New Adjuvant Technologies for a Marburg Virus Vaccine

描述（由申请人提供）：本申请是对PA-03-080作为探索性/发展性R21拨款的回应。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）一起作为疫苗制剂。由于马尔堡病毒（MBGV）是可用作生物恐怖制剂（即NIAID a类优先病原体）的最致命病毒之一，因此迫切需要开发针对该制剂的强效疫苗。佐剂不仅作为递送载体发挥着至关重要的作用，而且它们还能刺激以细胞溶解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长期的保护性免疫病毒感染至关重要。皂苷，特别是来自于石膏属植物、皂角属植物和皂角属植物的皂苷，对人体内的细菌、病毒和其他感染具有有效的免疫调节活性（包括体液和细胞介导）。然而，由于公认的毒性和稳定性问题，它们的使用受到限制。我们利用天然皂苷的结构活性数据QS-21和半合成皂苷制剂GPI-0100，提出了由石膏原酸（苷元）合成新型皂苷的方法。

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.