Novel Adjuvant Discovery in Vaccine Therapy

描述(由申请人提供)：用于对抗具有疫苗耐药性的癌症和传染病的疫苗的开发在很大程度上依赖于使用亚单位抗原的结构。虽然使用已定义的分子抗原在免疫反应靶向的安全性和精确度方面具有优势，但它们的免疫原性通常较低。通常，这些疫苗配方需要一种佐剂，一种增强免疫反应的物质。疫苗佐剂的关键作用在于它们能够(1)使原本无效的抗原得以使用，(2)将疫苗的益处扩大到反应差的人(例如，年长的或免疫功能受损的患者)，以及(3)对稀有和昂贵的抗原短缺(例如，在流行病中)产生“节省剂量”的效果。天然产物皂苷QS-21是许多前景看好的抗肿瘤和抗病毒疫苗临床试验的首选佐剂，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风险。这项拨款申请包括一种独特的多学科方法，用于制备、发现、评估和了解在癌症和传染病疫苗开发中至关重要的有效佐剂分子。这项研究计划的具体目标将包括：(1)开发新型高效的策略来合成设计的具有更高活性和稳定性且毒性降低的皂苷QS-21的非天然结构变体；(2)对这些新型化合物进行小鼠体内试验，以评估它们增强免疫反应的能力以及它们的特定毒性；(3)利用小动物放射成像技术、免疫组织学、细胞因子谱分析和亲和层析等技术来深入了解该佐剂迄今未知的作用机制。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，并有望在疫苗领域产生新的疗法。 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，这种物质本身不一定具有免疫原性，但显著增强患者对联合注射抗原的免疫反应。这项拨款申请包括一种独特的多学科方法，用于制备、发现、评估和了解在癌症和传染病疫苗开发中至关重要的有效佐剂分子。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，并有望在疫苗领域产生新的疗法。

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.