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

描述（由申请人提供）：疫苗接种是自200年前发明以来最成功的医学实践之一，并且已经成功地根除了许多严重的传染病（Plotkin，2005; Mortellaro等人，2011年）。尽管非常成功，但疫苗开发的现状不足以应对一些新出现、重新出现或持续存在的挑战。传染病仍然是全世界所有死亡的五分之一，每年造成至少1100万人死亡（Kieny等人，2005年）的报告。传统的疫苗学在对抗许多病原体方面失败了，这是由于抗原的高度变异性或对保护机制的理解不足。迅速开发新疫苗以防治持续存在的或新的疾病是一项紧迫的优先事项。虽然传统的经验方法是必要的，并可能为未来的成功铺平了道路，但至关重要的是要有新的方法，充分利用不断增加的免疫学知识。为此，最近开发的对抗癌症和疫苗耐药性传染病的疫苗严重依赖于结构上限定的亚单位抗原构建体。虽然这些候选疫苗有许多优点，但精制抗原的免疫原性往往较低，这就需要使用佐剂。佐剂是用于增强疫苗引发对共同施用的抗原的强烈且持久的免疫应答的能力的物质（Kensil等人，2004; Leroux-Roels，2010; Brunner等人，2010年）。它们在疫苗中发挥着重要作用 发展QS-21是一种有前途的独特佐剂，它是一种皂苷天然产物，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Th 1和Th 2型应答，当需要对纯化抗原的足够有效的细胞毒性T淋巴细胞（CTL）应答而没有毒性问题时，这对于开发针对癌症和细胞内病原体（例如HIV、TB和疟疾）的亚单位疫苗是极其重要的（Kensil等人，2004; 2006）。然而，天然皂苷QS-21具有固有的缺点（例如，其稀缺性、纯化困难和低产率、化学不稳定性、剂量限制性毒性），这阻止了其广泛使用，特别是在生产除用于危及生命的疾病（例如HIV感染或癌症）之外的可靠的人疫苗中。QS-21的局限性突出了对具有改进性质的新佐剂的需求。QS-21的结构修饰是一种有吸引力和可行的方法来满足需求。具体目的：合成基于QS-21的新型佐剂，并获得其初步的佐剂活性和毒性数据。 公共卫生相关性：该项目旨在设计和合成结构明确且化学稳定的新型佐剂，这些物质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性、新发和/或再发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.