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（由申请人提供）：登革热和疟疾是全球最广泛的媒介传播人类病原体，世界上有一半以上的人口居住在地方性地区。这些感染导致非特异性临床表现，严重程度从自限的发热疾病到败血性休克和死亡。确认的诊断依赖于准确的实验室测试，与改善患者结局有关。但是，这些药物的可用诊断测试通常缺乏敏感性或常规使用所需的性能特征。此外，尽管流行区域明显重叠和这些感染的临床表现，但尚未开发出区分登革热和疟疾的多重测定。当前应用的目的是利用登革热的敏感诊断测试，以鉴定与严重疾病相关的患者和vral因素，进一步描述了流行地区的登革热流行病学，并为登革热和疟疾开发了基于综合征的多重多重测试。为了实现这些目标，将研究来自尼加拉瓜和津巴布韦患者同类的样本。将使用尼加拉瓜的儿童进入医院的登革热，将确定病毒载荷阈值和患者危险因素，以预示着增加严重疾病的风险。单独的队列由2900名被诊断出患有非登革热疾病的尼加拉瓜的尼加拉瓜儿童进行测试，以确定需要特定特定登革热测试的非典型临床综合症。这种患者队列还将使我们能够在发现落登革热感染的检测中建立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路复用试验，该测试将用于津巴布韦本德山谷的这些病原体，该病原体在过去十年中经历了疟疾的复兴。这项研究将取决于我在斯坦福大学的传染病研究金奖学金开始的工作。在过去的两年中，我设计并验证了两个实时的登革热RT-PCR，这两者都比普遍的诊断更敏感。我现在正在寻求使用这些测定法研究登革热流行病学和病理生理学。其中一项测试是一种内部控制的RT-PCR用于PAN Dengue检测，是上面提到的登革热 - 马拉里亚多路复用测定法的起点。我的该提案的联合官员包括分子诊断专家，本杰明·平斯基博士，登革热病理生理学和流行病学，伊娃·哈里斯（Eva Harris）博士。我还召集了一个合作者和顾问团队，拥有丰富的全球健康，流行病学和诊断开发方面的丰富经验。斯坦福大学是追求临床导向研究和国际研究的理想环境。尽管我们的实验室包含完成本提案中概述的研究所需的设备，但我仍然可以访问校园内的19个核心设施。解决可能出现的问题。斯坦福大学促进了跨学科的合作，并提供了专注于开发新诊断的领先的学术研究人员和生物技术公司。该提案还包括位于登革热特有地区的两个国际遗址（Centro nacional de Diagnostico y referencia，Managua，Nicaragua）和Malaria（生物医学研究与培训研究所，Harare，Zimbabwe）。这些站点不仅可以访问研究登革热和疟疾所需的临床材料，而且还允许在资源有限的环境中与国际医学和能力建设专家合作。该提案的预期结果包括对两个地方性地区登革热流行病学的完善理解，对严重登革热的临床预测规则的验证以及全球最常见的媒介传播病原体的近乎保健多重分析的开发。为了追求这些目标而进行的研究代表了我的专业发展的下一步，将传染病研究金与作为独立全球健康研究员的职业生涯弥合。我的合伙人和合作者具有独特的资格来支持这项研究，三个具有免费资源的研究网站可以最大程度地获得成功的机会。