Implementation of a qPCR-based assay for the quantification of SARS-CoV-2-specific T cells in immunocompromised patients
实施基于 qPCR 的检测方法,对免疫功能低下患者的 SARS-CoV-2 特异性 T 细胞进行定量
基本信息
- 批准号:10580531
- 负责人:
- 金额:$ 28.02万
- 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:2023-09-18 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVAddressAntibodiesAntibody ResponseBacterial InfectionsBiological AssayBiological MarkersBiotechnologyBloodBlood specimenBypassCOVID-19COVID-19 assayCOVID-19 complicationsCOVID-19 vaccinationCXCL10 geneCancer PatientCellsCellular ImmunityClinicalCohort StudiesDataEnrollmentFlow CytometryGoalsHematologic NeoplasmsHematologyHumoral ImmunitiesIL2 geneImmuneImmune responseImmunityImmunocompromised HostImmunoglobulin GImmunosuppressionIndividualInfectionInfusion proceduresInstitutional Review BoardsInterferon Type IIMeasuresMediatingMethodsModelingMonitorMultiple MyelomaNatureOncologyOutcomePathway interactionsPatientsPeptidesPeripheral Blood Mononuclear CellPhasePlasma CellsPopulationPrevalenceProductionProxyPublishingQuality ControlRNA purificationRecommendationRecurrenceReportingSARS-CoV-2 antigenSARS-CoV-2 immunitySARS-CoV-2 infectionSARS-CoV-2 spike proteinSamplingSensitivity and SpecificitySocial DistanceSpecificitySteroidsT-Cell ActivationT-LymphocyteTestingTimeVaccinatedVaccinationVaccineeVaccinesValidationViralViral AntibodiesVirus DiseasesVulnerable PopulationsWhole BloodWorkantigen detectionantigen-specific T cellsbooster vaccinecancer cellchemotherapycohortcomorbiditycoronavirus diseasehypogammaglobulinemiamonocyteneutralizing antibodyneutrophilolder patientpassive antibodiespatient populationpreventprophylacticresponsetargeted treatmentvaccination strategy
项目摘要
SUMMARY
Long-term protection from viral infections is mediated by both the humoral and cellular immune pathways.
Multiple Myeloma (MM) is the second most common hematological malignancy in the US and is characterized
by clonal plasma cell production, resulting in immune suppression and recurrent bacterial and viral infections.
SARS-CoV-2-specific antibody quantification are currently being used as clinical endpoints to determine
immune protection against COVID-19, and this information is even more relevant in immunocompromised
individuals who lack a humoral response, but are protected by the cellular immunity (i.e. MM patients).
Despite the urgent need to quantify cellular immunity, the complexity and lack of scalability of traditional
methods (e.g. ELISpot, flow cytometry) to detect antigen-specific T cells has so far prevented large scale studies.
To address this problem, we developed a direct qPCR-based rapid T cell activation (dqTACT) assay based
on ex vivo stimulation of whole blood samples with a pool of viral peptides (i.e.immunodominant peptides
covering SARS-CoV-2 Spike protein),
SARS-CoV-2 antigen-specific T cells, and CXCL10,
followed by direct amplification of IFNG 𝛾 or IL2 which are produced by
which is produced by monocytes and neutrophils in
,
response
to
T cell activation.
The overarching aim of this proposal is to develop and implement a qPCR method that can be used as a proxy
to measure the presence and functionality of antigen specific T cells in MM patients. Specifically, we hypothesize
that SARS-CoV-2 specific T cells might be a biomarker of previous infection and of efficacy of vaccination
strategies, complementary to quantification of the humoral response.
In the UH2 phase, we will define analytical sensitivity and specificity and establish cut-off/thresholds and
appropriate positive and quality controls, accuracy and false result rate by comparing the dqTACT assay with
the gold standard assays such as flow cytometry and ELISpot for measuring cellular immune responses.
In the UH3 phase, we will test the presence and persistence of cellular immunity to SARS-CoV-2 in
convalescent and vaccinated myeloma patients. Well annotated patient populations will be used to define
sensitivity, specificity, and thresholds with response to clinical end-points, such as presence and persistence of
humoral and cellular immunity to SARS-CoV-2. We will estimate the prevalence of the markers within vaccinated
myeloma patients. We will then extend our studies and use banked as well as fresh samples from our large
myeloma/immunocompromised population and healthy controls enrolled in IRB approved studies.
The overarching goal is to use the dqTACT assay to test the presence of T cells due to natural infection or
vaccination in myeloma patients, possibly aiding in nationwide booster strategies or passive antibody infusion
support to protect these vulnerable population.
Key deliverables an assay to rapidly quantify the functionality of T cellular immunity at scale.
概括
长期保护病毒感染是由体液和细胞免疫病介导的。
多发性骨髓瘤(mm)是美国第二常见的血液学恶性肿瘤,其特征是
通过克隆浆细胞的产生,导致免疫抑制和复发性细菌和病毒感染。
SARS-COV-2特异性抗体定量目前被用作临床终点以确定
针对COVID-19的免疫保护,此信息在免疫功能低下更为相关
缺乏体液反应但受到细胞免疫学(即MM患者)保护的个体。
尽管迫切需要量化细胞免疫,但传统的复杂性和缺乏可扩展性
迄今为止,方法(例如ELISPOT,流式细胞仪)检测抗原特异性T细胞已经阻止了大规模研究。
为了解决此问题,我们开发了基于QPCR的直接T细胞激活(DQTACT)测定
在体内用病毒petides池刺激全血样品
覆盖SARS-COV-2尖峰蛋白),
SARS-COV-2抗原特异性T细胞和CXCL10,
然后直接扩增由IFNG 𝛾或IL2进行
由单核细胞和中性粒细胞在
,,,,
回复
到
T细胞激活。
该提案的总体目的是开发和实施一种可以用作代理的QPCR方法
测量MM患者中抗原特异性T细胞的存在和功能。具体来说,我们假设
SARS-COV-2特异性T细胞可能是先前感染和疫苗效率的生物标志物
策略,体液响应数量的完整性。
在UH2阶段,我们将定义分析灵敏度和特异性,并建立截止/阈值,并且
通过将DQTACT分析与
用于测量细胞免疫反应的流式细胞术和ELISPOT等金标准测定法。
在UH3阶段,我们将测试细胞免疫对SARS-COV-2的存在和持久性
康复和疫苗接种骨髓瘤患者。注释的患者人群将用于定义
敏感性,特异性和阈值对临床终点的反应,例如存在和持久性
对SARS-COV-2的体液和细胞免疫。我们将估计接种疫苗内标记的患病率
骨髓瘤患者。然后,我们将扩展学习,并使用库存的库以及大型的新鲜样品
IRB批准的研究中纳入了骨髓瘤/免疫功能低下的人群和健康对照。
总体目标是使用DQTACT分析来测试由于自然感染或
骨髓瘤患者的疫苗接种,可能有助于全国增强策略或被动抗体输注
支持保护这些脆弱人群。
钥匙可交付成果一种测定法,以迅速量化T细胞免疫的功能。
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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Ernesto Guccione其他文献
Ernesto Guccione的其他文献
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{{ truncateString('Ernesto Guccione', 18)}}的其他基金
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