Novel Adjuvant Discovery in Vaccine Therapy

描述（由申请人提供）：对抗疫苗抗性癌症和传染病的疫苗的开发显著依赖于采用亚单位抗原的构建体。虽然使用确定的分子抗原在免疫应答靶向的安全性和精确性方面提供了优势，但它们通常免疫原性较低。通常，这些疫苗制剂需要佐剂，一种增强免疫应答的物质。疫苗佐剂的关键作用在于它们能够（1）使得能够使用原本无效的抗原，（2）将疫苗的益处扩展到不良反应者（例如，老年或免疫受损的患者），和（3）对供应短缺的稀有和昂贵的抗原进行“剂量节省”（例如，流行病）。天然产物皂苷QS-21是许多有希望的抗肿瘤和抗病毒疫苗临床试验中的选择佐剂，尽管存在与毒性、化学不稳定性和缺乏纯形式可用性相关的责任。该资助申请包括一个独特的多学科方法，用于制备，发现，评估和理解癌症和传染病疫苗开发中必不可少的有效佐剂分子。 本研究计划的具体目标将包括：（1）开发新的和有效的策略，用于化学合成皂苷QS-21的设计非天然结构变体，这些变体具有改善的活性和稳定性以及减弱的毒性;（2）在小鼠中评价这些新化合物，以评估其增强免疫应答的能力，以及其特定的毒性特征;和（3）采用小动物放射成像技术、免疫组织学、细胞因子谱和亲和层析来深入了解佐剂的未知作用机制。这些努力将解决与这类极其复杂的佐剂相关的基本化学和免疫学问题，并有望在疫苗竞技场中产生新的治疗方法。 公共卫生相关性：抗肿瘤和抗病毒疫苗的成功通常需要使用佐剂，佐剂是一种本身不一定具有免疫原性但显著增强患者对共同施用的抗原的免疫应答的物质。该资助申请包括一个独特的多学科方法，用于制备，发现，评估和理解癌症和传染病疫苗开发中必不可少的有效佐剂分子。这些努力将解决对免疫反应增强至关重要的基本化学和免疫学问题，并有望在疫苗竞技场中产生新型疗法。

DESCRIPTION (provided by applicant): The development of vaccines to combat vaccine resistant cancers and infectious diseases has relied significantly on constructs employing subunit antigens. While the use of defined molecular antigens offers advantages in terms of safety and precision in immune response targeting, they are typically less immunogenic. Often, these vaccine formulations require an adjuvant, a substance that potentiates immune response. The critical roles of vaccine adjuvants lie in their ability to (1) enable the use of otherwise impotent antigens, (2) extend the benefits of vaccines to poor responders (e.g., older or immune-compromised patients), and (3) effect "dose-sparing" of rare and expensive antigens in short supply (e.g., in an epidemic). The natural product saponin QS-21 is the adjuvant of choice in numerous promising antitumor and antiviral vaccine clinical trials, despite liabilities associated with toxicity, chemical instability, and lack of availability in pure form. This grant application comprises a unique multi-disciplinary approach toward the preparation, discovery, evaluation, and understanding of potent adjuvant molecules essential in the development of vaccines for cancer and infectious diseases. The Specific Aims of this research program will involve: (1) the development of novel and efficient strategies for the chemical synthesis of designed non-natural structural variants of the saponin QS-21 possessing improved activity and stability with attenuated toxicity; (2) the evaluation of these novel compounds in mice to assess their ability to potentiate immune response, as well as their specific toxicity profiles; and (3) to employ small animal radio-imaging technologies, immunohistology, cytokine profiling, and affinity chromatography to gain insight into the adjuvant's as yet unknown mechanism of action. These efforts will address fundamental chemical and immunological questions associated with this extremely complex class of adjuvants, and holds the promise of yielding novel therapeutics in the vaccine arena. PUBLIC HEALTH RELEVANCE: The success of antitumor and antiviral vaccines often requires the use of an adjuvant, a substance that is itself not necessarily immunogenic, but significantly enhances the immune response of a patient to a co- administered antigen. This grant application comprises a unique multi-disciplinary approach toward the preparation, discovery, evaluation, and understanding of potent adjuvant molecules essential in the development of vaccines for cancer and infectious diseases. These efforts will address fundamental chemical and immunological questions central to immune response potentiation, and holds the promise of yielding novel therapeutics in the vaccine arena.