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

 描述（由申请方提供）：佐剂是添加到疫苗抗原中或与疫苗抗原联合使用以增强或加强对抗原的特异性免疫应答的试剂。它们在疫苗（特别是亚单位疫苗）中的使用对于疫苗效力、剂量节省以及针对病原体的快速和持久的免疫保护至关重要。然而，在美国，目前只有有限数量的佐剂被用作疫苗组分。新疫苗的开发因缺乏安全有效的佐剂而受到阻碍。新型佐剂的发现和开发已成为疫苗研究中的关键前沿工作。从皂树（Quillaja Saponaria）（QS）Molina树皮提取物中分离的皂苷疫苗佐剂，特别是QS-21，显示出有希望的佐剂活性。QS-21是最受欢迎的人类疫苗佐剂之一，已用于100多项针对癌症和各种传染病的疫苗临床试验。它也是目前制药行业在20多项临床试验中测试的组合佐剂的关键成分。然而，QS天然产物具有固有的缺点，如化学不稳定性，供应有限，纯化困难且产量低，以及剂量限制性毒性，这些都是其更广泛临床应用的障碍。仍然迫切需要具有增强的佐剂活性、降低的毒性、简化的制剂和改善的化学稳定性和合成可及性的结构确定的新的基于QS皂苷的佐剂。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是开发新佐剂的潜在线索。由于结构复杂性，定义的QS-17/18类似物的从头合成和免疫学研究尚未探索。在该应用中，我们提出了基于QS-17/18的新佐剂的有效合成。PI实验室最近开发的新糖基化方法将用于提高整体合成效率。这一应用是朝着我们开发用于临床的结构确定的疫苗佐剂的最终目标迈出的必要一步。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.