Human CD8+ and CD4+ T Cells Responses to Influenza Infection and Vaccination

人类 CD8 和 CD4 T 细胞对流感感染和疫苗接种的反应

• 批准号: 7701542
• 负责人: Masanori Terajima
• 金额: $ 45.69万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7701542
• 关键词: Address; Adult; Antibodies; Antibody Binding Sites; Antibody Formation; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8B1 gene; Categories; Cellular Immunity; Clinical Research; Clinical Services; Cytoprotection; Data; Dose; Elderly; Epitopes; Face; Flow Cytometry; Goals; Hemagglutinin; Human; Human Virus; Immune response; Immunity; Individual; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A virus; Laboratories; Lead; Licensing; Population; Proteins; Reagent; Recommendation; T-Lymphocyte; T-Lymphocyte Epitopes; Vaccination; Vaccines; Virus; Virus Diseases; cross reactivity; design; high risk; improved; influenza virus vaccine; influenzavirus; mouse model; neutralizing antibody; response; technology development; trivalent influenza vaccine; young adult

The overall goal of this project is to define the human T cell responses to influenza infection and to trivalent inactivated influenza vaccines (TIV) in younger and older adults. We hypothesize that (1) human T cell responses in younger adults will be greater than those in older adults to vaccination and to infection, (2) human CD4+ and CD8+ T cell responses will be lower to vaccine than to infection and (3) the TlV-induced T cell responses will correlate with the amount of internal proteins in the individual licensed vaccines. Influenza A virus hemagglutinin (HA) is a target of protective neutralizing antibodies, which are subtypespecific and vulnerable to antigenic drift. CD4+ and CD8+ T cell responses are thought to be more subtype cross-reactive. It is clear from studies in mouse models of influenza A virus infections that T cells can provide a second important line of defense, especially in the face of marked antigenic drift or shift due to emergence of viruses with changes in HA antibody combining sites, and there are also limited clinical studies which suggest the importance of T cells for protection, especially in a high-risk elderly population. There is, however, only a limited amount of data available on human T cell responses to influenza infection or vaccination. Importantly there appears to be more subtype cross-reactivity among influenza A virus T cell epitopes than to the antibody epitopes on HA. At present limited data suggest that current TIVs induce low to moderate CD4+ and CD8+ T cell responses. However, we found some individuals with high T cell responses to TIV. Recently, we and the other group also found the amount of influenza internal proteins in the TIVs differs. Despite the recommendation and use of about 100 million vaccine doses per year in the US alone, very little is known about TIVs induction of T cell responses and nothing is known about their contribution to vaccine associated protection. In Aim 1 we propose to analyze CD4+ and CD8+ T cell responses to TIV vaccination in younger and older adults. In these studies, we will also compare the three US-licensed TIVs for their ability to stimulate CD4+ and CD8+ T cell responses and for protection (in older adults). In Aim 2 we propose to characterize CD4+ and CD8+ T cell responses to natural influenza infections in younger and older adults and compare them to the CD4+ and CD8+ T cell responses induced by TIV. These analyses may lead to approaches towards improved influenza vaccines, which can protect against new and emerging influenza virus infections including H5N1 and other non-human strains.

该项目的总体目标是确定人类 T 细胞对流感感染的反应并 年轻人和老年人的三价灭活流感疫苗（TIV）。我们假设 (1) 人类 T 年轻人的细胞对疫苗接种和感染的反应将大于老年人， (2) 人类 CD4+ 和 CD8+ T 细胞对疫苗的反应低于对感染的反应，(3) TIV 诱导的 T 细胞反应将与个别许可疫苗中的内部蛋白质含量相关。 甲型流感病毒血凝素 (HA) 是保护性中和抗体的目标，该抗体是亚型特异性的 并且容易受到抗原漂移的影响。 CD4+ 和 CD8+ T 细胞反应被认为是更多的亚型 交叉反应。从甲型流感病毒感染小鼠模型的研究中可以清楚地看出，T 细胞可以 提供第二条重要的防线，特别是在面对由于以下原因导致的明显抗原漂移或转移时 HA抗体结合位点改变的病毒出现，临床研究也有限 这表明 T 细胞对于保护的重要性，尤其是在高危老年人群中。有， 然而，关于人类 T 细胞对流感感染的反应的可用数据有限，或者 疫苗接种。重要的是，甲型流感病毒 T 细胞之间似乎存在更多的亚型交叉反应性 表位比HA上的抗体表位。目前有限的数据表明当前的 TIV 诱导低 调节 CD4+ 和 CD8+ T 细胞反应。然而，我们发现一些 T 细胞水平较高的个体 对 TIV 的反应。最近，我们和另一个小组还发现了流感内部蛋白的含量 TIV 不同。尽管美国每年建议和使用约 1 亿剂疫苗 单独而言，我们对 TIV 诱导 T 细胞反应知之甚少，并且对它们的作用一无所知。 对疫苗相关保护的贡献。在目标 1 中，我们建议分析 CD4+ 和 CD8+ T 细胞 年轻人和老年人对 TIV 疫苗接种的反应。在这些研究中，我们还将比较这三者 美国许可的 TIV 能够刺激 CD4+ 和 CD8+ T 细胞反应并提供保护（在老年患者中） 成年人）。在目标 2 中，我们建议表征 CD4+ 和 CD8+ T 细胞对自然流感感染的反应 并将其与 TIV 诱导的 CD4+ 和 CD8+ T 细胞反应进行比较。 这些分析可能会导致改进流感疫苗的方法，从而预防流感 新出现的流感病毒感染，包括 H5N1 和其他非人类毒株。