Development of a Recombinant Subunit Vaccine for CCHF

CCHF 重组亚单位疫苗的开发

• 批准号: 8499241
• 负责人: DAVID E CLEMENTS
• 金额: $ 26.89万
• 依托单位: HAWAII BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-28 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499241
• 关键词: Address; Adjuvant; Advanced Development; Aerosols; Africa; Aluminum Hydroxide; Animals; Antigens; Antiviral Agents; Asia; Baculoviruses; Biological; Biological Assay; Biological Products; Blood; Brain; Bunyaviridae; Categories; Cell Culture Techniques; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); Cervarix; Cessation of life; Clinical; Clinical Trials; Communicable Diseases; Complex; Containment; Country; Crimean-Congo Hemorrhagic Fever Virus; Dengue; Development; Diagnostic Reagent; Disease; Dose; Drosophila genus; Drug Formulations; Eastern Europe; Engerix-B; Europe; Evaluation; Family; Fever; Flaviviridae; Flavivirus; Gardasil; Genome; Glycoproteins; Goals; Hawaii; Health; Hemorrhage; Hepatitis B Virus; Human; Human Bites; Human Papillomavirus; Immune response; Incidence; Individual; Infection; Influenza; Insecta; Japanese Encephalitis; Knockout Mice; Licensing; Measures; Medical; Methods; Middle East; Modeling; Molecular Conformation; Mus; Nairovirus; National Institute of Allergy and Infectious Disease; Nature; Orthobunyavirus; Phase; Production; Property; Protein Subunits; RNA; Recombinant Proteins; Recombinants; Research; Risk; Safety; Solutions; Strategic Planning; Structure; Subunit Vaccines; System; Technology; Testing; Texas; Tick-Borne Encephalitis; Ticks; Tissues; Universities; Vaccine Production; Vaccines; Viral; Viral Envelope Proteins; Viral Hemorrhagic Fevers; Virus; Virus Diseases; West Nile virus; Work; Yeasts; Yellow Fever Vaccine; base; biodefense; cGMP production; design; drug development; immunogenic; immunogenicity; improved; killings; meetings; member; mortality; mouse model; neutralizing antibody; new technology; novel; pathogen; pre-clinical; prevent; protective efficacy; public health relevance; response; success; transmission process; vaccine candidate; vaccine development; virus envelope; weapons

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.

描述（由申请人提供）：新出现和再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，制定措施减轻这些传染病的自然威胁以及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促进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。开发针对这些病原体的疫苗提供了一种减轻潜在威胁的策略。克里米亚-刚果出血热病毒（CCHFV）具有致病性强、致死率高的特点，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，因此将其列为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减轻这种威胁。新技术和生产方法可能对这类疾病威胁提供最有效的对策。这项拟议的研究旨在利用稳定的昆虫细胞系表达平台开发一种疫苗，以预防由CCHFV感染引起的疾病，该平台先前已被用于生产其他优先病原体的候选疫苗。该平台是基于重组亚基蛋白的生产，保持结构和免疫原性的完整性。针对登革热和西尼罗河病毒的候选疫苗已经在这个系统中生产出来，并且两种疫苗都已进入临床试验阶段。因此，该平台可以规模化生产cGMP，并满足FDA的监管要求。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质为设计和表达维持天然结构的重组亚基提出了挑战。在这个项目中使用的平台已经证明了生产具有天然构象的复杂病毒包膜蛋白的能力。成功表达的重组产品将使用两种具有剂量节约潜力的新型佐剂配方来评估其免疫原性。在免疫原性研究的基础上，重组蛋白和佐剂的选择组合将在利用最近开发的CCHFV小鼠攻击模型的保护功效研究中进行评估。除了开发疫苗外，所产生的蛋白质亚基还可用于开发诊断试剂，以及开发抗病毒药物的靶标。利用这一稳定的昆虫细胞平台成功开发出CCHFV疫苗，不仅将满足对安全有效的CCHFV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病毒重点病原体的其他疫苗铺平道路。