Protective Cell-Mediated Immunity Against Lethal H5N1 Influenza A 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养鸟类（以及少数人）的高致命性H5 N1甲型流感病毒可能会突然改变其宿主范围，并开始在全球范围内以极快的速度在人群中传播。虽然我们有一种有效的抗流感药物（奥司他韦），新一代H5N1疫苗也处于研制的后期阶段，而且流感病毒的研究、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肯定我们不会受到一种我们相对缺乏保护的病毒的打击。目前的福尔马林灭活疫苗促进高度特异性和有效的抗体应答，只要这是针对正确的病毒，但它们不刺激更具交叉反应性的细胞介导的免疫（CMI），可以提供某种程度的保护，以对抗广谱的流感病毒A。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，因为这些CMI效应物的更快出现充其量只能减轻疾病的严重程度，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细胞记忆，但定期加强免疫也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。本实验解决了先前暴露于异源甲型流感病毒，然后感染这些高毒力H5N1甲型流感病毒的小鼠（如人）中CMI应答的有效性和特征。将在初免、加强和攻毒实验中使用各种基因工程和抗性病毒，以研究保护的限度和如果要开发有效的CMI导向疫苗可能选择性促进的细胞机制。H5N1病毒是否具有倾向于破坏先前存在的CMI所赋予的保护的特定特征也将被讨论，以期确定可能用于克服这种影响的策略。这些研究应该使我们能够对如何促进有效的CMI对抗H5N1病毒有一个清晰的、机械的理解。

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.