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

该项目的总体目标是确定人类T细胞对流感感染的反应， 三价灭活流感疫苗（TIV）在年轻人和老年人。我们假设（1）人类T 年轻人对疫苗接种和感染的细胞应答将大于老年人， (2)人CD4+和CD8 + T细胞应答对疫苗的应答将低于对感染的应答，以及（3）TIV诱导的T细胞应答将低于对感染的应答。 T细胞应答将与单个许可疫苗中的内部蛋白质的量相关。 甲型流感病毒血凝素（HA）是保护性中和抗体的靶点，具有亚型特异性， 并且易受抗原漂移的影响。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到，T细胞可以 提供了第二道重要的防线，特别是在面对明显的抗原漂移或转变时， 出现HA抗体结合位点发生变化的病毒，临床研究也有限 这表明T细胞在保护方面的重要性，特别是在高危老年人群中。是的， 然而，关于人类T细胞对流感感染的应答的数据有限， 预防针重要的是，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， HA上的抗体表位。目前有限的数据表明，目前的TIV诱导低 中度CD4+和CD8 + T细胞应答。然而，我们发现一些高T细胞的人， 对TIV的回应最近，我们和另一个小组也发现了流感病毒内部蛋白的数量， TIV不同。尽管美国每年推荐和使用约1亿剂疫苗， 单独地，关于TIV诱导T细胞应答知之甚少，关于它们的免疫应答也一无所知。 对疫苗相关保护的贡献。在目的1中，我们提出分析CD4+和CD8 + T细胞 年轻人和老年人接种TIV疫苗的反应。在这些研究中，我们还将比较这三个 美国许可的TIV刺激CD4+和CD8 + T细胞应答的能力以及保护（老年人） 成人）。在目标2中，我们提出了表征自然流感感染的CD4+和CD8 + T细胞应答 在年轻人和老年人中，并将其与TIV诱导的CD4+和CD8 + T细胞应答进行比较。 这些分析可能会导致改进流感疫苗的方法， 新的和正在出现的流感病毒感染，包括H5N1和其他非人类毒株。

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.