Immune Response to High-Dose vs. Standard Dose Influenza Vaccine

描述（由申请人提供）：临床医生目前没有方法来预测老年人的流感疫苗反应，这些方法是可获得的且相对便宜。这项研究的长期目标是确定作为流感严重并发症的替代物（生物标志物）的T细胞反应，并可用于预测疫苗的有效性。这种松散的生物标志物将为临床医生提供能力，以决定谁可能受益于更新或更多的反应原性疫苗，如更高的抗原剂量疫苗，或谁可能需要在流感季节由于疫苗接种反应不足的化学预防。这项为期5年的提案是一项在5个流感季节中的每个季节对高剂量（HD）与标准剂量（SD）制剂的裂解病毒流感疫苗（SVV）进行随机研究，以确定疫苗介导的流感保护的关键决定因素，以及在体弱的老年受试者中接种新批准的高剂量流感疫苗如何增强这些免疫介质。本研究将使我们能够解决以下目标：目的I：确定新上市的高剂量疫苗在实现IFN？保护性增加方面是否优于标准剂量疫苗：IL-10比率和GrzB水平。我们的假设是高于IFN？阈值水平的受试者比例：接种疫苗后的IL-10比率（>10）和/或GrzB（>990 U/mg蛋白质）在接受高剂量SVV的那些中显著高于标准剂量SVV。目的II：评估虚弱程度与CMV状态和静息T细胞（bGrzB）中GrzB水平的相关性。脆弱代表了一种经过验证的 和可测量的老年人脆弱性增强的状态。我们的假设是，增加脆弱性将与较高的bGrzB水平呈正相关。目的III：建立疫苗介导的保护作用的预测因子，可用于即时检测。我们的假设是，虚弱，CMV血清阳性状态和bGrzB活性水平的增加与细胞溶解活性降低，减少Th 1：Th 2对流感攻击的反应，以及流感疾病的风险增加有关。

DESCRIPTION (provided by applicant): Clinicians currently do not have methods to predict influenza vaccine responses in older adults that are accessible and relatively inexpensive. The long-term goal of this research is to identify the T-cell responses that are surrogates (biomarkers) of serious complications of influenza and can be used to predict vaccine effectiveness. Such loosely termed biomarkers would provide clinicians with the ability to decide who might benefit from newer or more reactogenic vaccines, such as a higher antigen dose vaccine, or who might require chemoprophylaxis during influenza season due to inadequate response to vaccination. This 5-year proposal is a randomized study of split-virus influenza vaccine (SVV) in a high-dose (HD) vs. standard dose (SD) formulation in each of five influenza seasons to define the key determinants of vaccine-mediated protection against influenza and how these immunologic mediators may be enhanced by vaccination with a newly approved high-dose influenza vaccine in frail older subjects. This study will allow us to address the following aims: AIM I: Determine whether a newly marketed high dose vaccine performs better than standard doses in achieving protective increases in IFN?:IL-10 ratios and GrzB levels. Our hypothesis is that the proportion of subjects above the threshold level for the IFN?:IL-10 ratio (>10) and/or GrzB (>990 U/mg protein) following vaccination will be significantly higher in those receiving the high-dose SVV vs. standard-dose SVV. AIM II: Evaluate the association of degree of frailty to CMV status and GrzB levels in resting T cells (bGrzB). Frailty represents a validated and measurable state of enhanced vulnerability in older individuals. Our hypothesis is that increasing frailty will be positively associated with higher bGrzB levels. AIM III: Establish predictors of vaccine-mediated protection that can be developed for point-of-care testing. Our hypothesis is that increased levels of frailty, CMV seropositive status, and bGrzB activity are associated with lower cytolytic activity, diminished Th1:Th2 responses to influenza challenge, and an enhanced risk of an influenza illness.