IMPROVED ANTIGEN DETECTION TESTS FOR FILARIAL INFECTIONS

改进丝虫感染的抗原检测测试

• 批准号: 9509332
• 负责人: Philip Budge
• 金额: $ 17.34万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9509332
• 关键词: Adverse event; Adverse reactions; Africa; African; Antibodies; Antigens; Antiparasitic Agents; Applied Research; Area; Basic Science; Bedside Testings; Biological Assay; Biological Markers; Blood specimen; Central Africa; Certification; Cessation of life; Clinical Research; Communicable Diseases; Core Protein; Country; Detection; Development; Development Plans; Diagnosis; Diagnostic; Diagnostic tests; Disease; Dose; Drug usage; Encephalopathies; Environment; Epidemiology; Faculty; Filaria bancrofti; Filarial Elephantiases; Filariasis; Foundations; Funding; Future; Genes; Goals; Government; Human; Immunology; Individual; Industry; Infection; Internal Medicine; International; Interruption; Ivermectin; Knowledge; Laboratories; Loa; Loa loa; Loiasis; Mentors; Monitor; Monoclonal Antibodies; Nematoda; Onchocerciasis; Parasites; Parasitology; Patients; Persons; Pharmaceutical Preparations; Physicians; Population; Prevalence; Proteins; Public Health; Research; Research Personnel; Resources; Respiratory syncytial virus; Sampling; Scientist; Severe Adverse Event; Structure; Test Result; Testing; Time; Training; Translational Research; Universities; Washington; Work; World Health Organization; base; career; career development; cross reactivity; disability; experience; field study; global health; high risk; improved; neglected tropical diseases; novel; overtreatment; pathogen; programs; proteogenomics; public health intervention; public health research; research and development; skills; tool; transmission process; virology

PROJECT SUMMARY This project will identify and characterize biomarkers for human filarial infections and generate monoclonal antibodies against circulating filarial antigens that will be more specific than those used in current tests. The need for improved diagnostic tests is pressing at this time. The World Health Organization’s (WHO) Global Program to Eliminate Lymphatic Filariasis (GPELF) is rapidly moving towards its goal of global elimination of lymphatic filariasis (LF) by 2020. However, problems with diagnosis represent a major challenge to the program in Central Africa, where false positive results with the current filarial antigen tests may result in unnecessary and potentially harmful overtreatment of populations. Candidate I have more than 10 years of experience and training in biomedical, translational, and public health research. My doctoral studies on Respiratory Syncytial Virus gave me a broad understanding of principles of immunology, virology, and host-pathogen interactions. My more recent work in epidemiology has given me an appreciation of the scope and potential impact of global public health programs and of the critical importance of accurate diagnostic tools for public health programs and research. I am board certified in Internal Medicine with subspecialty certification as an Infectious Diseases clinician. This project supports my long-term career goal of becoming an independent investigator in the area of global infectious diseases with a focus on translational research of neglected tropical diseases; the project plan will also allow me to further develop my clinical research skills and knowledge of infectious diseases. Environment My surroundings at Washington University in St. Louis (WUSTL) are ideal for my proposed project and career development. The intellectual environment is outstanding and I intend to take advantage of this by completing a structured program of coursework focused on conducting field research in resource-poor settings. My mentor’s laboratory group has a tremendous amount of experience in basic and applied research in parasitology, and WUSTL is one of only a handful of research centers in the nation with strong expertise in filarial diseases. My mentor is the PI of the Death to Onchocerciasis and LF project (a large-scale global health project funded by the Bill and Melinda Gates Foundation), and has extensive expertise in parasitology, immunology, and international field research. This outstanding environment for filarial research was the reason I joined the WUSTL faculty in 2014. Research LF is one of the world’s leading causes of disability, and is one of a small number of infectious diseases that are potentially eradicable. WHO’s GPELF coordinates and supports the efforts of corporate, academic, governmental, and non-governmental partners to eliminate LF in 73 endemic countries through repeated cycles of mass drug administration (MDA) using industry-donated drugs. GPELF is the largest MDA-based public health intervention to date with more than 5.3 billion doses of antiparasitic medications distributed between 2000 and 2014 in 60 countries. Over 90% of the world’s LF burden (including all cases in Africa) is caused by the filarial nematode Wuchereria bancrofti (Wb), and all aspects of global elimination programs for bancroftian filariasis (mapping, MDA, surveillance, and verification) rely on diagnosis of LF using point-of-care tests that employ monoclonal antibodies to detect Wb circulating filarial antigen in blood samples. Recent studies have shown that these tests often produce falsely positive results with samples from people that are infected with Loa loa, a different filarial parasite that occurs in 11 countries in Central Africa. Inaccurate diagnostic test results can have serious or even fatal implications since drugs used in MDA for LF can cause serious adverse reactions (including encephalopathy and death) when taken by people with heavy L. loa infections. We hypothesize that falsely-positive filarial Wb antigen tests in patients with loiasis are due to the presence of a cross-reactive circulating L. loa antigen. This project aims to identify the circulating Loa antigen and develop assays that can distinguish the two infections. Improved diagnostic tests would significantly improve chances for control of loiasis and elimination of LF in the 11 Central African nations that have both of these diseases.

项目概要 该项目将识别和表征人类丝虫感染的生物标志物，并产生单克隆抗体 针对循环丝虫抗原的抗体将比当前测试中使用的抗体更具特异性。这 目前迫切需要改进诊断测试。世界卫生组织 (WHO) 全球 消除淋巴丝虫病计划 (GPELF) 正在迅速朝着全球消除淋巴丝虫病的目标迈进 到 2020 年，淋巴丝虫病 (LF) 将会出现。然而，诊断问题对 中部非洲的计划，当前丝虫抗原测试的假阳性结果可能会导致 对人群进行不必要且可能有害的过度治疗。 候选人 我在生物医学、转化和公共卫生研究方面拥有超过 10 年的经验和培训。 我对呼吸道合胞病毒的博士研究使我对呼吸道合胞病毒的原理有了广泛的了解 免疫学、病毒学和宿主-病原体相互作用。我最近在流行病学方面的工作给了我一个 认识到全球公共卫生计划的范围和潜在影响以及至关重要的 用于公共卫生计划和研究的准确诊断工具。我获得了内科委员会认证 作为传染病临床医生的亚专业认证。这个项目支持我的长期职业目标 成为全球传染病领域的独立研究者，重点关注转化 被忽视的热带病的研究；该项目计划还将使我能够进一步发展我的临床 传染病的研究技能和知识。 环境 圣路易斯华盛顿大学 (WUSTL) 的环境非常适合我提出的项目和职业生涯 发展。智力环境非常好，我打算利用这一点完成 一个结构化的课程计划，重点是在资源匮乏的环境中进行实地研究。我的 导师的实验室团队在基础和应用研究方面拥有丰富的经验 寄生虫学，WUSTL 是美国为数不多的在寄生虫学方面拥有丰富专业知识的研究中心之一。 丝虫病。我的导师是盘尾丝虫病死亡和 LF 项目（一个大规模的全球卫生项目）的 PI​​。 由比尔和梅琳达·盖茨基金会资助的项目），并在寄生虫学方面拥有丰富的专业知识， 免疫学和国际现场研究。丝虫研究的优越环境是其原因 我于 2014 年加入 WUSTL 教师。 研究 LF 是世界上导致残疾的主要原因之一，也是少数可导致残疾的传染病之一 是有可能根除的。世卫组织 GPELF 协调和支持企业、学术界、 政府和非政府合作伙伴通过反复试验在 73 个流行国家消除了 LF 使用行业捐赠的药物进行大规模药物管理（MDA）周期。 GPELF 是最大的基于 MDA 的 迄今为止已分发超过 53 亿剂抗寄生虫药物的公共卫生干预措施 2000 年至 2014 年间在 60 个国家/地区开展。全球 90% 以上的 LF 负担（包括非洲的所有病例）是 由丝虫线虫 Wuchereria bancrofti (Wb) 引起的，以及全球消除计划的各个方面 班克罗夫特丝虫病（绘图、MDA、监测和验证）依赖于使用现场护理对 LF 进行诊断 使用单克隆抗体检测血液样本中 Wb 循环丝虫抗原的测试。最近的 研究表明，这些测试经常会产生假阳性结果，这些结果来自于以下人群的样本： 感染 Loa loa，这是一种不同的丝虫寄生虫，存在于中非 11 个国家。不准确 诊断测试结果可能会产生严重甚至致命的影响，因为用于治疗 LF 的 MDA 药物可能会导致 重度 L. loa 患者服用时会出现严重不良反应（包括脑病和死亡） 感染。我们假设罗阿病患者丝虫 Wb 抗原检测呈假阳性是由于 存在交叉反应性循环 L. loa 抗原。该项目旨在识别循环的 Loa 抗原 并开发可以区分这两种感染的检测方法。改进的诊断测试将显着 提高 11 个中非国家控制罗阿病和消除 LF 的机会 这些疾病。