Human T Cell Responses to Vaccinia Vaccine

人类 T 细胞对牛痘疫苗的反应

• 批准号: 6881212
• 负责人: PHYLLIS Rudolph FLOMENBERG
• 金额: $ 31.4万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6881212
• 关键词: antigens; biotechnology; bioterrorism /chemical warfare; clinical research; cytotoxic T lymphocyte; dendritic cells; enzyme linked immunosorbent assay; human subject; immune response; leukocyte activation /transformation; neutralizing antibody; smallpox vaccine; structural genes; vaccine development; vaccinia virus; virus envelope

DESCRIPTION (provided by applicant): There is an urgent need to develop safer smallpox vaccines. One approach is the use of modified vaccinia virus Ankara (MVA), a highly attenuated vaccinia virus that does not replicate in human cells. In comparison to vaccinia virus, however, MVA is less immunogenic and may require higher doses and more frequent boosts. There also remain safety concerns about the use of a live attenuated virus and the potential presence of adventitious pathogens. Alternative approaches include the development of inactivated virus or recombinant protein vaccines. However, vaccine development is hampered because little is known about what proteins play an important role in the generation of protective immune responses to smallpox. Recently, 4 envelope proteins that induce neutralizing antibodies were identified, and DNA vaccination with a combination of all 4 genes protected mice from a lethal vaccinia infection. Although a vaccine will need to induce strong T cell responses, in addition to neutralizing antibodies, no information is available about the vaccinia protein targets recognized by T cells. In particular, CD4 T cells are required to enhance B cell, T cell, and innate immune responses to lytic viruses. As a first step, peripheral blood mononuclear cells from healthy adults previously immunized with vaccinia virus will be tested for virus-specific T cell responses. The goals of this study are: 1) to measure the frequencies of human T cell responses to vaccinia structural proteins; 2) to identify major CD4 and CD8 T cell epitopes within the above 4 envelope proteins; and 3) to analyze the frequencies of the T cell responses to these epitopes post-vaccination. It is anticipated that this work will provide new tools for the detection and monitoring of vaccinia-specific T cell responses from most individuals and will help develop new strategies for smallpox vaccine development.

描述（由申请人提供）：迫切需要开发更安全的天花疫苗。一种方法是使用改良的安卡拉痘苗病毒（MVA），这是一种高度减毒的痘苗病毒，不能在人体细胞中复制。然而，与痘苗病毒相比，MVA 的免疫原性较低，可能需要更高的剂量和更频繁的加强。对于减毒活病毒的使用和外来病原体的潜在存在也仍然存在安全问题。替代方法包括开发灭活病毒或重组蛋白疫苗。然而，疫苗的开发受到阻碍，因为人们对哪些蛋白质在天花保护性免疫反应的产生中发挥重要作用知之甚少。最近，鉴定出 4 种诱导中和抗体的包膜蛋白，并且使用所有 4 种基因组合进行 DNA 疫苗接种可以保护小鼠免受致命的牛痘感染。尽管除了中和抗体之外，疫苗还需要诱导强烈的 T 细胞反应，但目前还没有关于 T 细胞识别的痘苗蛋白靶标的信息。特别是，CD4 T 细胞需要增强 B 细胞、T 细胞和对裂解病毒的先天免疫反应。第一步，将测试先前接种牛痘病毒的健康成年人的外周血单核细胞的病毒特异性 T 细胞反应。本研究的目标是：1）测量人类 T 细胞对牛痘结构蛋白反应的频率； 2) 鉴定上述 4 种包膜蛋白内的主要 CD4 和 CD8 T 细胞表位； 3) 分析疫苗接种后 T 细胞对这些表位的反应频率。预计这项工作将为检测和监测大多数个体的痘苗特异性 T 细胞反应提供新工具，并将有助于制定天花疫苗开发的新策略。

项目成果

Human T-cell responses to vaccinia virus envelope proteins.

人类 T 细胞对痘苗病毒包膜蛋白的反应。

• DOI: 10.1128/jvi.00601-06
• 发表时间: 2006
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Tang,Jie;Murtadha,Mariam;Schnell,Matthias;Eisenlohr,LaurenceC;Hooper,Jay;Flomenberg,Phyllis
• 通讯作者: Flomenberg,Phyllis