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:
  • 金额:
    $ 14.37万
  • 依托单位:
  • 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

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.
“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。

项目成果

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Robert F Garry其他文献

Erratum to: Lassa hemorrhagic fever in a late term pregnancy from northern Sierra Leone with a positive maternal outcome: case report
  • DOI:
    10.1186/1743-422x-8-480
  • 发表时间:
    2011-10-25
  • 期刊:
  • 影响因子:
    3.800
  • 作者:
    Luis M Branco;Matt L Boisen;Kristian G Andersen;Jessica N Grove;Lina M Moses;Ivana J Muncy;Lee A Henderson;John S Schieffellin;James E Robinson;James J Bangura;Donald S Grant;Vanessa N Raabe;balu M Fonnie;Eleina M Zaitsev;Pardis C Sabeti;Robert F Garry
  • 通讯作者:
    Robert F Garry
RETRACTED ARTICLE: Reduced expression of Jak-1 and Tyk-2 proteins leads to interferon resistance in Hepatitis C virus replicon
  • DOI:
    10.1186/1743-422x-4-89
  • 发表时间:
    2007-09-18
  • 期刊:
  • 影响因子:
    3.800
  • 作者:
    Sidhartha Hazari;Lizeth Taylor;Salima Haque;Robert F Garry;Sander Florman;Ronald Luftig;Frederic Regenstein;Srikanta Dash
  • 通讯作者:
    Srikanta Dash
RETRACTED ARTICLE: Small interfering RNA targeted to stem-loop II of the 5' untranslated region effectively inhibits expression of six HCV genotypes
  • DOI:
    10.1186/1743-422x-3-100
  • 发表时间:
    2006-11-27
  • 期刊:
  • 影响因子:
    3.800
  • 作者:
    Ramesh Prabhu;Robert F Garry;Srikanta Dash
  • 通讯作者:
    Srikanta Dash
Proteomics computational analyses suggest that the bornavirus glycoprotein is a class III viral fusion protein (γ penetrene)
  • DOI:
    10.1186/1743-422x-6-145
  • 发表时间:
    2009-09-18
  • 期刊:
  • 影响因子:
    3.800
  • 作者:
    Courtney E Garry;Robert F Garry
  • 通讯作者:
    Robert F Garry
An invitation to recent graduates: publish your dissertation/thesis background section as a review in Virology Journal
  • DOI:
    10.1186/1743-422x-4-46
  • 发表时间:
    2007-06-02
  • 期刊:
  • 影响因子:
    3.800
  • 作者:
    Robert F Garry
  • 通讯作者:
    Robert F Garry

Robert F Garry的其他文献

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{{ truncateString('Robert F Garry', 18)}}的其他基金

Preclinical Evaluation of Advanced Pan-Lassa Immunotherapeutic Cocktails
先进的泛拉沙免疫治疗混合物的临床前评估
  • 批准号:
    10158449
  • 财政年份:
    2019
  • 资助金额:
    $ 14.37万
  • 项目类别:
Preclinical Evaluation of Advanced Pan-Lassa Immunotherapeutic Cocktails
先进的泛拉沙免疫治疗混合物的临床前评估
  • 批准号:
    10402339
  • 财政年份:
    2019
  • 资助金额:
    $ 14.37万
  • 项目类别:
Preclinical Evaluation of Advanced Pan-Lassa Immunotherapeutic Cocktails
先进的泛拉沙免疫治疗混合物的临床前评估
  • 批准号:
    10617738
  • 财政年份:
    2019
  • 资助金额:
    $ 14.37万
  • 项目类别:
Systems-level identification of host determinants of patient outcomes in Lassa fever and Ebola
拉沙热和埃博拉患者预后的宿主决定因素的系统级识别
  • 批准号:
    10374719
  • 财政年份:
    2018
  • 资助金额:
    $ 14.37万
  • 项目类别:
Project 1
项目1
  • 批准号:
    10558423
  • 财政年份:
    2018
  • 资助金额:
    $ 14.37万
  • 项目类别:
Systems-level identification of host determinants of patient outcomes in Lassa fever and Ebola
拉沙热和埃博拉患者预后的宿主决定因素的系统级识别
  • 批准号:
    10310605
  • 财政年份:
    2018
  • 资助金额:
    $ 14.37万
  • 项目类别:
Systems-level identification of host determinants of patient outcomes in Lassa fever and Ebola
拉沙热和埃博拉患者预后的宿主决定因素的系统级识别
  • 批准号:
    10579086
  • 财政年份:
    2018
  • 资助金额:
    $ 14.37万
  • 项目类别:
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
  • 财政年份:
    2017
  • 资助金额:
    $ 14.37万
  • 项目类别:
Preclinical evaluation of a potent Lassa fever immunotherapeutic antibody cocktail
有效的拉沙热免疫治疗抗体混合物的临床前评估
  • 批准号:
    9926211
  • 财政年份:
    2017
  • 资助金额:
    $ 14.37万
  • 项目类别:
Preclinical evaluation of a potent Lassa fever immunotherapeutic antibody cocktail
有效的拉沙热免疫治疗抗体混合物的临床前评估
  • 批准号:
    10176382
  • 财政年份:
    2017
  • 资助金额:
    $ 14.37万
  • 项目类别:

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