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
基本信息
- 批准号:10307527
- 负责人:
- 金额:$ 96.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-12-01 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimalsAntibodiesAntibody titer measurementAntigensArtificial nanoparticlesAutologousB cell repertoireB-LymphocytesBindingBiological AssayClinical ResearchCrystallizationCrystallographyDataDatabasesDevelopmentDiseaseElectron MicroscopyEngineeringEnzyme-Linked Immunosorbent AssayEpitope MappingEpitopesEvaluationFerritinFormulationFutureGenerationsGlycoproteinsGoalsHIV Envelope Protein gp120HIV vaccineHIV-1HumanImmune responseImmunizationImmunoglobulin GIn VitroInbred BALB C MiceKnock-in MouseMethodsMonitorMusMutationN-terminalNegative StainingOryctolagus cuniculusParticulatePrimatesProductionProtocols documentationReportingResearchResolutionSerology testSerumSignal TransductionSourceStructureSubunit VaccinesSurface AntigensT cell responseT-LymphocyteTestingVaccine DesignVaccine ResearchVaccinesVirusVirus-like particlebasedesignglycoprotein structureimmunogenicityimprovedin vivoin vivo evaluationnanoparticlenanoparticulateneutralizing antibodynext generation sequencingnonhuman primateresearch clinical testingresponsescale upvaccine candidatevaccine developmentvaccine platformvaccine strategy
项目摘要
Project Summary
The envelope glycoprotein (Env) of human immunodeficiency virus type 1 (HIV-1) harbors the epitopes of broadly
neutralizing antibodies (bNAbs) and is the main target of HIV-1 vaccine development. High-resolution structures
of BG505 SOSIP.664 trimers have provided a rational basis for vaccine design. Although current gp140 designs
can produce native-like trimers for selected strains after optimization, the underlying causes of Env metastability
are still unknown and a general design platform applicable to all HIV-1 strains and subtypes remains an unmet
challenge. Furthermore, despite the increasing appreciation for the advantages of virus-like particles (VLPs) in
bNAb elicitation, nanoparticulate display of native-like trimers has not been rigorously explored in HIV-1 vaccine
development. In this R01, we will develop HIV-1 vaccine candidates by combining trimer design, crystallography,
electron microscopy (EM), nanoparticle display, immunization, serological assays, antibody isolation, repertoire
sequencing, and antibody lineage analysis. In Aim 1, we will investigate the fundamental causes of HIV-1 Env
metastability and develop the uncleaved, prefusion-optimized (UFO) trimer platform. We hypothesize that gp41,
which contains a structurally strained heptad repeat 1 (HR1) with a disordered N-terminal bend (N-HR1), is the
source of metastability. We have designed 1st-generation UFO trimers with a modified N-HR1 and solved their
structures. We will develop an optimized UFO platform applicable to diverse Envs with high purity, yield, and
stability and select representative UFO trimers for vaccine development. We will assess trimer antigenicity using
a panel of bNAbs and non-NAbs and determine their atomic structures. In Aim 2, we will engineer stable gp140
trimer-presenting nanoparticles as vaccine candidates. We hypothesize that self-assembling nanoparticles with
underlying 3-fold axes can be used to display native-like gp140 trimers. We have reported gp140 nanoparticles
based on the 24-mer ferritin (12 nm) and 60-mer E2p (23nm). We will optimize UFO gp140 nanoparticles based
on ferritin, E2p, and a hyperstable 60-mer, I3-01 (25nm) for in vivo testing in Aim 3. We will validate nanoparticle
assembly by EM and evaluate nanoparticle antigenicity using a panel of antibodies. In Aim 3, we will assess the
immunogenicity and B-cell response for a subset of optimized UFO trimers and nanoparticles in WT mice, rabbits,
and nonhuman primates (NHPs). We hypothesize that UFO trimers can induce tier-2 NAbs in all animal models,
while gp140 nanoparticles displaying 8-20 UFO trimers can elicit tier-2 NAbs more effectively than trimers alone.
We will first screen UFO trimers and nanoparticles in WT mice and assess serum neutralization using purified
IgGs. We will select a small set of immunogens for rabbit immunization and advance the most promising ones
to NHPs. In our preliminary study, gp140 nanoparticles induced autologous tier-2 NAbs to BG505.T332N in mice
and rabbits within 6-8 weeks, supporting our approach. We will isolate vaccine-elicited tier-2 NAbs for functional
and structural studies and perform next-generation sequencing (NGS) to study B-cell repertoires and trace NAb
lineage development. Our goal is to identify the most effective vaccine candidates for future clinical studies.
项目摘要
人类免疫缺陷病毒1型(HIV-1)的包膜糖蛋白(Env)具有广泛的表位。
中和抗体(BNAbs),是HIV-1疫苗开发的主要目标。高分辨率结构
664个三聚体为疫苗设计提供了合理的依据。虽然目前的gp140设计
优化后能为选定的菌株产生类天然三聚体,环境亚稳性的根本原因
仍然是未知的,适用于所有HIV-1毒株和亚型的通用设计平台仍然没有满足
挑战。此外,尽管越来越多的人认识到病毒样颗粒(VLP)在
在HIV-1疫苗中还没有严格探索bNab诱导,纳米颗粒展示的原生类三聚体
发展。在这个R01中,我们将结合三聚体设计、结晶学、
电子显微镜(EM)、纳米颗粒展示、免疫、血清学检测、抗体分离、曲线谱
测序和抗体谱系分析。在目标1中,我们将调查HIV-1环境的根本原因
亚稳性,并开发未切割、预融合优化(UFO)三聚体平台。我们假设gp41,
它含有一个具有无序N-末端弯曲(N-HR1)的结构紧张的七肽重复序列1(HR1),是
亚稳性的来源。我们设计了第一代带有修饰N-HR1的UFO三聚体,并解决了它们的
结构。我们将开发一个优化的UFO平台,适用于各种环境,具有高纯度、高产量和
稳定性和选择具有代表性的UFO三聚体用于疫苗开发。我们将评估三聚体的抗原性
一组bNAb和非NaB,并确定它们的原子结构。在目标2中,我们将设计稳定的gp140
三聚体--将纳米颗粒作为候选疫苗。我们假设自组装的纳米粒子与
下面的三重轴可以用来显示原生的gp140三聚体。我们已经报道了gp140纳米颗粒
基于24-聚铁蛋白(12 Nm)和60-聚E2p(23 Nm)。我们将基于UFO gp140纳米颗粒进行优化
关于铁蛋白,E2p,和超稳定的60-聚体,I3-01(25 Nm),用于AIM 3的体内测试。我们将验证纳米颗粒
通过EM组装,并使用一组抗体评估纳米颗粒的抗原性。在目标3中,我们将评估
优化的UFO三聚体和纳米粒在WT小鼠、兔和小鼠的免疫原性和B细胞应答
和非人灵长类动物(NHP)。我们假设UFO三聚体可以在所有动物模型中诱导第二层NAB,
而显示8-20个UFO三聚体的gp140纳米粒子可以比单独显示三聚体更有效地诱导第二级NAB。
我们将首先在WT小鼠中筛选UFO三聚体和纳米颗粒,并使用纯化的
伊格斯。我们将选择一组小的免疫原用于兔的免疫,并提出最有希望的免疫原
致全国卫生与公众服务部。在我们的初步研究中,gp140纳米颗粒在小鼠体内诱导自体第2层NAB产生BG505.T332N
和兔子在6-8周内,支持我们的方法。我们将分离疫苗引发的第二层NAB,用于功能
和结构研究,并执行下一代测序(NGS)以研究B细胞谱系和跟踪NAB
世系发展。我们的目标是为未来的临床研究确定最有效的候选疫苗。
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(2)
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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:
$ 96.91万 - 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:
$ 96.91万 - 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:
$ 96.91万 - 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:
$ 96.91万 - 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:
9270983 - 财政年份:2016
- 资助金额:
$ 96.91万 - 项目类别:
Rational design and B cell responses of HIV epitope vaccines
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10056970 - 财政年份:2016
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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:
$ 96.91万 - 项目类别:
Structure-based immunogen design for hepatitis C virus
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- 批准号:
9091424 - 财政年份:2015
- 资助金额:
$ 96.91万 - 项目类别:
Env-Specific B Cell Repertoire Responses to NFL Trimer vaccines
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- 资助金额:
$ 96.91万 - 项目类别:
Novel HCV vaccine antigens targeting conserved neutralizing epitopes
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9903198 - 财政年份:
- 资助金额:
$ 96.91万 - 项目类别:
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