Viral/Immune parameters of Dengue and WNV in donors: blood safety implications

描述(由申请人提供)： 1999年西尼罗河病毒在美国的出现和2002年输血传播(TT)的演示提醒了全球血库界注意虫媒病毒流行对血液安全的影响。自2002年以来，该提案中的调查人员对感染西尼罗河病毒的捐赠者和暴露的接受者进行了系统的研究，并指导了捐赠者RNA(NAT)筛查和推迟政策，实际上消除了TT-西尼罗河病毒。我们还利用无与伦比的机会接触到WNV RNA+捐赠者，捕获了感染症状前阶段的个人。我们对病毒供体的系统纵向研究有助于了解西尼罗河病毒疾病的自然历史，并阐明病毒和宿主遗传以及决定发展为症状性西尼罗河病毒疾病的先天性和获得性免疫反应的复杂相互作用。然而，还需要进一步的工作来确定低水平的病毒单位在感染的早期恢复期的传染性，目前的NAT筛查没有检测到，其他的发病机制问题仍然需要通过正在进行的病毒捐赠者的登记、后续和合作研究来解决。登革热是世界上最重要的虫媒病毒，每年在世界热带/亚热带地区有5000-1亿人感染，2.5万人死亡。在美国大陆几十年没有登革热病例之后，过去几年美国南部记录了多起登革热病例，现在真正有可能扩大传播。虽然在流行国家很难确定医疗传播，但最近报告了两组TT-DENV，我们记录了中南美洲和波多黎各(PR)献血者中病毒血症的高比率，波多黎各是美国的一个领土，其血液供应由美国红十字会管理。虽然DENV是血液安全的最高优先风险之一，但由于缺乏关于病毒动力学和急性病毒血症传染性的系统数据，目前在流行地区没有对献血者进行常规筛查，这是推动开发/发放检测和制定献血者筛查指南所需的数据。这项建议中的调查人员将在FDA IND下的PR中实施敏感的NAT筛查，并对DENV+捐赠者展开后续研究，类似于对感染WNV的捐赠者进行的研究。通过定义病毒和免疫动态以及不同DENV血清型在初次和继发感染中的传染性持续时间，我们将加快实施适当的DENV供体筛选，并促进我们对DENV诊断和免疫发病机制的理解。还将建立一个全面的资料库，其中包括在西尼罗河病毒和登革热病毒感染的急性病毒血症阶段确定的捐赠者的血统样本，然后在病毒清除和出现症状感染的过程中进行跟踪。这些血浆和PBMC样本以及与临床和实验室数据相关联的数据库将被转移到NHLBI标本储存库，以便研究血液安全和西尼罗河病毒和登革热病毒发病机制的合格科学家可以访问这些独特的样本。 (摘要结束)

DESCRIPTION (provided by applicant): The emergence of WNV in the US in 1999 and demonstration of transfusion-transmission (TT) in 2002 alerted the global blood banking community of the blood safety implications of arbovirus epidemics. Since 2002, investigators in this proposal have conducted systematic research on WNV infected donors and exposed recipients and guided donor RNA (NAT) screening and deferral policies that have virtually eliminated TT-WNV. We also took advantage of unparalleled access to WNV RNA+ donors to capture individuals in the pre- symptomatic stage of infection. Our systematic longitudinal studies of viremic donors have contributed to understanding of the natural history of WNV diseases, and elucidated complex interactions of viral and host genetic and innate and adaptive immune responses that determine progression to symptomatic WNV disease. Further work is needed, however, to establish the infectivity of low-level viremic units in the early convalescent stage of infection not detected by current NAT screening, and additional pathogenesis questions remain to be addressed through ongoing enrollment and follow-up and collaborative study of viremic donors. Dengue is the most important arbovirus in the world, with 50-100 million infections and >25,000 deaths annually in tropical/semi-tropical regions of the world. After decades of absence of in the continental US, clusters of dengue cases have been documented in the southern US over the past several years, and expanded spread is now a real possibility. Although healthcare transmissions have been difficult to ascertain in endemic countries, two clusters of TT-DENV were recently reported, and we have documented high rates of viremia in blood donors in Central/South America and Puerto Rico (PR), a US territory whose blood supply is run by the American Red Cross. Although DENV is among the highest priority risks to blood safety, routine screening of donors is not currently conducted in epidemic regions due to lack of systematic data on viral dynamics and infectivity of acute viremia that is needed to drive development/licensure of tests and formulation of donor screening guidelines. The investigators in this proposal will implement sensitive NAT screening in PR under an FDA IND, and launch follow-up studies of DENV+ donors similar to those conducted on WNV infected donors. By defining viral and immune dynamics and the duration of infectivity in primary and secondary infections by different DENV serotypes, we will accelerate implementation of appropriate DENV donor screening and advance our understanding of DENV diagnostics and immunopathogenesis. A comprehensive repository will also be established of the pedigreed samples from donors identified in the acute viremia stages of WNV and DENV infections, and then followed through viral clearance and development of symptomatic infection. This repository of plasma and PBMC specimens and databases with linked clinical and laboratory data will be transferred to the NHLBI Specimen Repository so that these unique samples are accessible to qualified scientists studying blood safety and the pathogenesis of WNV and DENV. (End of Abstract)