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

用于疫苗开发的新型拉萨病毒糖蛋白的结构设计 摘要 拉沙热是一种经常致命的病毒性出血热(VHF)，在西非流行，并且有显著的 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 供人类使用的治疗学。啮齿动物水库在地理上进一步扩张的潜力， 病毒的采购和武器化，经常进口到北美和欧洲，以及 最近在人口稠密的尼日利亚出现了新的菌株，因此有必要发展广泛的 反应性、快效性、保护性疫苗。我们最近确定了LASV糖蛋白的结构 三聚体与来自拉沙热幸存者的中和单抗(MAb)形成复合体。这 突破性结构是整个禽流感病毒家族的第一个灌流三聚体。此应用程序将测试 这种新确定的结构可以指导设计新的LASV糖蛋白的假设 快速诱导针对当前抗原性多样化的病毒谱系的广泛保护性免疫反应。我们 现在将使用这种新的晶体结构作为进一步稳定天然三聚体的设计模板 疫苗研发。拟议的项目将建立在前景看好的重组泡囊的成功基础上。 口炎病毒(RVSV)埃博拉平台已经在西非进行埃博拉临床试验。在以下建议的研究中 里程碑1，我们将生产一组转基因的、结构稳定的LASV GPC构建物 模拟天然的灌流三聚体，有效地呈现广泛的中和表位。我们将建造， 验证并扩大复制能力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 LASV GPC构建可在近交系中广泛而快速地诱导免疫原性和卓越的疫苗效力 致死性拉沙热豚鼠模型。在里程碑4中，我们将展示最有效的LASV 表达GPC的疫苗候选疫苗对食蟹LASV不同谱系的保护作用 猕猴。在提议的项目结束时，我们将进入一流的临床前评估 拉萨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。 此应用程序包含杜兰大学及其分包商的专有/特权信息 请求不得向政府以外的人发布，除非是为了审查和 评估。

“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.