Influenza A in the aged: a novel vaccination strategy

描述（由申请人提供）：此R21申请是对项目公告PA-04-119的回应。流感是美国国立卫生研究院生物恐怖病原体清单上的C类（新发传染病）病原体。每年，仅在美国，自然发生的流感就造成大约36,000人死亡。其中90%以上的死亡发生在老年人中。大流行或人工流感袭击的后果对这一年龄组将是毁灭性的。这种不成比例的死亡率很大程度上是由于正常的、与年龄相关的免疫活力下降。针对新流感病毒株的疫苗生产至少需要6个月的时间，目前的流感疫苗仅对65岁以上的人群有效。流感疫苗策略的任何改进都将特别有益于老年人。通过采用一种新的抗原靶向系统，在适应性免疫和获得性免疫之间发挥作用，我们希望在老年人中刺激保护性异亚型流感免疫。该佐剂是C5a受体的反应选择性激动剂。与C5a激动剂偶联的抗原可诱导先天、体液和细胞免疫应答。使用一种成熟的小鼠模型，第一个特定目标将检查幼龄和老年动物在接种C5a激动剂直接与流感病毒偶联后产生的免疫反应。我们将详细检查CD4、CDS、B细胞和自然杀伤细胞的反应，比较老年人和年轻人的免疫反应。在第二个目标中，从第一个目标中获得的知识将用于检查老年人对流感挑战的保护，并与通过传统疫苗介导的保护进行比较。

DESCRIPTION (provided by applicant): This R21 application is in response to the program announcement PA-04-119. Influenza is a category C (emerging infectious disease) pathogen on the NIH bioterror pathogen list. Every year, naturally occurring influenza causes approximately 36,000 deaths in the United States alone. Over 90% of these deaths occur in the elderly population. The consequences of a pandemic or an engineered influenza attack would be devastating to this age group. This greatly disproportionate death rate is largely due to the normal, age- related decrease in immune vigor. Vaccine production against new flu strains takes a minimum of six months, and the current influenza vaccine is only of limited efficacy in people who are 65 years or older. Any improvement in influenza vaccine strategies would be of particular benefit to the elderly. By employing a novel antigen-targeting system that functions at the crossroads between adaptive and acquired immunity, we hope to stimulate protective heterosubtypic influenza immunity in the aged. This adjuvant is a response- selective agonist of the C5a receptor. Antigen coupled to this C5a agonist can induce innate, humoral and cellular immune response. Using a well-established mouse model, the first specific aim will examine the immune responses generated by young and aged animals following vaccination with the C5a agonist coupled directly to the influenza virus. We will examine the CD4, CDS, B cell, and natural killer cell responses in detail, comparing the aged immune response against that achieved in the young. In the second aim, the knowledge gained from the first aim will be used to examine protection against influenza challenge in the aged, as compared to protection mediated through the conventional vaccine.