Development of Structurally Defined QS-17/18-Based Vaccine Adjuvants

 说明(申请人提供)：佐剂是添加到疫苗抗原中或与疫苗抗原一起使用的试剂，以增强或增强对抗原的特定免疫反应。它们在疫苗中的使用(特别是与亚单位疫苗一起使用)对于疫苗效力、节省剂量以及针对病原体的快速和持久免疫保护至关重要。然而，在美国，目前只有有限数量的佐剂被用作疫苗成分。由于缺乏安全有效的佐剂，新疫苗的开发受到了阻碍。新型佐剂的发现和开发已成为疫苗研究的关键前线努力。皂素疫苗佐剂，特别是从Quillaja Saponaria(QS)Molina树皮提取物中分离出来的QS-21，显示出良好的佐剂活性。QS-21是最受欢迎的人类疫苗佐剂之一，已被用于100多项针对癌症和各种传染病的疫苗的临床试验。它也是目前制药业在20多项临床试验中测试的联合佐剂的关键成分。然而，QS天然产物具有化学不稳定、供应有限、提纯困难且产率低、毒性剂量有限等固有缺陷，这些都是其临床广泛应用的障碍。仍然迫切需要结构明确的新型QS皂苷类佐剂，具有增强佐剂活性、降低毒性、简化配方、改善化学稳定性和合成可及性的特点。我们最近的研究结果表明，QS树皮提取物的另外两个特征成分QS-17和QS-18未被开发出来，是开发新佐剂的潜在线索。由于结构的复杂性，已定义的QS-17/18类似物的从头合成和免疫学研究仍未被探索。在这一应用中，我们建议高效合成基于QS-17/18的新型佐剂。PI实验室最近开发的新的糖基化方法将被用来提高整体合成效率。这一应用是朝着我们开发用于临床的结构定义的疫苗佐剂的最终目标迈出的必要的一步。具体目的：合成并评价基于QS-17/18的疫苗佐剂。

 DESCRIPTION (provided by applicant): Adjuvants are agents added to, or used in conjunction with, vaccine antigens to augment or potentiate the specific immune response to the antigen. Their use in vaccines (especially with subunit vaccines) is crucial to vaccine efficacy, dose sparing, and rapid and durable immune protection against pathogens. However, only a limited number of adjuvants are currently used as vaccine components in the United States. New vaccine development is bottlenecked by the lack of safe and effective adjuvants. Discovery and development of novel adjuvants has emerged as a critical frontline effort in vaccine research. Saponin vaccine adjuvants, especially QS-21, isolated from the Quillaja Saponaria (QS) Molina tree bark extract, show promising adjuvant activity. QS-21 is one of the most sought after human vaccine adjuvants and has been used in over 100 clinical trials of vaccines against cancers and various infectious diseases. It is also a key component in the combination adjuvants currently being tested in over 20 clinical trials by the pharmaceutical industry. However, QS natural products have inherent drawbacks such as chemical instability, limited supply, difficult and low-yielding purification, and dose-limiting toxicity, which are the hurdles o their wider clinical use. There remains an imperative need of structurally-defined new QS saponin-based adjuvants with enhanced adjuvant activity, reduced toxicity, simplified formulation, and improved chemical stability and synthetic accessibility. Our recent research results indicate that the underexplored QS-17 and QS-18, the other two characterized components of QS tree bark extract, are potential leads for new adjuvant development. Due to the structural complexity, de novo synthesis and immunological study of defined QS-17/18 analogs remains unexplored. In this application, we propose efficient synthesis of QS-17/18-based new adjuvants. The new glycosylation approach recently developed in the PI's laboratory will be utilized to improve the overall synthetic efficiency. This application is a necessary step toward our ultimate goal of developing structurally defined vaccine adjuvants for clinical use. Specific aim: To synthesize and evaluate QS-17/18-based vaccine adjuvants.