Rational design and B cell responses of HIV epitope vaccines

HIV表位疫苗的合理设计和B细胞反应

基本信息

  • 批准号:
    9270983
  • 负责人:
  • 金额:
    $ 66.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-11-01 至 2021-10-31
  • 项目状态:
    已结题

项目摘要

Project Summary Many broadly neutralizing antibodies (bNAbs) recognize structurally discrete sites on the envelope glycoprotein (Env) of human immunodeficiency virus type-1 (HIV-1), such as the CD4-binding site (CD4bs), the strand C of variable regions 1 and 2 (V1V2), the N332 supersite at the base of variable region 3 (V3), and the membrane- proximal external region (MPER). Crystallography and electron microscopy (EM) have revealed how these bNAbs interact with individual epitopes, engineered Env domains, and gp140 trimers, providing a rational basis for vaccine design. The scaffolding method has been used to design novel antigens in hope to elicit epitope- specific, bNAb-like B cell responses. In this R01 application, we will combine the latest structural findings with novel technologies in protein design, B cell engineering and knock-in mouse, and next-generation sequencing (NGS) of B cell repertoire to develop and assess epitope-focused vaccine candidates for three bNAb epitopes. The specific aims (SAs) of our R01 proposal are: (1) to design epitope-focused immunogens for three sites of HIV-1 vulnerability. We hypothesize that the N332 supersite of V3 base, the trimeric V1V2 apex, and MPER can be presented by scaffolds and nanoparticles in their bNAb-bound conformations. In a preliminary study, we have designed a panel of antigens based on various principles such as epitope scaffolding, particulate display, and Fc presentation. We have performed structural and antigenic profiling for a subset of antigens with positive results, and will screen the whole panel of antigens to facilitate rational selection; (2) to assess epitope-focused immunogens in bNAb-presenting B cell lines and knock-in mice. We hypothesize that successfully designed epitope-focused immunogens can activate engineered bNAb-expressing B cells and elicit robust responses in bNAb knock-in mice. Previously, we have developed mouse B cell lines expressing CD4bs-, V1V2- and N332- specific bNAbs and b12 knock-in mouse, which were used to assess rationally designed HIV-1 immunogens. We will develop PGT145-, PGT121/128-, and 10E8-expressing B cell lines and knock-in mice and use these tools to assess epitope-focused immunogens selected in Aim 1; (3) to assess the trimer-prime/epitope-boost strategy and B cell responses in NHPs. We hypothesize that a gp140 trimer will elicit NAbs to diverse epitopes and sequential boosts with epitope-focused immunogens will direct B cell responses to the target epitopes. In our preliminary study, we have tested the epitope-focusing effect and neutralization for selected N332 antigens in C57BL/6 mice. Previously, we have conducted a longitudinal study of B cell responses to an HIV-1 gp140- foldon trimer in non-human primates (NHPs). Here, we will first test the trimer-prime/epitope-boost strategy in mice for different epitopes and then assess the immunogenicity and B cell responses in NHPs. In addition to serological assays, we will use antibody NGS to monitor the temporal B cell responses. Our proposed studies thus constitute an innovative and practical research project to develop epitope-focused HIV-1 vaccines.
项目摘要 许多广泛中和抗体(bNAb)识别包膜糖蛋白上结构上的离散位点, (Env)人免疫缺陷病毒1型(HIV-1)的C链,如CD 4结合位点(CD 4 bs), 可变区1和2(V1 V2)、位于可变区3(V3)基部的N332超位点和膜- 近端外部区域(MPER)。晶体学和电子显微镜(EM)揭示了这些 bNAb与单个表位、工程化Env结构域和gp 140三聚体相互作用,提供了合理的基础 用于疫苗设计。支架方法已被用于设计新的抗原,希望能引出表位- 特异性bNAb样B细胞应答。在此R 01应用程序中,我们将结合联合收割机的最新结构发现, 蛋白质设计、B细胞工程和基因敲入小鼠以及下一代测序方面的新技术 (NGS)的B细胞库,以开发和评估针对三个bNA B表位的表位聚焦疫苗候选物。 我们的R 01提案的具体目标(SA)是:(1)针对以下三个位点设计表位聚焦的免疫原: HIV-1的脆弱性。我们假设N332位于V3碱基的超位点,三聚体V1 V2顶点,MPER 可以通过支架和纳米颗粒以其bNAb结合的构象呈现。在初步研究中,我们 已经基于各种原理设计了一组抗原,例如表位支架,颗粒展示, Fc介绍我们已经对一个抗原子集进行了结构和抗原分析, 结果,并将筛选整个面板的抗原,以促进合理的选择;(2)评估表位集中 bNAb呈递B细胞系和敲入小鼠中的免疫原。我们假设成功设计的 表位聚焦的免疫原可以激活工程化的表达bNAb的B细胞, bNAb基因敲入小鼠。以前,我们已经开发了表达CD 4 bs-、V1 V2-和N332-的小鼠B细胞系, 特异性bNAbs和b12基因敲入小鼠,用于评估合理设计的HIV-1免疫原。 我们将开发表达PGT 145、PGT 121/128和10 E8的B细胞系和基因敲入小鼠,并使用这些细胞系和基因敲入小鼠。 评估目标1中选择的表位聚焦免疫原的工具;(3)评估三聚体-初免/表位-加强 策略和B细胞应答。我们假设gp 140三聚体将引发针对不同表位的NAb 用表位聚焦的免疫原连续加强将引导B细胞应答靶表位。在 在我们的初步研究中,我们已经测试了所选N332抗原的表位聚焦效应和中和作用 C57 BL/6小鼠。以前,我们已经进行了一项纵向研究,研究B细胞对HIV-1 gp 140的反应, 非人灵长类动物(NHP)中的折叠子三聚体。在这里,我们将首先在以下中测试三聚体-引发/表位-加强策略: 小鼠的不同表位,然后评估NHP中的免疫原性和B细胞应答。除了 血清学检测,我们将使用抗体NGS来监测时间B细胞反应。我们建议的研究 从而构成了一个创新的和实用的研究项目,以开发针对表位的HIV-1疫苗。

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(5)

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Jiang Zhu其他文献

Jiang Zhu的其他文献

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{{ truncateString('Jiang Zhu', 18)}}的其他基金

Novel HCV vaccine antigens and nanoparticles
新型 HCV 疫苗抗原和纳米颗粒
  • 批准号:
    10428301
  • 财政年份:
    2022
  • 资助金额:
    $ 66.18万
  • 项目类别:
Novel HCV vaccine antigens and nanoparticles
新型 HCV 疫苗抗原和纳米颗粒
  • 批准号:
    10557879
  • 财政年份:
    2022
  • 资助金额:
    $ 66.18万
  • 项目类别:
Uncleaved prefusion-optimized trimers on nanoparticles as HIV vaccines
纳米颗粒上未切割的预融合优化三聚体作为 HIV 疫苗
  • 批准号:
    10307527
  • 财政年份:
    2018
  • 资助金额:
    $ 66.18万
  • 项目类别:
Uncleaved prefusion-optimized trimers on nanoparticles as HIV vaccines
纳米颗粒上未切割的预融合优化三聚体作为 HIV 疫苗
  • 批准号:
    10062813
  • 财政年份:
    2018
  • 资助金额:
    $ 66.18万
  • 项目类别:
Uncleaved prefusion-optimized trimers on nanoparticles as HIV vaccines
纳米颗粒上未切割的预融合优化三聚体作为 HIV 疫苗
  • 批准号:
    10524053
  • 财政年份:
    2018
  • 资助金额:
    $ 66.18万
  • 项目类别:
Rational design and B cell responses of HIV epitope vaccines
HIV表位疫苗的合理设计和B细胞反应
  • 批准号:
    10056970
  • 财政年份:
    2016
  • 资助金额:
    $ 66.18万
  • 项目类别:
Novel HCV vaccine antigens targeting conserved neutralizing epitopes
针对保守中和表位的新型 HCV 疫苗抗原
  • 批准号:
    9096641
  • 财政年份:
    2016
  • 资助金额:
    $ 66.18万
  • 项目类别:
Structure-based immunogen design for hepatitis C virus
基于结构的丙型肝炎病毒免疫原设计
  • 批准号:
    9091424
  • 财政年份:
    2015
  • 资助金额:
    $ 66.18万
  • 项目类别:
Env-Specific B Cell Repertoire Responses to NFL Trimer vaccines
对 NFL 三聚体疫苗的环境特异性 B 细胞库反应
  • 批准号:
    9111304
  • 财政年份:
  • 资助金额:
    $ 66.18万
  • 项目类别:
Novel HCV vaccine antigens targeting conserved neutralizing epitopes
针对保守中和表位的新型 HCV 疫苗抗原
  • 批准号:
    9903198
  • 财政年份:
  • 资助金额:
    $ 66.18万
  • 项目类别:

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