Development of Enabling Vector/Antigen Expression Technology for an Orally-Delive

用于口服给药的载体/抗原表达技术的开发

基本信息

批准号：
8269534
负责人：
B. KIM LEE SIM
金额：
$ 141.2万
依托单位：
PROTEIN POTENTIAL, LLC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8269534
关键词：
Address Adverse effects Aerosols Animals Anthrax Vaccines Anthrax disease Antigens Bioterrorism Clinical Trials Combined Vaccines Contractor Cyclic GMP Development Disease Dose Drug Formulations Engineering Genetic Genetic Identity Genetic Techniques Genomics Glycerol Goals Grant Health Professional Immunization Immunologic Techniques Individual Lead Licensing Life Mass Vaccinations Methods Microbiological Techniques Modeling Mus Mutation Needles Oral Organism Oryctolagus cuniculus Plague Plague Vaccine Plasmids Population Preparation Production Rattus Recombinants Regimen Safety Staging Technology Temperature Toxic effect Typhoid Fever United States Vaccines Vial device anthrax protective factor cell bank design experience immunogenic immunogenicity oral vaccine pre-clinical protective efficacy vaccination schedule vaccine candidate vector

项目摘要

DESCRIPTION (provided by applicant): Vaccines provide a rational approach for assuring protection of large populations prior to or immediately following a bioterrorism attack. Our goal i to address three significant problems currently raised by bioterrorism threats: 1) need for an easy method of mass vaccination; 2) shortcomings of the current anthrax vaccine which requires needles and health professionals for administration, requires an extended vaccination schedule (6 doses over 18 months) and has concerns over adverse effects; and 3) the lack of a plague vaccine licensed in the United States. To address this challenge, we will exploit the extensive safety record of the existing live, oral typhoid fever vaccine, Ty21a, and our experience in engineering it to express the protective antigen (PA) of Bacillus anthracis, and to induce protection against lethal anthrax aerosol challenge in mice with this Ty21a-anthrax PA vaccine. We will utilize Ty21a as a vector to develop a multi-valent combination oral vaccine that will simultaneously protect against anthrax and plague. Further, we hypothesize that this vaccine can be formulated to be safe, stable, highly immunogenic and can be easily administered orally. The current application is aimed at completing the necessary final vaccine constructions, animal immunogenicity and efficacy studies, and full characterization (genetic, immunological, microbiological) of the final candidates. We will then construct master cell banks, conduct small-scale (10 liter) manufacture in compliance with current Good Manufacturing Practices, and dry the product for temperature stability and formulation into rapidly dissolvable wafers. The final vaccine preparation will be studied for genetic stability, safety, immunogenicity and efficacy in mouse, rabbit, and/or rat models of anthrax and plague disease. 1 clinical trial, and subsequent IND preparation and submission after all studies in this project have been completed. PUBLIC HEALTH RELEVANCE: Vaccines provide a rational approach for assuring protection of large populations prior to or immediately following a bioterrorism attack. Our goal is to address three significant problems currently raised by bioterrorism threats: 1) need for an easy method of mass vaccination; 2) shortcomings of the current anthrax vaccine which requires needles and health professionals for administration, requires an extended vaccination schedule (6 doses over 18 months) and has concerns over adverse effects; and 3) the lack of a plague vaccine licensed in the United States. To overcome these problems we will develop combination anthrax and plague vaccine that we hypothesize will be safe, stable, and highly immunogenic and can be easily administered orally.

描述（由申请人提供）：疫苗提供了一种合理的方法，以确保在生物恐怖袭击之前或之后立即保护大量人群。我们的目标是解决目前生物恐怖主义威胁引发的三个重大问题：1）需要一种简单的大规模疫苗接种方法； 2）现有炭疽疫苗的缺点是需要针头和卫生专业人员进行接种，需要延长疫苗接种时间（18个月内接种6剂），并且担心产生不良反应； 3）美国缺乏获得许可的鼠疫疫苗。为了应对这一挑战，我们将利用现有口服伤寒活疫苗 Ty21a 的广泛安全记录，以及我们对其进行工程设计以表达炭疽杆菌保护性抗原 (PA) 的经验，并诱导针对致命炭疽气溶胶的保护使用 Ty21a-炭疽 PA 疫苗对小鼠进行攻击。我们将利用 Ty21a 作为载体开发一种多价组合口服疫苗，可同时预防炭疽和鼠疫。此外，我们假设这种疫苗可以被配制为安全、稳定、高免疫原性并且可以容易地口服给药。目前的申请旨在完成必要的最终疫苗构建、动物免疫原性和功效研究，以及最终候选药物的全面表征（遗传、免疫学、微生物学）。然后，我们将构建主细胞库，按照现行良好生产规范进行小规模（10 升）生产，并对产品进行干燥以确保温度稳定性并配制为可快速溶解的晶圆。最终疫苗制剂将进行遗传稳定性、安全性、免疫原性研究以及在小鼠、兔和/或大鼠炭疽和鼠疫模型中的功效。 1项临床试验，以及本项目所有研究完成后的后续IND准备和提交。公共卫生相关性：疫苗提供了一种合理的方法，可确保在生物恐怖主义袭击之前或之后立即保护大量人口。我们的目标是解决目前生物恐怖主义威胁引发的三个重大问题：1）需要一种简单的大规模疫苗接种方法； 2）现有炭疽疫苗的缺点是需要针头和卫生专业人员进行接种，需要延长疫苗接种时间（18个月内接种6剂），并且担心产生不良反应； 3）美国缺乏获得许可的鼠疫疫苗。为了克服这些问题，我们将开发炭疽和鼠疫联合疫苗，我们假设该疫苗安全、稳定且具有高免疫原性，并且可以轻松口服。