New Adjuvant Technologies for a Marburg Virus Vaccine

描述(由申请人提供)：本申请是对PA-03-080作为试探性/发展性R21资助的回应。在此，我们建议开发一种新的合成皂素佐剂，与Marburg糖蛋白(MBGV GP)一起用作疫苗制剂。由于马尔堡病毒(MBGV)是最致命的病毒之一，可用作生物恐怖主义病原体(即NIAID A类优先病原体)，因此迫切需要开发一种针对该病原体的有效疫苗。佐剂不仅作为递送载体发挥着重要作用，而且还能刺激以细胞溶解T淋巴细胞为特征的体液免疫和细胞免疫，这对于产生有效的免疫反应和对病毒感染的长期保护性免疫至关重要。人参皂苷，特别是来自满天星属植物的皂苷，对细菌、病毒和其他感染具有很强的免疫调节活性(体液和细胞介导性)。然而，由于公认的毒性和稳定性问题，它们的使用受到限制。我们建议利用已建立的天然皂苷QS-21和半合成皂苷制剂GPI-0100的构效数据，以石膏原酸(苷元)为原料合成新型皂苷。 这些新佐剂将在使用卵清蛋白(OVA)的小鼠模型中进行有效性筛选。然后将对最有效的新佐剂进行稳定性和急性毒性评估。它还将在使用OVA的豚鼠模型中进行评估。这样获得的数据将提供给USAMRIID的Hevey博士。他将在MBGV GP疫苗制备中使用最好的佐剂，并在豚鼠模型中使用MBGV进行致命气雾剂攻击，然后通过皮下途径对幸存者进行致命攻击。 开发一种具有良好特性的单一皂苷物种不仅将为马尔堡提供一种潜在有用的新疫苗，而且应该会在针对其他感染性病原体的重要疫苗方面具有应用价值。此外，这些研究还将为第二代改良皂素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预防危险病原体的理解。

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.