Integrating human and non-human primate data to understand the acquisition of pre-erythrocytic immunity in the face of previous malaria exposure
整合人类和非人类灵长类动物数据,以了解在面对先前的疟疾暴露时获得红细胞前免疫力
基本信息
- 批准号:10570273
- 负责人:
- 金额:$ 102.86万
- 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:2022-02-10 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAffectAfrica South of the SaharaAgeAnimal ModelAnimalsAntigen-Antibody ComplexAreaBiological MarkersBloodBlood specimenBone MarrowCD8-Positive T-LymphocytesCellsChronicClinicalClinical TrialsComplexDataDiseaseErythrocytesEuropeExhibitsGoalsHumanImmuneImmune EvasionImmune responseImmune systemImmunityImmunizationImmunologic MarkersImmunologicsImmunologyImmunosuppressionIncidenceIndividualInfectionInfection preventionInflammationInflammatoryInnate Immune ResponseLaboratoriesLiverMacaca mulattaMacaca nemestrinaMalariaMalaria VaccinesMapsMeasuresModelingNatural ImmunityParasitemiaParasitesPatternPerformancePeripheralPersonsPlasmodiumPrimatesPublishingResourcesSamplingScientistSiteSporozoitesSymptomsT-LymphocyteTestingTissue SampleTissuesVaccinatedVaccinationVaccinesacute infectionadaptive immune responseadaptive immunityanimal databasechronic infectioncircumsporozoite proteinclinical trial participantdensitydesigndisorder controlefficacy trialexperienceexposed human populationhuman dataimmunogenicityimmunoregulationinsightinter-institutionalmalaria infectionmodel buildingmouse modelnonhuman primatenovelperipheral bloodresponsetissue resident memory T celltransmission processvaccine candidatevaccine efficacyvaccine trialvolunteer
项目摘要
ABSTRACT
Pre-erythrocytic (PE) malaria vaccines that completely prevent infection in malaria non-endemic regions have
often failed to achieve equally high-level protection when tested in endemic regions. Data from animal models
and humans has identified certain factors that may be contributing to this difference. Active or previous
Plasmodium infections rank highly amongst these factors because infection is known to significantly impact
innate and adaptive immune responses to malaria vaccines. We hypothesize that previous malaria exposure is
a key driver of the suboptimal immunity observed in clinical trials of PE vaccines in endemic areas. However, a
full assessment of how such conditions affect pre-erythrocytic immune responses is lacking in large part
because much of the protective immune repertoire against PE malaria exists as tissue resident memory T cells
in the liver, which is inaccessible in human clinical trials. Here, we propose to address this question of malaria
vaccine hyporesponsiveness in endemic regions by performing vaccine studies in previously-infected versus
naïve non-human primates (NHP) where we can study the tissue-specific response down to the single cell
level and integrate these with data from peripheral blood samples from similarly-vaccinated human clinical trial
participants in endemic and non-endemic regions. Our exhaustive studies in NHPs will be specifically guided
by hypotheses derived directly from human data. The emerging high-density data will then be used to identify
mechanisms, build models and formulate concrete hypotheses that can then be validated across a number of
clinical trial samples with the overall goal of elucidating patterns or biomarkers that map with protection/lack of
protection and immunogenicity/lack of immunogenicity in malaria-naïve and -experienced volunteers. Thus, we
aim to: 1) define protective liver-resident PE immunity at the single cell level; 2) identify the mechanisms by
which previous malaria exposure impacts baseline and innate immunity; 3) build models of the complex
interplay between baseline, innate, and adaptive immunity and; 4) use these to identify strategies to overcome
hyporesponsiveness to PE vaccines in endemic areas. This U01 project combines an inter-institutional, inter-
disciplinary team of basic, translational, and clinical scientists from within and outside malaria whose unique
expertise, resources, and collaborative style will create breakthroughs insights about this highly complex yet
critically important vaccine challenge.
抽象的
完全预防疟疾非流行地区感染的前红细胞(PE)疟疾疫苗
当在流行地区进行测试时,来自动物模型的数据往往无法达到同样高水平的保护。
人类已经确定了可能导致这种差异的某些因素。
疟原虫感染在这些因素中名列前茅,因为已知感染对影响显着
我们认为以前的疟疾暴露是对疟疾疫苗的先天性和适应性免疫反应。
这是流行地区 PE 疫苗临床试验中观察到的免疫欠佳的关键驱动因素。
很大程度上缺乏对此类情况如何影响红细胞前免疫反应的全面评估
因为针对 PE 疟疾的大部分保护性免疫组库以组织驻留记忆 T 细胞的形式存在
在人类临床试验中无法达到的肝脏中,我们建议解决疟疾的这个问题。
通过在既往感染者和已感染者中进行疫苗研究来了解流行地区的疫苗反应低下
幼稚的非人类灵长类动物 (NHP),我们可以研究单个细胞的组织特异性反应
将这些数据与来自类似疫苗接种的人类临床试验的外周血样本的数据进行整合
我们对 NHP 的详尽研究将受到专门指导。
然后,将使用从人类数据中得出的假设来识别直接出现的高密度数据。
机制,建立模型并制定具体的假设,然后可以在多个方面进行验证
临床试验样本的总体目标是阐明与保护/缺乏相关的模式或生物标志物
未接触过疟疾和有过疟疾经验的志愿者的保护和免疫原性/缺乏免疫原性。
目的是:1) 在单细胞水平上定义保护性肝脏驻留 PE 免疫;2) 确定机制;
以前的疟疾暴露会影响基线和先天免疫;3)建立复杂的模型;
基线免疫、先天免疫和适应性免疫之间的相互作用;4) 利用这些来确定克服的策略
该 U01 项目结合了跨机构、跨机构的研究。
由来自疟疾内外的基础科学家、转化科学家和临床科学家组成的学科团队,其独特的
专业知识、资源和协作方式将为这个高度复杂的领域带来突破性的见解
至关重要的疫苗挑战。
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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Sean C Murphy其他文献
Subcutaneous Administration of a Monoclonal Antibody to Prevent Malaria.
皮下注射单克隆抗体预防疟疾。
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:158.5
- 作者:
K. Kayentao;A. Ongoiba;Anne C Preston;Sara A. Healy;Zonghui Hu;Jeff Skinner;S. Doumbo;Jing Wang;H. Cisse;Didier Doumtabe;Abdrahamane Traoré;Hamadi Traore;Adama Djiguiba;Shanping Li;Mary E. Peterson;Shinyi Telscher;Azza H. Idris;William C Adams;Adrian B McDermott;S. Narpala;Bob C Lin;Leonid Serebryannyy;S. Hickman;Andrew J McDougal;Sandra Vazquez;Matthew Reiber;Judy A Stein;Jason G Gall;Kevin Carlton;P. Schwabl;Siriman Traore;Mamadou Keita;Amatigué Zéguimé;Adama Ouattara;M’Bouye Doucoure;Amagana Dolo;Sean C Murphy;D. E. Neafsey;S. Portugal;Abdoulaye A Djimde;B. Traore;Robert A. Seder;Peter D. Crompton - 通讯作者:
Peter D. Crompton
Clinical performance validation of the STANDARD G6PD test: A multi-country pooled analysis
标准 G6PD 测试的临床性能验证:多国汇总分析
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:3.8
- 作者:
W. Adissu;Marcelo Brito;E. Garbin;M. Macedo;W. Monteiro;Sandip Kumar Mukherjee;Jane Myburg;Mohammad Shafiul Alam;G. Bancone;Pooja Bansil;Sampa Pal;Abhijit Sharma;S. Zobrist;Andrew Bryan;C. Chu;Santasabuj Das;G. Domingo;A. Hann;James G. Kublin;M. Lacerda;Mark Layton;B. Ley;Sean C Murphy;F. Nosten;D. Pereira;Richard N. Price;A. Talukdar;D. Yilma;E. Gerth - 通讯作者:
E. Gerth
Sean C Murphy的其他文献
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{{ truncateString('Sean C Murphy', 18)}}的其他基金
DDT-BMQ-0000100 Qualification of the Plasmodium falciparum 18S rRNA biomarker for malaria-endemic controlled human malaria infection studies
DDT-BMQ-0000100 疟疾流行控制人类疟疾感染研究中恶性疟原虫 18S rRNA 生物标志物的鉴定
- 批准号:
10836140 - 财政年份:2023
- 资助金额:
$ 102.86万 - 项目类别:
Integrating human and non-human primate data to understand the acquisition of pre-erythrocytic immunity in the face of previous malaria exposure
整合人类和非人类灵长类动物数据,以了解在面对先前的疟疾暴露时获得红细胞前免疫力
- 批准号:
10343399 - 财政年份:2022
- 资助金额:
$ 102.86万 - 项目类别:
DDT-BMQ-0000107 Qualification of the Plasmodium falciparum 18S rRNA biomarker for malaria field studies
DDT-BMQ-0000107 用于疟疾现场研究的恶性疟原虫 18S rRNA 生物标志物的鉴定
- 批准号:
10616035 - 财政年份:2022
- 资助金额:
$ 102.86万 - 项目类别:
Development of an oral liver-targeted prime-and-trap malaria vaccine
开发口服肝脏靶向引发和诱捕疟疾疫苗
- 批准号:
10533280 - 财政年份:2020
- 资助金额:
$ 102.86万 - 项目类别:
Development of an oral liver-targeted prime-and-trap malaria vaccine
开发口服肝脏靶向引发和诱捕疟疾疫苗
- 批准号:
10308679 - 财政年份:2020
- 资助金额:
$ 102.86万 - 项目类别:
Establishing the Feasibility of using daily Dried Blood Spots (DBS) to study the Natural History of Low-density Asymptomatic Malaria Infection to Inform Malaria Elimination
建立利用每日干血斑 (DBS) 研究低密度无症状疟疾感染自然史的可行性,为消除疟疾提供信息
- 批准号:
9974963 - 财政年份:2020
- 资助金额:
$ 102.86万 - 项目类别:
Establishing the Feasibility of using daily Dried Blood Spots (DBS) to study the Natural History of Low-density Asymptomatic Malaria Infection to Inform Malaria Elimination
建立利用每日干血斑 (DBS) 研究低密度无症状疟疾感染自然史的可行性,为消除疟疾提供信息
- 批准号:
10116276 - 财政年份:2020
- 资助金额:
$ 102.86万 - 项目类别:
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