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

Area of Science:

• Infectious Diseases
• Vaccinology
• Microbiology

Background:

• Tuberculosis (TB) remains a leading global infectious cause of death, with complex clinical outcomes poorly modeled in animals.
• Controlled human infection models (CHIMs) offer accelerated vaccine development but have faced ethical barriers for Mycobacterium tuberculosis due to safety concerns.
• Recent advances in bacterial engineering have produced safer M. tuberculosis strains, potentially enabling ethical CHIM studies.

Purpose of the Study:

• To address the practical and ethical considerations for conducting pulmonary Mycobacterium tuberculosis CHIM studies.
• To outline essential safety measures, including dose optimization and risk mitigation for M. tuberculosis CHIMs.
• To define key clinical, microbiological, immunological, and radiological endpoints for effective TB vaccine development using CHIMs.

Main Methods:

• Review of ethical considerations for M. tuberculosis CHIMs in diverse settings.
• Analysis of safety parameters, including challenge dose and protection of third parties.
• Prioritization of relevant endpoints for vaccine efficacy assessment.

Main Results:

• Engineered safe strains of M. tuberculosis may overcome previous ethical objections to CHIMs.
• Practical guidelines are proposed for optimizing safety and minimizing risks in M. tuberculosis CHIMs.
• A framework for selecting critical endpoints is presented to maximize the utility of CHIMs for TB vaccine research.

Conclusions:

• M. tuberculosis CHIMs, utilizing advanced bacterial engineering, present a viable strategy to accelerate TB vaccine development.
• Careful consideration of ethical issues and safety protocols is paramount for successful implementation.
• Defining robust endpoints is crucial for maximizing the scientific return and translational impact of these models.