Using aerosol Bacille Calmette-Guérin in non-human primates to model the immune response to Mycobacterium Tuberculosis: a translational bridge between preclinical models and clinical trials

Tuberculosis (TB) is a major cause of death worldwide. We have a limited understanding of how the human immune system responds to Mycobacterium tuberculosis (M.tb), the main infectious agent that causes TB. In this project, non-human primates (NHPs) were exposed by aerosol to 1x107 colony forming units (CFU) of Bacille Calmette-Guérin (aeBCG). BCG is a live attenuated strain of Mycobacterium bovis, which can be used as a model of M.tb infection, and was safe to deliver to NHPs in a controlled manner. The immune response to aeBCG was characterised across different tissue compartments: blood, broncho-alveolar lavage (BAL), lymph nodes (LNs) and lung. There was little overall change in the immune parameters measured in either rhesus or cynomolgus macaques (RM or CM) at Day 2 (D2), D7 or D14 after aeBCG. Expression of cluster of differentiation-161 (CD161) on lymphocyte subsets was an early marker of this response at Week 2 (Wk2). Purified Protein Derivative (PPD)-specific interferon-gamma (IFNg)-producing spot forming unit (SFU) frequency increased from Wk4 to Wk16 after aeBCG. The peak immune response, measured by flow cytometry was at Wk12. PPD-specific immunoglobulin-G (IgG) titre increased at Wk9 in serum. The kinetic of the immune response to aeBCG measured was similar, but delayed, compared to the previously published immune response to intradermal (ID) BCG6, 8. The aeBCG delivery method (mask or mouthpiece) had no effect on the observed changes in immune parameters. Data from animals in both delivery groups were combined (n=16). A parallel experimental clinical medicine study showed the peak immune response to 1x107 CFU aeBCG in humans was at D7 (McShane group, Oxford – ClinicalTrials.gov ID: NCT03912207). The differences in immune response kinetic detected between NHPs and humans shown in this project have not been previously described and merit further study.