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

描述(由申请人提供)：疫苗为确保在生物恐怖主义袭击之前或之后立即保护大量人口提供了一种合理的方法。我们的目标一是解决生物恐怖主义威胁目前提出的三个重大问题：1)需要一种简单的大规模疫苗接种方法；2)目前的炭疽疫苗存在缺点，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个月内接种6剂)，并担心副作用；以及3)缺乏在美国获得许可的鼠疫疫苗。为了应对这一挑战，我们将利用现有口服活伤寒疫苗Ty21a的广泛安全记录和我们在设计它方面的经验来表达炭疽杆菌保护性抗原(PA)，并用这种Ty21a-炭疽PA疫苗诱导小鼠免受致命的炭疽气雾剂攻击。我们将利用Ty21a作为载体，开发一种同时预防炭疽和鼠疫的多价联合口服疫苗。此外，我们假设这种疫苗可以制成安全、稳定、高度免疫原性的疫苗，并且可以很容易地口服。目前的应用旨在完成必要的最终疫苗构建、动物免疫原性和效力研究，以及最终候选疫苗的充分表征(遗传、免疫学、微生物学)。然后，我们将构建主细胞库，按照当前的良好制造规范进行小规模(10升)生产，并将产品干燥以确保温度稳定性和配方成为可快速溶解的晶片。最终的疫苗制备将进行遗传稳定性、安全性和免疫原性的研究。 在炭疽和鼠疫的小鼠、兔子和/或大鼠模型中的有效性。1个临床试验，以及在该项目的所有研究完成后随后的IND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.