Assessing immunogenicity of LepVax: a new leprosy vaccine in clinical development

项目摘要/摘要 麻风分枝杆菌感染会导致麻风，这是一种皮肤科和神经系统疾病，是 全球非外伤性毁容和残疾的主要原因。尽管多药疗法(MDT) 报告病例数量减少，麻风持续存在，需要新的干预策略来维持 并推动进一步削减。我们已经开发出一种定义的亚单位疫苗，称为LepVax，它能够 预防给小鼠提供麻风杆菌，可减轻麻风杆菌的负担。用实验感染的方式感染螳螂， 我们已经证明，暴露后使用LepVax进行预防可以缓解和延迟神经中断 由麻风杆菌感染引起。最近在美国完成的一项第一阶段临床试验表明，该疫苗是 在人类体内是安全的。来自第一阶段试验的初步数据显示，疫苗特异性免疫球蛋白的诱导能力很强 抗体。此处建议的研究将使额外的免疫原性评估能够完成 这是第一项人类研究，通过表征疫苗特异性体液和细胞的数量和质量 回应。其余的拟议活动将使我们能够以最佳方式为疫苗评估做准备- 在流行区目标人群中进行的资助1b期试验中的诱导反应 (巴西)。首先，我们将优化四种关键的免疫原性检测方法，包括酶联免疫吸附试验、干扰素γ-ELISpot、细胞内 细胞因子染色和细胞因子多重分析，用于LepVax抗原。接下来，我们将进行化验 验证研究，以确保方法是具体的，并产生可靠的数据。最后，我们将评估 已用于结核病领域作为麻风生物标志物的几种探索性分析 疾病状况。在多个疾病领域，生物标记物已被证明在测量疾病状态和 提供疫苗效力的免疫关联，以支持概念验证研究并加速疫苗接种 发展。利用麻风病人治疗期间收集的内部标本和健康接触者 作为对照，我们将评估三种检测方法，包括血清蛋白多重分析、免疫表型分析、 分枝杆菌生长抑制试验。通过完成第一次免疫原性表征- 在人体试验中，这些研究将有助于将一种有前途的新麻风病候选疫苗推向临床测试 在流行国家和受感染的个人。验证研究将确保来自阶段的数据 1B试验对于目标人群的剂量选择是可靠和可靠的。最后，我们将利用我们的 在结核病方面的经验，以筛选和排名在其他地方已成功的分析，以供未来纳入 作为潜在疾病状态生物标记物的研究，可能成为更广泛的麻风病的变革性工具 菲尔德。

PROJECT SUMMARY/ABSTRACT Mycobacterium leprae infection causes leprosy, a dermatological and neurological disease that is among the leading causes of non-traumatic disfigurements and disabilities worldwide. Although multidrug therapy (MDT) has reduced reported case numbers, leprosy persists and new intervention strategies are required to maintain and promote further reductions. We have developed a defined subunit vaccine, called LepVax, which is capable of reducing M. leprae burden when provided prophylactically to mice. Using experimental infection in armadillos, we have shown that post-exposure prophylaxis with LepVax alleviates and delays the neurologic disruptions caused by M. leprae infection. A recently completed Phase 1 clinical trial in the US indicated that the vaccine is safe in humans. Preliminary data from the Phase 1 trial demonstrate robust induction of vaccine-specific IgG antibodies. The studies proposed here will enable additional immunogenicity assessments to be completed for this first-in-human study by characterizing magnitude and quality of vaccine-specific humoral and cellular responses. The remaining proposed activities will allow us to optimally prepare for evaluations of vaccine- induced responses in a funded Phase 1b trial in being conducted in target populations in an endemic region (Brazil). First, we will optimize four key immunogenicity assays, including ELISA, IFNγ-ELISpot, intracellular cytokine staining, and a cytokine multiplex assay, for use with the LepVax antigen. Next, we will perform assay validation studies to ensure that the methods are specific and produce reliable data. Finally, we will evaluate several exploratory assays that have been used in the tuberculosis field for utility as biomarkers for leprosy disease status. In multiple disease fields, biomarkers have proved useful in measuring disease status and in providing immune correlates of vaccine efficacy that can enable proof of concept studies and accelerate vaccine development. Using in-house specimens collected during treatment of leprosy patients and healthy contact controls, we will evaluate three assays including a serum protein multiplex assay, an immunophenotyping panel, and a mycobacterial growth inhibition assay. By completing the immunogenicity characterization from the first- in-human trial, these studies will serve to advance a promising new leprosy vaccine candidate into clinical testing in endemic countries and exposed individuals. The validation studies will ensure that the data from the Phase 1b trial is robust and reliable for informing dose selection in target populations. Lastly, we will leverage our experience in tuberculosis to screen and rank assays that have been successful elsewhere for inclusion in future studies as potential disease status biomarkers, which could be a transformative tools for the broader leprosy field.