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）的证明提醒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，该提案中的研究人员对感染WNV的供体和暴露的受体进行了系统的研究，并指导了供体RNA（NAT）筛查和推迟政策，这些政策几乎消除了TT-WNV。我们还利用了前所未有的获得西尼罗河病毒RNA+供体的机会来捕获感染症状前阶段的个体。我们对病毒血症供体的系统性纵向研究有助于了解WNV疾病的自然史，并阐明了病毒和宿主遗传以及先天性和适应性免疫反应的复杂相互作用，这些反应决定了症状性WNV疾病的进展。然而，还需要进一步的工作，以确定目前NAT筛查未检测到的感染早期恢复期低水平病毒血症单位的感染性，并且通过正在进行的招募和随访以及对病毒血症供体的合作研究，仍需解决其他发病机制问题。 登革热是世界上最重要的虫媒病毒，在世界的热带/亚热带地区，每年有5000万至1亿人感染和> 25，000人死亡。在美国大陆消失了几十年之后，过去几年在美国南部记录了登革热病例的集群，现在扩大传播是真实的可能性。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）献血者的高病毒血症率，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。尽管DENV是血液安全的最高优先级风险之一，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，目前尚未在流行地区进行献血者的常规筛查，而这些数据是推动检测开发/许可和制定献血者筛查指南所需的。本提案中的研究者将根据FDA IND在PR中实施敏感的NAT筛查，并启动DENV+供体的随访研究，类似于在WNV感染供体中进行的研究。通过定义病毒和免疫动力学以及不同DENV血清型在原发和继发感染中的感染性持续时间，我们将加速实施适当的DENV供体筛查，并推进我们对DENV诊断和免疫发病机制的理解。 还将建立一个全面的储存库，储存在WNV和DENV感染的急性病毒血症阶段确定的来自供体的谱系样本，然后通过病毒清除和症状感染的发展。该血浆和PBMC标本库以及具有相关临床和实验室数据的数据库将转移到NHLBI标本库，以便研究血液安全性和WNV和DENV发病机制的合格科学家可以访问这些独特的样本。 (End摘要）

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)