Engineering sustainable squalene analogues for novel vaccine adjuvant emulsions

设计用于新型疫苗佐剂乳液的可持续角鲨烯类似物

• 批准号: 9541529
• 负责人: Christopher B Fox
• 金额: $ 80.64万
• 依托单位: ACCESS TO ADVANCED HEALTH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-16 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9541529
• 关键词: Adjuvant; Antigens; Biological; Biomedical Engineering; Brazil; California; Characteristics; Chemical Engineering; Chemicals; Data; Development; Dose; Emulsions; Engineering; Environmental Engineering technology; Evaluation; Event; Formulation; Government-Sponsored Programs; Human; Immune response; In Vitro; Industrialization; Infectious Diseases Research; Influenza; Influenza A Virus, H5N1 Subtype; Isoprene; Literature; Liver; Modification; Molecular Weight; North Carolina; Oils; Organism; Pathway interactions; Pharmacologic Substance; Plant Extracts; Plant Sources; Polymer Chemistry; Polymers; Preclinical Testing; Production; Program Sustainability; Property; Reagent; Recombinants; Reporting; Research Institute; Route; Shapes; Shark; Source; Squalene; Structure; Structure-Activity Relationship; Subunit Vaccines; Technology; Terpenes; Testing; Time; Triglycerides; Universities; Vaccine Adjuvant; Vaccine Production; Vaccines; Water; Work; Yeasts; analog; base; clinical development; experience; immunogenicity; improved; in vivo; in vivo Model; innovation; isoprenoid; monomer; mouse model; novel; novel vaccines; pandemic influenza; programs; research clinical testing; technology development; vaccine efficacy

Project Summary Global pandemic influenza vaccine production capacity is insufficient to meet the expected demand in the event of a highly lethal influenza pandemic. Current H5N1 vaccines require high antigen doses (e.g. 90 μg) or are combined with squalene-based oil-in-water emulsion adjuvants for enhanced and broadened immunogenicity as well as antigen dose sparing. Squalene is a naturally occurring oligoisoprene (i.e. a very low molecular weight polymer of isoprene) derived from shark liver, a source with sustainability concerns. Moreover, the biological mechanisms of action of squalene are still not well understood and no systematic comparison of the adjuvant activity of squalene emulsions compared to emulsions based on analog oligoisoprenes has been reported in the literature. This proposal defines a program to develop the sustainable production of various oligoisoprene analogues of squalene using bioengineered organisms and synthetic polymer chemistry. Selected structures will then be formulated in oil-in-water emulsions and evaluated for physicochemical stability. Importantly, we propose to identify structure-activity relationships (SAR) by employing squalene and oligoisoprene analogues in in vitro human and in vivo mouse models in combination with an H5N1 influenza antigen. Moreover, the ability to further enhance adjuvant activity by chemical modification to improve physicochemical properties of selected oligoisoprene structures will be evaluated. The technology generated could be applicable to many other vaccines that have need of emulsion-based adjuvants for antigen dose sparing or enhanced immune responses.

项目摘要 全球大流行性流感疫苗产能不足以满足事件中的预期需求 一场致命的流感大流行目前的H5 N1疫苗需要高的抗原剂量（例如90 μg），或者 与基于角鲨烯的水包油乳剂佐剂组合以增强和扩大免疫原性 以及抗原剂量节省。角鲨烯是一种天然存在的低聚异戊二烯（即分子量非常低的 异戊二烯聚合物）来源于鲨鱼肝，这是一种具有可持续性问题的来源。此外，生物 角鲨烯的作用机制仍然没有很好的理解，也没有系统的比较佐剂 与基于类似物低聚异戊二烯的乳液相比，角鲨烯乳液的活性已经在 文学该提案确定了开发各种低聚异戊二烯的可持续生产的计划 使用生物工程生物和合成聚合物化学的角鲨烯类似物。选定的结构将 然后配制成水包油乳液并评价其物理化学稳定性。重要的是我们 建议通过使用角鲨烯和低聚异戊二烯类似物来确定结构-活性关系（SAR）， 体外人和体内小鼠模型与H5 N1流感抗原的组合。此外，能力 为了进一步增强佐剂活性，通过化学修饰来改善所选的 将评价低聚异戊二烯结构。所产生的技术可以应用于许多其他疫苗 其需要基于乳剂的佐剂以节省抗原剂量或增强免疫应答。