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New Adjuvant Technologies for a Marburg Virus Vaccine

马尔堡病毒疫苗的新佐剂技术

基本信息

批准号：
7103977
负责人：
ASHISH KUMAR PATHAK
金额：
$ 25.03万
依托单位：
WESTERN ILLINOIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7103977
关键词：
Marburg virus biotechnology bioterrorism /chemical warfare cell mediated lymphocytolysis test cellular immunity enzyme linked immunosorbent assay guinea pigs humoral immunity immunomodulators laboratory mouse nonhuman therapy evaluation synthetic vaccines terpene saponin vaccine development vaccine evaluation viral vaccines virus protein

项目摘要

DESCRIPTION (provided by applicant): This application is in response to PA-03-080 as an exploratory/developmental R21 grant. Herein, we propose to develop a new synthetic saponin adjuvant to be used with the Marburg glycoprotein (MBGV GP) as a vaccine preparation. Since Marburg virus (MBGV) is one of the most deadly viruses that can be used as a bioterrorism agent (i.e., a NIAID Category A priority pathogen), there is an urgent need to develop a potent vaccine for this agent. Adjuvants not only play a crucial role as delivery vehicles, but they also stimulate humoral and cell-mediated immunity characterized by cytolytic T-lymphocytes, which is critical for the generation of an effective immune response and long term protective immunity against viral infections. Saponins, especially from Gypsophilla species, Saponaria officinalis, and Quillaja saponaria Molina, possess potent immunomodulating activity (both humoral and cell mediated) in humans for bacterial, viral, and other infections. However, their use is limited due to recognized toxicity and stability issues. We propose the synthesis of novel saponins from gypsogenic acid (aglycone) utilizing the established structure-activity data of natural saponins, QS-21, and a semi-synthetic saponin preparation, GPI-0100. These new adjuvants will be screened for their efficacy in a mouse model using ovalbumin (OVA). The most potent new adjuvant will then be evaluated for its stability and acute toxicity. It will also be evaluated in a guinea pig model using OVA. The data thus obtained will be provided to Dr. Hevey at USAMRIID. He will utilize the best adjuvant in a MBGV GP vaccine preparation and evaluate it in a guinea pig model using lethal aerosol challenge with MBGV, followed by lethal challenge of survivors by the subcutaneous route. The development of a well-characterized single saponin species will not only provide a potentially useful new vaccine for Marburg, but should have application for important vaccines against other infectious agents. In addition, these studies will provide direction for the second-generation development of improved saponin adjuvants. Furthermore, their use as fluorescent probes should help elucidate the mechanism of action of this class of adjuvants, increasing our understanding of how to better modulate an immune response and better protect against dangerous pathogens.

描述（由申请人提供）：本申请是对 PA-03-080 的回应，作为探索性/开发性 R21 拨款。在此，我们建议开发一种新的合成皂苷佐剂，与马尔堡糖蛋白（MBGV GP）一起用作疫苗制剂。由于马尔堡病毒 (MBGV) 是可用作生物恐怖主义制剂的最致命的病毒之一（即 NIAID A 类优先病原体），因此迫切需要开发针对该制剂的有效疫苗。佐剂不仅作为递送载体发挥着至关重要的作用，而且还能刺激以溶细胞 T 淋巴细胞为特征的体液和细胞介导的免疫，这对于产生有效的免疫反应和针对病毒感染的长期保护性免疫至关重要。皂苷，尤其是来自满天星、皂树和皂树的皂苷，对人类细菌、病毒和其他感染具有有效的免疫调节活性（体液和细胞介导）。然而，由于公认的毒性和稳定性问题，它们的使用受到限制。我们建议利用已确定的天然皂苷 QS-21 和半合成皂苷制剂 GPI-0100 的结构活性数据，从石膏酸（糖苷配基）合成新型皂苷。将使用卵清蛋白（OVA）在小鼠模型中筛选这些新佐剂的功效。然后将评估最有效的新佐剂的稳定性和急性毒性。还将使用 OVA 在豚鼠模型中对其进行评估。由此获得的数据将提供给 USAMRIID 的 Hevey 博士。他将在 MBGV GP 疫苗制剂中使用最好的佐剂，并使用 MBGV 致命气溶胶攻击，然后通过皮下途径对幸存者进行致命攻击，在豚鼠模型中对其进行评估。开发一种具有良好特征的单一皂苷种类不仅可以为马尔堡病毒提供一种潜在有用的新疫苗，而且应该可以应用于针对其他传染原的重要疫苗。此外，这些研究将为第二代改良皂苷佐剂的开发提供方向。此外，它们作为荧光探针的使用应有助于阐明此类佐剂的作用机制，增加我们对如何更好地调节免疫反应并更好地防御危险病原体的理解。