Optimizing glycan shield coverage, germline B cell receptor binding and epitope diversity of V2-apex targeted HIV-1 Env immunogens
优化聚糖屏蔽覆盖、种系 B 细胞受体结合和 V2-apex 靶向 HIV-1 Env 免疫原的表位多样性
基本信息
- 批准号:10241429
- 负责人:
- 金额:$ 85.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-19 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS VaccinesAffinityAmino AcidsAnimal ModelAnimalsAntibodiesAntibody ResponseAntibody SpecificityAntigensAutologousAvidityB-Cell Antigen ReceptorB-Cell Receptor BindingB-LymphocytesBindingCD4 Positive T LymphocytesCaviaCell LineageComplementCountryDataDevelopmentDoseEpitopesEventEvolutionFrequenciesGoalsHIV vaccineHIV-1HIV-1 vaccineHumanImmunizeInfectionMacaca mulattaMapsMasksMembraneMessenger RNAMonkeysMonoclonal AntibodiesNucleosidesPathway interactionsPatternPerformancePhasePolysaccharidesPrevalencePropertyPublic HealthRegimenResistanceRhesusTestingTranslatingVaccinatedVaccinationVaccine DesignVaccine ResearchVaccinesVariantbasebioinformatics toolcomplementarity-determining region 3costdesignimprovedin vivolipid nanoparticleneutralizing antibodyneutralizing monoclonal antibodiesnovelnovel vaccinesrectalresponsesimian human immunodeficiency virustissue culturevaccine deliveryvaccine efficacyvectorvirtual
项目摘要
PROJECT SUMMARY
A central goal in HIV/AIDS vaccine research is the elicitation of broadly neutralizing antibodies (bNAbs). Here,
we propose to leverage three recent discoveries from our groups to generate novel envelope (Env) immunogens
that target the V1V2 region of the trimer apex. By studying the evolution of the HIV-1 Env glycan shield, we
discovered that unshielded regions (“glycan holes”) in transmitted founder (TF) Envs are negatively associated
with bNAb development, suggesting that strain-specific glycan holes delay or subvert bNAb development (1).
Generating bNAb sensitivity signatures to design novel Signature-based Epitope Targeted (SET) vaccines, we
found that V2-SET immunogens induced broader and more potent tier 2 heterologous NAbs in guinea pigs than
wild-type Envs, indicating that inclusion of bNAb signatures significantly improved vaccine performance (2).
Studying 20 novel SHIVs in ~100 rhesus macaques (RMs) (3), we found that ~15% of animals developed varying
degrees of heterologous breadth by 6-24 months, with the most common bNAb specificity targeting the V2 apex
(Table 1). However, bNAb induction in SHIV infection is still infrequent, thus providing a unique experimental
setting to test iterative Env design improvements in a manner that is faster and less costly than human trials.
Our hypothesis is that by (i) minimizing distracting glycan hole epitopes, (ii) increasing Env affinity for V2 apex
bNAb precursors, (iii) increasing relevant epitope diversity in vaccine boosts, and (iv) incorporating B cell lineage
immunogen designs, we will improve V2 bNAb germline engagement and bNAb lineage maturation. We have
selected the CRF.AG.T250 (T250) and CAP256SU (CAP256) Envs as baseline immunogens, because both
have generated V2 apex bNAbs in SHIV infected RMs (Table 1). In Aim #1, we will optimize the Env glycan
shield and V2 germline targeting properties of T250 and CAP256 Envs, test their replication potential and tier 2
antigenicity in SHIV vectors, and down-select the best performing set for subsequent infection of RMs. In Aim
#2, we will compare the bNAb induction capacity of SHIVs expressing wildtype (WT), glycan-optimized (GLY-
OPT), and glycan and germline-optimized (GLY/UCA-OPT) versions of the same Env in RMs and determine the
envelope-antibody (Env-Ab) coevolution pathways in all animals that develop neutralization breadth. In Aim #3,
we will rationally design new V2 apex directed immunogens using Env-Ab co-evolution data and the V2-SET
strategy as a guide, and deliver them using nucleoside-modified mRNA containing lipid nanoparticles
(mRNA/LNPs) that express stabilized, membrane bound gp160s. We will prime RMs with the best performing
Env from Aim #2, and then compare the bNAb induction capacity of this Env with that of two boosting regimens
specifically designed to increase relevant epitope diversity. Immunized RMs will receive a low-dose repetitive
rectal SHIV challenge to assess their level of protection as recently described (4) and to study their breakthrough
infections. By simultaneously applying multiple vaccine improvement strategies, we expect to improve V2 apex
bNAb induction in RMs and translate these findings into more effective vaccines for humans.
项目总结
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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Beatrice H Hahn其他文献
Beatrice H Hahn的其他文献
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{{ truncateString('Beatrice H Hahn', 18)}}的其他基金
Optimizing glycan shield coverage, germline B cell receptor binding and epitope diversity of V2-apex targeted HIV-1 Env immunogens
优化聚糖屏蔽覆盖、种系 B 细胞受体结合和 V2-apex 靶向 HIV-1 Env 免疫原的表位多样性
- 批准号:
10021396 - 财政年份:2019
- 资助金额:
$ 85.9万 - 项目类别:
Optimizing glycan shield coverage, germline B cell receptor binding and epitope diversity of V2-apex targeted HIV-1 Env immunogens
优化聚糖屏蔽覆盖、种系 B 细胞受体结合和 V2-apex 靶向 HIV-1 Env 免疫原的表位多样性
- 批准号:
10686018 - 财政年份:2019
- 资助金额:
$ 85.9万 - 项目类别:
Optimizing glycan shield coverage, germline B cell receptor binding and epitope diversity of V2-apex targeted HIV-1 Env immunogens
优化聚糖屏蔽覆盖、种系 B 细胞受体结合和 V2-apex 靶向 HIV-1 Env 免疫原的表位多样性
- 批准号:
10468221 - 财政年份:2019
- 资助金额:
$ 85.9万 - 项目类别:
Studies of the precursor of the human AIDS virus in its natural chimpanzee host
对黑猩猩天然宿主中人类艾滋病病毒前体的研究
- 批准号:
9186500 - 财政年份:2015
- 资助金额:
$ 85.9万 - 项目类别:
Restriction of HIV-1 transmission by type 1 interferons
1 型干扰素限制 HIV-1 传播
- 批准号:
8786805 - 财政年份:2014
- 资助金额:
$ 85.9万 - 项目类别:
Restriction of HIV-1 transmission by type 1 interferons
1 型干扰素限制 HIV-1 传播
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9275913 - 财政年份:2014
- 资助金额:
$ 85.9万 - 项目类别:
Harnessing type 1 IFN-stimulated antiviral mechanisms for HIV vaccine design
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- 批准号:
8705846 - 财政年份:2014
- 资助金额:
$ 85.9万 - 项目类别:
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