The leishmaniases are globally important parasitic diseases for which no human vaccines are currently available. To facilitate vaccine development, we conducted an open label observational study to establish a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis caused by L. major. Between 24th January and 12th August 2022, we exposed 14 (8F, 6M) participants to infected Phlebotomus duboscqi. The primary objective was to demonstrate effectiveness (take rate) and safety (absence of CL lesion at 12 months), whereas secondary and exploratory objectives included rate of lesion development, parasite load and analysis of local immune responses by immunohistology and spatial transcriptomics. We estimated an overall take rate for CL development of 64% (9/14), or 82% (9/11) if calculated using only participants having confirmed bites following exposure. Lesion development was terminated by therapeutic biopsy in 10 participants with confirmed bites. 2/10 had one and 1/10 had two lesion recurrences 4-8 months after biopsy that were treated successfully with cryotherapy. No severe or serious adverse events were recorded, but scarring was evident as expected. 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 controlled human infection model offers opportunities for rapid vaccine candidate selection and a greater understanding of immune-mediated protection and pathology. The study was registered at ClinicalTrials.gov Identifier: NCT04512742

PMK and CJNL are co-authors of a patent protecting the gene insert used in Leishmania candidate vaccine ChAd63-KH (Europe 10719953.1; India 315101). The authors declare no other competing interests.

NCT04512742.

This work was funded by a Developmental Pathways Funding Scheme award (MR/R014973 to PMK, CJNL, AL, PV and CLJ). This award is jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 programme supported by the European Union. PV and JS were partially supported by European Regional Development Funds (project CePaViP 16_019/0000759).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by the UK Health Research Agency South Central - Hampshire A Research Ethics Committee (IRAS Project ID:286420; 20/SC/0348) and the Hull York Medical School Ethical Review Committee (Approval No. 2073). The study sponsor was University of York. The study was prospectively registered at ClinicalTrials.gov Identifier: NCT04512742.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The additional datasets generated, analysed, and supporting the conclusions of this study are available upon reasonable request (including a detailed proposal for its use) from VP, HA, SD, CJNL, AML, and PMK, and with agreement from the study sponsor. Processed spatial transcriptomics data is available at 10.5281/zenodo.10018477 with instructions and code at https://github.com/jipsi/chim. Raw transcriptomic data has been deposited in GEO (GSE263298) available from: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE263298

https://github.com/jipsi/chim

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE263298