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

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由生物恐怖主义威胁引起的三个重大问题：1）需要一种简单的大规模疫苗接种方法; 2）目前炭疽疫苗的缺点，需要针头和卫生专业人员进行管理，需要延长疫苗接种时间表（18个月内6剂），并担心不良反应; 3）缺乏在美国获得许可的鼠疫疫苗。为了应对这一挑战，我们将利用现有活的口服伤寒疫苗Ty 21 a的广泛安全记录，以及我们在工程上表达炭疽芽孢杆菌保护性抗原（PA）的经验，并利用这种Ty 21 a-炭疽PA疫苗诱导小鼠对致死性炭疽气溶胶攻击的保护。我们将利用Ty 21 a作为载体，开发一种多价组合口服疫苗，同时预防炭疽和鼠疫。此外，我们假设这种疫苗可以配制成安全、稳定、高度免疫原性并且可以轻松口服。目前的申请旨在完成必要的最终疫苗构建、动物免疫原性和有效性研究以及最终候选疫苗的全面表征（遗传学、免疫学、微生物学）。然后，我们将构建主细胞库，按照现行药品生产质量管理规范进行小规模（10升）生产，并干燥产品以获得温度稳定性和配制成快速溶解的薄片。将研究最终疫苗制剂的遗传稳定性、安全性、免疫原性 以及在炭疽和鼠疫的小鼠、兔和/或大鼠模型中的功效。1项临床试验，并在本项目所有研究完成后进行后续IND的准备和提交。

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.