Development of a novel adjuvant for vaccine sparing

开发一种新型疫苗备用佐剂

基本信息

批准号：
8784190
负责人：
Maria Elena Bottazzi
金额：
$ 119.76万
依托单位：
NEW YORK BLOOD CENTER
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：
2013-01-15 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8784190
关键词：
Address Adjuvant Adjuvanticity Aluminum Antibodies Antibody Response Antigens Bacteria Biological Assay Bird Flu vaccine Buffers Clinical Clinical Trials Communicable Diseases Consumption Cyclic GMP Dendritic Cells Dendritic cell activation Development Development Plans Disease Outbreaks Dose Drug Formulations Effectiveness Equilibrium Excipients Fermentation Ferrets Generations Health Helminths Human Immune response Immunity Immunization In Vitro Inactivated Vaccines Infectious Agent Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H5N1 Subtype Licensing Modeling Mus Onchocerca volvulus Parasites Preparation Process Production Property Proteins Recombinants Regimen Reproducibility Research Institute Series Severe Acute Respiratory Syndrome Solutions System T cell response Technology Technology Transfer Testing Time TimeLine Toll-Like Receptor 2 Toxic effect Toxicology Vaccination Vaccine Adjuvant Vaccines Viral Vaccines Yeasts anti-influenza aqueous asparaginase base biochemical tools cell bank clinical lot co-infection cost effective cytokine design disorder control efficacy testing frontier immunogenicity improved in vivo influenza virus strain influenza virus vaccine influenzavirus information processing innovation meetings neutralizing antibody novel pandemic disease pandemic influenza pre-clinical product development response stability testing toll-like receptor 4 vaccine candidate vaccine development vaccine effectiveness vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): There is urgent need worldwide for the development of new and improved vaccines to control infectious diseases, including influenza. Vaccination remains the most cost-effective biomedical approach for controlling these diseases, but developing and producing the flu vaccines in sufficient quantities has proved problematic. To date, clinical trials with aluminum-based adjuvants (alum)-the only ones licensed in the U.S.-in combination with pandemic influenza virus vaccines, have failed to provide evidence of a significant immunostimulating effect on influenza-specific responses. A promising solution to the supply problem is to incorporate an antigen-sparing adjuvant(s) into vaccine formulations, prompting the search for alternative adjuvants capable of safely boosting protective anti-influenza antibody titers to minimize immunogen consumption, while still enhancing vaccine efficacy and thus increasing the number of available vaccine doses. We have identified a naturally occurring secreted protein with intrinsic immunostimulatory properties from Onchocerca volvulus (rASP-1) and showed that it is a powerful immunostimulatory adjuvant; it promotes a balanced Th1/Th2 antibody response and cellular responses to several soluble vaccine candidate antigens, and commercial inactivated viral vaccines, including trivalent-inactivated flu vaccines (TIV). Further, the rASP-1 protein induces maturation and activation of naive human DCs and potentiates their activity as APCs. It also stimulates Th1-biased cytokine secretion from normal PBMCs via the activation of dendritic cells (DCs) and the TLR2 and TLR4 receptors, suggesting that rASP-1 is a novel immunostimulatory adjuvant. We propose to maximize its promising beneficial applications by designing a focused preclinical and product development approach that will ultimately produce a highly effective and safe rASP-1 adjuvanted flu vaccine in a simple aqueous formulation that requires a minimal antigen quantity per dose. By enhancing vaccine efficacy in this way, we can effectively increase the number of vaccine doses available. We plan to develop a scalable production process for the rASP-1 adjuvant using the yeast expression system; it will feature a series of critical assays used for in-process, buffer formulation, release, and stability testing. We will evaluate functionality and potency in vitro an then validate the induction of the desired antibody and cellular responses after one immunization with the co-administered TIV flu vaccine in mice and ferrets using minimal immunogen consumption. We are confident the project will produce all the information and processes necessary for compilation/ submission of an IND and entry into clinical development of the rASP-1 adjuvant for human use. The application has three aims: 1) process development, characterization, buffer formulation, and stability testing of the rASP-1 adjuvant; 2) efficacy testing of the rASP-1 adjuvanted flu vaccine using antigen dose sparing; and 3) technology transfer, cGMP manufacture, GLP toxicology, and IND preparation.

描述（由申请人提供）：全世界迫切需要开发新的和改进的疫苗来控制包括流感在内的传染病。疫苗接种仍然是控制这些疾病的最具成本效益的生物医学方法，但事实证明，开发和生产足够数量的流感疫苗存在问题。迄今为止，铝佐剂（明矾）（美国唯一获得许可的佐剂）与大流行性流感病毒疫苗结合的临床试验未能提供证据证明对流感特异性反应具有显着的免疫刺激作用。解决供应问题的一个有希望的解决方案是将保留抗原的佐剂纳入疫苗配方中，从而促使人们寻找能够安全提高保护性抗流感抗体滴度以最大限度地减少免疫原消耗的替代佐剂，同时仍然增强疫苗功效，从而增加可用疫苗剂量的数量。我们从盘尾丝虫 (rASP-1) 中鉴定出一种具有内在免疫刺激特性的天然分泌蛋白，并表明它是一种强大的免疫刺激佐剂；它促进平衡的 Th1/Th2 抗体反应和细胞对几种可溶性疫苗候选抗原和商业灭活病毒疫苗（包括三价灭活流感疫苗 (TIV)）的反应。此外，rASP-1 蛋白诱导初始人类 DC 的成熟和激活，并增强其作为 APC 的活性。它还通过激活树突状细胞 (DC) 以及 TLR2 和 TLR4 受体，刺激正常 PBMC 分泌 Th1 偏向的细胞因子，表明 rASP-1 是一种新型免疫刺激佐剂。我们建议通过设计有针对性的临床前和产品开发方法来最大限度地发挥其有希望的有益应用，最终以简单的水剂配方生产出高效且安全的 rASP-1 佐剂流感疫苗，每剂所需的抗原量最少。通过这种方式增强疫苗功效，我们可以有效增加可用疫苗剂量的数量。我们计划使用酵母表达系统开发 rASP-1 佐剂的可扩展生产工艺；它将包括一系列用于过程中、缓冲液配制、释放和稳定性测试的关键测定。我们将在体外评估功能和效力，然后使用最少的免疫原消耗对小鼠和雪貂联合施用 TIV 流感疫苗进行一次免疫后验证所需抗体和细胞反应的诱导。我们相信该项目将产生编制/提交 IND 以及进入人用 rASP-1 佐剂临床开发所需的所有信息和流程。该申请具有三个目标：1) rASP-1 佐剂的工艺开发、表征、缓冲液配方和稳定性测试； 2) 使用抗原剂量节约法测试 rASP-1 佐剂流感疫苗的功效； 3）技术转让、cGMP生产、GLP毒理学和IND准备。