Prevalence, Pathogenesis, and Persistence of Lassa Fever in West Africa

项目概要 拉沙病毒 (LASV) 是拉沙热的病原体，是一种持续存在的全球公共卫生威胁， 感染和死亡的人数比所有埃博拉疫情的总和还多。与埃博拉病毒和其他病毒不同 出血热 (VHF)、拉沙热在西非常年流行，导致 每年约有 30 万人感染和 5 000 人死亡，主要发生在利比里亚、塞拉利昂和 几内亚。世界卫生组织（WHO）报告说，拉沙热的发病率正在增加， 也许是气候变化的结果，该疾病的严重程度和病死率也是如此。 由于 LASV 已被输入到非流行国家——已报告病例超过 32 例，三分之一 其中致命——加强拉沙热检测和管理的重要性延伸 超越西非。其中许多死亡可以通过更好的诊断、支持性措施来预防 临床护理和治疗。然而，尽管拉沙热是西非的一个主要原因， 仍然没有得到充分的诊断、研究，并且在很大程度上被忽视。出于这些原因，世界卫生组织在 2016 年 发布了一份研发蓝图号召性用语，其中将 LASV 确定为“首要任务” “新出现的病原体”很可能在不久的将来引起严重的疫情，迫切需要 被研究。西非的内乱加上医疗保健和研究基础设施不足 阻碍了对这种高度优先病原体的临床研究，从而限制了我们对 拉沙热的真正负担、致病机制和幸存者的传染性。的 该提案的主要目标是利用埃博拉疫情期间建立的临床基础设施 填补我们对拉沙热理解的关键空白。具体来说：  在 AIM I 中，我们将在利比里亚 Bong 县的 Phebe 医院建立分子诊断—— 拉沙热高流行区以确定急性拉沙热的患病率 入院的发热患者以及既往 LASV 暴露的血清阳性率。  在 AIM II 中，我们将探讨急性和恢复期拉沙热的假定致病机制 包括免疫激活、内皮功能障碍和生殖器中病毒抗原的持续存在 隔间。  在 AIM III 中，我们将描述 LASV 在血液、精液和 宫颈阴道液以确定病毒脱落的持续时间并评估其传染性 PCR 阳性样本。 我们将在与医疗保健部门建立密切而牢固的工作关系的背景下开展这项工作 我们在西非建立了领先的临床研究基础设施 我们在利比里亚招募、登记、纵向跟踪和采样了 300 多例埃博拉病例 幸存者。这些队列的建立使我们的团队能够确定我们方法的可行性 并制定、试点和完善在疫情期间维持高质量数据收集所需的程序 VHF 的研究。这项工作还使我们能够建立和支持能力。我们在利比里亚的团队 研究方法方面的培训，并被鼓励制定自己的建议。我们有 还建立了最先进的分子诊断实验室，并验证了诊断平台 在 Phebe 医院检测血液、精液和阴道液中的埃博拉 RNA 并对该站点进行了培训 在质量控制方面。这一经验将应用于拉沙热的研究。总的来说，拟议的 这项工作将为拉沙热流行病学、发病机制和 区室病毒动力学，并将提供数据源泉，为公共政策和 个人护理。此外，在受灾最严重的地区之一重建了拉沙热中心 这些领域将促进正在进行的研究，以推进这种致命疾病的管理和预防 传染病。虽然有关拉沙热的许多内容仍未得到充分研究，但很明显，每年都会发生这种情况 感染导致的死亡人数将超过所有其他出血性病毒死亡人数的总和。我们什么 提出的是一系列早就该进行的研究。

PROJECT SUMMARY Lassa virus (LASV), the causative agent of Lassa fever, is a persistent global public health threat that has infected and killed more people than all Ebola outbreaks combined. Unlike Ebola and other viral hemorrhagic fevers (VHF), Lassa fever is perennial and endemic in West Africa resulting in approximately 300,000 infections and 5,000 deaths each year, principally in Liberia, Sierra Leone, and Guinea. The World Health Organization (WHO) reports that the incidence of Lassa fever is increasing, perhaps as a consequence of climate change, as is the severity and case fatality rate of the disease. As LASV has been imported into non-endemic countries – with more than 32 cases reported, one third of which were fatal – the significance of enhanced detection and management of Lassa fever extends beyond West Africa. Many of these deaths could be prevented with better diagnostics, supportive clinical care, and therapeutics. Yet despite being a major cause of death in West Africa, Lassa fever remains under-diagnosed, understudied, and largely ignored. For these reasons, in 2016, the WHO released a research and development blueprint call-to-action, which identified LASV as a “top priority emerging pathogen” that is likely to cause a severe outbreak in the near future and urgently needs to be studied. Civil unrest coupled with inadequate healthcare and research infrastructure in West Africa have prevented clinical research on this high-priority pathogen, thereby limiting our understanding of the true burden of Lassa fever, the pathogenic mechanisms, and the infectivity of survivors. The primary goal of this proposal is to leverage clinical infrastructure established during the Ebola epidemic to fill critical gaps in our understanding of Lassa fever. Specifically:  In AIM I we will establish molecular diagnostics at Phebe Hospital in Bong county, Liberia – a hyper-endemic area for Lassa fever to determine the prevalence of acute Lassa fever among admitted febrile patients as well as the seroprevalance of prior LASV exposure.  In AIM II we will probe putative pathogenic mechanisms of acute and convalescent Lassa fever including immune activation, endothelial dysfunction, and persistence of viral antigens in genital compartments.  In AIM III we will characterize the compartmental dynamics of LASV in blood, semen and cervical-vaginal fluid to determine the duration of viral shedding and assess the infectivity of PCR-positive samples. We will conduct this work in the context of close and strong working relationships with healthcare leaders in West Africa and a well-developed infrastructure for clinical research we have established in Liberia where we have recruited, enrolled, and longitudinally followed and sampled over 300 Ebola survivors. Establishment of these cohorts allowed our team to determine the feasibility of our approach and develop, pilot, and refine the procedures needed to sustain high-quality data collection during the study of VHFs. This work also allows us to build and support capacity. Our team in Liberia has been trained in research methodology and is being encouraged to develop their own proposals. We have also established a state-of-the-art molecular diagnostic lab and validated a diagnostic platform for the detection of Ebola RNA in blood, semen, and vaginal fluid at Phebe Hospital and have trained this site in quality control. This experience will be applied to the study of Lassa fever. Collectively, the proposed work will provide a much-needed characterization of Lassa fever epidemiology, pathogenesis, and compartmental viral dynamics and will provide a wellspring of data that will inform public policy and individual care. Furthermore, the re-establishment of a Lassa fever center in one of the hardest hit areas will facilitate on-going research to advance the management and prevention of this deadly infectious disease. While much about Lassa fever remains understudied, it is clear that each year this infection will continue to kill more people than all other hemorrhagic viruses combined. What we propose is a series of studies that are long overdue.