Leukocyte Signaling in the Elderly and Vaccine Immunogenicity

老年人的白细胞信号转导和疫苗免疫原性

• 批准号: 8088907
• 负责人: DAVID BRAM LEWIS
• 金额: $ 40万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8088907
• 关键词: Leukocyte; Signaling; Elderly; Vaccine; Immunogenicity

DESCRIPTION (provided by applicant): Influenza viral infection continues to cause disproportionate mortality in the elderly (those 65 years of age or older) despite a high level of annual immunization of this population with inactivated trivalent influenza vaccine (TIV). The efficacy and immunogenicity of TIV in the elderly overall is substantially lower than in younger adults, although there is substantial individual variation for reasons that are not well understood. TIV, which contains the hemagglutinin (HA) and neuraminidase (NA) major viral surface proteins and is unadjuvanted, provides protection mainly by inducing neutralizing antibodies to HA. Influenza-specific CD4 T-cell responses induced by TIV may contribute to the antibody response and, in conjunction with CD8 T-cell responses, may enhance viral clearance in the event that infection occurs despite vaccination. It is unclear to what extent the inclusion of potent adjuvants for adaptive immunity, such as cationic lipid/DNA complexes (CLDC) could boost immunogenicity in the elderly to TIV and other vaccines. A phase II human study sponsored by Juvaris Biotherapeutics, Inc., is evaluating the safety, efficacy and dose requirement of a single intramuscular dose of TIV/CLDC for optimal influenza-specific humoral and T-cell responses in 472 elderly men and women. As part of this study, GLP-certified assays of influenza-specific antibody and CD4 and CD8 T-cell responses at baseline and at multiple time points post-vaccination are in progress. The availability of these immunogenicity results, along with multiple aliquots of cryopreserved PBMCs, provides a unique opportunity to determine predictors of vaccine immunogenicity in the elderly in this project. The central hypothesis is that impaired humoral and T-cell immunogenicity to TIV in some of the elderly reflects intrinsic limitations in the signaling of antigen-presenting cells (APCs), B cells, and T cells, and that these limitations are, in turn, the result of alterations of mRNA expression by microRNAs (miRNAs). This hypothesis will be tested by determining if immunogenicity after TIV or TIV/CLDC vaccination of these elderly subjects can be predicted by the capacity of their monocytes, B cells, and T cells to signal after engagement of receptors for cytokines, e.g., IL-21, innate immune ligands, e.g., CpG DNA, and antigen, i.e., the B-cell and T-cell receptors, as assessed by an improved phospho-flow cytometric assay. In parallel, the frequency of the major subsets of monocytes, B cells, and CD4 and CD8 T- cells will be determined by polychromatic flow cytometry, which will be important in the interpretation of the phospho-flow results. The leukocyte subsets and the stimuli that are most robust predictors of TIV or TIV/CLDC immunogenicity will then be evaluated for their basal and stimulus-dependent levels of mRNA and miRNA expression, focusing on changes that are known to or are likely to influence signaling. Together, these studies will define the predictive value and biological importance of the level of leukocyte subset signaling in generating adaptive immune responses to TIV and TIV/CLDC in the elderly. They will also provide new mechanistic insights as to the role that specific mRNAs and miRNAs play in regulating signaling and activation-induced gene expression involved in vaccine immunogenicity. PUBLIC HEALTH RELEVANCE (provided by applicant): A major limitation in using vaccines to prevent infections, such as influenza, in high-risk populations, such as the elderly, is that it is difficult to predict whether an immunization will be effective in sufficiently boosting the immune response to protect that individual from the infectious disease. This research will identify tests of the function of white blood cells of the immune system that can be used to predict whether vaccination of an elderly individual for influenza will be likely to sufficiently stimulate the immune system to provide that individual with protection from infection. These tests will help use current vaccines more effectively, and will also help in the development of a new, more potent vaccine for influenza that uses an adjuvant, a substance added to vaccines to boost the immune response.

描述（由申请人提供）：尽管对这种灭活的三价流感疫苗（TIV）的人群的年度免疫接种，但流感病毒感染仍会导致老年人（65岁或65岁以上）的老年人死亡率不成比例。 TIV在老年人总体上的疗效和免疫原性大大低于年轻人，尽管由于原因尚不清楚的原因存在很大的差异。 TIV含有血凝素（HA）和神经氨酸酶（Na）主要病毒表面蛋白，并且未经加热，主要通过诱导对HA的中和抗体提供保护。由TIV诱导的流感特异性CD4 T细胞反应可能有助于抗体反应，并且与CD8 T细胞反应结合使用，在感染尽管疫苗接种的情况下发生感染时，可能会增强病毒清除率。目前尚不清楚在多大程度上纳入了适应性免疫的有效佐剂，例如阳离子脂质/DNA复合物（CLDC）可以提高老年人对TIV和其他疫苗的免疫原性。尤瓦里斯Biotherapeutics，Inc。赞助的II期人类研究正在评估单一肌肉内剂量的TIV/CLDC的安全性，功效和剂量需求，用于472名男性和女性的最佳流感特异性体液和T细胞反应。作为这项研究的一部分，在基线和疫苗接种后多个时间点进行了流感特异性抗体，CD4和CD8 T细胞反应的GLP认证测定正在进行中。这些免疫原性结果的可用性，以及多种冷冻保存PBMC的等分试样，为确定该项目中老年人的疫苗免疫原性预测指标提供了独特的机会。中心假设是，在某些老年人中对TIV的体液和T细胞免疫原性受损反映了抗原呈递细胞（APC），B细胞和T细胞信号的内在限制，而这些限制又是microRNAS（mirNAS）的MRNA表达改变的结果。该假设将通过确定这些老年受试者的TIV或TIV/CLDC接种后的免疫原性是否可以通过其单核细胞，B细胞和T细胞的能力来预测受体在受体接合细胞因子后的信号发信号，例如IL-21，例如IL-21，例如IL-21，IL-21，IL-21，IL-21，IL-2，INSATE INSATE IMMANE IMMANE LIGANTAS，例如B-C.，Cpg dna，cp dna，cp dna，cp dna，cpel and that，cp dna，c。受体，通过改进的磷酸流细胞仪测定法评估。同时，单核细胞，B细胞，CD4和CD8 T细胞的主要子集的频率将由多色流式细胞仪确定，这对于解释磷酸流的结果将很重要。然后，将评估白细胞亚群和TIV/CLDC免疫原性的最强大预测指标的刺激，然后评估其基础和刺激依赖性mRNA和miRNA表达水平，重点是已知或可能影响信号的变化。总之，这些研究将定义白细胞子集信号水平在老年人对TIV和TIV/CLDC产生适应性免疫反应中的预测价值和生物学重要性。他们还将提供有关特定mRNA和miRNA在调节疫苗免疫原性中涉及的信号传导和激活诱导的基因表达中所起的作用的新机械见解。 公共卫生相关性（由申请人提供）：使用疫苗预防高危人群中的流感疫苗（例如老年人）的主要局限性，即很难预测免疫能够有效地有效地增强免疫反应以保护该人免受感染性疾病的侵害。这项研究将确定免疫系统白细胞功能的测试，可用于预测对流感的老年人的疫苗接种是否可能充分刺激免疫系统，以使该人免受感染的保护。这些测试将有助于更有效地使用当前的疫苗，还将有助于开发用于使用佐剂的新型，更有效的疫苗，该疫苗是使用辅助剂的，一种添加到疫苗的物质来增强免疫反应。