Transcriptomic Signatures of Influenza Vaccine Responses

摘要 本申请的广泛的长期目标是鉴定先天性和辅助性T（Th）细胞转录组学特征 免疫反应，并进一步了解性别依赖的人类免疫反应，以两个独特的 在老年男性和女性人群中接种甲型流感/H3 N2疫苗。全面 测量先天性和适应性（CD 4 +T辅助细胞）免疫反应的频谱，以最近的FDA- 许可的MF 59佐剂流感亚单位疫苗（MF 59 Flu）和高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 在特征明确的队列中（65岁及以上）。早期的先天免疫反应对于 发展强大的适应性免疫，在再次暴露于流感时提供保护。同样， 免疫应答提供T细胞帮助，这对于建立保护性体液免疫是必不可少的。知之甚少 关于性别对这些流感疫苗后先天性和Th辅助反应的影响。在这 应用，我们提出了两个平行的具体目标（一个集中在先天免疫反应和其他 这两种疫苗的CD 4 +Th应答）。我们的目标将测试以下假设：1）疫苗类型 （MF 59流感vs HDFlu）和/或性别与先天性和Th细胞免疫应答的变化相关; 2） HDFlu中Ag剂量的增加导致先前基因/基因集的更大激活/抑制 与对标准剂量流感疫苗的免疫应答相关; 3）MF 59佐剂导致 与HDFlu相比，其他基因/基因集的激活/抑制; 4）转录组特征 (gene与免疫应答相关的表达模式）介导疫苗类型（或 性别）与免疫结果;和5）先天或Th细胞免疫结果和相应的 转录组标记将预测体液免疫的标志物（HAI滴度和记忆B细胞ELISPOT 响应）。完成这些具体目标将使我们能够剖析分子机制， MF 59 Flu和HDFlu增强流感高危老年人的先天性和Th免疫应答 疾病，确定特定的基因组参与基于性别的免疫反应的差异，并可能允许 鉴定疫苗免疫原性的新相关性。

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.