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.

项目总结 疫苗接种的成功需要对疫苗产生强烈的免疫反应 接种抗原以提供对许多传染性疾病的长期保护性免疫 疾病。为了实现这一目标，通常需要添加疫苗佐剂，即 一种能增强人体对疫苗的免疫反应的物质。然而，只有一个 很少有安全记录广泛且毒性最小的人类疫苗佐剂被批准用于 临床应用。目前，需要更多的研究来确定新的佐剂，不仅是 显著增强对特定疫苗的免疫应答，但也必须最低限度 有毒，临床使用最安全。在努力发现新的疫苗佐剂的过程中，一种 从药用植物中筛选出47个具有免疫刺激作用的皂苷类化合物 溶血活性导致了新的令人兴奋的疫苗佐剂的发现。在四十个人中- 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显示出显著增强的佐剂活性，几乎 直接与QS-21相比，毒性可以忽略不计，QS-21已成为 无数的临床试验。然而，从自然资源中获取它们是一个复杂的过程 提取和纯化的结果导致分钟的生产。因此，隔离 如果需要足够的数量，大豆皂苷在经济上是不可行的，也是不可持续的 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 人类使用的佐剂的纯度和质量，必须开发一种合成来源来 大豆皂苷将被用作临床相关佐剂。这项提议的目标将是 通过化学合成来解决这些挑战，以获得足够数量的 纯种形式的大豆皂苷。这一努力将提供定义明确的大豆皂苷，而不需要批量到 批量变异，并为研究它们作为疫苗佐剂的作用和探索提供工具 发现改良非天然大豆皂苷的结构佐剂效价谱 佐剂。