SE REGIONAL CENTER FOR EXCELLENCE FOR EMERGING INFECTIONS & BIODEFENSE

东南部新发感染卓越区域中心

• 批准号: 7349221
• 负责人: Rafi Ahmed
• 金额: $ 4.01万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-09 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349221
• 关键词: Poxviridae; Poxviridae disease; active immunization; antigens; bioterrorism /chemical warfare; chemokine; conditioning; cytokine; dendritic cells; genes; genome; immune response; structural genes; vaccinia virus

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Concerns about the potential use of variola as an agent of bioterrorism have recently resulted in decisions to re-initiate smallpox vaccination programs. However, the currently available vaccinia virus (VV)-based smallpox vaccines (eg, Dryvax) are associated with high rates of adverse reactions and are not safe for use in immunodeficient individuals or those with a variety of common medical conditions. As such, development of new smallpox vaccines that are substantially safer, but of equivalent or better immunogenic potency than the current VV vaccine preparations is imperative. While certain attenuated strains of VV, especially modified vaccinia Ankara (MVA), have highly desirable safety features and impressive immunogenicity when used to express heterologous antigens, a variety of data suggest that MVA may be an insufficiently immunogenic vaccine to reliably engender protective responses against variola or other highly pathogenic orthopoxviruses. However, we have recently discovered important aspects of the nature of how both replication-competent VV and replication-restricted MVA interact with host dendritic cells (DCs) that suggest promising approaches to increase the protective potential of MVA as a smallpox vaccine. The overall goal of the proposal is to modify the currently available strain of MVA, so that novel vaccine variants are derived with preserved safety profiles, but with substantially enhanced abilities to raise durable, high level cellular and humoral immune responses that are cross-reactive with major virulent orthopoxviruses. To accomplish this goal, we propose to (1) delete from the MVA genome, residual viral immune evasion genes;(2) express within recombinant MVAs specific cytokines and chemokines that promote DC recruitment and activation; and (3) express specific late viral structural gene products from early vaccinia promoters in recombinant MVAs to facilitate induction of increased host protective immune responses against key orthopoxvirus antigen

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。人们对Variola作为生物恐怖主义的潜在使用的担忧最近导致了重新启动天花疫苗接种计划的决定。但是，目前可用的离子疫苗病毒（VV）的天花疫苗（例如Dryvax）与高反应率相关，并且在免疫缺陷的个体或患有多种常见医疗状况的患者中不安全。因此，与当前的VV疫苗制剂相比，新型天花疫苗的开发基本更安全，但具有同等或更好的免疫原性。虽然某些VV菌株，尤其是修饰的Vacinia ankara（MVA），当用于表达异源抗原的时，具有高度理想的安全性和令人印象深刻的免疫原性，但各种数据表明MVA可能是一种不足的免疫原性，可以可靠地对voliola或其他高度致病性或其他高度病或其他高度抗性或其他高度抗性。但是，我们最近发现了具有复制能力的VV和复制限制的MVA与宿主树突状细胞（DC）相互作用的重要方面，这些方面提出了有希望的方法来提高MVA作为天花疫苗的保护潜力。该提案的总体目标是修改当前可用的MVA菌株，以使新型的疫苗变体具有保留的安全概况，但具有显着提高的能力，可以提高耐用的，高级的细胞和体液免疫反应，这些反应与主要毒品的orthopoxviruse交叉反应。为了实现这一目标，我们建议（1）从MVA基因组中删除残留的病毒免疫逃避基因；（2）在重组MVAS特异性细胞因子和趋化DC募集和激活的重组特异性细胞因子和趋化因子中表达； （3）从重组MVA中的早期疫苗启动子中表达特定的晚期病毒结构基因产物，以促进诱导增加的宿主保护性免疫反应，以针对关键的正托病毒抗原