New Adjuvant Technologies for a Marburg Virus Vaccine

描述（由申请人提供）：本申请是对PA-03-080的回应，作为探索性/发展性R21资助。在此，我们建议开发一种新的合成皂苷佐剂，用于与马尔堡糖蛋白（MBGV GP）作为疫苗制剂。由于马尔堡病毒（MBGV）是可用作生物恐怖剂的最致命的病毒之一（即，NIAID A类优先病原体），迫切需要开发针对该病原体的有效疫苗。佐剂不仅作为递送载体发挥关键作用，而且它们还刺激以细胞溶解性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应答和针对病毒感染的长期保护性免疫至关重要。皂苷，特别是来自石头花属物种、肥皂草和皂树的皂苷，在人类中对细菌、病毒和其他感染具有有效的免疫调节活性（体液和细胞介导的）。然而，由于公认的毒性和稳定性问题，它们的使用受到限制。我们提出利用天然皂苷QS-21和半合成皂苷制剂GPI-0100的已建立的结构-活性数据从石膏原酸（苷元）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在豚鼠模型中进行评价。由此获得的数据将提供给USAMRIID的Hevey博士。他将在MBGV GP疫苗制剂中使用最佳佐剂，并在豚鼠模型中使用MBGV致死性气溶胶激发，然后通过皮下途径对存活者进行致死性激发进行评价。 一个良好的特点单一的皂苷物种的发展，不仅提供了一个潜在的有用的新疫苗马尔堡，但应该有针对其他传染性病原体的重要疫苗的应用。 此外，这些研究将为第二代改进皂苷佐剂的开发提供方向。此外，它们作为荧光探针的用途应该有助于阐明这类佐剂的作用机制，增加我们对如何更好地调节免疫反应和更好地抵御危险病原体的理解。

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.