Development of New Bivalent Cross-Protective Arenaviral Vaccines

描述(申请人提供)：在NIAID A类优先病原体中，高致病性ArenaVirus，Lassa，Junun，Machupo是主要的病毒种类。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进一步开发和优化基于甲型病毒的VLPV(病毒样颗粒载体)技术(正在申请专利)，作为针对高致病性禽流感病毒的预防性生物防御疫苗的通用平台。利用这项技术和合理的疫苗设计，我们将开发出：(I)具有增强的免疫原性和对远亲LASV基因型的交叉保护潜力的双价LASV疫苗；(Ii)JUNV和MACV双价疫苗。VLPV技术将转移到制造环境并扩大规模，以生产用于非人类灵长类动物临床前试验的GLP级疫苗。特异性目的I：合理设计表达ArenaVirus糖蛋白的多价VLPV，增强免疫原性和交叉反应性。其目的是设计：(I)表达LASV gp的VLPV能够通过传统的MHC I肽递呈和交叉引发诱导CD8+T细胞对远亲LASV谱系I和IV的强烈反应；ii)表达JUNV和MACV gp的VLPV能够诱导针对这两种病原体的中和抗体；以及iii)优化甲型病毒双顺反子复制子结构，用于产品开发。特异性目的II：实验动物免疫原性和交叉反应性VLPV疫苗的筛选过程中安全测试。特定目的III：NHP的临床前安全性、免疫原性和有效性。毒素批次疫苗产品将在我们最近开发的NHP挑战模型中进行安全性、免疫原性和有效性测试。该项目的主要目标是进一步开发和优化类病毒颗粒载体技术，作为针对高致病性ARENA病毒Lassa-Junin-Machupo的预防性生物防御疫苗的通用平台。VLPV技术将转移到制造环境并放大生产GLP级疫苗，用于非人类灵长类动物的安全性、免疫原性和有效性研究

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