Development of New Bivalent Cross-Protective Arenaviral Vaccines

新型二价交叉保护性沙病毒疫苗的开发

• 批准号: 8249031
• 负责人: Igor S. Lukashevich
• 金额: $ 82.27万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249031
• 关键词: Advanced Development; Adverse event; Affect; Africa; Alphavirus; Am 80; Animals; Antigen-Presenting Cells; Antigens; Arenavirus; Attenuated Live Virus Vaccine; Bolivian Hemorrhagic Fever Virus; CD8B1 gene; Categories; Cavia; Cells; Cessation of life; Cross-Priming; DNA; Development; Ebola virus; Ensure; Environment; Equilibrium; Filovirus; Frequencies; Generic Drugs; Genes; Genetic; Genotype; Geographic Distribution; Glycoproteins; Goals; Human; Immunization; Individual; Junin virus; Lassa Fever; Lassa virus; Lead; Legal patent; Modeling; Mus; National Institute of Allergy and Infectious Disease; Nucleoproteins; Old World Arenaviruses; Peptides; Preclinical Testing; Preventive; Process; Production; Public Health; Recombinants; Replicon; Safety; South Africa; Structural Protein; Structure; T cell response; Tacaribe Complex Viruses; Technology; Technology Transfer; Testing; United States National Institutes of Health; Vaccination; Vaccine Design; Vaccines; Viral; Viral Hemorrhagic Fevers; Virus; Virus-like particle; base; biodefense; cross reactivity; design; environmental change; immunogenic; immunogenicity; neutralizing antibody; next generation; nonhuman primate; particle; pathogen; peptide I; pre-clinical; product development; promoter; recombinant virus; safety testing; scale up; vaccine safety; vector; vector vaccine

DESCRIPTION (provided by applicant): Highly pathogenic arenaviruses, Lassa, Junun, Machupo, are dominant viral species among NIAID Category A Priority Pathogens. The development of safe and efficacious vaccines against these pathogens with particular emphasis on multivalent and cross protective strategy and advanced platform technology is one of the priorities of NIH/NIAID. The main goal of this project is an advanced development and optimization of alphavirus-based VLPV (virus-like-particle-vectors) technology (patent is pending) as a generic platform for preventive biodefense vaccines against highly pathogenic arenaviruses. Using this technology and rational vaccine design we will develop: (i) a bivalent LASV vaccine with enhanced immunogenicity and cross-protective potential against distantly-related LASV genotypes, and (ii) a bivalent JUNV&MACV vaccine. The VLPV technology will be transferred to a manufacturing environment and scaled-up to produce GLP-grade vaccines for preclinical testing in nonhuman primates. SPECIFIC AIM I: Rational Design of Multivalent VLPV Expressing Arenaviral Glycoproteins with Enhanced Immunogenicity and Cross-Reactivity. The goal of this aim is to design: (i) VLPV expressing LASV GP able to induce strong CD8+ T cell responses to distantly-related LASV lineages, I and IV, through the conventional MHC I peptide presentation and through cross-priming; ii) VLPV expressing JUNV&MACV GP to induce neutralizing Abs against both pathogens; and iii) to optimize alphavirus bi-cistronic replicon structures for product development. SPECIFIC AIM II: Selection of Immunogenic and Cross-Reactive Recombinant VLPV Vaccines in Experimental Animals. In-process Safety Testing. SPECIFIC AIM III: Pre-Clinical Safety, Immunogenicity, and Efficacy in NHP. Tox Lot vaccine products will be tested for Safety, Immunogenicity, and Efficacy in the NHP challenge model we recently developed. The main goal of this project is an advanced development and optimization of Virus-Like-Particle-Vectors technology as a generic platform for preventive biodefense vaccines against highly pathogenic arenaviruses, Lassa-Junin-Machupo. The VLPV technology will be transferred to a manufacturing environment and scaled-up to produce GLP-grade vaccines for Safety, Immunogenicity, and Efficacy Studies in non-human primates

描述（由申请方提供）：高致病性沙粒病毒（拉沙病毒、Junun病毒、Machupo病毒）是NIAID A类优先病原体中的主要病毒种。开发针对这些病原体的安全有效的疫苗，特别强调多价和交叉保护策略以及先进的平台技术，是NIH/NIAID的优先事项之一。该项目的主要目标是先进开发和优化基于甲病毒的VLPV（病毒样颗粒载体）技术（专利正在申请中），作为针对高致病性沙粒病毒的预防性生物防御疫苗的通用平台。使用该技术和合理的疫苗设计，我们将开发：（i）具有增强的免疫原性和针对远缘相关LASV基因型的交叉保护潜力的二价LASV疫苗，和（ii）二价JUNV&MACV疫苗。VLPV技术将转移到生产环境中，并扩大规模生产GLP级疫苗，用于非人灵长类动物的临床前试验。特定目的I：表达沙粒病毒糖蛋白的多价VLPV的合理设计，其具有增强的免疫原性和交叉反应性。该目的的目标是设计：（i）VLPV表达LASV GP，其能够通过常规MHC I肽呈递和通过交叉引发诱导对远缘相关LASV谱系I和IV的强CD 8 + T细胞应答; ii）VLPV表达JUNV和MACV GP以诱导针对两种病原体的中和Ab;和iii）优化甲病毒双顺反子复制子结构用于产品开发。特定目的II：在实验动物中选择免疫原性和交叉反应性重组VLPV疫苗。过程中安全性检测。特定目的III：NHP的临床前安全性、免疫原性和有效性。将在我们最近开发的NHP攻毒模型中检测Tox批次疫苗产品的安全性、免疫原性和有效性。该项目的主要目标是病毒样颗粒载体技术的先进开发和优化，作为针对高致病性沙粒病毒Lassa-Junin-Machupo的预防性生物防御疫苗的通用平台。VLPV技术将转移到生产环境中，并扩大规模生产GLP级疫苗，用于非人灵长类动物的安全性、免疫原性和有效性研究