A BCG Skin Challenge Model for Assessing TB Vaccines

Controlled Human infection models (CHIM) are valuable tools for assessing relevant biological activity in vaccine candidates, with the potential to accelerate Tuberculosis vaccine development into the clinic. Tuberculosis infection poses significant constraints on the design of a CHIM using the causative agent Mycobacterium tuberculosis. As a safer alternative, we propose a challenge model using the attenuated vaccine agent Mycobacterium bovis BCG as a surrogate for Mycobacterium tuberculosis, and intradermal (skin) challenge as an alternative to pulmonary infection. We have developed a unique non-invasive imaging system based on fluorescent reporters to quantitatively measure bacterial load over time, thereby determining a relevant biological vaccine effect. We assessed the utility of this model to measure the effectiveness of two TB vaccines: the currently licenced BCG and a novel subunit vaccine candidate. To assess the efficacy of the skin challenge model a pharmacometric model was built describing the decline of fluorescence over time. The results show that vaccination is a statistically significant factor which reduced the fluorescence readout of both fluorophores. The higher decline in vaccinated mice correlated with bacterial burden in the lungs. This supports the fluorescence output from the skin as a reflection of vaccine induced functional pulmonary immune responses. This novel non-invasive approach allows for repeated measurements from the challenge site, providing a dynamic readout of vaccine induced responses over time. This BCG skin challenge model represents an important contribution to the ongoing development of controlled challenge models for Tuberculosis.