Development of the Next Generation of Conjugate Vaccines
下一代结合疫苗的开发
基本信息
- 批准号:9750619
- 负责人:
- 金额:$ 84.64万
- 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:2018-07-25 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdjuvantAdultAffinityAgeAnimalsAnniversaryAnti-Bacterial AgentsAntibiotic ResistanceAntibodiesAntibody AffinityAntibody FormationAntibody SpecificityAntibody titer measurementAntifungal AgentsAntigensB-LymphocytesBacteriaBindingBiological ModelsCD4 Positive T LymphocytesCarbohydratesCarrier ProteinsCell MaturationCellsCommunitiesConjugate VaccinesCoupledCouplingDendritic CellsDependenceDevelopmentDiseaseDisease ResistanceElderlyEnvironmentEukaryotaFamilyGenerationsGlycolipidsGlycopeptidesGoalsHaemophilus Influenzae B VaccineHaemophilus influenzaeHistocompatibility Antigens Class IIHumanImmune responseImmune systemImmunocompromised HostImmunoglobulin GImmunologicsImmunologyIncidenceIndividualInfluenza B VirusKnowledgeLightMammalsMemory B-LymphocyteMolecularMusNeisseriaNormal CellOligosaccharidesOpsoninOrganismPathogenicityPeptidesPneumococcal InfectionsPneumococcal vaccinePolysaccharidesPopulationProcessProductionProkaryotic CellsProteinsPublishingRecombinantsSafetySeriesSerotypingSeverity of illnessSomatic MutationSpecificityStreptococcus pneumoniaeStructureSurfaceSystemT cell responseT-LymphocyteTestingTherapeutic AgentsTimeVaccinationVaccine DesignVaccinesWaterX-Ray Crystallographybasecapsuledesignenhancing factorflexibilityfungushuman diseaseimmunogenicimprovedin vivolymph nodesmicrobialmimicrymolecular recognitionnanomolarneutralizing antibodynext generationnovel diagnosticsnovel strategiesnovel vaccinesparticlepathogenic bacteriapreclinical studyprogramsresistant strainresponsesuccesssugartool
项目摘要
Project Summary
Conjugate vaccines of the first generation have been effective at reducing incidence and severity of
diseases caused by Haemophilus influenza B, Streptococcus pneumoniae, and Neisseria meningitides
bacteria in individuals with fit immune systems. Their success in immunocompromised patients and elders, two
fast growing populations, has been very limited. In addition, the approach used for their development and
production is inappropriate to respond to rapidly emerging new pathogenic strains. The next generation of
these glycan-targeting vaccines must introduce radically different concepts to produce vaccines against
emerging bacterial and fungal diseases for which the glycan capsule is an ideal target for neutralizing
antibodies. The fast selection of antibiotic-resistant strains makes this need even more urgent.
We embarked on this task using Streptococcus pneumoniae (Sp) as a model system, with the working
hypothesis that the limiting factor of current conjugate anti-glycan vaccines was the low quality of T cell help.
We recently published examples of a new approach using two prototypical glycans from Sp. Anti-glycan
antibodies with an accumulation of somatic mutations, exquisite specificity and low-nanomolar affinities were
generated. Apo- and glycan bound structures revealed a unique mode of glycan binding. The production of
these antibodies was totally dependent on CD4 T cell help and the presence of an NKT cell adjuvant, and
protected animals against microbial challenge. These results suggest that we have developed a modular
system capable of harnessing the anti-glycan response. To advance to pre-clinical studies, and understand the
immunology of glycan recognition we will carry out three specific aims to expand our approach to develop
vaccines based on the concept of synthetic microbial mimics. Aim 1: Optimization of the antigen and
display platform. Mono- to tetrasaccharide motifs can define the 13 serotypes that prevail in human diseases
and are included in licensed conjugate vaccines. We will attach minimal antigenic structures of all 13 serotypes
to our immunogenic platform in ways designed to enhance T cell recognition and dependency. Antibody
specificity will be examined on glycan micro-arrays. The immunological rules of B and T cell glycan recognition
will be defined. Aim 2: Molecular recognition of glycans by high affinity antibodies and T cells. We will
explore the structural rules of glycan recognition by B and T cells using x-ray crystallography. These studies
will inform the design of optimal antigenic oligosaccharides. Aim 3: Increasing safety and potency in vivo.
We hypothesize that some of the same factors that enhance the quality of anti-protein immune response will
also apply to peptide-displayed glycans, particularly improved efficiency of delivery to the lymph node and
capture of the vaccine by dendritic cells. This will be tested with the attachment of known opsonins to the
particle to develop the concept of microbial mimicry. Finally, each optimized platform will be tested in bacterial
challenge in mice.
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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Luc Teyton其他文献
Luc Teyton的其他文献
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{{ truncateString('Luc Teyton', 18)}}的其他基金
Molecular basis of glycan recognition by T and B cells
T 和 B 细胞识别聚糖的分子基础
- 批准号:
10549648 - 财政年份:2023
- 资助金额:
$ 84.64万 - 项目类别:
Leveraging Human iPSC-derived beta-cells to Probe Antigen Specificity of Anti-islet Memory T Cells in T1D
利用人 iPSC 衍生的 β 细胞探测 T1D 中抗胰岛记忆 T 细胞的抗原特异性
- 批准号:
10589556 - 财政年份:2023
- 资助金额:
$ 84.64万 - 项目类别:
Multidimensional development of high-affinity anti-glycan antibodies to fight deadly bacterial infections
多维开发高亲和力抗聚糖抗体以对抗致命细菌感染
- 批准号:
10549640 - 财政年份:2023
- 资助金额:
$ 84.64万 - 项目类别:
Mechanistic Studies of Combination Adjuvants to Target B Cells in Vaccines
疫苗中针对 B 细胞的组合佐剂的机理研究
- 批准号:
10599324 - 财政年份:2021
- 资助金额:
$ 84.64万 - 项目类别:
Mechanistic Studies of Combination Adjuvants to Target B Cells in Vaccines
疫苗中针对 B 细胞的组合佐剂的机理研究
- 批准号:
10218993 - 财政年份:2021
- 资助金额:
$ 84.64万 - 项目类别:
Mechanistic Studies of Combination Adjuvants to Target B Cells in Vaccines
疫苗中针对 B 细胞的组合佐剂的机理研究
- 批准号:
10397167 - 财政年份:2021
- 资助金额:
$ 84.64万 - 项目类别:
Early diagnosis and mechanistic studies of type 1 diabetes using single cell analysis
使用单细胞分析进行 1 型糖尿病的早期诊断和机制研究
- 批准号:
10362605 - 财政年份:2019
- 资助金额:
$ 84.64万 - 项目类别:
Early diagnosis and mechanistic studies of type 1 diabetes using single cell analysis
使用单细胞分析进行 1 型糖尿病的早期诊断和机制研究
- 批准号:
9884757 - 财政年份:2019
- 资助金额:
$ 84.64万 - 项目类别:
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