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）：新兴和重新出现的传染病在全球范围内继续构成严重的健康威胁。因此，制定减轻自然的措施以及对这些传染病的潜在生物恐怖主义威胁是一项重要努力。 NIAID的生物形式研究战略计划专门旨在促进可以提供解决方案以减轻A，B类和C优先病原体构成的威胁的研究。针对这些病原体的疫苗开发提供了减轻潜在威胁的策略。 Crimean-Congo出血热病毒（CCHFV）是一种重要的人类病原体，因为它能力导致严重疾病及其死亡率高。 CCHFV被归类为C类优先病原体，因为它可以用作生物剂。目前尚无有效的疫苗或疗法可用于减轻这种威胁。新技术和生产方法可能会对这种疾病威胁提供最有效的反应。拟议的研究旨在开发一种疫苗，以使用稳定的昆虫细胞线表达平台来预防由CCHFV感染引起的疾病，该平台以前已用于为其他优先病原体生产候选疫苗。该平台基于维持结构和免疫原性完整性的重组亚基蛋白的产生。针对登革热和西尼罗河病毒的候选疫苗已经在该系统中产生，并且都参加了临床试验。因此，可以将该平台缩放以进行CGMP生产并满足FDA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质在设计和表达维持类似天然的结构的重组亚基时面临着挑战。该项目中提出的平台具有显示具有天然构象的复杂病毒包膜蛋白的能力。使用具有剂量保留潜力的两种新型辅助配方，将对成功表达的重组产物进行免疫原性评估。基于免疫原性研究，将在使用最近开发的CCHFV小鼠挑战模型的保护效力研究中评估重组蛋白和辅助素的选定组合。除了疫苗开发外，生产的蛋白质亚基可用于开发诊断试剂，以及抗病毒药药发育的靶标。利用这种稳定的昆虫细胞平台的CCHFV疫苗的成功开发不仅满足了针对CCHFV的安全有效疫苗的需求，还将有助于证明该平台的实用性，并为开发针对NIAID病毒优先病原体的其他疫苗开发。