Killed Rhabdoviruses as Novel Anthrax Vaccines

描述（由申请人提供）：炭疽在人类中的自然发生率很低，直到世纪才开始发展为生物武器工具。从那时起，使用炭疽的生物恐怖主义威胁是美国和国外的主要风险，因此炭疽杆菌被列为NIAID A类优先病原体。对于大多数传染病，对抗炭疽的最佳策略是有效的疫苗。然而，现有的针对炭疽的人疫苗由于高毒性发生率和适度的、短暂的体液免疫应答而经历主要问题。本提案的目标是使用利用病毒衣壳（RNP）或病毒粒子作为炭疽保护性抗原PA的载体的新方法来开发改进的人类炭疽疫苗。我们假设，根据我们的研究结果，重组狂犬病病毒（RV）核糖核蛋白（RNP）或病毒粒子提出的外源抗原诱导有效的体液反应，RV为基础的载体也是优秀的诱导强大的和保护性的B细胞对炭疽的反应。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辅助细胞应答和炭疽保护性抗原（PA）以高度组织化的方式呈递给免疫系统上级使用重组炭疽PA。在第一个目标中，嵌合RV核蛋白-PA融合蛋白被用作强B细胞抗原。第二个目的是提出使用灭活的RV颗粒作为有效的疫苗载体来展示炭疽PA蛋白。对于这两个目的，我们将通过ELISA、增殖测定以及体外和体内毒性中和测定来跟踪用各种构建体接种的小鼠中的免疫应答。最后，对小鼠中最有希望的构建体进行炭疽攻击实验将表明诱导的反应是否能预防炭疽感染。

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.