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

基本信息

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
项目类别：
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

项目摘要

“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.

“基于结构的新型LASSA病毒糖蛋白用于疫苗开发” 抽象的 Lassa Fever是一种经常致命的病毒出血热（VHF），在西非是内在的，而且很重要对公共卫生的威胁，数十万年感染。没有批准的疫苗或用于人类使用的治疗。啮齿动物储层的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，以及在被人口稠密的尼日利亚，新型菌株的最新出现必要的开发反应性，快速作用，保护疫苗。我们最近确定了LASV糖蛋白的结构三聚体具有源自LASSA热冲浪者的中和单克隆抗体（mAb）。这开创性结构是整个Arenavirus家族的第一个预选触发因素。此应用程序将测试这种新确定的结构可以指导新型LASV糖蛋白的设计的假设迅速引起广泛保护的免疫反应，以抵抗电流，抗原多样的病毒谱系。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。拟议的项目将基于承诺的重组囊泡的成功西非埃博拉病毒临床试验已经在西非埃博拉病毒中已经进行了气孔炎病毒（RVSV）。在提出的研究中里程碑1，我们将生成一组普遍修改的结构稳定的LASV GPC构建体模仿天然的预融合三聚体，并有效地呈现广泛中和的表位。我们将构建验证并扩大复制能力，单次注射二价或三价RVSV疫苗的候选者在里程碑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构造，引起巨大和快速的免疫原性以及近代的疫苗效率优质豚鼠致命的Lassa热模型。在里程碑4中，我们将证明最有效的LASV 表达GPC的疫苗候选候选疫苗对cynomolgus中LASV的潜水谱系的保护猕猴。在拟议计划的结论结束时，我们将输入对第一类的临床前评估 LASSA病毒和埃博拉病毒的二价疫苗，这是世界上两个最致命的病毒剂出血发烧。该申请包含图兰大学及其分包商的专有/特权信息要求不向政府以外的人释放，除了审查目的和评估。