Novel Vaccination Strategies Against Epidemic and Pandemic Influenza Viruses to I

说明(申请人提供)：流感既是重大的公共卫生威胁，也是NIAID生物防御C类优先病原体。仅在美国，每年就有大约3.6万人死于感染常见的甲型流感病毒。这些死亡中近90%是老年人。尽管目前的流感疫苗覆盖了65%的成年人口，但这些死亡病例还是发生了。此外，高致病性H5N1禽流感病毒可导致60%的感染者死亡。人们担心大流行随时可能发生。因此，迫切需要了解影响诱导最佳流感免疫的因素，并开发新的疫苗接种策略，以获得更好的保护性免疫。这些策略应该考虑到年龄导致的流感易感性增加。因此，这项提议的长期目标是改进目前的疫苗接种战略，并促进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，特别是老年人口。我们推测，年龄在I型干扰素诱导/信号传递中的作用与病毒的干扰素-I逃避策略相结合，可能会对流感特异性保护性免疫产生不利影响。这项建议验证了这一假设，并探索了新的疫苗接种策略，以在启动过程中诱导RIG-I介导的I型干扰素信号通路，作为诱导增强对流感病毒的保护性免疫的手段。目的1研究是否可以通过干扰病毒的干扰素-I逃避策略来最小化流感免疫中的年龄依赖性缺陷，目的2检测干扰素-I信号对天然免疫系统细胞在产生流感特异性适应性反应中的作用，目的3检测在启动过程中增强的干扰素信号对流感特异性记忆适应性的影响，目的4探索新的疫苗接种策略，在启动过程中增强RIG-I介导的I型干扰素信号，以提高免疫反应的免疫原性、持久性和保护性。人类流行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、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流感疫苗接种策略，特别是在老年人中，而且对各种疾病的新疫苗接种策略也有影响。公共卫生相关性：这项提议的长期目标是设计新的和改进的疫苗接种战略，以控制流行和大流行性流感病毒。这一知识不仅有助于改进流感疫苗接种战略，特别是在老年人中，而且对各种疾病的新疫苗接种战略也有影响。

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.