Structure-based design of novel Lassa virus glycoproteins for vaccine development

“用于疫苗开发的新型拉沙病毒糖蛋白的基于结构的设计” 摘要 拉沙热是一种致命的病毒性出血热（VHF），在西非流行，是一种重要的流行病。 每年有数十万人感染，对公共卫生构成威胁。没有批准的疫苗或 用于人类的治疗剂。啮齿动物水库进一步地理扩张的潜力， 病毒的采购和武器化，经常进口到北美和欧洲， 最近在人口稠密尼日利亚出现新菌株， 反应性、快速作用、保护性的疫苗。我们最近确定了LASV糖蛋白的结构， 与来自拉沙热幸存者的中和单克隆抗体（MAb）复合的三聚体。这 突破性的结构是整个沙粒病毒家族的第一个融合前三聚体。该应用程序将测试 这一新确定的结构可以指导设计新的LASV糖蛋白的假设， 快速引发针对当前抗原性不同的病毒谱系的广泛保护性免疫应答。我们 现在将使用这种新的晶体结构作为设计模板，用于进一步稳定天然三聚体， 疫苗研发。拟议的项目将建立在成功的一个有前途的重组囊泡 口腔炎病毒（rVSV）埃博拉平台已经在西非埃博拉临床试验。在根据 里程碑1，我们将产生一组遗传修饰的、结构稳定的LASV GPC构建体， 模拟天然融合前三聚体并有效地呈递广泛中和表位。我们将建设， 验证并扩大可复制的单次注射二价或三价rVSV候选疫苗 在里程碑2中表达优化的LASV GPC和EBOV GP。里程碑3的目的是向下选择 在远交种中引发广泛且快速的免疫原性和上级疫苗功效的LASV GPC构建体 致死性拉沙热豚鼠模型。在里程碑4中，我们将证明最有效的LASV 表达GPC的候选疫苗在食蟹猴中增强对LASV不同谱系的保护 猕猴在拟议的计划结束时，我们将进入临床前评价一流的 拉沙病毒和埃博拉病毒的双价疫苗，这两种病毒是世界上最致命的两种病毒的病原体。 出血热 本申请包含杜兰大学及其分包商的专有/特权信息 不得将请求透露给政府以外的人，除非是为了审查的目的， 评价。

“Structure-based design of novel Lassa virus glycoproteins for vaccine development” ABSTRACT Lassa fever is an often-fatal viral hemorrhagic fever (VHF) that is endemic in West Africa, and a significant threat to public health with hundreds of thousands of annual infections. There are no approved vaccines or therapeutics for human use. The potential for further geographic expansion of the rodent reservoirs, the ease of procurement and weaponization of the virus, the frequent importation to North America and Europe, and the recent emergence of novel strains in densely populated Nigeria necessitate development of broadly reactive, fast-acting, protective vaccines. We recently determined the structure of the LASV glycoprotein trimer in complex with neutralizing monoclonal antibodies (MAbs) derived from Lassa fever survivors. This ground-breaking structure is the first prefusion trimer for the entire arenavirus family. This application will test the hypothesis that this newly determined structure can guide design of novel LASV glycoproteins that rapidly elicit broadly protective immune responses against current, antigenically diverse virus lineages. We will now use this novel crystal structure as a design template for further stabilization of native trimers for vaccine development. The proposed project will build on the success of a promising recombinant vesicular stomatitis virus (rVSV) Ebola platform already in West African Ebola clinical trials. In studies proposed under Milestone 1, we will produce a set of genetically modified, structurally stable LASV GPC constructs that mimic native prefusion trimers and effectively present broadly neutralizing epitopes. We will construct, validate and scale up a replication-competent, single-injection bivalent or trivalent rVSV vaccine candidate expressing optimized LASV GPC and EBOV GP in Milestone 2. The aim of Milestone 3 is to down-select LASV GPC constructs that elicit broad and rapid immunogenicity and superior vaccine efficacy in an outbred guinea pig model of lethal Lassa fever. In Milestone 4, we will demonstrate that the most effective LASV GPC-expressing vaccine candidate elicits protection against diverse lineages of LASV in cynomolgus macaques. At the conclusion of the proposed program we will enter pre-clinical evaluation of a first-in-class bivalent vaccine for Lassa virus and Ebola virus, the causative agents of two of the world's deadliest hemorrhagic fevers. This application contains proprietary/priviledged information that Tulane University and its subcontractors request not be released to persons outside the Government, except for the purposes of review and evaluations.