Novel Vaccination Strategies Against Epidemic and Pandemic Influenza Viruses to I

描述（由申请人提供）：流感是一种主要的公共卫生威胁，也是NIAID生物防御C类优先病原体。仅在美国，每年就有大约36000人死于感染普遍流行的甲型流感病毒。其中近90%的死亡是老年人。尽管目前的流感疫苗已覆盖成年人口的50%至65%，但仍发生了这些死亡。此外，高致病性H5N1禽流感病毒在受感染者中造成60%的死亡率。人们担心大流行随时可能发生。因此，迫切需要了解影响最佳流感免疫诱导的因素，并开发新的疫苗接种策略，以产生更好的保护性免疫。这些策略应考虑到年龄介导的流感易感性增高。因此，这项建议的长期目标是改进目前的疫苗接种战略，并有助于设计新的疫苗接种战略，以控制流行病和大流行性流感病毒，特别是针对老年人。我们假设年龄介导的i型干扰素（IFN-I）诱导/信号传导结合病毒IFN-I规避策略可能对流感特异性保护性免疫产生不利影响。本研究验证了这一假设，并探索了在启动过程中诱导rig - 1介导的i型干扰素信号通路的新疫苗接种策略，作为诱导增强流感病毒保护性免疫的手段。Aim 1研究年龄依赖性流感免疫缺陷是否可以通过干扰病毒IFN-I逃避策略来最小化；Aim 2测试IFN-I信号对先天免疫系统细胞产生流感特异性适应性反应的贡献；Aim 3研究启动过程中增强的IFN-I信号对流感特异性记忆适应性的影响；探索在启动过程中增强rig - 1介导的i型干扰素信号的新型疫苗接种策略，以提高免疫反应的免疫原性、持久性和保护能力。人类流行病和大流行性禽流感毒株将在具有良好特征的小鼠呼吸道感染模型中进行测试，使用尖端试剂/技术，如TCR转基因、敲除小鼠、过继细胞转移、骨髓嵌合体和MHC四聚体。这一知识不仅有助于改进针对流感的疫苗接种策略，特别是在老年人中，而且对针对各种疾病的新型疫苗接种策略也有影响。公共卫生相关性：本建议的长期目标是设计新的和改进的疫苗接种战略，以控制流行性和大流行性流感病毒。这一知识不仅有助于改进针对流感的疫苗接种策略，特别是在老年人中，而且对针对各种疾病的新型疫苗接种策略也有影响。

DESCRIPTION (provided by applicant): Influenza is both a major public health threat and a NIAID bio defense category C priority pathogen. About 36,000 people die every year in the United States alone due to infection with commonly circulating influenza A viruses. Nearly 90% of these deaths are in elderly people. These deaths occur despite the fact that current influenza vaccines reach >65% of the adult population. Moreover, highly pathogenic avian H5N1 viruses cause 60% mortality in infected individuals. It is feared that a pandemic can happen at any time. Thus, there is an urgent need for an understanding of factors that influence induction of optimal influenza immunity, and for developing novel vaccination strategies that can elicit better protective immunity. These strategies should consider the age-mediated heightened susceptibility to influenza. The long-term objective of this proposal, therefore, is to both improve current vaccination strategies and contribute to the design of novel vaccination strategies to control epidemic and pandemic influenza viruses with particular regard to the elderly population. We hypothesize that age mediated effects in type-I interferon (IFN-I) induction/signaling combined with viral IFN-I evasive strategies may adversely affect influenza- specific protective immunity. This proposal tests this hypothesis and explores novel vaccination strategies for inducing RIG-I mediated type-I interferon signaling pathways during priming as means of inducing enhanced protective immunity against influenza viruses. Aim 1 examines whether age- dependent defects to influenza immunization can be minimized by interfering with viral IFN-I evasive strategies, Aim 2 tests the contribution of IFN-I signals on cells of innate immune system in generating influenza specific adaptive response, Aim 3 examines the effect of enhanced IFN-I signaling during priming on influenza-specific memory fitness, and Aim 4, explores novel vaccination strategies that enhance RIG-I mediated type-I interferon signals during priming to increase the immunogenicity, durability, and protective ability of immune response. Human epidemic and pandemic avian influenza strains will be tested in the well-characterized respiratory infection models in mice using cutting edge reagents/techniques such as TCR transgenic, knockout mice, adoptive cell transfers, bone marrow chimeras, and MHC tetramers. This knowledge not only contributes to improved vaccination strategies against influenza, especially in elderly, but also has implications for novel vaccination strategies against a variety of diseases. PUBLIC HEALTH RELEVANCE: The long-term objectives of this proposal are to design novel and improved vaccination strategies to control epidemic and pandemic influenza viruses. This knowledge will not only contribute to improved vaccination strategies against influenza, especially in elderly, but also has implications for novel vaccination strategies against a variety of diseases.