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 24^th January and 12^th 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.

中文翻译：

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白蛉传播皮肤利什曼病受控人体感染模型的安全性、有效性和皮肤免疫反应

利什曼病是全球重要的寄生虫病，目前尚无人类疫苗。为了促进疫苗开发，我们进行了一项开放标签观察研究，以建立由白蛉传播的由硕大利什曼病引起的皮肤利什曼病的受控人类感染模型。 2022 年 1 月 24^{日至 8月}12 日期间，我们将 14 名（8F，6M）名参与者暴露于受感染的杜波斯白蛉（Phlebotomus duboscqi ） 。主要目标是证明有效性（接受率）和安全性（12 个月时无 CL 病变），而次要和探索性目标包括病变发展率、寄生虫负载以及通过免疫组织学和空间转录组学分析局部免疫反应。我们估计 CL 发展的总体接受率为 64% (9/14)，如果仅使用暴露后确认被咬伤的参与者进行计算，则为 82% (9/11)。 10 名确诊被咬伤的参与者通过治疗性活检终止了病变发展。活检后 4-8 个月，2/10 的患者出现 1 次病变复发，1/10 的患者出现 2 次病变复发，并通过冷冻疗法成功治愈。没有记录到严重或严重的不良事件，但疤痕如预期的那样明显。所有参与者在 12 个月以上的随访中均无病变。我们提供了人类 CL 病变中免疫细胞分布和细胞因子/趋化因子表达的第一个全面图谱，揭示了离散的免疫生态位。这种受控的人类感染模型为快速候选疫苗选择和更好地了解免疫介导的保护和病理学提供了机会。