Structure-based design of broad flavivirus immunogens

广泛黄病毒免疫原的基于结构的设计

基本信息

  • 批准号:
    10685350
  • 负责人:
  • 金额:
    $ 73.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-24 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

SUMMARY Dengue virus is a mosquito-transmitted flavivirus that causes an estimated 390 million human infections each year. There are four serotypes of Dengue (DENV1-4) that co-circulate in hyperendemic regions. Primary infection by a single DENV serotype results in febrile illness and subsequent durable immunity to that serotype. Secondary infections by heterotypic serotypes can lead to severe shock syndrome and death. Severe Dengue disease is caused in part by cross-reactive antibodies elicited during primary infection that can bind heterologous DENV serotypes but cannot neutralize them. Instead, these non-neutralizing antibodies facilitate entry and infection in Fcγ receptor-positive cells, thus causing "antibody-dependent enhancement" (ADE) of infection. While a live-attenuated four-component chimeric vaccine was recently deployed in 19 countries and Europe, this vaccine does not protect naïve individuals against symptomatic or severe infection, and may even exacerbate disease in some cases. Furthermore, the global emergence of Zika virus (ZIKV), and the potential for ADE between DENV and ZIKV, raises concerns for vaccine strategies containing most or all epitopes in the E glycoprotein. Nonetheless, the isolation and characterization of protective and, in some cases, broadly-neutralizing antibodies indicates that certain epitopes within the E glycoprotein may have the capacity to elicit broadly protective responses. Here, we utilize innovative protein engineering approaches to develop “immune-focused” antigens as potential vaccine candidates, in which epitopes that induce non-neutralizing antibodies are masked by engineered mutations or glycosylation. Our hypothesis is that masking of these unfavorable epitopes will skew the immune response toward a stronger neutralizing, protective, and broad response. Aims 1 and 2 focus on critical epitopes in DENV and ZIKV E domain III (EDIII), and Aim 3 explores glycan masking of the ZIKV E prefusion dimer to immune focus on the E-dimer epitope (EDE). EDIII is attractive for subunit vaccine design because it is the target of potently neutralizing and protective antibodies for both DENV and ZIKV. However, immunization with wild-type EDIII protein results in induction of both neutralizing and non-neutralizing antibodies that engage a variety of epitopes. We have used phage display to mask unproductive epitopes of DENV and ZIKV EDIIIs by mutation, while maintaining neutralizing epitopes. These “resurfaced EDIIIs” (rsDIIIs) will be conjugated to protein nanoparticles and their capacity to induce neutralizing and protective antibody response in mice evaluated. To immune focus the prefusion E dimer on the EDE, we have developed a mammalian display system that allows for rapid evaluation of E dimer constructs for binding to EDE mAbs. We will utilize this system to screen variants with multiple engineered glycosylation sites that mask the surface outside of the EDE. The most promising candidates will be tested for their capacity to induce EDE-like mAbs in mice. This work will provide a proof-of-concept for novel subunit vaccine candidates against DENV, ZIKV, and possibly other flaviviruses of global concern.
总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Jonathan R. Lai其他文献

The alphavirus determinants of intercellular long extension formation
细胞间长延伸形成的甲病毒决定因素
  • DOI:
    10.1128/mbio.01986-24
  • 发表时间:
    2024-12-17
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Caroline K. Martin;Judy J. Wan;Peiqi Yin;Thomas E. Morrison;William B. Messer;Vanessa Rivera-Amill;Jonathan R. Lai;Nina Grau;Félix A. Rey;Thérèse Couderc;Marc Lecuit;Margaret Kielian
  • 通讯作者:
    Margaret Kielian
A two-component cocktail of engineered DIII nanoparticles elicits broadly neutralizing antibody responses against dengue virus in mice
一种由工程化DIII纳米颗粒组成的双组分鸡尾酒在小鼠中引发了针对登革热病毒的广泛中和抗体反应
  • DOI:
    10.1016/j.isci.2025.112534
  • 发表时间:
    2025-06-20
  • 期刊:
  • 影响因子:
    4.100
  • 作者:
    Margarette C. Mariano;Helen S. Jung;Olivia Vergnolle;Keith Haskell;Lamount R. Evanson;Gregory Quevedo;Julia C. Frei;Karen Tong;Larissa B. Thackray;Michael S. Diamond;Jonathan R. Lai
  • 通讯作者:
    Jonathan R. Lai

Jonathan R. Lai的其他文献

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{{ truncateString('Jonathan R. Lai', 18)}}的其他基金

Developing a new bispecific antibody mimicking rapid antigen-specific memory CD8+ T cell-mediated protection
开发一种新型双特异性抗体,模仿快速抗原特异性记忆 CD8 T 细胞介导的保护
  • 批准号:
    10742118
  • 财政年份:
    2023
  • 资助金额:
    $ 73.88万
  • 项目类别:
Structure-based design of broad flavivirus immunogens
广泛黄病毒免疫原的基于结构的设计
  • 批准号:
    10494281
  • 财政年份:
    2021
  • 资助金额:
    $ 73.88万
  • 项目类别:
Eliciting and isolating neutralizing antibodies against Powassan virus
引发并分离针对波瓦桑病毒的中和抗体
  • 批准号:
    10459523
  • 财政年份:
    2021
  • 资助金额:
    $ 73.88万
  • 项目类别:
Eliciting and isolating neutralizing antibodies against Powassan virus
引发并分离针对波瓦桑病毒的中和抗体
  • 批准号:
    10290425
  • 财政年份:
    2021
  • 资助金额:
    $ 73.88万
  • 项目类别:
Structure-based design of broad flavivirus immunogens
广泛黄病毒免疫原的基于结构的设计
  • 批准号:
    10390845
  • 财政年份:
    2021
  • 资助金额:
    $ 73.88万
  • 项目类别:
Engineered Dengue EDIIIs as Broad Immunogens
作为广泛免疫原的工程登革热 EDIII
  • 批准号:
    9224550
  • 财政年份:
    2017
  • 资助金额:
    $ 73.88万
  • 项目类别:
Methods to Identify High-Affinity Antibodies that Target Tumor-Associated Glycans
鉴定针对肿瘤相关聚糖的高亲和力抗体的方法
  • 批准号:
    8504989
  • 财政年份:
    2011
  • 资助金额:
    $ 73.88万
  • 项目类别:
Methods to Identify High-Affinity Antibodies that Target Tumor-Associated Glycans
鉴定针对肿瘤相关聚糖的高亲和力抗体的方法
  • 批准号:
    8294534
  • 财政年份:
    2011
  • 资助金额:
    $ 73.88万
  • 项目类别:
Methods to Identify High-Affinity Antibodies that Target Tumor-Associated Glycans
鉴定针对肿瘤相关聚糖的高亲和力抗体的方法
  • 批准号:
    8034536
  • 财政年份:
    2011
  • 资助金额:
    $ 73.88万
  • 项目类别:
Targeting Viral Envelope Glycoproteins with Synthetic Antibodies
用合成抗体靶向病毒包膜糖蛋白
  • 批准号:
    7952441
  • 财政年份:
    2010
  • 资助金额:
    $ 73.88万
  • 项目类别:

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