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

• 批准号: 10438220
• 负责人: Robert F Garry
• 金额: $ 14.37万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-14 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438220
• 关键词: Achievement; Adopted; Africa; African; Animal Model; Antibodies; Arenavirus; Cavia; Cell membrane; Clinical Trials; Collaborations; Communicable Diseases; Complex; Crystallization; Development; Ebola; Ebola Vaccines; Ebola virus; Ebola virus envelope glycoprotein; Epitopes; Europe; Evaluation; Family; GP2 gene; GTPBP1 gene; Geography; Glycoproteins; Goals; Government; HIV; Human; Immune response; Immunology; Industry; Infection; Injections; Lassa Fever; Lassa virus; Macaca fascicularis; Memory B-Lymphocyte; Monkeys; Nigeria; North America; Persons; Production; Public Health; Reagent; Recombinants; Rodent; Role Concepts; Structure; Surface; Survivors; Technology; Testing; Therapeutic; Time; Universities; Vaccine Design; Vaccines; Validation; Vesicular stomatitis Indiana virus; Viral Hemorrhagic Fevers; Viral Load result; Virion; Virus; Virus-Cell Membrane Interaction; base; cross reactivity; design; human monoclonal antibodies; immunogenic; immunogenicity; monomer; multidisciplinary; neutralizing monoclonal antibodies; nonhuman primate; novel; porcine model; preclinical evaluation; programs; response; scale up; structural biology; success; vaccine candidate; vaccine development; vaccine efficacy; weapons

“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.

“用于疫苗开发的新型拉沙病毒糖蛋白的结构设计” 抽象的 拉沙热是一种经常致命的病毒性出血热 (VHF)，在西非流行，是一种重要的疾病 每年有数十万例感染，对公众健康构成威胁。没有批准的疫苗或 供人类使用的疗法。啮齿动物宿主进一步地理扩张的潜力， 病毒的采购和武器化，频繁输入到北美和欧洲，以及 最近在人口稠密的尼日利亚出现了新菌株，需要广泛开发 反应性、速效、保护性疫苗。我们最近确定了 LASV 糖蛋白的结构 三聚体与源自拉沙热幸存者的中和单克隆抗体 (MAb) 形成复合物。这 突破性的结构是整个沙粒病毒家族的第一个预融合三聚体。该应用程序将测试 假设这一新确定的结构可以指导新型 LASV 糖蛋白的设计 快速引发针对当前抗原多样化病毒谱系的广泛保护性免疫反应。我们 现在将使用这种新颖的晶体结构作为设计模板，以进一步稳定天然三聚体 疫苗开发。拟议的项目将建立在有前途的重组囊泡的成功基础上 口腔炎病毒（rVSV）埃博拉平台已经在西非埃博拉临床试验中。在下提出的研究中 里程碑 1，我们将生产一套经过基因改造、结构稳定的 LASV GPC 构建体， 模仿天然预融合三聚体并有效地呈现广泛的中和表位。我们将建设、 验证并扩大具有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 构建体在近交系中引发广泛、快速的免疫原性和卓越的疫苗功效 致命拉沙热的豚鼠模型。在里程碑 4 中，我们将证明最有效的 LASV 表达 GPC 的候选疫苗可在食蟹猴中引发针对多种 LASV 谱系的保护 猕猴。在拟议计划结束时，我们将进入一流的临床前评估 拉沙病毒和埃博拉病毒的二价疫苗，这两种病毒是世界上最致命的两种病毒的病原体 出血热。 该应用程序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员，除非出于审查和 评价。