Presented by

Dr. Jonathan Blackburn

Tuberculosis disease (TB) remains a major global health challenge today, despite the availability of vaccine and an armoury of small molecule drugs. Notably, response rates to the century-old bacillus Calmette-Guerin (BCG) vaccine vary widely, for reasons that remain poorly understood. We have therefore developed a lung-oriented controlled human infection model of tuberculosis disease to better understand TB immunopathogenesis across a spectrum of disease susceptibilities. We recruited 106 healthy South African participants who had previously either single or multiple bouts of TB disease, a latent TB infection, or who appeared to have sterilising immunity. Live BCG, sterile PPD and saline were bronchoscopically instilled into separate lung segments (n = 65). A control group (n = 34) underwent a single bronchoscopy without challenge.

Bronchoalveolar lavage (BAL) samples were collected before and 3 days after challenge and analysed using mass spectrometry-based proteomics and antigen microarrays, in order to quantify cellular and antibody immune signatures as a function of challenge and disease susceptibility.

We observed that immune responses were highly compartment specific (BAL vs. blood) and localized to the challenged lung segments. We also found that in general, adaptive responses increased in magnitude with increasing disease susceptibility, but that these were highly heterogeneous within a challenge- and susceptibility group, which may have implications for future research on vaccine design and administration.