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疗实践之一，已经成功地根除了许多严重的传染病（Plotkin, 2005； Mortellaro等人，2011）。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、重新出现的或持续存在的挑战。传染病仍然造成全世界五分之一的死亡，每年至少造成1 100万人死亡（Kieny等人，2005年）。由于抗原高度变异或对保护机制了解不足，传统疫苗学在对抗许多病原体方面失败了。针对持续存在的或新的疾病迅速开发新的疫苗是一项紧迫的优先事项。虽然传统的经验方法是必要的，并且可能为未来的成功铺平了道路，但重要的是要有充分利用不断增加的免疫学知识的新方法。为此目的，最近研制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确定的亚单位抗原结构。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能力的物质，使其对共同给药的抗原产生强烈而持久的免疫反应（Kensil等人，2004年；Leroux-Roels， 2010年；Brunner等人，2010年）。它们在疫苗中起着关键作用

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.