Synthesis and Evaluation of Carbohydrate Vaccine Adjuvants

碳水化合物疫苗佐剂的合成与评价

• 批准号: 10642889
• 负责人: Hien M Nguyen
• 金额: $ 63.57万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-10 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642889
• 关键词: Adjuvant; Antibody Response; Antigen-Presenting Cells; Antigens; Applications Grants; Azides; B-Lymphocytes; Biodistribution; CD8-Positive T-Lymphocytes; Carbohydrates; Cell Maturation; Chemistry; Clinical; Clinical Trials; Communicable Diseases; Development; Ethers; Evaluation; Exhibits; Fluorescein; Fluorides; Galactose; Generations; Glucose; Glycosides; Goals; High Pressure Liquid Chromatography; Human; Hydrogen Bonding; Hydroxyl Radical; Hypocotyl; Immune response; Immunity; Immunologics; Immunology; In Vitro; Iowa; Label; Link; Mediating; Medicinal Plants; Metabolic; Methods; Natural Products; Natural Source; Oligosaccharides; Plasma; Process; Production; QS21; Regulation; Respiratory Syncytial Virus Vaccines; Role; Safety; Saponins; Source; Soyasapogenol; Soyasaponin; Structure; Structure-Activity Relationship; T cell response; Therapeutic; Toxic effect; Universities; Vaccination; Vaccine Adjuvant; Vaccines; Variant; aluminum sulfate; carbene; catalyst; chemical synthesis; clinical application; clinically relevant; combat; cost effective; cytokine; glycosylation; immunogenicity; improved; in vivo; mouse model; multidisciplinary; novel; novel vaccines; preclinical evaluation; screening; soy; success; tool; vaccinology

PROJECT SUMMARY The success of vaccination requires the generation of a strong immune response to the inoculated antigens in order to provide long-term protective immunity against many infectious diseases. To achieve this goal often requires the addition of vaccine adjuvants, substances that a substance that boosts the body’s immune response to the vaccine. However, there are only a few human vaccine adjuvants with an extensive safety record and minimal toxicity approved for clinical use. At presence, more studies are needed to identify novel adjuvants that not only significantly enhance the immune response for a particular vaccine, but also must be minimally toxic and maximally safe for clinical use. In efforts to discover novel vaccine adjuvants, an in vivo screening of forty-seven saponins from medicinal plants for their immunostimulatory and hemolytic activities has led to the discovery of new exciting vaccine adjuvants. Among forty- seven saponins evaluated, soyasaponins have emerged as the most potent adjuvants. These newly-discovered carbohydrates exhibited a significantly enhanced adjuvant activity with almost negligible toxicity when directly compared to QS-21 which has emerged as a vaccine adjuvant in numerous clinical trials. However, obtaining them from natural sources is a complicated process of extraction and purification that result in the production of minute. As a result, isolation of soyasaponins is economically unfeasible and unsustainable if sufficient quantities are required for immunological studies and clinical applications. Since FDA has strict regulations regarding to the purity and quality of adjuvants for use in human, a synthetic source must be developed for soyasaponins to be utilized as clinically relevant adjuvants. The objective of this proposal will address these challenges through the chemical synthesis for procuring sufficient quantities of soyasaponins in pure form. This effort will deliver well-defined soyasaponins without batch-to- batch variation and provide tools for studies of their roles as vaccine adjuvants and exploration of structure-adjuvant potency profiles for the discovery of non-natural soyasaponin improved adjuvants.

项目概要 疫苗接种的成功需要对病原体产生强烈的免疫反应 接种抗原，以提供针对许多传染性病毒的长期保护性免疫力 疾病。为了实现这一目标通常需要添加疫苗佐剂、 一种增强人体对疫苗免疫反应的物质。然而，只有一个 少数具有广泛安全记录和最小毒性的人类疫苗佐剂被批准用于 临床使用。目前，需要更多的研究来鉴定新型佐剂，这些佐剂不仅 显着增强特定疫苗的免疫反应，但也必须最小化 有毒且临床使用最安全。在努力发现新型疫苗佐剂的过程中， 体内筛选药用植物中 47 种皂苷的免疫刺激和 溶血活性导致了新的令人兴奋的疫苗佐剂的发现。其中四十—— 对七种皂苷进行了评估，大豆皂苷已成为最有效的佐剂。这些 新发现的碳水化合物表现出显着增强的佐剂活性，几乎 与已作为疫苗佐剂出现的 QS-21 直接比较时，毒性可以忽略不计 大量的临床试验。然而，从天然来源获取它们是一个复杂的过程 提取和纯化，从而产生分钟。结果，隔离 如果需要足够的数量，大豆皂苷在经济上是不可行和不可持续的 用于免疫学研究和临床应用。由于 FDA 对以下方面有严格的规定 为了保证用于人类的佐剂的纯度和质量，必须开发一种合成来源 大豆皂苷可用作临床相关佐剂。该提案的目标是 通过化学合成来应对这些挑战，以获取足够数量的 纯大豆皂苷。这项工作将提供明确的大豆皂苷，无需分批- 批次变化并为研究其作为疫苗佐剂的作用和探索提供工具 用于发现非天然大豆皂苷的结构-佐剂效力谱的改进 佐剂。