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: 8452138
• 负责人: Masanori Terajima
• 金额: $ 31.39万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8452138
• 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; Flow Cytometry; Goals; Hemagglutinin; Human; Human Virus; Immune response; Immunity; Individual; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A virus; Influenza vaccination; Laboratories; Lead; Licensing; Population; Proteins; Reagent; Recommendation; T cell response; 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; young adult; 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; Flow Cytometry; Goals; Hemagglutinin; Human; Human Virus; Immune response; Immunity; Individual; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A virus; Influenza vaccination; Laboratories; Lead; Licensing; Population; Proteins; Reagent; Recommendation; T cell response; 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; 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定义人类T细胞对流感感染的反应和对 年轻和老年人的三价灭活流感疫苗（TIV）。我们假设（1）人类 年轻人的细胞反应将大于老年人对疫苗接种和感染的反应， （2）人类CD4+和CD8+ T细胞反应对疫苗的反应将低于感染和（3）TLV诱导的 T细胞反应将与单个许可疫苗中的内部蛋白质量相关。 流感病毒血凝素（HA）是保护性中和抗体的靶标，是亚型 容易受到抗原漂移的影响。 CD4+和CD8+ T细胞响应被认为是更亚型的 交叉反应。从对流感的小鼠模型A病毒感染的研究可以清楚地看出，T细胞可以 提供第二种重要的防御线，尤其是面对明显的抗原漂移或由于 病毒的出现随HA抗体组合位点的变化，并且临床研究也有限 这表明T细胞对保护的重要性，尤其是在高危老年人群中。有， 但是，仅有关人类T细胞对流感感染的反应的可用数据有限的数据或 疫苗接种。重要的是，流感病毒T细胞中似乎有更多的亚型交叉反应性 比例比HA上的抗体表位。目前有限的数据表明当前TIV诱导低 到中度的CD4+和CD8+ T细胞反应。但是，我们发现有些人具有高T细胞 对TIV的回应。最近，我们和另一个小组还发现 TIV有所不同。尽管在美国建议和使用约1亿次疫苗剂量 独自一人，关于T细胞反应的TIV诱导鲜明，对它们的响应一无所知 对疫苗相关保护的贡献。在AIM 1中，我们建议分析CD4+和CD8+ T细胞 对年轻和老年人的TIV疫苗接种的反应。在这些研究中，我们还将比较三个 我们许可的TIV刺激CD4+和CD8+ T细胞反应的能力和保护（在较旧的情况下） 成年人）。在AIM 2中，我们建议表征CD4+和CD8+ T细胞对天然流感感染的反应 在年轻和老年人中，将它们与TIV诱导的CD4+和CD8+ T细胞反应进行了比较。 这些分析可能会导致改善流感疫苗的方法，以防止 新的和新兴的流感病毒感染，包括H5N1和其他非人类菌株。