Tobacco-based Sustainable Squalene for Novel Vaccine Adjuvant Emulsions

用于新型疫苗佐剂乳液的基于烟草的可持续角鲨烯

• 批准号: 10545289
• 负责人: Connor R. Gorman
• 金额: $ 25.7万
• 依托单位: SYNSHARK LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545289
• 关键词: Adjuvant; Adjuvanticity; Agriculture; Applications Grants; Bacteriology; Biomanufacturing; Businesses; Caliber; Carbon; Chemistry; Climacteric; Collaborations; Communicable Diseases; Controlled Environment; Crude Extracts; Department of Energy; Development; Disease Vectors; Economics; Emulsions; Endogenous Retroviruses; Engineering; Environment; FPS-FES Oncogene; Feasibility Studies; Food; Fruit; Genes; Goals; Growth; Guidelines; Health; Human; Hypersensitivity; Immune response; Immunity; Immunology; Inflammatory; Institutes; Journals; Kilogram; Laboratories; Lead; Link; Liquid substance; Liver; Medical; Methods; Microbiology; Middle East Respiratory Syndrome Coronavirus; Modeling; Molecular Genetics; National Institute of Allergy and Infectious Disease; Nature; Neurology; North Carolina; Oils; Pathway interactions; Pharmacologic Substance; Phase; Plant Leaves; Plant Sources; Plants; Play; Preparation; Production; Psychiatry; RNA vaccine; Research; Resistance; Risk; Role; Route; SARS coronavirus; Science; Series; Shark; Small Business Innovation Research Grant; Soapbush; Soil; Source; Squalene; Stress; Surface; System; T cell response; T-Cell Activation; T-Lymphocyte; Techniques; Technology; Terpenes; Testing; The science of Mycology; Tobacco; Training and Education; Transplantation; Trees; Triterpenes; United States Food and Drug Administration; Universities; Vaccine Adjuvant; Vaccine Research; Vaccines; Veterinarians; Weather; Weight; base; biomaterial compatibility; commercialization; cost; innovation; interest; lipid nanoparticle; manufacturing facility; metabolic engineering; neurosurgery; news; novel; novel vaccines; pandemic disease; partition chromatography; pathogen; pollutant; product development; programs; promoter; response; technology development; vaccine development; vaccine efficacy

Project Summary/Abstract In this grant application, SynShark (SBA Certified Small Business), in collaboration with North Carolina State University, will demonstrate a new plant source for pharmaceutical grade squalene as a natural adjuvant. The team will utilize novel plant-engineering routes to stabilize squalene yields in tobacco, and discover methods to manufacture and isolate the molecule for rapid pandemic response. This research matches the interests of the National Institute of Allergy and Infectious Diseases (NIAID) with three of its divisions: Division of Aids (DAIDS), Division of Allergy, Immunology and Transplantation (DAIT) and Division of Microbiology and Infectious Diseases (DMID). Specific branches and programs under these divisions with relevant statements of needs are: (i) the Vaccine Research Program (DAIDS), (ii) Basic Immunology Branch (DAIT), (iii) SBIR Adjuvant Research Program – Bacteriology and Mycology Branch (DMID). The ultimate goal of this activity is the successful commercialization and public benefit of a rapidly derived natural adjuvant based on plant squalene which is completely biocompatible. Adjuvants have a key role in promotion of vaccine efficacy through eliciting a stronger immune response and reducing the volumetric need of active ingredient. By all accounts, evidence was available that SARS-CoV-1 immunity relied on T-cell activation and that vaccines should account for that. Synthetic adjuvants being used by the current regulated SARS-CoV-1 vaccines are not simulating a strong T-cell response, while natural squalene known to enhance the magnitude of the T-cell response. But pharmaceutical squalene is sourced from shark ‘livering’, conveying: 1) the risk of associated pollutants and pathogens, and 2) public resistance. On the other hand, the other natural adjuvant Quillaja Saponaria oil, costs it’s manufacture Fujifilm Diosynth (in the Novavax SARS-CoV-1 vaccine) more than $100,000 per kilogram. This has led to Fujifilm Diosynth’s support of this application. Through terpenoid metabolic engineering, SynShark has already managed to successfully shift the fundamental carbon allocation pathways within tobacco allowing for increased accumulation of the triterpene squalene. The Phase I tasks being introduced are directly related to the commercialization plan to deliver to the market a non-animal sourced natural adjuvant which is grown indoors through proven tobacco pharmaceutical techniques. The Phase I period is planned to take this innovative and disruptive terpene sourcing technology to fruition by enabling the application of SynShark’s research advancements in molecular genetics. During Phase I, the tobacco plant will be engineered to study the feasibility of squalene production directly on the leaf surface by placing the constructs under trichome-specific promoters, thereby stabilizing yield in a manner best suited for controlled indoor growing. In the Phase II period, SynShark, through committed collaborators, will establish scalability of manufacturing and purification under US Food and Drug Administration guidelines.

项目总结/摘要 在这项拨款申请中，SynShark（SBA认证小企业）与北卡罗来纳州州立大学合作， 将展示药用级角鲨烯作为天然佐剂的新植物来源。该团队将利用新的 植物工程路线，以稳定烟草中的角鲨烯产量，并发现制造和分离角鲨烯的方法。 快速大流行反应的分子。这项研究符合国家过敏研究所的兴趣， 传染病（NIAID），下设三个部门：艾滋病部门（DAIDS），过敏，免疫学和 移植（DAIT）和微生物学和传染病部（DMID）。具体的分支机构和方案 这些部门下的相关需求声明包括：（i）疫苗研究计划（DAIDS），（ii）基本 免疫学分支（DAIT），（iii）SBIR佐剂研究计划-细菌学和真菌学分支（DMID）。 这项活动的最终目标是使一种迅速获得的自然资源成功地商业化并造福于公众。 基于完全生物相容的植物角鲨烯的佐剂。佐剂在疫苗推广中起着关键作用 通过引发更强的免疫应答和减少活性成分的体积需求来提高功效。所有 据报道，有证据表明SARS-CoV-1免疫依赖于T细胞活化，疫苗应考虑 的想要进行目前受管制的SARS-CoV-1疫苗所使用的合成佐剂不能模拟强T细胞 已知天然角鲨烯可增强T细胞反应的幅度。但是药用角鲨烯 来源于鲨鱼的“肝脏”，传达了：1）相关污染物和病原体的风险，2）公众的抵制。对 另一方面，另一种天然佐剂Quillaja Saponaria油，成本是由Fujifilm Diosynth制造的（在Novavax SARS-CoV-1疫苗）每公斤超过10万美元。这使得Fujifilm Diosynth支持这一应用。 通过萜类化合物代谢工程，SynShark已经成功地改变了 烟草内的碳分配途径允许增加三萜角鲨烯的积累。I期 正在引入的任务与向市场提供非动物来源的商业化计划直接相关， 通过成熟的烟草制药技术在室内种植的天然佐剂。第一阶段是 计划通过应用这种创新和破坏性的萜烯采购技术来实现 SynShark在分子遗传学方面的研究进展。在第一阶段，烟草厂将被设计成研究 通过将构建体放置在毛状体特异性条件下直接在叶表面产生角鲨烯的可行性 促进剂，从而以最适合于受控室内生长的方式稳定产量。在第二阶段，SynShark， 通过承诺的合作者，将建立美国食品和药物管理局的生产和纯化的可扩展性， 行政指导方针。