Researchers say they have developed a novel, safe, and effective way to infect volunteers with the parasite that causes leishmaniasis and measure the body’s immune response, bringing a vaccine for the neglected tropical disease a step closer. The team from the University of York and Hull York Medical School, which described their work “Safety and reactogenicity of a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis” in Nature Medicine, believes their approach lays the foundations for vaccine development and for testing new preventative measures.
Leishmaniasis is caused by infection with microscopic Leishmania parasites that are transmitted into the skin during the bite of an infected sand fly. The disease affects over one million people every year, the majority developing a slow to heal ulcer at the site of the infection. Though the ulcer eventually heals, the scar has a significant impact on quality of life, especially for women and children and when the infection is on the face.
No vaccines or drugs are currently available to prevent people from becoming infected with leishmaniasis, in part due to the difficulties and costs associated with conducting clinical trials in the countries where these diseases are most common.
“This is a landmark study that now provides a new approach to test vaccines and preventative measures for leishmaniasis in a rapid and cost-effective way,” said Paul Kaye, PhD, lead investigator, from the Hull York Medical School at the University of York. “It also allows us to learn more about how our immune system fights the infection. Thanks to the generosity of the volunteers that took part in our study, we are now well-positioned to bring new hope to those that are affected by this disease.”
“Research on skin diseases that affect people in the UK and in developing countries is a priority at the Medical School,” added Alison Layton, PhD, clinical lead for the study, from the Medical School’s Center for Skin Research. “This study, which demonstrates that this infection model is safe and well tolerated by participants, exemplifies our global approach to skin health and has the potential to impact the lives of many millions worldwide.”
The study, which builds on achievements by the University of York and its international partners, involved 14 volunteers recruited from around York. The volunteers were exposed to sand flies infected with a parasite species that causes one of the mildest forms of leishmaniasis. The researchers followed the development of the lesion at the site of the sand fly bite to evaluate the progress of the infection and then terminated the infection by biopsy of the skin. The scientists then studied the biopsy to examine the immune responses at the site of infection.
“Between 24 January and 12 August 2022, we exposed 14 participants to L. major-infected Phlebotomus duboscqi. The primary objective was to demonstrate effectiveness of lesion development (take rate) and safety (absence of CL lesion at 12 months). Secondary and exploratory objectives included rate of lesion development, parasite load and analysis of local immune responses by immunohistology and spatial transcriptomics,” wrote the investigators.
“Lesion development was terminated by therapeutic biopsy (between days 14 and 42 after bite) in ten participants with clinically compatible lesions, one of which was not confirmed by parasite detection. We estimated an overall take rate for CL development of 64% (9/14). Two of ten participants had one and one of ten participants had two lesion recurrences 4–8 months after biopsy that were treated successfully with cryotherapy. No severe or serious adverse events were recorded, but as expected, scarring due to a combination of CL and the biopsy procedure was evident. All participants were lesion free at >12-month follow-up.
“We provide the first comprehensive map of immune cell distribution and cytokine/chemokine expression in human CL lesions, revealing discrete immune niches. This CHIM [controlled human infection model] offers opportunities for vaccine candidate selection based on human efficacy data and for a greater understanding of immune-mediated pathology.”
This major new approach uses natural transmission by sand fly to initiate infection and advanced technologies, allowing the researchers to track the infection and the body’s immune response in real-time, say the researchers, who also expect that the model will accelerate efforts to test new vaccines and understand how immunity to infection arises.
The team now hopes to use their model to design clinical trials to test a vaccine developed at Hull York Medical School, along with other candidate vaccines available in the future. Controlled human infection models have already been used to support the development of vaccines for cholera, malaria, influenza, dengue fever, and most recently COVID-19.
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