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

描述（由申请人提供）：临床医生目前没有可获得且相对便宜的方法来预测老年人的流感疫苗反应。这项研究的长期目标是确定作为流感严重并发症替代物（生物标志物）的t细胞反应，并可用于预测疫苗的有效性。这种松散命名的生物标志物将使临床医生能够决定哪些人可能受益于更新或更具反应性的疫苗，例如更高抗原剂量的疫苗，或者由于对疫苗接种反应不足，哪些人可能需要在流感季节进行化学预防。这项为期5年的研究是对分裂病毒流感疫苗（SVV）在5个流感季节中的高剂量（HD）和标准剂量（SD）配方进行随机研究，以确定疫苗介导的流感保护的关键决定因素，以及如何通过接种新批准的高剂量流感疫苗在体弱的老年受试者中增强这些免疫介质。本研究将使我们能够解决以下目标：目的1：确定新上市的高剂量疫苗是否比标准剂量疫苗在实现IFN保护性增加方面表现更好？：IL-10比值及GrzB水平。我们的假设是，高于IFN阈值水平的受试者比例？接种高剂量SVV者接种后IL-10比值（>0）和/或GrzB （bbb990 U/mg蛋白）显著高于标准剂量SVV者。目的II：评估静止T细胞中CMV状态的脆弱程度和GrzB水平（bGrzB）的关系。脆弱代表一种验证

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.