Killed Rhabdoviruses as Novel Anthrax Vaccines

描述（由申请人提供）：直到20世纪，炭疽热作为一种生物武器工具开始发展，炭疽热在人类中自然发生的风险很低。从那时起，使用炭疽的生物恐怖主义威胁在美国和国外都是一个主要的风险，因此炭疽杆菌被列为NIAID的a类优先病原体。对于大多数传染病，对抗炭疽热的最佳策略是有效的疫苗。然而，现有的人类炭疽疫苗由于毒性发生率高和适度的、短暂的体液免疫反应而存在重大问题。本提案的目标是利用病毒衣壳（RNP）或病毒粒子作为炭疽保护性抗原PA载体的新方法开发一种改进的人类炭疽疫苗。我们假设，基于我们的发现，重组狂犬病毒（RV）核糖核蛋白（RNP）或病毒粒子呈报的外源抗原诱导了有效的体液反应，基于RV的载体也很好地诱导了针对炭疽的强保护性b细胞反应。我们提出了两个不同的目的来解决我们的工作假设，即RV介导的t辅助反应(s)和炭疽保护性抗原（PA）以高度有组织的方式提交给免疫系统优于使用重组炭疽保护性抗原。在第一个实验中，嵌合RV核蛋白- pa融合蛋白被用作强b细胞抗原。第二个目标提出使用杀死的RV颗粒作为有效的疫苗载体来显示炭疽PA蛋白。为了这两个目的，我们将通过ELISA、增殖试验以及体外和体内毒性中和试验来跟踪接种不同结构的小鼠的免疫反应。最后，最有希望构建的小鼠炭疽攻击实验将表明诱导反应是否对炭疽感染具有保护作用。

DESCRIPTION (provided by applicant): Anthrax posed only a low risk with minimal natural occurrence in humans until the 20th century, when its development as a bioweapons tool began. Since then, bioterrorism threat using Anthrax is a major risk in the US and abroad and therefore bacillus anthracis has been classified as NIAID Category A Priority Pathogen. As for most infectious diseases, the best strategy against Anthrax is an effective vaccine. However, the existing human vaccine against Anthrax experiences major problems due to a high incidence of toxicity and modest, transient humoral immune responses. The goal of this proposal is the development of an improved human Anthrax vaccine using the novel approach of utilizing a viral capsid (RNP) or virion as a carrier for the Anthrax protective antigen PA. We hypothesize, based on our findings that foreign antigens presented by recombinant rabies virus (RV) ribonucleoprotein (RNP) or virions induce potent humoral responses, that RV-based vectors are also excellent to induce strong and protective B-cell responses against Anthrax. Two different Aims are proposed to address our working hypothesis that RV mediated T-helper response(s) and the presentation of Anthrax protective antigen (PA) to the immune system in a highly organized manner is superior to the use of recombinant Anthrax PA. In the first Aim, chimeric RV nucleoprotein-PA fusion proteins are used as strong B-cell antigens. The second Aim proposes the use of killed RV particles as an efficient vaccine carrier to display anthrax PA protein. For both Aims, we will follow the immune responses in mice vaccinated with various constructs by ELISA, proliferation assays, and in vitro and in vivo toxicity neutralization assays. Lastly, Anthrax challenge experiments of the most promising constructs in mice will indicate if the inducted responses are protective against Anthrax infection.