Development of a Recombinant Subunit Vaccine for CCHF

描述(申请人提供)：新出现和再次出现的传染病继续在世界范围内构成严重的健康威胁。因此，制定措施以减轻这些传染病的自然和潜在的生物恐怖主义威胁是一项重要的努力。NIAID生物防御研究战略计划专门针对能够提供解决方案的研究，以减轻A、B和C类优先病原体构成的威胁。针对这些病原体的疫苗的开发为减轻潜在威胁提供了一种战略。克里米亚-刚果出血热病毒(CCHFV)因其致病能力强、病死率高，是一种重要的人类病原体。由于担心CCHFV可能被用作生物制剂，CCHFV被列为C类优先病原体。目前还没有广泛可用的有效疫苗或疗法来缓解这种威胁。新的技术和生产方法可能为应对这种疾病威胁提供最有效的应对措施。这项拟议的研究旨在开发一种疫苗，利用一个稳定的昆虫细胞系表达平台来预防CCHFV感染引起的疾病，该平台以前曾被用于生产其他优先病原体的候选疫苗。该平台基于重组亚单位蛋白的生产，以保持结构和免疫原性的完整性。该系统已经生产了针对登革热和西尼罗河病毒的候选疫苗，两种疫苗都已进入临床试验。因此，该平台可以用于cGMP的生产，并满足FDA的监管要求。将评估CCHFV Gn和GC包膜糖蛋白的表达。病毒包膜糖蛋白的复杂性给设计和表达保持天然结构的重组亚单位带来了挑战。本项目中建议使用的平台具有生产具有天然构象的复杂病毒包膜蛋白的能力。成功表达的重组产物将使用两种具有剂量节约潜力的新型佐剂配方进行免疫原性评估。根据免疫原性研究，选定的重组蛋白和佐剂的组合将在利用最近开发的CCHFV小鼠攻击模型进行的保护效果研究中进行评估。除了疫苗开发外，生产的蛋白质亚基还可用于开发诊断试剂，以及抗病毒药物开发的靶标。利用这一稳定的昆虫细胞平台成功开发出CCHFV疫苗，不仅将满足对CCHFV安全有效疫苗的需求，还将有助于展示该平台的实用性，并为开发针对NIAID病毒优先病原体的更多疫苗铺平道路。

DESCRIPTION (provided by applicant): Emerging and reemerging infectious diseases continue to pose serious health threats world-wide. Consequently, the development of measures to mitigate the natural, as well as potential bioterrorist threats of these infectious diseases is an important endeavor. The NIAID Strategic Plan for Biodefense Research is specifically directed at promoting research that can provide solutions to mitigate the threat posed by Category A, B, and C priority pathogens. The development of vaccines against these pathogens provides a strategy to mitigate the potential threat. Crimean-Congo hemorrhagic fever virus (CCHFV) is a significant human pathogen due to it ability cause severe disease and its high fatality rate. CCHFV is classified as a category C priority pathogen due the concern that it could be used as a biological agent. There is currently no effective vaccine or therapy that is widely available to mitigate such a threat. New technologies and production methods may offer the most effective responses to such disease threats. The proposed research aims to develop a vaccine to protect against disease caused by infection with CCHFV using a stable insect cell line expression platform that has previously been used to produce vaccine candidates for other priority pathogens. The platform is based on the production of recombinant subunit proteins that maintain structural and immunogenic integrity. Candidate vaccines against dengue and West Nile virus have already been produced in this system and both have entered clinical trials. Thus, this platform can be scaled for cGMP production and meet FDA regulatory requirements. The expression of the CCHFV Gn and Gc envelope glycoprotein will be evaluated. The complex nature of viral envelope glycoproteins presents challenges in designing and expressing recombinant subunits that maintain native-like structure. The platform proposed for use in this project has the demonstrated capability of producing complex viral envelope proteins with native-like conformation. Successfully expressed recombinant products will be evaluated for immunogenic potential using two novel adjuvant formulations that have dose sparing potential. Based on immunogenicity studies, selected combinations of recombinant proteins and adjuvant will be evaluated in protective efficacy studies utilizing a recently developed mouse challenge model for CCHFV. In addition to vaccine development, the protein subunits produced can be used for development of diagnostic reagents, as well as targets for antiviral drug development. The successful development of a CCHFV vaccine utilizing this stable insect cell platform will not only meet the need for a safe and effective vaccine against CCHFV, it will also help to demonstrate the utility of the platform and pave the way for the development of additional vaccines against NIAID viral priority pathogens.