Pathway to a controlled human infection model for Leishmania major

Parkash, Vivak

Abstract

Leishmaniasis is a neglected tropical disease that disproportionately affects those afflicted by malnutrition and poverty. The insect vector, the sand fly, is increasingly found in temperate climates, due to the effects of climate change. There is a wide spectrum of clinical disease, from visceral leishmaniasis which affects internal organs causing hepatosplenomegaly and immune dysregulation, to cutaneous leishmaniasis which can causing disfiguring skin lesions. The particular disease that an individual exhibits is dependent upon the species of Leishmania involved, but also many host-related factors. The sand fly has been shown to be integral to not only disease spread, but also disease initiation with components from the sand fly salivary gland emitted during biting. These sand fly salivary gland proteins assist the parasite in evading the host immune defences to allow replication and infection to occur. There is a high degree of genetic homogeneity between Leishmania species, and so research focusing on one species of Leishmania can help in finding new treatments and control strategies for the whole genus. There are no current vaccines for leishmaniasis licensed for human use, and limited treatment options, all of which now have shown evidence of resistance. One method to accelerate vaccine candidate selection at an early stage of development is the use of controlled human infection models (CHIMs). These CHIMs have been used for many infectious diseases, including parasitic, bacterial and viral pathogens, as a measured process to assess novel therapeutic agents.
This thesis describes the key steps taken in developing a novel sand fly initiated CHIM for Leishmania major, a form of the disease which causes predominantly localised skin lesions. The first step was a public involvement (PI) exercise to assess public acceptability and perception of a CHIM approach using infected sand flies. This exercise reinforced the need for clarity of information, but also safety checkpoints to allow for participant confidence in the processes. This PI group activity directly influenced the methodology of the proposed work. The next step was a study demonstrating the safety and efficacy of a protocol using infected sand fly biting on human volunteers (the FLYBITE study). Acceptability was confirmed post-study by focus group, which also impacted on future study considerations. Finally, an efficacious and safe novel CHIM for sand fly initiated cutaneous leishmaniasis on human volunteers was developed, which now has the potential to be used for emerging vaccine candidates in the development pipeline.

Citation

Parkash, V. Pathway to a controlled human infection model for Leishmania major. (Thesis). Hull York Medical School. https://hull-repository.worktribe.com/output/4790646

• Thesis Type: Thesis
• Deposit Date: Aug 22, 2024
• Keywords: Medical sciences
• Public URL: https://hull-repository.worktribe.com/output/4790646
• Additional Information: Hull York Medical School; University of York and University of Hull
• Award Date: Oct 1, 2023