Project 2_Nilla
项目2_妮拉
基本信息
- 批准号:10339444
- 负责人:
- 金额:$ 36.81万
- 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:2021-02-04 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AdolescentAdultAffinityAllelesAnimal ModelAnimalsAntibodiesAntibody FormationAntibody ResponseAntigensB cell repertoireB-LymphocytesBinding SitesBloodCell LineageCell SeparationCell surfaceCharacteristicsCommunitiesComplexDatabasesDevelopmentElectron MicroscopyEpitopesEvaluationEvolutionFine needle aspiration biopsyFramework RegionsGenesGeneticGoalsHIVHIV Envelope Protein gp120HIV-1HaplotypesHeterozygoteHumanImmuneImmunityImmunizationImmunizeImmunoglobulin Somatic HypermutationIndividualLaboratoriesLightLiposomesMacacaMacaca mulattaMasksMediatingMemory B-LymphocyteMessenger RNAMethodsMonoclonal AntibodiesMutationNegative StainingOryctolagus cuniculusPlasma CellsPolysaccharidesPrimatesPropertyProteinsRecombinantsRegimenResearchResearch PersonnelResistanceResolutionSamplingSerumShapesSpecificityStructureStructure of germinal center of lymph nodeTestingTimeVaccinationVaccine DesignVaccinesVariantVirusWorkbasechronic infectioncomputerized toolsdesigndraining lymph nodeexperimental studyimprovedinnovationinterestjuvenile animallipid nanoparticlemature animalneutralizing antibodynext generation sequencingnonhuman primatenovelprogramsprotective effectresponsetime usetoolvaccine evaluation
项目摘要
Summary
Circulating (tier 2) HIV-1 variants are highly resistant to antibody-mediated neutralization, making broadly
effective vaccine design a major challenge. Encouragingly, work in our previous HIVRAD program
demonstrated that Ab responses capable of cross-neutralizing multiple heterologous tier 2 viruses were
elicited by targeted N-glycan deletion priming and heterologous glycan restorative Env trimer-liposome
boosting. The isolation of two monoclonal antibodies with broadly neutralizing activity from these studies
and high-resolution structures in complex with native-like trimers revealed that one mAb targeted the
conserved CD4 binding site (CD4bs) and the other targeted the gp41:gp120 interface region,
substantiated this result. In the current application, we will build on these efforts by evaluating responses
elicited by well-ordered, novel, trimer-based immunogens inoculated into Indian origin rhesus macaques.
In addition to the use pf protein-based trimers, we will test trimer platforms based on administration of
mRNA lipid nanoparticles as described in Project 1.
In Project 2, we will characterize B cell responses elicited by vaccine regimens evaluated in Indian origin
rhesus macaques in Core B by rapid, high-throughput monoclonal antibody (mAb) isolation to
define the targeted epitopes and guide both the choice of boosting immunogens and, if needed, trimer
redesign by eliminating or masking unwanted non-neutralizing immunodominant responses for
subsequent immunization studies. We will interact with the investigators in Core C, who also will generate
information about immunodominant Ab responses through their negative stain electron microscopy
(nsEM)-based method for evaluation of vaccine-induced serum responses. Using the Env-specific mAbs,
we will further determine how Env-specific antibody lineages evolve over time using Next Generation
Sequencing (NGS) and IgDiscover, a computational tool optimized for use in rhesus macaques. We will
generate individualized databases of macaque germline VDJ alleles for precise gene assignments, which
is necessary for correct conclusions about Ab affinity maturation and SHM levels. We will further use
the IgDiscover results and the new haplotype module to investigate if certain alleles, or combinations of
alleles, predispose to elicitation of neutralizing Ab responses in either adult of juvenile macaques. We
will investigate the level of expansion of neutralizing and non-neutralizing Ab lineages over time and
ask if vaccine-induced neutralizing Ab lineages persist in long-lived immune compartments such
as memory B cells and plasma cells, which are critical for the long-term protective effects of vaccines.
概括
循环(第 2 层)HIV-1 变异体对抗体介导的中和作用具有高度抵抗力,因此广泛
有效的疫苗设计是一个重大挑战。令人鼓舞的是,参与我们之前的 HIVRAD 计划
证明能够交叉中和多种异源 2 级病毒的抗体反应
由靶向 N-聚糖缺失引发和异源聚糖恢复性 Env 三聚体脂质体引发
助推。从这些研究中分离出两种具有广泛中和活性的单克隆抗体
与天然三聚体复合的高分辨率结构表明,一种单克隆抗体靶向
保守的 CD4 结合位点 (CD4bs) 和另一个针对 gp41:gp120 界面区域,
证实了这一结果。在当前的应用程序中,我们将通过评估响应来建立这些努力
由接种到印度恒河猴中的有序的、新型的、基于三聚体的免疫原引发。
除了使用基于蛋白质的三聚体之外,我们还将测试基于管理的三聚体平台
mRNA 脂质纳米颗粒如项目 1 中所述。
在项目 2 中,我们将表征在印度原产地评估的疫苗方案引起的 B 细胞反应
通过快速、高通量单克隆抗体 (mAb) 分离核心 B 中的恒河猴
定义目标表位并指导增强免疫原和三聚体(如果需要)的选择
通过消除或掩盖不需要的非中和免疫显性反应来重新设计
随后的免疫研究。我们将与 Core C 中的调查员互动,他们也将生成
通过负染色电子显微镜获得有关免疫显性抗体反应的信息
基于 nsEM 的方法,用于评估疫苗诱导的血清反应。使用 Env 特异性单克隆抗体,
我们将使用下一代进一步确定 Env 特异性抗体谱系如何随时间演变
测序 (NGS) 和 IgDiscover(一种针对恒河猴进行优化的计算工具)。我们将
生成猕猴种系 VDJ 等位基因的个体化数据库,以进行精确的基因分配,
对于 Ab 亲和力成熟和 SHM 水平的正确结论是必要的。我们将进一步利用
IgDiscover 结果和新的单倍型模块可用于研究某些等位基因或某些等位基因的组合
等位基因,倾向于在成年或幼年猕猴中引发中和抗体反应。我们
将调查中和性和非中和性抗体谱系随时间的扩展水平
询问疫苗诱导的中和抗体谱系是否持续存在于长寿的免疫区室中,例如
例如记忆 B 细胞和浆细胞,它们对于疫苗的长期保护作用至关重要。
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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Gunilla Karlsson Hedestam其他文献
Gunilla Karlsson Hedestam的其他文献
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{{ truncateString('Gunilla Karlsson Hedestam', 18)}}的其他基金
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