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: 10202410
• 负责人: Robert F Garry
• 金额: $ 117.29万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202410
• 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.

基于结构的新型拉沙病毒糖蛋白疫苗设计