PACIFIC NW REGIONAL CENTER OF EXCELLENCE NHP CORE YELLOW FEVER

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，但不一定是研究者所在的机构。 黄热病病毒（YFV）是一种临床相关的黄病毒和NIAID C类优先病原体。YFV通常通过蚊子传播，世界卫生组织估计，城市黄热病每年造成20万例病例和3万例死亡。目前在美国使用的YFV活疫苗YF-VAX？对YFV感染提供了显著的保护，但在某些情况下，接种疫苗的风险可能超过益处。例如，YF-VAX疫苗接种导致每百万剂接种1至2例疫苗相关死亡-包括年轻健康成人的死亡。在脆弱人群（如老年人）中不良事件的发生率要高得多，而活疫苗在其他脆弱人群（如婴儿或具有免疫疾病（如胸腺切除术或胸腺功能障碍史）的个体）中正式禁忌。在这个项目中，我们提出的证据表明，我们已经开发出一种新的疫苗平台，提供了一种有效和安全的替代活病毒疫苗。我们表明，使用过氧化氢的病毒灭活增强抗原性和免疫原性相比，其他方法，如基于甲醛的灭活技术。利用这个疫苗平台，我们建议开发一种新的YFV疫苗，用于健康个体和有活病毒疫苗免疫禁忌症的脆弱人群。这项工作将涉及1）开发适当严格的YFV感染模型，2）分析和优化灭活YFV疫苗制剂，以及3）表征疫苗介导的免疫应答和对临床相关强毒株YFV致死性攻击的保护。这种第二代YFV疫苗的研制将代表50年来YFV疫苗接种的首次进展，并为免疫脆弱人群提供急需的疫苗替代方案。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Yellow fever virus (YFV) is a clinically relevant flavivirus and an NIAID Category C Priority Pathogen. YFV is typically spread by mosquitoes and the World Health Organization has estimated that urban yellow fever causes 200,000 cases and 30,000 deaths annually. The current live YFV vaccine used in the United States, YF-VAX¿, has provided significant protection against YFV infection but the risks of vaccination may in some circumstances outweigh the benefits. For instance, immunization with YF-VAX¿ results in 1 to 2 vaccineassociated deaths per million doses administered -including fatalities in young, otherwise healthy adults. Adverse events occur at much higher rates in vulnerable populations such as the elderly, and the live vaccine is formally contraindicated in other vulnerable populations such as infants or individuals with immune disorders such as a history of thymectomy or thymic dysfunction. In this project, we present evidence demonstrating that we have developed a novel vaccine platform that provides an effective and safe alternative to live virus vaccines. We show that virus inactivation using hydrogen peroxide enhances antigenicity and immunogenicity in comparison with other approaches such as formaldehyde-based inactivation techniques. Using this vaccine platform, we propose the development of a new YFV vaccine for use in both healthy individuals and vulnerable populations that have contraindications for immunization with live viral vaccines. This work will involve 1) development of an appropriately rigorous YFV infection model, 2) analysis and optimization of an inactivated YFV vaccine formulation, and 3) characterization of vaccinemediated immune responses and protection against lethal challenge with clinically relevant strains of virulent YFV. The establishment of this second-generation YFV vaccine will represent the first advance in YFV vaccination in 50 years and provide a much needed vaccine alternative for immunologically vulnerable populations.