YELLOW FEVER VACCINATION OF THE AGED AND IMMUNOCOMPROMISED

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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。 目前的YFV活疫苗，YF-VAX <$，对YFV感染提供了显着的保护，但接种疫苗的风险可能超过收益。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  包括年轻健康的成年人的死亡。 在老年人等脆弱人群中，不良事件的发生率要高得多，而活疫苗在其他脆弱人群中是正式禁忌的，如婴儿或免疫疾病患者。 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，3）表征疫苗介导的免疫应答和对临床相关YFV强毒株致死性攻击的保护。 这种第二代YFV疫苗的建立将代表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品。总之，我们已经成功地建立了一个强毒的YFV攻击模型，恒河猴，设计和验证了一种新的方法来量化的毒力YFV菌株，不适合传统的空斑试验，并启动了我们的疫苗效力研究。此外，我们已经发表了3篇论文（或正在出版），并将在未来2-6个月内提交2篇论文。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The World Health Organization has estimated that urban yellow fever causes 200,000 cases and 30,000 deaths annually. The current live YFV vaccine, YF-VAX¿, has provided significant protection against YFV infection but the risks of vaccination may outweigh the benefits. For instance, immunization with YF-VAX¿ results in 1 to 2 vaccine-associated 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. 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 vaccine-mediated 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. In summary, we have successfully established a virulent YFV challenge model in rhesus macaques, designed and validated a new approach to quantify virulent YFV strains that are not amenable to traditional plaque assays, and have initiated our vaccine efficacy studies. Moreover, we have 3 papers published (or in press) and will submit 2 more papers within the next 2-6 months.