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 (CHIM) of sand fly-transmitted cutaneous leishmaniasis (CL) caused by Leishmania major. 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. 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 offers opportunities for vaccine candidate selection based on human efficacy data and for a greater understanding of immune-mediated pathology. ClinicalTrials.gov identifier: NCT04512742 .

Center for Geographic Medicine and Tropical Diseases Chaim Sheba Medical Center and the School of Medicine Tel Aviv University Tel Aviv Israel

Department of Microbiology and Molecular Genetics Kuvin Center for the Study of Infectious and Tropical Diseases IMRIC The Hebrew University Hadassah Medical School Jerusalem Israel

Department of Parasitology Faculty of Science Charles University Prague Czech Republic

Skin Research Centre Hull York Medical School York UK

York and Scarborough Teaching Hospitals NHS Foundation Trust York UK

York Biomedical Research Institute Hull York Medical School University of York York UK

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Mann, S. et al. A review of leishmaniasis: current knowledge and future directions. Curr. Trop. Med. Rep.8, 121–132 (2021). PubMed PMC

Okwor, I. & Uzonna, J. Social and economic burden of human leishmaniasis. Am. J. Trop. Med. Hyg.94, 489–493 (2016). PubMed PMC

World Health Organization. Global leishmaniasis surveillance: 2019–2020, a baseline for the 2030 roadmap https://www.who.int/publications/i/item/who-wer9635-401-419 (2021).

Bailey, F. et al. Cutaneous leishmaniasis and co-morbid major depressive disorder: a systematic review with burden estimates. PLoS Negl. Trop. Dis.13, e0007092 (2019). PubMed PMC

Bilgic-Temel, A., Murrell, D. F. & Uzun, S. Cutaneous leishmaniasis: a neglected disfiguring disease for women. Int. J. Womens Dermatol.5, 158–165 (2019). PubMed PMC

Bern, C., Maguire, J. H. & Alvar, J. Complexities of assessing the disease burden attributable to leishmaniasis. PLoS Negl. Trop. Dis.2, e313 (2008). PubMed PMC

Le Rutte, E. A., Coffeng, L. E., Malvolti, S., Kaye, P. M. & de Vlas, S. J. The potential impact of human visceral leishmaniasis vaccines on population incidence. PLoS Negl. Trop. Dis.14, e0008468 (2020). PubMed PMC

Kaye, P. M. et al. Vaccine value profile for leishmaniasis Vaccine41 Suppl 2, S153–S175 (2023). PubMed

World Health Organization. Strategic Advisory Group of Experts on Immunization Meeting Report https://terrance.who.int/mediacentre/data/sage/SAGE_eYB_Mar2023.pdf (2023).

Malvolti, S., Malhame, M., Mantel, C. F., Le Rutte, E. A. & Kaye, P. M. Human leishmaniasis vaccines: use cases, target population and potential global demand. PLoS Negl. Trop. Dis.15, e0009742 (2021). PubMed PMC

Mohan, S. et al. Estimating the global demand curve for a leishmaniasis vaccine: a generalisable approach based on global burden of disease estimates. PLoS Negl. Trop. Dis.16, e0010471 (2022). PubMed PMC

Kaye, P. M. et al. Overcoming roadblocks in the development of vaccines for leishmaniasis. Expert Rev. Vaccines20, 1419–1430 (2021). PubMed PMC

Working Group on Research Priorities for Development of Leishmaniasis Vaccines et al. Vaccines for the leishmaniases: proposals for a research agenda. PLoS Negl. Trop. Dis.5, e943 (2011). PubMed PMC

Younis, B. M. et al. Safety and immunogenicity of ChAd63-KH vaccine in post-kala-azar dermal leishmaniasis patients in Sudan. Mol. Ther.29, 2366–2377 (2021). PubMed PMC

Volpedo, G. et al. The history of live attenuated Centrin gene-deleted Leishmania vaccine candidates. Pathogens11, 431 (2022). PubMed PMC

Cooper, M. M., Loiseau, C., McCarthy, J. S. & Doolan, D. L. Human challenge models: tools to accelerate the development of malaria vaccines. Expert Rev. Vaccines18, 241–251 (2019). PubMed

Roobsoong, W., Yadava, A., Draper, S. J., Minassian, A. M. & Sattabongkot, J. The challenges of Plasmodium vivax human malaria infection models for vaccine development. Front. Immunol.13, 1006954 (2022). PubMed PMC

Koopman, J. P. R., Driciru, E. & Roestenberg, M. Controlled human infection models to evaluate schistosomiasis and hookworm vaccines: where are we now? Expert Rev. Vaccines20, 1369–1371 (2021). PubMed

Pritchard, D. I. et al. Controlled infection of humans with the hookworm parasite Necator americanus to accelerate vaccine development: the Human Hookworm Vaccination/Challenge Model (HVCM). Curr. Top. Microbiol. Immunol.10.1007/82_2021_237 (2021). PubMed

Melby, P. C. Experimental leishmaniasis in humans: review. Rev. Infect. Dis.13, 1009–1017 (1991). PubMed

Pacheco-Fernandez, T. et al. Revival of leishmanization and leishmanin. Front. Cell. Infect. Microbiol.11, 639801 (2021). PubMed PMC

Khamesipour, A. et al. Leishmanization: use of an old method for evaluation of candidate vaccines against leishmaniasis. Vaccine23, 3642–3648 (2005). PubMed

Serafim, T. D. et al. Leishmaniasis: the act of transmission. Trends Parasitol.37, 976–987 (2021). PubMed

Peters, N. C. et al. Vector transmission of Leishmania abrogates vaccine-induced protective immunity. PLoS Pathog.5, e1000484 (2009). PubMed PMC

Ashwin, H. et al. Characterization of a new Leishmania major strain for use in a controlled human infection model. Nat. Commun.12, 215 (2021). PubMed PMC

Parkash, V. et al. A clinical study to optimise a sand fly biting protocol for use in a controlled human infection model of cutaneous leishmaniasis (the FLYBITE study). Wellcome Open Res.6, 168 (2021). PubMed PMC

Parkash, V. et al. Assessing public perception of a sand fly biting study on the pathway to a controlled human infection model for cutaneous leishmaniasis. Res. Involv. Engagem.7, 33 (2021). PubMed PMC

Serarslan, G., Ekiz, O., Ozer, C. & Sarikaya, G. Dermoscopy in the diagnosis of cutaneous leishmaniasis. Dermatol. Pract. Concept.9, 111–118 (2019). PubMed PMC

Basra, M. K. A., Salek, M. S., Camilleri, L., Sturkey, R. & Finlay, A. Y. Determining the minimal clinically important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data. Dermatology230, 27–33 (2015). PubMed

Toussaint, A. et al. Sensitivity to change and minimal clinically important difference of the 7-item Generalized Anxiety Disorder Questionnaire (GAD-7). J. Affect. Disord.265, 395–401 (2020). PubMed

Clenet, M. L., Gagnon, F., Moratalla, A. C., Viel, E. C. & Arbour, N. Peripheral human CD4+CD8+ T lymphocytes exhibit a memory phenotype and enhanced responses to IL-2, IL-7 and IL-15. Sci. Rep.7, 11612 (2017). PubMed PMC

Overgaard, N. H., Jung, J. W., Steptoe, R. J. & Wells, J. W. CD4+/CD8+ double-positive T cells: more than just a developmental stage? J. Leukoc. Biol.97, 31–38 (2015). PubMed

McGovern, N. et al. Human dermal CD14+ cells are a transient population of monocyte-derived macrophages. Immunity41, 465–477 (2014). PubMed PMC

Reynolds, G. et al. Developmental cell programs are co-opted in inflammatory skin disease. Science371, eaba6500 (2021). PubMed PMC

Kleshchevnikov, V. et al. Cell2location maps fine-grained cell types in spatial transcriptomics. Nat. Biotechnol.40, 661–671 (2022). PubMed

Molinier-Frenkel, V., Prevost-Blondel, A. & Castellano, F. The IL4I1 enzyme: a new player in the immunosuppressive tumor microenvironment. Cells8, 757 (2019). PubMed PMC

Dey, N. S. et al. IL-32 producing CD8+ memory T cells and Tregs define the IDO1 / PD-L1 niche in human cutaneous leishmaniasis skin lesions. Preprint at medRxiv10.1101/2024.01.02.23300281 (2024).

Kolberg, L. et al. g:Profiler-interoperable web service for functional enrichment analysis and gene identifier mapping (2023 update). Nucleic Acids Res.51, W207–W212 (2023). PubMed PMC

Kunkel, E. J. et al. Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes. Am. J. Pathol.160, 347–355 (2002). PubMed PMC

Oulee, A. et al. Identification of genes encoding antimicrobial proteins in Langerhans cells. Front. Immunol.12, 695373 (2021). PubMed PMC

Zhao, H., Huang, M. & Jiang, L. Potential roles and future perspectives of chitinase 3-like 1 in macrophage polarization and the development of diseases. Int. J. Mol. Sci.24, 16149 (2023). PubMed PMC

Reales-Calderon, J. A., Aguilera-Montilla, N., Corbi, A. L., Molero, G. & Gil, C. Proteomic characterization of human proinflammatory M1 and anti-inflammatory M2 macrophages and their response to Candida albicans. Proteomics14, 1503–1518 (2014). PubMed

Xiong, D., Wang, Y. & You, M. A gene expression signature of TREM2hi macrophages and γδ T cells predicts immunotherapy response. Nat. Commun.11, 5084 (2020). PubMed PMC

Dai, H., Wang, L., Li, L., Huang, Z. & Ye, L. Metallothionein 1: a new spotlight on inflammatory diseases. Front. Immunol.12, 739918 (2021). PubMed PMC

Azab, A. S., Kamal, M. S., el-Haggar, M. S., Metawaa, B. A. & Hindawy, D. S. Early surgical treatment of cutaneous leishmaniasis. J. Dermatol. Surg. Oncol.9, 1007–1012 (1983). PubMed

Darton, T. C. et al. Using a human challenge model of infection to measure vaccine efficacy: a randomised, controlled trial comparing the typhoid vaccines M01ZH09 with placebo and Ty21a. PLoS Negl. Trop. Dis.10, e0004926 (2016). PubMed PMC

Kimblin, N. et al. Quantification of the infectious dose of Leishmania major transmitted to the skin by single sand flies. Proc. Natl Acad. Sci. USA105, 10125–10130 (2008). PubMed PMC

Stamper, L. W. et al. Infection parameters in the sand fly vector that predict transmission of Leishmania major. PLoS Negl. Trop. Dis.5, e1288 (2011). PubMed PMC

Kirstein, O. D. et al. Minimally invasive microbiopsies: a novel sampling method for identifying asymptomatic, potentially infectious carriers of Leishmania donovani. Int. J. Parasitol.47, 609–616 (2017). PubMed PMC

Jacintho, A. P. P. et al. Expression of matrix metalloproteinase-2 and metalloproteinase-9 in the skin of dogs with visceral leishmaniasis. Parasitol. Res.117, 1819–1827 (2018). PubMed

Murase, L. S. et al. The role of metalloproteases in Leishmania species infection in the New World: a systematic review. Parasitology145, 1499–1509 (2018). PubMed

Sghaier, R. M. et al. Healed lesions of human cutaneous leishmaniasis caused by Leishmania major do not shelter persistent residual parasites. Front. Cell. Infect. Microbiol.12, 839216 (2022). PubMed PMC

Kapulu, M. et al. Fourth Controlled Human Infection Model (CHIM) meeting—CHIMs in endemic countries, May 22–23, 2023. Biologicals85, 101747 (2024). PubMed PMC

Parkash, V., Kaye, P. M., Layton, A. M. & Lacey, C. J. Vaccines against leishmaniasis: using controlled human infection models to accelerate development. Expert Rev. Vaccines20, 1407–1418 (2021). PubMed PMC

Kaye, P. M., Parkash, V., Layton, A. M. & Lacey, C. J. N. The utility of a controlled human challenge model for developing leishmaniasis vaccines. In Vaccines for Neglected Pathogens: Strategies, Achievements and Challenges (ed Christodoulides, M.) 263–279 (Springer, 2023).

Scott, P. & Novais, F. O. Cutaneous leishmaniasis: immune responses in protection and pathogenesis. Nat. Rev. Immunol.16, 581–592 (2016). PubMed

Chaves, M. M. et al. The role of dermis resident macrophages and their interaction with neutrophils in the early establishment of Leishmania major infection transmitted by sand fly bite. PLoS Pathog.16, e1008674 (2020). PubMed PMC

Lee, S. H. et al. M2-like, dermal macrophages are maintained via IL-4/CCL24–mediated cooperative interaction with eosinophils in cutaneous leishmaniasis. Sci. Immunol.5, eaaz4415 (2020). PubMed PMC

Ajdary, S., Alimohammadian, M. H., Eslami, M. B., Kemp, K. & Kharazmi, A. Comparison of the immune profile of nonhealing cutaneous leishmaniasis patients with those with active lesions and those who have recovered from infection. Infect. Immun.68, 1760–1764 (2000). PubMed PMC

Miramin-Mohammadi, A. et al. Immune response in cutaneous leishmaniasis patients with healing vs. non-healing lesions. Iran. J. Microbiol.12, 249–255 (2020). PubMed PMC

ElHassan, A. M., Gaafar, A. & Theander, T. G. Antigen-presenting cells in human cutaneous leishmaniasis due to Leishmania major. Clin. Exp. Immunol.99, 445–453 (1995). PubMed PMC

Louzir, H. et al. Immunologic determinants of disease evolution in localized cutaneous leishmaniasis due to Leishmania major. J. Infect. Dis.177, 1687–1695 (1998). PubMed

Boussoffara, T. et al. Histological and immunological differences between zoonotic cutaneous leishmaniasis due to Leishmania major and sporadic cutaneous leishmaniasis due to Leishmania infantum. Parasite26, 9 (2019). PubMed PMC

Karmakar, S. et al. Preclinical validation of a live attenuated dermotropic Leishmania vaccine against vector transmitted fatal visceral leishmaniasis. Commun. Biol.4, 929 (2021). PubMed PMC

Rodgers, M. R., Popper, S. J. & Wirth, D. F. Amplification of kinetoplast DNA as a tool in the detection and diagnosis of Leishmania. Exp. Parasitol.71, 267–275 (1990). PubMed

Zappia, L. & Oshlack, A. Clustering trees: a visualization for evaluating clusterings at multiple resolutions. Gigascience7, giy083 (2018). PubMed PMC

A clinical study to optimise a sand fly biting protocol for use in a controlled human infection model of cutaneous leishmaniasis (the FLYBITE study)

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ClinicalTrials.gov
NCT04512742