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（由申请人提供）：所有负责任的政府都非常关心高度致命的H5N1流感A型病毒，这些病毒一直在杀死大量的野生和家禽（和几个人（以及一些人）（以及一些人），这可能会突然改变其宿主范围，并在人类种群中极快地开始在全球范围内扩散到全球范围。尽管我们有一种有效的抗激素药物（Oseltamivir），但一种新的生成H5N1疫苗正处于高级发展阶段，流感病毒研究，监测和公共卫生网络是第一类，这些病毒的能力是这些病毒的能力，这些病毒均可以非常迅速地不确定我们对Virus的影响很少，我们将不对这一不利的保护。当前的福尔马林灭活疫苗促进了高度特异性和有效的抗体反应，只要这是针对正确病毒的，但它们不会刺激更具交叉反应性的细胞介导的免疫（CMI），可以为广泛的流感病毒提供一定的保护。问题是，我们是否应该考虑也诱导病毒特异性CD4+和CD8+“记忆” T细胞的疫苗策略，因为知道CMI的这些效应者的迅速出现充其量会充其量会改善疾病的严重程度而不是完全防止感染？尽管许多人已经拥有一些特定流感的T细胞记忆，但在实时病毒挑战挑战后，常规增强也可能会大大增加这些记忆T细胞的数量和召回反应的迅速性。本实验探讨了CMI反应在以前（像人类一样）先前暴露于异源性流感病毒的小鼠中的有效性和特征，然后感染了这些高毒性H5N1流感病毒。如果要开发有效的CMI-CMI-tiromin疫苗，将使用多种基因工程和重新分类病毒用于研究保护的限制以及可以选择性促进的细胞机制。 H5N1病毒是否具有倾向于颠覆预先存在的CMI保护的保护的特殊特征，也将被解决，以期识别可能用来打败这种影响的策略。这些研究应该使我们能够对如何促进H5N1病毒有效的CMI有清晰的机械理解。