Once Bitten: Detecting the World???s Most Common Vector-Borne Pathogens

一旦被咬：检测世界上最常见的媒介传播病原体

• 批准号: 8677493
• 负责人: Jesse Waggoner
• 金额: $ 17.99万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-18 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677493
• 关键词: Address; Affect; Area; Biological Assay; Biomedical Research; Biotechnology; Bite; Caring; Central America; Cessation of life; Characteristics; Child; Clinical; Collaborations; Communicable Diseases; Core Facility; Data; Databases; Dengue; Dengue Virus; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Differential Diagnosis; Disease; Disease Outcome; Environment; Epidemiology; Equipment; Etiology; Fellowship; Fever; Fostering; Frequencies; Functional disorder; Future; Goals; Hospitals; Human; Immunoglobulin M; Incidence; Individual; Infection; Institutes; International; Intervention; Laboratories; Life; Malaria; Medicine; Mentors; Molecular; Nicaragua; Nicaraguan; Outcome; Patient Care; Patients; Performance; Population; Proteins; Public Health; Publishing; Qualifying; Reaction; Research; Research Personnel; Research Support; Research Training; Resources; Rest; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Sampling; Septic Shock; Serologic tests; Serological; Severities; Site; Southern Africa; Syndrome; Testing; Time; Universities; Vaccines; Validation; Viral; Viral Load result; Virus Diseases; Work; Zimbabwe; base; burden of illness; career; clinical decision-making; clinical material; cohort; design; epidemiologic data; experience; global health; improved; novel diagnostics; pathogen; point of care; public health relevance; response; success; vector; vector control; viral detection

DESCRIPTION (provided by applicant): Dengue and malaria are the most widespread vector-borne human pathogens worldwide, with over half of the world's population living in endemic areas. These infections result in non-specific clinical manifestations that range in severity from a self-limited febrile illness to septic shock and death. A confirmed diagnosis, which relies on accurate laboratory tests, is associated with improved patient outcomes. Available diagnostic tests for these agents, however, often lack sensitivity or the performance characteristics necessary for routine use. Furthermore, multiplex assays that distinguish between dengue and malaria have not been developed, despite significant overlap in the endemic area and clinical presentation of these infections. The objectives of the current application are to utilize sensitive diagnostic tests for dengue in order to identify patient and vral factors associated with severe disease, further delineate dengue epidemiology in endemic regions, and develop a syndrome-based multiplex test for dengue and malaria. In order to accomplish these objectives, samples from cohorts of patients in Nicaragua and Zimbabwe will be studied. Using Nicaraguan children admitted to the hospital for dengue, viral load thresholds and patient risk factors will be identified that portend an increased risk of severe disease. A separate cohort of 2,900 febrile Nicaraguan children diagnosed with a non-dengue illness will be tested for dengue to identify atypical clinical syndromes that warrant specific dengue testing. This cohort of patients will also allow us to establish the sensitivity of serological responses fo the detection of missed dengue infections. Finally, we have developed a dengue and malaria multiplex test that will be employed in the study of these pathogens in the Honde Valley of Zimbabwe, which has experienced a resurgence of malaria over the past decade. This research will build off of work started during my fellowship in infectious diseases at Stanford University. During the past two years, I have designed and validated two real-time dengue RT-PCRs, which have both proven more sensitive than prevailing diagnostics. I am now seeking to employ these assays to study dengue epidemiology and pathophysiology. One of these tests, an internally con- trolled RT-PCR for pan-dengue detection, served as the starting point for the dengue-malaria multiplex assay mentioned above. My co-mentors for this proposal include experts in molecular diagnostics, Dr. Benjamin Pinsky, and dengue pathophysiology and epidemiology, Dr. Eva Harris. I have also assembled a team of collaborators and consultants with a wealth of experience in global health, epidemiology, and diagnostics development. Stanford University represents an ideal environment for the pursuit of clinically oriented research and international studies. While our laboratory contains the equipment necessary for the completion of the research outlined in this proposal, I will still have access to nineteen core facilities on campus o address questions that may arise. Stanford fosters cross-disciplinary collaborations and provides access to leading academic researchers and biotechnology companies focused on the development of new diagnostics. This proposal also includes two international sites located in areas endemic for dengue (Centro Nacional de Diagnostico y Referencia, Managua, Nicaragua) and malaria (Biomedical Research and Training Institute, Harare, Zimbabwe). These sites not only provide access to the clinical material necessary for the study of dengue and malaria, they allow for collaboration with experts in international medicine and capacity building in resource limited settings. The expected outcomes of this proposal include a refined understanding of dengue epidemiology in two endemic regions, the validation of a clinical prediction rule for severe dengue, and the development of a near-care multiplex assay for the most common vector-borne pathogens worldwide. Research performed in pursuit of these aims represents the next step in my professional development, bridging infectious disease fellowship with a career as an independent global health investigator. My co-mentors and collaborators are uniquely qualified to support this research, and three study sites with complimentary resources maximize the opportunities for success.

描述(申请人提供)：登革热和疟疾是世界上传播最广泛的媒介传播的人类病原体，世界上一半以上的人口生活在流行地区。这些感染导致非特异性的临床表现，其严重程度从自限性发热性疾病到感染性休克和死亡不等。确诊的诊断依赖于准确的实验室测试，这与患者预后的改善有关。然而，可用于这些试剂的诊断测试往往缺乏灵敏度或常规使用所必需的性能特征。此外，尽管登革热和疟疾的流行地区和临床表现有很大重叠，但尚未开发出区分登革热和疟疾的多重检测方法。目前应用的目标是利用对登革热的敏感诊断测试，以确定与严重疾病相关的患者和病毒因素，进一步描述流行地区的登革热流行病学，并开发一种针对登革热和疟疾的基于症状的多重测试。为了实现这些目标，将对尼加拉瓜和津巴布韦患者队列的样本进行研究。利用因登革热住院的尼加拉瓜儿童，将确定预示严重疾病风险增加的病毒载量阈值和患者风险因素。另有2900名尼加拉瓜发烧儿童被诊断为非登革热疾病，他们将接受登革热测试，以确定需要进行特定登革热测试的非典型临床症状。这组患者还将使我们能够建立检测漏诊登革热感染的血清学反应的敏感性。最后，我们开发了一种登革热和疟疾多重测试，将用于研究津巴布韦洪德山谷的这些病原体，该山谷在过去十年中经历了疟疾的死灰复燃。这项研究将建立在我在斯坦福大学担任传染病研究员期间开始的工作基础上。在过去的两年里，我设计并验证了两种实时登革热RT-PCR，事实证明，这两种方法都比主流诊断方法更敏感。我现在正在寻求使用这些化验方法来研究登革热流行病学和病理生理学。其中一项检测是用于泛登革热检测的内部控制RT-PCR，作为上文提到的登革热-疟疾多重检测的起点。这项提议的共同导师包括分子诊断学专家本杰明·平斯基博士和登革热病理生理学和流行病学博士伊娃·哈里斯博士。我还组建了一个合作者和顾问团队，他们在全球卫生、流行病学和诊断学发展方面拥有丰富的经验。斯坦福大学是追求面向临床的研究和国际研究的理想环境。虽然我们的实验室拥有完成本提案中概述的研究所需的设备，但我仍然可以使用校园内的19个核心设施来解决可能出现的问题。斯坦福大学促进跨学科合作，并为专注于新诊断开发的领先学术研究人员和生物技术公司提供机会。该提案还包括位于登革热流行地区(尼加拉瓜马那瓜国家诊断中心)和疟疾流行地区(津巴布韦哈拉雷生物医学研究和培训研究所)的两个国际地点。这些网站不仅提供登革热和疟疾研究所需的临床材料，还允许在资源有限的情况下与国际医学专家进行合作和能力建设。这项提议的预期结果包括：对两个流行地区的登革热流行病学有更深入的了解，对严重登革热的临床预测规则得到验证，以及为全世界最常见的病媒传播病原体开发一种临终关怀的多重检测方法。为追求这些目标而进行的研究代表着我职业发展的下一步，将传染病研究与独立全球卫生调查员的职业生涯联系起来。我的合作导师和合作者是唯一有资格支持这项研究的人，三个拥有免费资源的学习网站最大限度地增加了成功的机会。