Novel VLP Adjuvant based on the VesiVax system

基于 VesiVax 系统的新型 VLP 佐剂

基本信息

批准号：
8720689
负责人：
Gary Fujii
金额：
$ 30万
依托单位：
MOLECULAR EXPRESS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720689
关键词：
Acquired Immunodeficiency Syndrome Adjuvant Agonist Animal Model Animals Antibodies Antigen Targeting Antigens Biological Biological Assay Buffers Caliber Carbohydrates Cause of Death Chimeric Proteins Cholera Toxin Collection Communicable Diseases Communities Control Groups Developing Countries Development Drug Delivery Systems Drug Formulations Engineering Enzyme-Linked Immunosorbent Assay Gagging HIV HIV vaccine Health High Pressure Liquid Chromatography Human Immune response Immunity Immunization Infection Lipids Liposomes Medicine Methods Modeling Molecular Monitor Mus Oryctolagus cuniculus Particle Size Peptides Pharmaceutical Preparations Phase Precipitation Preparation Production Proteins Research Route SIV Sales Saliva Sampling Serum Small Business Innovation Research Grant Solutions Spleen Staging Surface System Techniques Technology Testing Toll-like receptors Vaccinated Vaccines Vesicle Viral Antigens Virus Diseases Virus-like particle base college commercialization cost effective design engineering design flexibility immunogenic in vitro Assay in vivo light scattering lymph nodes meetings neutralizing antibody nonhuman primate novel virus phase 1 study prophylactic public health relevance research clinical testing response simian human immunodeficiency virus toll-like receptor 4 unilamellar vesicle vaccine development

项目摘要

DESCRIPTION (provided by applicant): Molecular Express specializes in the design and engineering of functionalized liposomes for drug delivery and vaccine development. In previous studies, an extensive set of liposome formulations were screened to establish the optimal lipid combination that meets certain physicochemical parameters and provides strong immune responses in animals. These unilamellar vesicles have diameters of approximately 100 nm, are stable (i.e., no aggregation, precipitation or degradation of the components for over a year) in biological buffer solutions, and are commercially scalable. The immunogenic liposome compositions form the basis of a vaccine platform technology called the VesiVax(r) system. The VesiVax(r) system was designed to be easily manipulated, so that target antigens could be displayed from the surface of the immunogenic liposomes for subsequent use in immunization studies. Vaccines based on the VesiVax(r) system can be engineered using two formats: i) target antigens or adjuvant proteins can be engineered to be expressed as a fusion protein with a hydrophobic domain (HD), which facilitates its incorporation into the liposomes or; ii) target antigens or adjuvants in the form of proteins, peptides or carbohydrates can be attached via conjugation to the surface of the liposomes (i.e., conjugatable adjuvant lipid vesicles; CALVs). The flexibility of the VesiVax(r) platform allows both antigens and adjuvants to be formulated together into the liposomes thus maximizing the immune response. In this SBIR AT Phase I proposal, we intend to establish the utility of the VesiVax(r) CALV platform as an effective adjuvant for virus-like particles (VLPs). To demonstrate this concept, we propose to prepare VesiVax(r) CALV formulations containing different Toll-like Receptor (TLR) agonists and then conjugating them to VLPs that have been designed to express HIV antigens (HIV-VLPs) (Specific Aim 1). The VesiVax(r) CALV HIV-VLPs will then be tested in mouse and rabbit models (Specific Aim 2). These studies are potentially of high impact because demonstration that: I) the VesiVax(r) CALVs can adjuvant VLPs would have an immediate impact through increasing sales of the CALV line of research kits; II) the sublingual route of administration stimulates potent immune responses would be another useful application of the VesiVax(r) technology and; III) one or more VesiVax(r) CALV HIV-VLP formulations stimulate potent HIV antibody neutralization activity in the in vitro assays will set the stage for the selection of one or more of these candidates to undergo further testing in non-human primates prior to final selection of a VesiVax(r) CALV HIV-VLP candidate that will be advanced to clinical testing. Such a vaccine will provide the basis for a cost effective HIV immunization strategy that could be implemented on a global scale.

描述（由申请人提供）：Molecular Express 专门从事用于药物输送和疫苗开发的功能化脂质体的设计和工程。在之前的研究中，筛选了大量的脂质体配方，以建立满足某些理化参数并在动物中提供强烈免疫反应的最佳脂质组合。这些单层囊泡的直径约为 100 nm，在生物缓冲溶液中稳定（即一年以上组分不会聚集、沉淀或降解），并且可商业扩展。免疫原性脂质体组合物构成了称为VesiVax(r)系统的疫苗平台技术的基础。 VesiVax(r) 系统的设计易于操作，因此可以从免疫原性脂质体的表面展示目标抗原，以便随后用于免疫研究。基于 VesiVax(r) 系统的疫苗可以使用两种形式进行设计：i) 靶抗原或佐剂蛋白可以设计为具有疏水结构域 (HD) 的融合蛋白，这有利于其掺入脂质体中； ii) 蛋白质、肽或碳水化合物形式的靶抗原或佐剂可以通过缀合附着到脂质体的表面（即，可缀合佐剂脂质囊泡；CALV)。 VesiVax(r) 平台的灵活性允许将抗原和佐剂一起配制到脂质体中，从而最大限度地提高免疫反应。在此 SBIR AT 第一阶段提案中，我们打算建立 VesiVax(r) CALV 平台作为病毒样颗粒 (VLP) 有效佐剂的效用。为了证明这一概念，我们建议制备包含不同 Toll 样受体 (TLR) 激动剂的 VesiVax(r) CALV 制剂，然后将它们与旨在表达 HIV 抗原 (HIV-VLP) 的 VLP 结合（具体目标 1）。随后将在小鼠和兔子模型中测试 VesiVax(r) CALV HIV-VLP（具体目标 2）。这些研究具有潜在的巨大影响力，因为证明： I) VesiVax(r) CALV 可以辅助 VLP 将通过增加 CALV 系列研究试剂盒的销量产生直接影响； II) 舌下给药途径刺激有效的免疫反应将是 VesiVax(r) 技术的另一个有用的应用； III) 一种或多种 VesiVax(r) CALV HIV-VLP 制剂在体外测定中刺激有效的 HIV 抗体中和活性，这将为选择其中一种或多种候选药物在非人类灵长类动物中进行进一步测试奠定基础。最终选择 VesiVax(r) CALV HIV-VLP 候选药物，该候选药物将进入临床测试。这种疫苗将为可在全球范围内实施的具有成本效益的艾滋病毒免疫策略提供基础。