacterial biomarkers that can serve as systemic measures of pathogen load in a BCG-orientated human lung challenge model (TB- LOAD)

TB control requires an effective vaccine, but development has been challenging due to several reasons, including the lack of a suitable human challenge model (which facilitated successful malaria and cholera vaccines). ~6 years ago, we developed the first-in-human ‘TB’ lung challenge model using an attenuated strain (BCG; part of M.tb Complex). Such models provide insights into immunopathogenesis and likely accelerate development and down-selection of newer TB vaccines and drugs. However, prioritising a specific vaccine or drug will depend on developing a systemic measure of ‘pathogen load clearance’ as mycobacteria often infect several organs in tandem. More rapid clearance of pathogens would favour one immunotherapeutic intervention over another (this approach is a critical step in TB drug development pipelines). Thus, lack of a reliable ‘reduction-in-pathogen-load’ metric remains a canonical roadblock to leveraging the human lung challenge model for vaccine, drug, and diagnostics development. To address this critical issue, in this proof-of-concept study, we propose to study blood, urine, and respiratory compartments in tandem using newer and novel TB diagnostic readouts, involving both host and pathogen biomarkers, in healthy volunteers challenged with different doses of BCG administered via the bronchoscopic or nebulised route (Figure 1). Key words: tuberculosis; vaccine development; human challenge