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
- 来源:
- 关键词:AddressAntibodiesAntibody ResponseAntigensB cell repertoireB-Cell ActivationB-Cell DevelopmentB-LymphocytesBinding SitesBiochemicalBiological AssayC57BL/6 MouseCell LineCell LineageCollaborationsComplexCrystallographyDevelopmentDissectionElectron MicroscopyEngineeringEnzyme-Linked Immunosorbent AssayEpitopesEvaluationGenotypeGlycoproteinsHIVHIV vaccineHIV-1HIV-1 vaccineHepatitis C AntigensImmunizationImmunizeImmunoglobulin Variable RegionImmunologicsIn VitroIndividualKnock-in MouseKnowledgeLawsLengthLettersLongitudinal StudiesMembraneMethodsMolecularMolecular ConformationMonitorMusParticulatePathway interactionsPeptidesPolysaccharidesProtein EngineeringReportingResearch Project GrantsResolutionRespiratory syncytial virusSerologicalSiteStructureTestingVaccinationVaccine DesignVaccinesVariantVirusbasecellular engineeringcost effectivedesignexperimental studyimmunogenicityin vivoinnovationinterestmonomermouse modelnanoparticleneutralizing antibodynew technologynext generation sequencingnonhuman primatenovelresponsescaffoldsuccesstoolvaccine candidatevaccine developmentward
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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{{ 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
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$ 66.18万 - 项目类别:
Novel HCV vaccine antigens and nanoparticles
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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
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10307527 - 财政年份:2018
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Uncleaved prefusion-optimized trimers on nanoparticles as HIV vaccines
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10062813 - 财政年份:2018
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