Controlled human infection with Mycobacterium tuberculosis: practical considerations for clinical trials

Authors:

• Seshadri, Chetan
• Flynn, JoAnne L
• Maiello, Pauline
• Schnappinger, Dirk
• Wilkinson, Robert J
• Gordon, Stephen B
• Mwandumba, Henry C
• Jambo, Kondwani C
• Hoft, Daniel F
• Rubin, Eric J
• Jamrozik, Euzebiusz
• Fortune, Sarah M
• Kublin, James G

Details:

The Lancet Microbe, 2026-01-23

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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.