DESIGN AND SYNTHESIS OF STRUCTURALLY DEFINED QS-21-BASED SYNTHETIC ADJUVANTS

说明(申请人提供)：疫苗接种是自200年前发明以来最成功的医疗实践之一，并已成功地根除了许多严重的传染病(Plotkin，2005；Mortearo等人，2011年)。虽然非常成功，但目前的疫苗开发状况不足以应对一些新出现的、重新出现的或持久的挑战。传染病仍然是全世界死亡人数的五分之一，每年至少导致1100万人死亡(Kieny等人，2005年)。由于抗原变异性高或对保护机制缺乏了解，传统疫苗学在对抗许多病原体方面失败了。迅速开发针对持续性或新型疾病的新疫苗是当务之急。虽然传统的经验方法是必要的，可能已经为未来的成功铺平了道路，但充分利用日益增长的免疫学知识的新方法至关重要。为此，最近开发的对抗癌症和疫苗耐药传染病的疫苗在很大程度上依赖于结构上定义的亚单位抗原结构。尽管这些候选疫苗有很多优点，但精制的抗原往往免疫原性较低，这就需要使用佐剂。佐剂是用来增强疫苗对联合接种抗原的强烈和持久免疫反应能力的物质(Kensil等人，2004年；Leroux-Roels，2010年；Brunner等人，2010年)。它们在疫苗中起着至关重要的作用 发展。一种前景看好的独特佐剂是QS-21，这是一种皂素天然产品，已在许多癌症和传染病疫苗临床试验中进行了评估。它刺激Th1和Th2类型的反应，当需要对纯化的抗原有足够强大的细胞毒性T淋巴细胞(CTL)反应而没有毒性问题时，这对于开发针对癌症和细胞内病原体(例如艾滋病毒、结核病和疟疾)的亚单位疫苗极其重要(Kensil等人，2004年；2006年)。然而，天然皂苷QS-21有其固有的缺陷(如稀缺性、提纯困难和产量低、化学不稳定性、剂量限制毒性)，这些缺点阻碍了其广泛使用，特别是在生产除用于HIV感染或癌症等危及生命的疾病之外的可靠的人类疫苗方面。QS-21的局限性突出了对性能改善的新佐剂的需求。QS-21的结构改造是解决这一需求的一种有吸引力的可行方法。具体目的：合成基于QS-21的新型佐剂，并获得其初步的佐剂性和毒性数据。 与公共卫生相关：该项目旨在设计和合成结构明确、化学稳定的新型佐剂，这些佐剂可以增强疫苗引发强烈和持久免疫反应的能力。这是朝着开发针对持续、新出现和/或再次出现的传染病以及各种癌症的新疫苗迈出的关键一步。

DESCRIPTION (provided by applicant): Vaccination is one of the most successful medical practices since its invention 200 years ago, and has been successful in eradicating many severe infectious diseases (Plotkin, 2005; Mortellaro et al., 2011). Although very successful, the current state of vaccine development is not adequate to meet some emerging, re- emerging or persistent challenges. Infectious diseases are still responsible for one-fifth of all deaths worldwide, killing at least 11 million people every year (Kieny et al., 2005). Conventional vaccinology has failed in fighting many pathogens due to either high antigen variability or poor understanding of protection mechanisms. Rapid development of new vaccines against the persistent or new diseases is an urgent priority. While the conventional empirical approach has been necessary and may have paved the way to future success, it is vital to have new approaches that make full use of ever increasing immunological knowledge. To this end, the recent development of vaccines to combat cancer and vaccine-resistant infectious diseases has relied heavily on structurally defined subunit antigen constructs. Although there are many advantages of these vaccine candidates, the refined antigens are often less immunogenic, which necessitates the use of adjuvants. Adjuvants are the substances applied to enhance the ability of a vaccine to elicit strong and durable immune responses to a co-administered antigen (Kensil et al., 2004; Leroux-Roels, 2010; Brunner et al., 2010). They play crucial roles in vaccine development. One promising and unique adjuvant is QS-21, a saponin natural product that has been evaluated in many cancer and infectious disease vaccine clinical trials. It stimulates both Th1 and Th2 type responses, which are extremely important for the development of subunit vaccines against cancers and intracellular pathogens (e.g. HIV, TB and malaria) when a sufficiently potent cytotoxic T lymphocyte (CTL) response to purified antigens without toxicity issues is desired (Kensil et al., 2004; 2006). However, the natural saponin QS-21 has inherent drawbacks (e.g. its scarcity, difficulty and low-yielding in purification, chemical instability, an dose-limiting toxicity) which prevent it from wide use, especially in the production of reliable human vaccines other than for life-threatening diseases, such as HIV infection or cancer. The limitation of QS-21 highlights the need for new adjuvants with improved properties. Structural modification of QS-21 is an attractive and feasible method to address the need. Specific aim: To synthesize QS-21-based new adjuvants and obtain their preliminary adjuvanticity and toxicity data. PUBLIC HEALTH RELEVANCE: This project is to design and synthesize structurally defined and chemically stable new adjuvants, substances that can enhance the ability of a vaccine to elicit strong and durable immune responses. It is a crucial step toward developing new vaccines against persistent, emerging and/or re-emerging infectious diseases, and various cancers.