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

项目总结 拉萨病毒(LASV)是拉沙热的病原体，是一种持续的全球公共卫生威胁。 感染和死亡的人数超过了所有埃博拉疫情的总和。与埃博拉和其他病毒不同 出血热(VHF)，拉沙热是西非常年流行的疾病，导致 每年约有300,000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)报告称，拉沙热的发病率正在上升， 也许是由于气候变化，这种疾病的严重性和病死率也是如此。 由于LASV已被输入非流行国家--报告的病例超过32例，三分之一 其中是致命的-加强对拉沙热的检测和管理的意义延伸到 在西非之外。这些死亡中的许多都可以通过更好的诊断、支持性 临床护理和治疗学。然而，尽管拉沙热是西非的主要死亡原因，但它 仍然诊断不足，研究不足，基本上被忽视。出于这些原因，2016年，世卫组织 发布了一份研发蓝图--行动号召，其中将LASV确定为“首要任务” 可能在不久的将来引起严重暴发的新病原体，迫切需要 被研究。西非国内动乱加上医疗和研究基础设施不足 阻碍了对这种高优先级病原体的临床研究，从而限制了我们对 拉沙热的真实负担、致病机制和幸存者的传染性。这个 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 填补我们对拉沙热认识上的重大空白。具体地说，就是： 我们将在利比里亚邦县的菲贝医院建立分子诊断学 拉沙热高度流行区确定急性拉沙热流行率 入院的发热患者以及以前接触LASV的血清效价。 在AIM II中，我们将探讨急性和恢复期拉沙热的可能致病机制 包括免疫激活、内皮功能障碍和病毒抗原在生殖器中的持久性 车厢。 在AIM III中，我们将描述LASV在血液、精液和 宫颈-阴道液以确定病毒排出的持续时间并评估病毒的传染性 聚合酶链反应阳性样本。 我们将在与医疗保健密切而牢固的工作关系的背景下开展这项工作 以及我们在西非建立的完善的临床研究基础设施 我们在利比里亚招募了300多名埃博拉病毒，并对其进行了纵向跟踪和采样 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、试行和完善必要的程序，以在 甚高频的研究。这项工作还使我们能够建设和支持能力。我们在利比里亚的团队一直在 他们接受了研究方法方面的培训，并被鼓励提出自己的建议。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 在菲比医院检测血液、精液和阴道液中的埃博拉RNA，并对此进行了培训 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，建议的 这项工作将提供拉沙热流行病学、发病机制和 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新建立了拉萨发烧中心 地区将促进正在进行的研究，以推进对这种致命疾病的管理和预防 传染病。虽然许多关于拉沙热的研究仍然很少，但很明显，每年 感染导致的死亡人数将继续超过所有其他出血性病毒的总和。我们要做的是 求婚是一系列早就应该进行的研究。

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.