Harnessing controlled human infection models to accelerate vaccine development for neglected tropical diseases: Lessons from leishmaniasis.

BACKGROUND: Controlled Human Infection Models (CHIMs) offer a powerful approach to expedite vaccine development by enabling early evaluation of vaccine candidate efficacy and immune responses. Their role is increasingly relevant for neglected tropical diseases (NTDs), where traditional trial approaches may be slow, costly, or unfeasible. This review explores the scientific, ethical and translational dimensions of CHIMs, with a focus on the recently developed Leishmania major CHIM for cutaneous leishmaniasis (CL).

METHODS: A narrative synthesis of peer-reviewed literature and regulatory guidance documents published over the past two decades was conducted, with additional insights drawn from original fieldwork and the first-in-human sand fly-transmitted CHIM for CL. Considerations included CHIM design principles, immunological outcomes, safety considerations and translational utility, including integration with omics and early phase trials.

RESULTS: CHIMs provide early efficacy data, help identify immune correlates of protection and facilitate the prioritisation of vaccine candidates. The Leishmania major CHIM demonstrated safety, high participant acceptability and revealed insights into lesion kinetics and host-parasite interactions. Ethical and regulatory frameworks remain heterogeneous across regions, limiting scalability. Barriers to CHIM deployment in low- and middle-income countries include infrastructure, governance and community engagement challenges.

CONCLUSIONS: CHIMs represent a critical translational tool for NTD vaccine research. Lessons from the CL CHIM underscore the potential and challenges of broader implementation. Harmonised regulation, ethical innovation and global collaboration will be essential for future impact.