Abstract
Controlled human infection models (CHIMs) can accelerate vaccine development for infectious diseases. Mycobacterium tuberculosis is a human-adapted pathogen that is the leading infectious cause of death worldwide. M tuberculosis infection results in a spectrum of clinical outcomes that are incompletely modelled in animals. To date, the risks of infection, prolonged treatment, and sequelae related to CHIMs with M tuberculosis have been considered ethically unacceptable. However, recent advances in bacterial engineering have resulted in safe strains that could permit M tuberculosis CHIM studies with reduced risks. In this Personal View, we address the practical considerations for conducting a pulmonary M tuberculosis CHIM study. We summarise the ethical issues of M tuberculosis CHIM studies in tuberculosis-endemic and non-endemic settings; describe safety considerations, such as optimising the challenge dose and minimising risks to third parties; and outline and prioritise clinical, microbiological, immunological, and radiological endpoints that would render such a model useful for vaccine development.