Challenges in Developing a Controlled Human Tuberculosis Challenge Model.

Controlled human infection models (CHIMs) have provided pivotal scientific advancements, contributing to the licensure of new vaccines for many pathogens. Despite being one of the world's oldest known pathogens, there are still significant gaps in our knowledge surrounding the immunobiology of Mycobacterium tuberculosis (M. tb). Furthermore, the only licensed vaccine, BCG, is a century old and demonstrates limited efficacy in adults from endemic areas. Despite good global uptake of BCG, tuberculosis (TB) remains a silent epidemic killing 1.4 million in 2019 (WHO, Global tuberculosis report 2020). A mycobacterial CHIM could expedite the development pipeline of novel TB vaccines and provide critical understanding on the immune response to TB. However, developing a CHIM for such a complex organism is a challenging process. The first hurdle to address is which challenge agent to use, as it would not be ethical to use virulent M. tb. This chapter describes the current progress and outstanding issues in the development of a TB CHIM. Previous and current human studies include both aerosol and intradermal models using either BCG or purified protein derivative (PPD) as a surrogate agent. Future work investigating the use of attenuated M. tb is underway.