Novel Vaccination Strategies Against Epidemic and Pandemic Influenza Viruses to I

针对流行性和大流行性流感病毒的新疫苗接种策略

基本信息

批准号：
8227808
负责人：
MURALI KRISHNA KAJA
金额：
$ 38.36万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8227808
关键词：
Address Adenovirus Vector Adjuvant Adoptive Cell Transfers Adult Affect Age Aging Antigens Avian Influenza Avian Influenza A Virus B-Lymphocytes Binding Birds Bone Marrow Categories Cells Cessation of life Chimera organism Clinical Trials Clonal Expansion Data Defect Disease Dose Double-Stranded RNA Elderly Epidemic Event Fright Generations Goals Grant Health Human Immune Immune response Immune system Immunity Individual Infection Inflammatory Inflammatory Response Influenza Influenza A Virus, H5N1 Subtype Influenza A virus Influenza vaccination Interferon Type I Interferons Investigation Knockout Mice Knowledge Laboratories Link Mediating Memory Modeling Mus National Institute of Allergy and Infectious Disease Polymerase Population Predisposition Production Proteins Public Health Publishing RNA Reagent Respiratory Tract Infections Role Signal Induction Signal Pathway Signal Transduction Stimulus System T-Lymphocyte Techniques Testing Time Transgenic Organisms United States Vaccinated Vaccination Vaccines Viral Virulent Virus adaptive immunity age related aged aluminum sulfate base cellular targeting clinically relevant design egg fitness follow-up immunogenicity improved in vivo influenza virus vaccine influenzavirus meetings mortality novel pandemic disease pandemic influenza pathogen prevent programs research study respiratory response sensor success targeted delivery tripolyphosphate vaccination strategy young adult

项目摘要

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.

描述（由申请人提供）：流感既是主要的公共卫生威胁，又是NIAID生物防御类别C优先病原体。仅在美国，每年大约有36,000人死亡，这是由于通常循环的流感病毒感染。这些死亡中有近90％是老年人。尽管当前的流感疫苗达到了成年人口的65％，但仍会发生这些死亡。此外，高度致病性的鸟类H5N1病毒在感染个体中导致60％的死亡率。人们担心会随时发生大流行。因此，迫切需要了解影响诱导最佳流感免疫力的因素，并制定新型的疫苗接种策略，以产生更好的保护性免疫。这些策略应考虑年龄介导的对流感的敏感性的提高。因此，该提案的长期目标是改善当前的疫苗接种策略，并有助于设计新颖的疫苗接种策略，以控制对老年人口的流行病和大流行性流感病毒。我们假设I型干扰素（IFN-I）诱导/信号传导与病毒IFN-I回避策略相结合的年龄介导的作用可能会对流感特定的保护性免疫产生不利影响。该提案检验了该假设，并探讨了在启动过程中诱导RIG-I介导的I型干扰素信号通路的新型疫苗接种策略，作为诱导对流感病毒的保护性免疫的手段。 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在启动过程中增强RIG-I介导的I型干扰素信号的策略，以提高免疫反应的免疫原性，耐用性和保护能力。使用尖端试剂/技术（例如TCR转基因，基因敲除小鼠，收养细胞转移，骨髓嵌合体和MHC Tetramers），将在小鼠特征良好的呼吸道感染模型中测试人类流行性和大流行性禽流感菌株。这些知识不仅有助于改善针对流感的疫苗接种策略，尤其是在老年人中，而且对针对各种疾病的新型疫苗接种策略具有影响。公共卫生相关性：该提案的长期目标是设计新颖和改进的疫苗接种策略，以控制流行病和大流行性流感病毒。这些知识不仅有助于改善针对流感的疫苗接种策略，尤其是在老年人中，而且对针对各种疾病的新型疫苗接种策略具有影响。