Killed Rhabdoviruses as Novel Anthrax Vaccines

描述(由申请人提供)：炭疽病在人类中的自然发生率很低，风险很低，直到20世纪，炭疽病作为生物武器工具的开发才开始。从那时起，使用炭疽菌的生物恐怖主义威胁是美国和国外的一个主要风险，因此炭疽杆菌被归类为NIAID A类优先病原体。至于大多数传染病，对抗炭疽的最好策略是有效的疫苗。然而，现有的人用炭疽疫苗由于毒性高和适度、短暂的体液免疫反应而存在重大问题。这项建议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的载体，开发一种改进的人类炭疽疫苗。基于我们的发现，我们推测，重组狂犬病病毒(RV)核糖核蛋白(RNP)或病毒粒子呈现的外来抗原可以诱导强大的体液反应，基于RV的载体在诱导针对炭疽的强大和保护性B细胞反应方面也是优秀的。我们提出了两个不同的目标来解决我们的工作假设，即轮状病毒介导的T辅助反应(S)和以高度有组织的方式向免疫系统递送炭疽保护性抗原(PA)优于使用重组炭疽PA。在第一个目的中，以RV核蛋白-PA融合蛋白作为强B细胞抗原。第二个目的是提出使用灭活轮状病毒颗粒作为有效的疫苗载体来展示炭疽PA蛋白。为了达到这两个目的，我们将通过ELISA法、增殖试验以及体外和体内毒性中和试验来跟踪不同结构物免疫小鼠的免疫反应。最后，在小鼠身上对最有希望的结构进行炭疽挑战实验，将表明诱导的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.