A Self-Adjuvanting Virus Like Particle Vaccine Platform for Emerging Viruses
针对新兴病毒的自我佐剂病毒样颗粒疫苗平台
基本信息
- 批准号:10711617
- 负责人:
- 金额:$ 76.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-08 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAdjuvantAlphavirusAnimalsAntibodiesAntigen-Presenting CellsAntigensArbovirusesBiologicalCell LineCell physiologyCellsCellular ImmunityChemicalsChikungunya virusClinicalCyclic GMPDNADinucleoside PhosphatesDisparityEncapsulatedEnzymesExhibitsFlavivirusGenesGenomeGoalsGrowthHumanImmuneImmune responseImmune signalingImmunityImmunologic StimulationImmunological ModelsImmunologicsImmunotherapeutic agentIn VitroInjectionsInnate Immune ResponseLigandsLinkMacaca mulattaMammalsMediatingMethodsMicrobeModelingMolecularMusOutcomePattern recognition receptorPeriodicityPhenotypePredispositionProcessProteinsPurinesRNAReactionRoleSafetySignaling ProteinSiteStimulator of Interferon GenesStructureSystemTechnologyVaccinationVaccine AdjuvantVaccinesViralVirionVirusVirus ReplicationVirus-like particleZika Virusadaptive immune responseadaptive immunityclinical developmentdraining lymph nodeefficacy evaluationexosomeextracellulargene inductionimmune functionimmunogenicimmunoregulationimprovedin vitro Modelin vivoin vivo Modelmouse modelnonhuman primatenovelnovel vaccinespathogenic microbepharmacologicrecruitresponsesmall moleculetranscriptomicsvaccination outcomevaccine efficacyvaccine platform
项目摘要
Project Summary
The goals of this R01 proposal include the molecular and immunological characterization of vaccine adjuvant
activity associated with processes mediated by the protein Stimulator of Interferon Genes (STING). Vaccines
comprised of inert antigen are often only weakly immunogenic and thus require co-administration of adjuvants
to augment immunostimulation. Unfortunately, very few adjuvants are approved for clinical use and the
mechanisms of adjuvant-associated enhancement are poorly understood. STING is a pattern recognition
receptor that detects purine-containing cyclic dinucleotides (CDN) synthesized by either bacterial cyclases or
the host enzyme cyclic GMP-AMP (cGAMP) synthase (cGAS) following its sensing of cytosolic DNA.
Pharmacologic activation of STING greatly enhances vaccine efficacy as indicated by antibody and cell-mediated
protection against diverse microbial pathogens. Furthermore, endogenously synthesized cGAMP is naturally
released from cells in exosomes and virus particles. We exploited this phenomenon by constructing cell lines
that express constitutively active cyclases that we then used to produce immunogenic virus-like particles (VLP).
We now show that VLP derived from unrelated emerging flavi- and alphaviruses efficiently encapsulate bioactive
CDN and stimulate STING-dependent activity in vivo. Since extracellular CDNs are highly susceptible to
degradation and disperse quickly from the site of injection, we hypothesize that this simple approach represents
a transformative technological improvement for harnessing STING-directed adjuvant effects in the draining
lymph node. We also predict this will be a highly adaptable platform and propose to explore the extent to which
it is applicable to potentially emerging virus types. Experimentally, this also represents a unique investigative
model that will allow in vivo characterization of the innate and molecular correlates of adaptive immunity that are
potentiated by targeted STING activity. We thus hypothesize that the enhancement of antigen-directed immune
responses by STING-based adjuvants is functionally linked to key molecular and cellular processes that are
discernable using our proposed vaccines and experimental systems. We plan to explore this using an integrated
approach that uses molecular transcriptomic analysis, mouse models of immune profiling, and nonhuman
primate models of viral growth and protective immunity devised by our group.
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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VICTOR Robert DEFILIPPIS其他文献
VICTOR Robert DEFILIPPIS的其他文献
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{{ truncateString('VICTOR Robert DEFILIPPIS', 18)}}的其他基金
Anti-tumor efficacy of novel cGAS-STING pathway agonists
新型 cGAS-STING 通路激动剂的抗肿瘤功效
- 批准号:
10286612 - 财政年份:2021
- 资助金额:
$ 76.76万 - 项目类别:
Anti-tumor efficacy of novel cGAS-STING pathway agonists
新型 cGAS-STING 通路激动剂的抗肿瘤功效
- 批准号:
10430274 - 财政年份:2021
- 资助金额:
$ 76.76万 - 项目类别:
Mechanistic Exploration of cGAS-STING-Mediated Vaccine Enhancement
cGAS-STING 介导的疫苗增强机制探索
- 批准号:
10318966 - 财政年份:2019
- 资助金额:
$ 76.76万 - 项目类别:
Mechanistic Exploration of cGAS-STING-Mediated Vaccine Enhancement
cGAS-STING 介导的疫苗增强机制探索
- 批准号:
10534676 - 财政年份:2019
- 资助金额:
$ 76.76万 - 项目类别:
THE ROLE OF CYTOMEGALOVIRUS PHOSPHOPROTEIN 65 IN VIRUS REPLICATON IN VIVO
巨细胞病毒磷酸蛋白65在体内病毒复制中的作用
- 批准号:
7958465 - 财政年份:2009
- 资助金额:
$ 76.76万 - 项目类别:
THE ROLE OF CYTOMEGALOVIRUS PHOSPHOPROTEIN 65 IN VIRUS REPLICATON IN VIVO
巨细胞病毒磷酸蛋白65在体内病毒复制中的作用
- 批准号:
7715956 - 财政年份:2008
- 资助金额:
$ 76.76万 - 项目类别:
THE ROLE OF CYTOMEGALOVIRUS PHOSPHOPROTEIN 65 IN VIRUS REPLICATON IN VIVO
巨细胞病毒磷酸蛋白65在体内病毒复制中的作用
- 批准号:
7561989 - 财政年份:2007
- 资助金额:
$ 76.76万 - 项目类别:
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