Transcriptomic Signatures of Influenza Vaccine Responses

摘要 该应用程序的广泛长期目标是识别先天和辅助性T细胞(Th)转录特征 免疫反应和加深我们对性别依赖的人类免疫反应的理解 在老年男性和女性人群中接种甲型H3N1流感疫苗。我们将全面 测量先天性和获得性(CD4+T辅助细胞)免疫反应的频谱，以应对最近的FDA- 许可的MF59佐剂流感亚单位疫苗(MF59Flu)和大剂量裂解流感病毒疫苗 (HDFlu)使用系统生物学方法，结合详细的临床和实验室免疫表型分析 在一个特征良好的队列中(65岁及以上)。早期的先天免疫反应对 发展强大的适应性免疫，在再次接触流感时提供保护。同样，Th 应答为建立保护性体液免疫提供必要的T细胞帮助。鲜为人知 关于性别对这些流感疫苗后先天和Th辅助反应的影响。在这 应用，我们提出了两个平行的特定目标(一个集中在先天免疫反应上，另一个集中在 对这两种疫苗的CD4+Th反应)。我们的目标将检验以下假设：1)疫苗类型 (MF59Flu与HDFlu)和/或性别与先天和Th细胞免疫反应的变化有关；2) HDFlu中增加的Ag剂量导致先前更大的基因/基因集的激活/抑制 与标准剂量流感疫苗的免疫反应有关；3)MF59佐剂导致 与HDFlu相比，激活/抑制额外的基因/基因集；4)转录特征 (与免疫反应相关的基因表达模式)调节疫苗类型(或 性)与免疫结果；以及5)先天或Th细胞免疫结果和相应的 转录特征将预测体液免疫的标志物(HAI滴度和记忆B细胞ELISPOT 回应)。这些特定目标的完成将使我们能够剖析 MF59Flu和HDFlu增强流感高危老年人的先天和Th免疫反应 疾病，识别涉及基于性别的免疫反应差异的特定基因集，并可能允许 疫苗免疫原性新相关因素的鉴定。

ABSTRACT The broad long-term goal of this application is to identify innate and T helper (Th) cell transcriptomic signatures of immune response and further our understanding of sex-dependent human immune responses to two unique influenza A/H3N2 vaccines in a population of older adult males and females. We will comprehensively measure the spectrum of innate and adaptive (CD4+T helper cell) immune responses to the recently FDA- licensed MF59-adjuvanted influenza subunit vaccine (MF59Flu) and the high-dose split influenza virus vaccine (HDFlu) using a systems biology approach, combined with detailed clinical and laboratory immunophenotyping in a well-characterized cohort (65 years of age and older). Early innate immune responses are critical to the development of robust adaptive immunity that confers protection upon re-exposure to influenza. Likewise, Th responses provide T cell help essential for the establishment of protective humoral immunity. Little is known about the effect of sex on innate and Th helper responses following these influenza vaccines. In this application, we propose two parallel Specific Aims (one focused on innate immune responses and the other on CD4+Th responses to these two vaccines). Our Aims will test the following hypotheses: 1) that vaccine type (MF59Flu vs HDFlu) and/or sex are associated with variations in innate and Th cell immune response; 2) that the increased Ag dose in HDFlu results in greater activation/suppression of the genes/genesets previously associated with immune responses to standard dose influenza vaccine; 3) that the MF59 adjuvant results in activation/suppression of additional genes/genesets compared to HDFlu; 4) that transcriptomic signatures (gene expression patterns associated with immune responses) mediate the association of vaccine type (or sex) with immune outcomes; and 5) that the innate or Th cell immune outcomes and corresponding transcriptomic signatures will predict markers of humoral immunity (HAI titer and memory B cell ELISPOT response). Completion of these Specific Aims will allow us to dissect the molecular mechanisms by which MF59Flu and HDFlu enhance innate and Th immune responses in older persons at high risk of influenza disease, identify specific genesets involved in sex-based differences in immune response, and may allow the identification of new correlates of vaccine immunogenicity.