Project 2: PanbetaCoV protein vaccine design

项目2:PanbetaCoV蛋白疫苗设计

基本信息

  • 批准号:
    10327524
  • 负责人:
  • 金额:
    $ 421.74万
  • 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:
    2021-09-16 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Abstract – Project 2 Animal betacoronaviruses (betaCoVs), such as those that gave rise to SARS-CoV-1, MERS, and now SARS- CoV-2, represent a significant, continuous threat to human health. Vaccines can provide pre-existing immunity to future zoonotic coronaviruses. A major limitation of the current effective vaccines to SARS-CoV-2 is that they likely will only protect SARS-CoV-2 isolates that are nearly identical to the Wuhan isolate used in the vaccines. Thus, the world remains vulnerable to SARS-CoV-2 mutational escape variants and from future animal betacoronavirus spillover events that have pandemic potential. Vaccine development that addresses this vulnerability is urgently needed. Project 2 will support this Program’s overall goal to develop vaccines that will prevent future betaCoV pandemics and SARS-CoV-2 escape variants by designing vaccine immunogens that elicit broadly neutralizing antibodies (bnAb) to provide protective immunity across the betaCoV genus. Structurally conserved neutralizing epitopes exist on betaCoV spike proteins, and we hypothesize that vaccines that elicit broadly protective antibodies to these sites can be developed. In preliminary studies, we have isolated cross-reactive neutralizing antibodies from SARS-CoV-1 or SARS-CoV-2-infected or recovered humans and used structural determination to precisely define their betaCoV bnAb epitopes. Our vaccine design strategy involves using computational and structural- based design techniques to develop immunogens that preferentially present these and additionally identified bnAb epitopes. Each immunogen design will be displayed on the surface of nanoparticles to enhance antigen avidity and antigen trafficking to germinal centers and follicular dendritic cells. We have demonstrated a proof-of-concept for our strategy using a multimerized SARS-CoV-2 receptor binding domain (RBD)- ferritin nanoparticle that induces high titers of antibodies that neutralize diverse human and animal Sarbecoviruses (group 2b) in immunized macaques. In Aim 1, we will isolate new antibodies to define additional bnAb epitopes and establish the full spectrum of regions on the surface of betaCoV S proteins that are capable of inducing bnAbs to animal betaCoVs in groups 2b and 2c. In Aim 2, we will utilize cutting-edge computational immunogen design methods to design broadly neutralizing epitope-focused immunogens. These immunogens have the spike protein fixed in conformations that expose neutralizing epitopes or are spike subunits that are truncated or resurfaced to remove irrelevant, non-neutralizing, or betaCoV strain-specific neutralizing epitopes while retaining broadly neutralizing epitopes. In Aim 3, we will immunize wild-type mice with these novel immunogens and evaluate their ability to induce human betaCoV bnAbs that can protect animals from viral challenge. Project 2 will impact the field by generating cross-reactive neutralizing antibodies that could be translated into therapeutics, elucidating new broadly neutralizing epitopes on the betaCoV spike protein, and defining the design principles for epitope-focused immunogens that elicit protective immunity to betaCoVs.
摘要-项目2

项目成果

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Kevin Wiehe其他文献

Kevin Wiehe的其他文献

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{{ truncateString('Kevin Wiehe', 18)}}的其他基金

Project 2: PanbetaCoV protein vaccine design
项目2:PanbetaCoV蛋白疫苗设计
  • 批准号:
    10842503
  • 财政年份:
    2021
  • 资助金额:
    $ 421.74万
  • 项目类别:
Immunogen design to elicit polyclonal bNAb responses to the V3 glycan supersite
免疫原设计引发对 V3 聚糖超级位点的多克隆 bNAb 反应
  • 批准号:
    10631904
  • 财政年份:
    2017
  • 资助金额:
    $ 421.74万
  • 项目类别:
Immunogen design to elicit polyclonal bNAb responses to the V3 glycan supersite
免疫原设计引发对 V3 聚糖超级位点的多克隆 bNAb 反应
  • 批准号:
    10370985
  • 财政年份:
    2017
  • 资助金额:
    $ 421.74万
  • 项目类别:

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