Combining innovative molecular adjuvanting approaches with novel adenoviral vector delivery to generate a universal influenza vaccine
将创新的分子佐剂方法与新型腺病毒载体递送相结合以产生通用流感疫苗
基本信息
- 批准号:10519005
- 负责人:
- 金额:$ 52.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdenovirus VectorAdjuvantAdoptive TransferAntibodiesAntibody ResponseAntigen TargetingAntigensB-LymphocytesBenchmarkingBronchoalveolar LavageCD3 AntigensCD8B1 geneCMV promoterCellsCellular ImmunityClinicalCold ChainsComplementDNA cassetteDataData EngineeringDoseEffectivenessEngineeringEnzyme-Linked Immunosorbent AssayEpidemicEpitopesFemaleFundingHemagglutininHumanHumoral ImmunitiesImmuneImmune SeraImmune responseImmune systemImmunityImmunizationImmunoglobulin AImmunoglobulin GImmunologicsIn VitroIndividualInflammationInfluenza A virusIntramuscularLeadLungLymphocyteMeasuresMediatingMembrane GlycoproteinsModelingMolecularMorbidity - disease rateMucous MembraneMusNeuraminidaseNucleoproteinsOutcomePTPRC genePeptidesPhenotypePhylogenetic AnalysisPlayPopulationProcessProductionProteinsPublishingPulmonary PathologyReadinessRegimenRegulationResearchRoleRouteSafetySeroprevalencesSerumSpleenStainsSystemT-LymphocyteTestingUltracentrifugationVaccinatedVaccinationVaccine AntigenVaccinesValidationVariantViralViral AntigensVirusWorkZoonosesantigen-specific T cellsbasecesium chloridecomparativecostcost effectivecross reactivitycytokinedelivery vehicledraining lymph nodeefficacy testingeggenhanced green fluorescent proteinexosomeextracellular vesicleshomologous recombinationhuman pathogenimmunogenicimmunogenicityin vivoinfluenza virus vaccineinfluenzavirusinnovationinnovative technologieslung histologymaleneutralizing antibodynovelpandemic coronaviruspandemic diseasepandemic preparednessparticlepathogenpre-clinicalpreclinical evaluationrespiratory pathogenresponseseasonal influenzauniversal influenza vaccineuniversal vaccinevaccine evaluationvaccine platformvaccine safetyvectorvector vaccine
项目摘要
SUMMARY: Influenza A viruses (IAVs) are important human pathogens, which cause seasonal epidemics and
sporadic pandemics. The ongoing threat posed by emerging zoonotic influenza viruses, for which humans are
immunologically naïve, represents a major global concern. Current influenza vaccines elicit narrow, strain-
specific immunity, are overly reliant on egg-based manufacturing, have a prolonged production process, and fail
to elicit robust cellular and humoral immune responses to multiple IAV antigens (Ags) simultaneously. The
variable effectiveness of seasonal influenza vaccines, has highlighted the importance of investing in the early
pre-clinical evaluation of innovative vaccines which could elicit immune responses with increased breadth
against emerging viruses/variants. Efforts to develop a universal influenza virus vaccine, capable of providing
broad and long-lived protection against seasonal and pandemic subtypes, are focused on inducing immune
responses directed towards highly conserved epitopes on influenza virus Ags such as the stalk of the major
surface glycoprotein hemagglutinin (HA), the neuraminidase (NA) or the internal nucleoprotein (NP).
In this R01, we will develop an innovative, optimized, universal influenza vaccine platform to overcome
issues associated with current vaccines. Preliminary data generated through R21 funding enabled the
identification of lead headless HAs for group 1 IAVs, and demonstrated that we can successfully encode at least
two Ags in a single expression cassette. We will now build upon these data and engineer bi- or tri-cistronic Ag
cassettes encoding our lead headless HAs in combination with NA and/or NP. We will augment and broaden
immune recognition of the immunosubdominant HA stalk, or long overlooked NA, by using employing a fusion-
Ag based molecular adjuvanting approach called “exosome-display”, which facilitates targeting of Ags to host-
derived extracellular vesicles including exosomes in vivo. Exosomes play important roles in the regulation of
immunity, and we have demonstrated that exosome-display can dramatically increase the immunogenicity of a
model Ag encoded by two distinct adenoviral (Ad) vector platforms. Optimized, “adjuvanted” Ag expression
cassettes will be engineered into Ad vectored vaccines with low seroprevalence in humans, allowing in vivo
tethering of Ag to host-derived exosomes. This could potentiate immune responses by increasing recognition of
the encoded Ag by the immune system. Finally, we will comprehensively evaluate and phenotype the immune
profile of these universal vaccines in single-shot regimens, and test efficacy in lethal challenge with heterologous
and heterosubtypic IAVs. Ad vectors have risen to prominence during the coronavirus pandemic, due to their
ease of manufacturing, cheap cost, the possibility for thermostabilization with minimal losses to immunogenicity
under cold-chain free conditions, making them ideal candidates for equitable global distribution. Therefore, the
Ad-based universal influenza vaccines described in this R01 would be suited to stockpiling for pandemic
preparedness, and could provide “universal” protection following a single shot.
摘要:甲型流感病毒(iav)是重要的人类病原体,可引起季节性流行和传染性疾病
项目成果
期刊论文数量(0)
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Lynda Coughlan其他文献
Lynda Coughlan的其他文献
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{{ truncateString('Lynda Coughlan', 18)}}的其他基金
Combining innovative molecular adjuvanting approaches with novel adenoviral vector delivery to generate a universal influenza vaccine
将创新的分子佐剂方法与新型腺病毒载体递送相结合以产生通用流感疫苗
- 批准号:
10653245 - 财政年份:2022
- 资助金额:
$ 52.66万 - 项目类别:
Exosome-display as a strategy to enhance the immunogenicity of SARS-CoV-2 vaccines based on adenoviral vectors
外泌体展示作为增强基于腺病毒载体的 SARS-CoV-2 疫苗免疫原性的策略
- 批准号:
10363963 - 财政年份:2020
- 资助金额:
$ 52.66万 - 项目类别:
Exosome-display as a strategy to enhance the immunogenicity of SARS-CoV-2 vaccines based on adenoviral vectors
外泌体展示作为增强基于腺病毒载体的 SARS-CoV-2 疫苗免疫原性的策略
- 批准号:
10161344 - 财政年份:2020
- 资助金额:
$ 52.66万 - 项目类别:
Generation of a polycistronic universal influenza virus vaccine based on rare species adenoviral vectors
基于稀有物种腺病毒载体的多顺反子通用流感病毒疫苗的制备
- 批准号:
10358297 - 财政年份:2019
- 资助金额:
$ 52.66万 - 项目类别:
Generation of a polycistronic universal influenza virus vaccine based on rare species adenoviral vectors
基于稀有物种腺病毒载体的多顺反子通用流感病毒疫苗的制备
- 批准号:
9806521 - 财政年份:2019
- 资助金额:
$ 52.66万 - 项目类别:
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