Enhancing cytotoxic lymphocytes in a TB vaccine strategy
在结核病疫苗策略中增强细胞毒性淋巴细胞
基本信息
- 批准号:10580073
- 负责人:
- 金额:$ 77.35万
- 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:2022-02-25 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:Acute DiseaseAerosolsAgonistAnimal ModelAnimalsAreaB-LymphocytesBCG VaccineBacille Calmette-Guerin vaccinationBioinformaticsBloodCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCause of DeathCellsCessation of lifeCommunicable DiseasesControl GroupsDataDiseaseDoseFrequenciesGenetic TranscriptionGranulomaHIVHumanImmuneImmune responseImmunologic MarkersImmunologicsImmunologyIndustry CollaborationInfectionInfection preventionInterleukin-15IntravenousLungLung diseasesLymphocyteMacaca mulattaMachine LearningMalignant NeoplasmsMalignant neoplasm of urinary bladderMediastinal lymph node groupMediatingMethodsMicrobiologyModelingModernizationMonitorMucosal Immune ResponsesMycobacterium tuberculosisMyeloid CellsOutcomePET/CT scanPathologyPopulationPreventionProliferatingPulmonary InflammationRandomizedRegimenResearchRoleRouteSIVScourgeSiteSurrogate MarkersT-LymphocyteTechniquesTestingTissuesTuberculosisTuberculosis VaccinesVaccinatedVaccinationVaccinesVirulentX-Ray Computed Tomographyacute infectionaerosolizedbiomarker identificationcell typecomparative efficacycomparison controlcytotoxiccytotoxicitydesignimmunogenicityimprovedinsightintravenous administrationmultidimensional datamycobacterialnonhuman primatenovelnovel vaccinespreventrecruitresponsesingle-cell RNA sequencingsuccesstooltranslation to humanstranslational potentialvaccination outcomevaccination protocolvaccine efficacyvaccine strategyvaccine-induced immunity
项目摘要
ABSTRACT: Currently BCG is the most widely administered vaccine worldwide against
tuberculosis (TB). Yet, TB remains one of the most common causes of death from an infectious
disease globally underscoring its limited efficacy. We have shown that BCG’s vaccine efficacy
can be improved if administered by a different route or dose. In fact, intravenous BCG
vaccination resulted in 90% protection in a non-human primate model of TB but this method is
impractical to conduct on a population scale. Features associated with protection include the
presence of CD8 and CD4 T cells in the airways and lung resident T cells. In this proposal we
plan to mimic this immune response and improve upon the existing BCG vaccine in a strategy
that we call “enhanced prime and pull”. We propose to use N-803, an IL-15 agonist, to enhance
the frequency of innate CD8 cells and boost the effects of high dose, intradermal BCG. This is
followed by a dose of aerosolized BCG to pull vaccine-induced immune cells into the areas and
propagate resident T cells in the lungs. Using an animal model that recapitulates human TB, we
will utilized state-of-the-art modern tools such as PET CT, large scale immunologic profiling both
at a transcriptional and flow cytometric level and machine learning techniques. Immunogenicity
in blood and airway immune cells will examined among vaccine and control groups prior to
infection with Mycobacterium tuberculosis (Aim 1). After infection, we will then compare the
ability of the vaccine regimen to prevent infection and/or lower bacterial burden compared to
controls (Aim 2). We will examine the immune responses (including the presence of tissue
resident T cells) in the granuloma, lungs and mediastinal lymph nodes in the context of
bacterial burden among vaccinated and control groups. Lastly, machine learning techniques will
be used to identify immune parameters that correlate with protection in the context of
vaccines. The proposed studies are likely to reveal important information about the role of
innate cytotoxic CD8 cell and their role in vaccine induced protection and mechanisms of
recruiting mucosal immune responses. We may also gain important insights into key surrogate
markers of protection sorely needed in the TB field.
摘要:目前,卡介苗是世界范围内使用最广泛的抗结核疫苗。
结核病(TB)。然而,结核病仍然是感染性疾病最常见的死亡原因之一,
这种疾病在全球范围内强调了其有限的疗效。我们已经证明卡介苗的疫苗效力
如果通过不同的途径或剂量给药,事实上,静脉注射卡介苗
疫苗接种在结核病的非人灵长类动物模型中产生90%的保护,但这种方法
在人口规模上不切实际。与保护相关的功能包括
气道中存在CD 8和CD 4 T细胞以及肺驻留T细胞。在本提案中,我们
计划模仿这种免疫反应,并在现有的BCG疫苗的基础上进行改进,
我们称之为“增强的启动和拉动”我们建议使用N-803,一种IL-15激动剂,以增强
先天性CD 8细胞的频率,并增强高剂量皮内BCG的作用。这是
接着是一剂雾化的卡介苗,将疫苗诱导的免疫细胞拉到这些区域,
在肺中繁殖常驻T细胞。使用一个重现人类结核病的动物模型,我们
将利用最先进的现代工具,如PET CT,大规模免疫分析,
在转录和流式细胞术水平和机器学习技术。免疫原
在疫苗组和对照组之前,将检查血液和气道中的免疫细胞
结核分枝杆菌感染(目的1)。感染后,我们将比较
疫苗方案预防感染和/或降低细菌负荷的能力,
对照组(目标2)。我们将检查免疫反应(包括组织的存在
常驻T细胞)在肉芽肿,肺和纵隔淋巴结的背景下,
接种组和对照组的细菌负荷。最后,机器学习技术将
可用于鉴定与以下情况下的保护相关的免疫参数:
疫苗。拟议的研究可能会揭示有关以下作用的重要信息:
先天性细胞毒性CD 8细胞及其在疫苗诱导保护中的作用和机制
募集粘膜免疫应答。我们还可以获得重要的见解,关键替代
结核病领域迫切需要的保护标志物。
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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JoAnne L. Flynn其他文献
This information is current as Infection Mycobacterium tuberculosis during Antimicrobial Responses with Caseation Mediated − Early Host Immunity Control of Lesion Sterilization by Balancing Computational Modeling Predicts IL-10
此信息是当前的感染结核分枝杆菌在干酪介导的抗菌反应期间通过平衡计算模型预测 IL-10 进行病灶灭菌的早期宿主免疫控制
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:0
- 作者:
Nicholas A. Cilfone;Christopher B Ford;Simeone Marino;Joshua T Mattila;H. Gideon;JoAnne L. Flynn;Denise E. Kirschner;J. Linderman - 通讯作者:
J. Linderman
Modeling pathogen and host: <em>in vitro</em>, <em>in vivo</em> and <em>in silico</em> models of latent <em>Mycobacterium tuberculosis</em> infection
- DOI:
10.1016/j.ddmod.2005.05.019 - 发表时间:
2005-06-01 - 期刊:
- 影响因子:
- 作者:
P. Ling Lin;Denise Kirschner;JoAnne L. Flynn - 通讯作者:
JoAnne L. Flynn
emIn silico/em identification and synthesis of a multi-drug loaded MOF for treating tuberculosis
- DOI:
10.1016/j.jconrel.2022.10.024 - 发表时间:
2022-12-01 - 期刊:
- 影响因子:11.500
- 作者:
Abhinav P. Acharya;Kutay B. Sezginel;Hannah P. Gideon;Ashlee C. Greene;Harrison D. Lawson;Sahil Inamdar;Ying Tang;Amy J. Fraser;Kush V. Patel;Chong Liu;Nathaniel L. Rosi;Stephen Y. Chan;JoAnne L. Flynn;Christopher E. Wilmer;Steven R. Little - 通讯作者:
Steven R. Little
This information is current as Infection in BALB / c Mice tuberculosis Mycobacterium the Control of Chronic The Chemokine Receptor CXCR 3 Attenuates
此信息当前为 BALB / c 小鼠结核分枝杆菌感染控制慢性趋化因子受体 CXCR 3 减弱
- DOI:
- 发表时间:
2007 - 期刊:
- 影响因子:0
- 作者:
S. Chakravarty;Jiayong Xu;Bao Lu;Craig Gerard;JoAnne L. Flynn;John Chan - 通讯作者:
John Chan
SARS-CoV-2 Receptor ACE2 is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Enriched in Specific Cell Subsets Across Tissues
SARS-CoV-2 受体 ACE2 是人气道上皮细胞中的干扰素刺激基因,富含组织中的特定细胞亚群
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
Carly N Ziegler;Samuel J. Allon;Sarah K Nyquist;Ian M. Mbano;Vincent N Miao;Yuming Cao;Ashraf S. Yousif;Julia Bals;B. Hauser;J. Feldman;Christoph Muus;Marc H Wadsworth Ii;S. Kazer;T. Hughes;B. Doran;G. J. Gatter;Marko Vukovic;C. Tzouanas;F. Taliaferro;Zhiru Guo;Jennifer P. Wang;Daniel F Dwyer;K. Buchheit;Joshua A. Boyce;Nora A. Barrett;T. Laidlaw;Shaina L. Carroll;Lucrezia Colonna;V. Tkachev;Alison Yu;Henqi Betty Zheng;H. Gideon;Caylin G. Winchell;P. Lin;Bonnie Berger;A. Leslie;JoAnne L. Flynn;Sarah M Fortune;R. Finberg;Leslie S. Kean;Manuel Garber;Aaron Schmidt;D. Lingwood;A. Shalek;J. Ordovas;Hca Lung Biological Network - 通讯作者:
Hca Lung Biological Network
JoAnne L. Flynn的其他文献
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{{ truncateString('JoAnne L. Flynn', 18)}}的其他基金
Enhancing cytotoxic lymphocytes in a TB vaccine strategy
在结核病疫苗策略中增强细胞毒性淋巴细胞
- 批准号:
10462928 - 财政年份:2022
- 资助金额:
$ 77.35万 - 项目类别:
Dissecting the pathogenesis of HIV-TB Immune reconstitution inflammatory syndrome
剖析 HIV-TB 免疫重建炎症综合征的发病机制
- 批准号:
10097199 - 财政年份:2020
- 资助金额:
$ 77.35万 - 项目类别:
Dissecting the pathogenesis of HIV-TB Immune reconstitution inflammatory syndrome
剖析 HIV-TB 免疫重建炎症综合征的发病机制
- 批准号:
10451735 - 财政年份:2020
- 资助金额:
$ 77.35万 - 项目类别:
Dissecting the pathogenesis of HIV-TB Immune reconstitution inflammatory syndrome
剖析 HIV-TB 免疫重建炎症综合征的发病机制
- 批准号:
10667439 - 财政年份:2020
- 资助金额:
$ 77.35万 - 项目类别:
Dissecting the pathogenesis of HIV-TB Immune reconstitution inflammatory syndrome
剖析 HIV-TB 免疫重建炎症综合征的发病机制
- 批准号:
10240712 - 财政年份:2020
- 资助金额:
$ 77.35万 - 项目类别:
Predicting protective T-cell responses in Tuberculosis using a systems biology approach
使用系统生物学方法预测结核病中的保护性 T 细胞反应
- 批准号:
9072491 - 财政年份:2016
- 资助金额:
$ 77.35万 - 项目类别:
The Effects of M. tuberculosisInfection on Lung Microbiome in Macaques
结核分枝杆菌感染对猕猴肺部微生物组的影响
- 批准号:
9018134 - 财政年份:2016
- 资助金额:
$ 77.35万 - 项目类别:
An adjuvant that promotes TH1/TH17 and CD8 T cells in a tuberculosis vaccine
一种在结核疫苗中促进 TH1/TH17 和 CD8 T 细胞的佐剂
- 批准号:
8607041 - 财政年份:2013
- 资助金额:
$ 77.35万 - 项目类别:
An adjuvant that promotes TH1/TH17 and CD8 T cells in a tuberculosis vaccine
一种在结核疫苗中促进 TH1/TH17 和 CD8 T 细胞的佐剂
- 批准号:
8994259 - 财政年份:2013
- 资助金额:
$ 77.35万 - 项目类别:
An adjuvant that promotes TH1/TH17 and CD8 T cells in a tuberculosis vaccine
一种在结核疫苗中促进 TH1/TH17 和 CD8 T 细胞的佐剂
- 批准号:
9208083 - 财政年份:2013
- 资助金额:
$ 77.35万 - 项目类别:
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