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Protective Cell-Mediated Immunity Against Lethal H5N1 Influenza A Viruses

针对致命性 H5N1 甲型流感病毒的保护性细胞介导的免疫

基本信息

批准号：
7849033
负责人：
PETER C DOHERTY
金额：
$ 39.61万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7849033
关键词：
Address Animal Model Antibodies Antibody Formation Antibody-mediated protection Area Birds CD4 Positive T Lymphocytes CD8B1 gene Cellular Immunity Characteristics Child Dendritic Cells Development Effectiveness Effector Cell Engineering Epidemiology Equilibrium Far East Ferrets Formalin Funding Generations Genes Government Granzyme Growth Hemagglutinin Hospitals Human Humoral Immunities Immune response Immunization Immunology Inactivated Vaccines Infection Infection prevention Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H3N2 Subtype Influenza A Virus, H5N1 Subtype Influenza A virus Institution Integrins Interferons Kinetics Knockout Mice Knowledge Laboratories Laboratory Animals Lead Licensing Life Measures Mediating Memory Modeling Molecular Virology Monitor Mus Mutate Mutation Natural Killer Cells Nature Neuraminidase Onset of illness Oseltamivir Ovalbumin Peptides Phase Population Population Surveillance Production Proteins Public Health Reagent Reassortant Viruses Recovery Research Research Personnel Response Elements SELL gene Services Severities Severity of illness Site Source Staging T cell response T memory cell T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes TNF gene Thinking Transgenic Mice Vaccines Variant Virulence Virulent Virus Virus Diseases Wild Type Mouse anti-influenza drug authority cell type cross reactivity cytokine domestic bird enzyme linked immunospot assay immunogenic immunopathology influenza virus vaccine influenzavirus killings memory recall mouse model mutant neutralizing antibody pandemic disease perforin positional cloning prevent programs protective effect research study response virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): All responsible governments are greatly concerned about the possibility that the highly lethal H5N1 influenza A viruses that have been killing large numbers of wild and domestic birds (and a few people) in South East Asia may suddenly change their host range and begin to spread globally, with extreme rapidity, among human populations. Though we have an effective anti-influenza drug (Oseltamivir), a new-generation H5N1 vaccine is in an advanced stage of development, and the influenza virus research, surveillance and public health networks are first class, the capacity of these viruses to mutate very rapidly means that there is no way to be absolutely sure that we will not be hit by a virus against which we relatively little protection. The current formalin-inactivated vaccines promote a highly specific and effective antibody response, provided this is directed against exactly the right virus, but they do not stimulate the more cross-reactive cell-mediated immunity (CMI) that can give some measure of protection against a broad spectrum of influenza A viruses. The question is, should we be thinking about vaccine strategies that also induce virus-specific CD4+ and CD8+ "memory" T cells, in the knowledge that the more rapid emergence of these effectors of CMI will, at best, ameliorate the severity of the disease rather than prevent infection completely? Though it is the case that many people will already have some influenza-specific T cell memory, it is also likely that regular boosting will greatly increase both the numbers of these memory T cells and the rapidity of the recall response following live virus challenge. The present experiments address the effectiveness and characteristics of the CMI response in mice that have (like people) previously been exposed to heterologous influenza A viruses, then infected with these highly virulent H5N1 influenza A viruses. A variety of genetically engineered and reassortant viruses will be used in prime, boost and challenge experiments to investigate the limits of protection and the cellular mechanisms that might be selectively promoted if an effective CMI- directed vaccine were to be developed. Whether the H5N1 viruses have particular characteristics that tend to subvert the protection conferred by pre-existing CMI will also be addressed, in the hope of identifying strategies that might be used to defeat such effects. These studies should allow us to develop a clear, mechanistic understanding of how to promote effective CMI against the H5N1 viruses.

描述(申请人提供)：所有负责任的政府都非常担心，在东南亚杀死大量野生和家禽(以及一些人)的高致命性H5N1甲型流感病毒可能会突然改变宿主范围，并开始在全球人口中以极快的速度传播。尽管我们有一种有效的抗流感药物(奥司他韦)，新一代H5N1疫苗正处于后期开发阶段，流感病毒研究、监测和公共卫生网络也是一流的，但这些病毒的变异能力非常迅速，这意味着没有办法绝对确定我们不会受到一种我们相对缺乏保护的病毒的攻击。目前的福尔马林灭活疫苗促进了高度特异和有效的抗体反应，只要这是针对正确的病毒，但它们不能刺激更多的交叉反应细胞介导的免疫(CMI)，可以对广泛的甲型流感病毒提供一定程度的保护。问题是，我们是否应该考虑同时诱导病毒特异性的CD4+和CD8+“记忆”T细胞的疫苗策略，因为我们知道，CMI这些效应分子的更快出现充其量只会改善疾病的严重性，而不是完全预防感染？虽然许多人已经有了一些流感特异性T细胞的记忆，但定期增强也很可能会大大增加这些记忆T细胞的数量和活病毒攻击后回忆反应的速度。本实验旨在研究CMI反应在小鼠身上的有效性和特征，这些小鼠以前曾接触过异源甲型流感病毒，然后感染了这些高毒力的H5N1甲型流感病毒。各种基因工程病毒和重组病毒将用于启动、增强和挑战实验，以研究保护的限度和可能被选择性促进的细胞机制，如果要开发有效的CMI指导的疫苗。还将讨论H5N1病毒是否具有倾向于颠覆先前存在的CMI所赋予的保护的特定特征，以期确定可能用于击败这种影响的策略。这些研究应该使我们能够对如何促进有效的预防H5N1病毒的CMI有一个明确的、机械性的理解。