PhD defence: Exploring protective and pathogenic immune responses in the non-human primate model of tuberculosis

To this day, tuberculosis, caused by Mycobacterium tuberculosis (Mtb), kills over 1,5 million people annually. The lack of an effective vaccine, accurate diagnostics and knowledge concerning protective immunity hamper the elimination of this disease. This thesis, by modeling and investigating tuberculosis in non-human primates (NHPs), aims to address these issues, while simultaneously attempting to refine and improve the model.

By comparing immune responses after Mtb infection or vaccination, several immune-correlates of protection could be identified. Immune responses in the lung especially, appeared to be of critical importance in influencing disease outcome. NHP that were more resistant to tuberculosis disease exhibited stronger innate immune responses in the lung, while more disease-susceptible animals displayed more suppressive immune responses in peripheral blood.

Also, BCG vaccination via the lung resulted in a unique local immune response and increased protection from infection and disease compared to vaccination through the skin. Pulmonary vaccination with MTBVAC, a novel tuberculosis vaccine under development, also conferred this protective response. Lastly, biomaterial from these and other studies was used to investigate the association of a potential new biomarker for tuberculosis disease severity. Besides the identification of these protective immune responses, the NHP tuberculosis model has been significantly refined, by the development of a repeated Mtb exposure model, which more closely resembles how humans are exposed to the bacterium.

Taken together, the NHP studies described in this thesis have added to the model and contributed to our knowledge of protective tuberculosis immunity, thereby furthering the efforts towards elimination of tuberculosis.