Development of VesiVax Carbohydrate Conjugation Chemistry

VesiVax 碳水化合物共轭化学的发展

• 批准号: 8593016
• 负责人: Gary Fujii
• 金额: $ 29.43万
• 依托单位: MOLECULAR EXPRESS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8593016
• 关键词: Adjuvant; Agonist; Amines; Animals; Antibodies; Antigen Targeting; Antigens; Bacteria; Biological; Body Weight decreased; Buffers; C-terminal; Caliber; Carbohydrates; Chemistry; Chimeric Proteins; Chromatography; Citrobacter freundii; Communicable Diseases; Conjugate Vaccines; Coupled; Couples; Coupling; Cyclic GMP; Cysteine; Development; Diphtheria Toxin; Disease; Dose; Drug Delivery Systems; Drug Formulations; Engineering; Esters; Goals; Grooming; Immune response; Immunization; Immunologist; Inbred BALB C Mice; Lead; Lipids; Liposomes; Lysine; Maleimides; Malignant Neoplasms; Methods; Modeling; Modification; Molecular; Monitor; Mus; Outcome; Peptides; Performance; Phase; Polysaccharides; Precipitation; Procedures; Proteins; Publishing; Regulation; Research Personnel; Salmonella enterica; Salmonella typhimurium; Sampling; Scaffolding Protein; Series; Serum; Small Business Innovation Research Grant; Solutions; Surface; System; Technology; Testing; Typhoid Fever; Typhoid Vaccine; Vaccination; Vaccines; Vesicle; Vi antigen; Vi capsular polysaccharide; Virus; base; commercialization; cost; cross reacting material 197; design; engineering design; flexibility; fungus; immunogenic; interest; meetings; monophosphoryl lipid A; mouse model; mutant; pathogen; protective efficacy; public health relevance; response; screening; toll-like receptor 4; tool; unilamellar vesicle; vaccine candidate; vaccine development

DESCRIPTION: In response to PA-10-150, we will test the hypothesis that the VesiVax(R) Conjugatable Adjuvant Lipid Vesicle (CALV) platform can provide an efficient method to develop carbohydrate conjugate vaccines that stimulates superior immune responses to unconjugated carbohydrate antigens and also provides more flexibility to control the immune response to carbohydrate antigens over currently employed conjugate vaccine technologies. To demonstrate the utility of the VesiVax(R) CALV platform for this purpose, we propose to develop a polysaccharide conjugation technology with the commercialization goal of producing an easy-to-use modification to the VesiVax(R) CALV line of products. It is anticipated that successful execution of this project will provide a new tool that will enable immunologists and vaccinologists to evaluate their carbohydrate antigens of interest. Polysaccharides are emerging as promising vaccine targets for a variety of pathogens including viruses, bacteria, fungi, and cancers. In this SBIR Phase I application, we will develop a simple carbohydrate conjugation method that couples polysaccharide antigens to free amines on either a protein scaffold or liposomes containing lipid amines. Specifically, using the capsular polysaccharide Vi from Salmonella enterica (typhi) as our model carbohydrate antigen, we will couple Vi directly to VesiVax(R) CALVs containing a Toll-like Receptor 4 (TLR4) agonist or to a protein scaffold based on the mutant of diphtheria toxin known as CRM197 engineered to have a C-terminal cysteine residue (CRM197-Cys). The Vi-CRM197-Cys will then be conjugated to the VesiVax(R) CALVs. The VesiVax(R) Vi CALV conjugates containing the TLR4 agonist will then be tested in a mouse model of immunization to demonstrate the utility of the proposed approach.

产品说明：针对PA-10-150，我们将检验以下假设：VesiVax（R）可结合佐剂脂质囊泡（CALV）平台可提供一种开发碳水化合物结合疫苗的有效方法，该方法可刺激对未结合碳水化合物抗原的上级免疫应答，并提供比目前采用的结合疫苗技术更大的灵活性来控制对碳水化合物抗原的免疫应答。为了证明VesiVax（R）CALV平台在这方面的实用性，我们建议开发一种多糖结合技术，其商业化目标是对VesiVax（R）CALV系列产品进行易于使用的修饰。预计该项目的成功实施将提供一种新的工具，使免疫学家和疫苗学家能够评估他们感兴趣的碳水化合物抗原。多糖是一种有前途的疫苗靶点，用于治疗病毒、细菌、真菌和癌症等多种病原体。在SBIR第一阶段的应用中，我们将开发一种简单的碳水化合物结合方法，将多糖抗原与蛋白质支架或含有脂胺的脂质体上的游离胺偶联。具体地，使用来自肠道沙门氏菌（伤寒）的荚膜多糖Vi作为我们的模型碳水化合物抗原，我们将Vi直接偶联到含有Toll样受体4（TLR 4）激动剂的VesiVax（R）CALV或偶联到基于白喉毒素突变体（称为CRM 197）的蛋白质支架，所述突变体被工程化以具有C末端半胱氨酸残基（CRM 197-Cys）。然后将Vi-CRM 197-Cys与VesiVax（R）CALV偶联。然后将在小鼠免疫模型中测试含有TLR 4激动剂的VesiVax（R）Vi CALV缀合物，以证明所提出的方法的实用性。