International Collaboration in Infectious Disease Research on Lassa fever

 描述(申请人提供)：拉沙热是一种由拉萨病毒(LASV)引起的急性且往往致命的出血性疾病，拉萨病毒是一种阿拉伯病毒。拉沙热是一种人畜共患传染病，由纳塔尔沼虾(多哺乳类“大鼠”)传播给人类。世界上拉沙热发病率最高的是塞拉利昂东部省份。LF的体征和症状在接触病毒后1-3周出现，具有高度的变异性，可能包括发热、面部肿胀、结膜注射和呕吐。弗兰克出血的发生率不到三分之一，但预后不佳。存活的LF患者的体征和症状在发病2-3周后开始消退，但完全恢复可能需要数月或更长时间。凯内马政府医院(KGH)在整个1970年代和1980年代是拉沙热临床和实验室研究的重要场所。1991年至2002年塞拉利昂的暴力内战，有时被称为血钻战争，迫使1993年在KGH的拉沙热研究暂停。敌对行动停止后，我们的拉沙热研究人员联盟和其他合作伙伴开始重建KGH的科学基础设施，重点是改进拉沙热的实验室诊断。目前还没有针对肝功能衰竭的疫苗，抗病毒药物利巴韦林治疗肝功能衰竭的疗效仍然存在争议。迫切需要制定流行病学和临床措施，以应对塞拉利昂和整个西非拉沙热造成的公共卫生挑战。前景看好的下一代拉沙热诊断免疫分析，包括快速检测，需要作为流行病学和临床管理工具进一步发展。拉萨ICIDR的总体假设是，进一步发展研究能力，重点是培训塞拉利昂工作人员，将使KGH拉沙热研究计划成为NIAID前景光明的拉沙热诊断、治疗、免疫疗法和疫苗组合的人类临床试验的特殊资源。总体的具体目标(按优先顺序列出)是：目标1.进一步加强和利用过去十年杜兰大学和KGH拉沙热方案之间建立的对称和高成效的伙伴关系；目标2.促进KGH实验室和临床研究能力的发展，特别重视培训塞拉利昂工作人员；以及目标3.鼓励未来与其他研究小组的合作关系，从而改进该次区域拉沙热的检测、预防、改善和治疗。项目1：第二代拉沙热重组免疫分析能否有效地用作拉沙热的就诊诊断和监测工具；以及项目2：拉沙热结局的临床和病毒学决定因素是什么，是否有可能确定拉沙热感染和拉沙热结局的生物标志物。通过拟议的研究，我们将使用第二代拉沙热重组免疫分析方法获得有关拉沙热自然病史和接触拉沙热人群的人口分布的新信息。我们还将阐明获得严重或致命LASV感染的危险因素。这一新信息将指导对公共卫生规划和政策的循证投资。我们还将通过病程定义拉沙热病理生物学的生物标记物。查明这些因素可导致采取循证方法来降低拉沙热的死亡率。我们还建议向前迈出重要的一步，以应对拉沙热的挑战，即发展进行人体临床试验的能力。

 DESCRIPTION (provided by applicant): Lassa fever is an acute and often-fatal hemorrhagic disease caused by Lassa virus (LASV), an arenavirus. Lassa fever is a zoonotic infection, transmitted to humans by Mastomys natalensis (the multimammate "rat"). The highest incidence of Lassa fever in the world is in the Eastern Province of Sierra Leone. Signs and symptoms of LF, which occur 1-3 weeks after virus exposure, are highly variable, and can include fever, facial swelling, conjunctival injection, and vomiting. Frank bleeding occurs in less than a third of cases, but confers a poor prognosis. Signs and symptoms in LF patients who survive begin to subside 2-3 weeks after onset, but full recovery can require many months or longer. Kenema Government Hospital (KGH) was an important site for Lassa fever clinical and laboratory research throughout the 1970s and 1980s. The violent civil conflict in Sierra Leone from 1991 to 2002, sometimes referred to as the Blood Diamonds War, forced suspension of Lassa fever research at KGH in 1993. Following cessation of hostilities, our consortium of Lassa fever researchers and other partners began rebuilding the scientific infrastructure at KGH, with a major focus of the development of improved laboratory diagnosis for Lassa fever. There is no vaccine for LF and the efficacy of the antiviral drug ribavirin in treating LF remains a matter of controversy. There is an urgent need to develop epidemiological and clinical measures to combat the public health challenges posed by Lassa fever in Sierra Leone and across West Africa. Promising next-generation Lassa fever diagnostic immunoassays, including rapid tests, require further development as epidemiological and clinical management tools. The overall hypothesis of the Lassa ICIDR is that further development of research capacity, with emphasis on training Sierra Leonean staff, will permit the KGH Lassa fever research program to emerge as an exceptional resource for human clinical trials of NIAID's promising portfolio of Lassa fever diagnostics, therapeutics, immunotherapeutics and vaccines. The Overall Specific Aims (listed in priority order) are: Aim 1. Further enhance and utilize the symmetrical and highly productive partnership developed over the last decade between Tulane University and the Lassa fever program at KGH; Aim 2. Promote the development of laboratory and clinical research capacity at KGH, with a particular emphasis on training Sierra Leonean staff; and Aim 3. Encourage future collaborative relationships with other research groups leading to improvements in detection, prevention, amelioration, and treatment of Lassa fever in the subregion. Research question(s) to be addressed in the Lassa ICIDR Projects include for Project 1: Can second generation Lassa fever recombinant immunoassays be used effectively as point-of-care diagnostics and surveillance tools for Lassa fever, and for Project 2: What are the clinical and virological determinants of Lassa Fever outcome and is it possible to identify biomarkers of LASV infection and Lassa Fever outcome. Through the proposed research we will acquire new information regarding the natural history of Lassa fever and the demographic distribution of people exposed to LASV using second generation Lassa fever recombinant immunoassays. We will also elucidate risk factors for acquiring serious or fatal LASV infection. This new informatio will guide evidence-based investments for public health programming and policy. We will also define biomarkers of Lassa fever pathobiology through the course of illness. Identification of these factors could lead to evidence-based approaches to reduce mortality from Lassa fever. We also propose to take a major step forward to confront the challenges of Lassa fever, namely developing the capacity to perform human clinical trials.