Protective Cell-Mediated Immunity Against Lethal H5N1 Influenza A Viruses

描述（由申请人提供）：所有负责任的政府都非常担心在东南亚造成大量野生和家禽（以及少数人）死亡的高致命性H5N1甲型流感病毒可能突然改变其宿主范围，并开始在全球人群中以极快的速度传播。虽然我们有一种有效的抗流感药物（奥司他韦），新一代H5N1疫苗正处于开发的后期阶段，流感病毒的研究、监测和公共卫生网络是一流的，但这些病毒非常迅速地变异的能力意味着，我们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袭击。目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，前提是这种反应是针对正确的病毒，但它们不能刺激更具交叉反应性的细胞介导免疫（CMI），而这种免疫可以对广谱甲型流感病毒提供一定程度的保护。问题是，我们是否应该考虑疫苗策略，也诱导病毒特异性CD4+和CD8+“记忆”T细胞，在认识到这些CMI效应物的更快出现，最多只能减轻疾病的严重程度，而不是完全预防感染？尽管许多人已经拥有一些流感特异性T细胞记忆，但也有可能定期增强将大大增加这些记忆T细胞的数量，并在活病毒攻击后迅速召回反应。本实验探讨了小鼠（像人一样）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CMI反应的有效性和特征。多种基因工程和重组病毒将用于启动、增强和挑战实验，以研究如果开发出有效的CMI定向疫苗，可能选择性促进的保护限度和细胞机制。还将讨论H5N1病毒是否具有倾向于破坏预先存在的CMI所赋予的保护的特殊特征，以期确定可能用于挫败此类影响的策略。这些研究应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、机械的认识。

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.