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

评估 LepVax 的免疫原性：临床开发中的新型麻风疫苗

• 批准号: 9894569
• 负责人: MALCOLM S DUTHIE
• 金额: $ 22.12万
• 依托单位: HDT BIO CORPORATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-21 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894569
• 关键词: Address; Animal Model; Antibodies; Antigens; Biological Assay; Biological Markers; Blood specimen; Brazil; Case Study; Charge; Chimeric Proteins; Chronic Disease; Clinical; Clinical Trials; Country; Data; Dermatologic; Detection; Disease; Dose; Ensure; Enzyme-Linked Immunosorbent Assay; Family Dasypodidae; Flow Cytometry; Funding; Future; Genus Mycobacterium; Goals; Gold; Growth; Human; IgG1; Immune; Immune response; Immunoglobulin G; Immunophenotyping; Incidence; Individual; Infection; Intercept; Interferon Type II; Intervention; Leprosy; Licensure; London; Lymphocyte Activation; Measures; Methods; Modeling; Mus; Mycobacterium bovis; Mycobacterium leprae; Nervous system structure; Neurologic; Organism; Output; Patients; Performance; Phase I Clinical Trials; Phase Ib Trial; Prophylactic treatment; Public Health; Regimen; Reporting; Risk; Safety; Sampling; Serum; Serum Proteins; Skin; Specific qualifier value; Specificity; Specimen; Stains; Subunit Vaccines; Target Populations; Tuberculosis; Vaccination; Vaccine Clinical Trial; Vaccines; Whole Blood; Work; World Health Organization; anti-leprosy vaccine; candidate marker; clinical development; cytokine; disability; experience; first-in-human; global health; human study; immunogenicity; mycobacterial; neglected tropical diseases; nervous system disorder; phase I trial; programs; prophylactic; public health priorities; research clinical testing; response; tool; transmission process; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; validation studies

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.

项目总结/摘要 麻风分枝杆菌感染导致麻风病，这是一种皮肤和神经系统疾病， 这是全世界非创伤性毁容和残疾的主要原因。虽然多药治疗（MDT） 报告的病例数已经减少，麻风病仍然存在，需要新的干预战略来维持 并促进进一步减排。我们已经开发了一种定义明确的亚单位疫苗，称为LepVax， 减少M。预防性提供给小鼠时的麻风病负担。利用犰狳实验感染， 我们已经证明，暴露后预防与LepVax减轻和延迟神经系统的破坏， 支原体引起麻风病感染最近在美国完成的一项1期临床试验表明， 在人类中安全。来自I期试验的初步数据证明了疫苗特异性IgG的稳健诱导 抗体的此处拟定的研究将能够完成额外的免疫原性评估， 这项首次在人体内进行的研究，通过表征疫苗特异性体液和细胞免疫的强度和质量， 应答剩余的拟议活动将使我们能够为疫苗评估做最佳准备- 在流行地区的目标人群中进行的受资助的1b期试验中诱导的反应 （巴西）。首先，我们将优化四种关键的免疫原性检测方法，包括ELISA、IFNγ-ELISpot、细胞内 细胞因子染色和细胞因子多重测定，用于与LepVax抗原一起使用。接下来，我们将进行分析 验证研究，以确保方法的特异性和产生可靠的数据。最后，我们将评估 已在结核病领域用作麻风病生物标志物的几种探索性试验 疾病状态。在多个疾病领域，生物标志物已被证明可用于测量疾病状态并在临床上应用。 提供疫苗效力的免疫相关性，从而能够进行概念验证研究并加速疫苗接种。 发展使用麻风病人和健康接触者治疗期间采集的室内标本 对照，我们将评估三种测定，包括血清蛋白多重测定，免疫表型组， 和分枝杆菌生长抑制测定。通过完成第一个- 在人体试验中，这些研究将有助于推动一种有希望的新麻风疫苗候选物进入临床试验 在流行国家和接触者中。验证研究将确保阶段数据 1b试验对于告知目标人群的剂量选择是稳健和可靠的。最后，我们将利用 在结核病方面的经验，以筛选和排名已在其他地方成功纳入未来的检测方法 研究作为潜在的疾病状态生物标志物，这可能是更广泛的麻风病的变革工具 领域