Rational Anthrax Vaccine with Structural Epitopes on VLP

描述(由申请人提供)：现有的炭疽疫苗AVA会引起严重的副作用，需要多次接种，当面临炭疽生物恐怖威胁时，无法进行预防性疫苗预防。尽管重组炭疽保护性抗原(PA)免疫可能提供对感染的实质性保护，基于PA的候选疫苗使用未经批准的人类使用的佐剂。我们建议设计和开发具有内在佐剂能力的下一代重组炭疽疫苗，该疫苗基于PA表位在自组装病毒样颗粒(VLP)表面的多重呈现。由于最近解决了PA蛋白和最主要的VLP载体-乙肝核心(HBC)颗粒的高分辨率结构，设计PA-VLP嵌合疫苗的合理方法现在成为可能。在PA蛋白的功能和免疫原性描述方面也取得了实质性进展。我们将把这些知识与先进的分子建模相结合，以确保功能VLP的折叠和组装具有最佳的PA表位展示。这项可行性研究是一项平台工作，将使该方法合法化，同时提供有效的疫苗。无毒、无感染的重组PA-HBc嵌合蛋白将作为疫苗进一步开发。成功的PA-HBC设计将为将炭疽毒力的其他成分纳入VLP疫苗配方提供基础技术，而不会损害安全性或生产成本。

DESCRIPTION (provided by applicant): The existing anthrax vaccine, AVA, causes serious side effects and requires multiple immunizations, precluding preventive vaccine prophylaxis when faced with an anthrax bioterrorist threat. Though recombinant anthrax protective antigen (PA) immunity may provide a substantial level of protection against infection, PA-based vaccine candidates utilize adjuvants not approved for human use. We propose to design and develop next generation recombinant anthrax vaccines with intrinsic adjuvant capabilities, based on multiple presentation of PA epitopes on the surface of self-assembling virus-like particles (VLP). A rational approach to designing PA-VLP chimeric vaccines is now possible due to the recently solved high-resolution structures of both PA protein and hepatitis B core (HBc) particle-the most prominent VLP carrier. There is also substantial progress in functional and immunogenic descriptions of the PA protein. We will combine this knowledge with advanced molecular modeling to ensure folding and assembly of functional VLP with optimal PA epitope display. This feasibility study is a platform work which will legitimize the approach while providing an effective vaccine. Nontoxic and non-infectious recombinant PA-HBc chimeric protein will be further developed as a vaccine. Successful PA-HBc design would provide a basis technology for inclusion of other components of anthrax virulence into the VLP vaccine formulation without compromising safety or production cost.