Enhanced POC assay for TB in HIV-infected children based on the ultrasensitive detection of the urinary form of the lipoarabinomannan antigen
基于尿形式阿拉伯脂甘露聚糖抗原的超灵敏检测,增强 HIV 感染儿童结核病的 POC 检测
基本信息
- 批准号:10611413
- 负责人:
- 金额:$ 74.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-14 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:5 year oldAffinityAliquotAntibodiesAntigenic DiversityAntigensAreaAvidityB-LymphocytesBindingBiological AssayBiological MarkersCD4 Positive T LymphocytesCarbohydratesCharacteristicsChildChildhoodCollaborationsCollectionDetectionDevicesDiagnosisDiagnosticEngineeringEpitopesFreezingFutureGenerationsGlycolipidsGoalsHIVHIV InfectionsHIV SeronegativityHIV-1HIV/TBHumanImmuneImmunologicsIndustrializationInfectionKenyaLateralLeadLibrariesLinkMannosidesMemory B-LymphocyteMethodsMonoclonal AntibodiesMycobacterium tuberculosisNaturePatient SelectionPatientsPediatric cohortPolysaccharidesPopulationProductionPropertyRandomizedReagentSamplingSerumSourceSouth AfricanSpecificityStandardizationStructureSurfaceTestingTuberculosisTuberculosis diagnosisUrineVariantVertebral columnWorkXyloseYeastsco-infectioncohortdetection assaydetection platformdiagnosis standardefficacy testinghuman monoclonal antibodiesimmunoreactivityimprovedlateral flow assaylipoarabinomannanmanmanufacturemortalitymycobacterialnovelpatient screeningpoint of carescreeningsugarurinary
项目摘要
Abstract
TB remains a major source of mortality in young children in endemic areas, particularly in areas where there is
a high rate of HIV infection. These children are difficult to diagnose with existing assays, and it is believed that
many of the >230,000 children who died because of TB in 2017 could have been saved with better diagnostics.
A highly promising biomarker for diagnosing TB is lipoarabinomannan (LAM), a major mycobacterial surface
glyolipid that accumulates at different concentrations in the great majority of actively infected TB patients. Our
lab has recently made major contributions towards understanding the diversity of the antigenic properties of
LAM and the complexity of the humoral immune rsponse against this antigen. One surprising discovery
resulting from our work is that the urinary form of TB LAM (uLAM) is antigenically distinct from the bacterially
associated form (ManLAM), and we have identified novel combinations of monoclonal antibodies that allow the
sensitive and specific detection of uLAM. This has recently led to the production of a new lateral flow assay
(the Fujifilm SILVAMP TB LAM assay) that has a significantly increased sensitivity for uLAM over that of the
commercial assay. However, despite this improvement, the sensitivity and robustness of this assay is still not
sufficient to meet the WHO requirements for an optimal assay. This proposal will build on our previous work to
further improve the affinities and specificities of our existing reagents, and identify new reagents with increased
sensitivity and accuracy for uLAM. To better understand the nature of uLAM and provide standardized samples
for future assays we will solate large volumes (~ 2L) of urine from positive patients with a range of uLAM levels,
and freeze away multiple aliquots of these samples for future use. A selected set of these urines will be used to
purify high concentrations of uLAM from multiple patients, and the structural and immunological properties of
these antigens will be compared. We have engineered forms of existing capture and detection reagents that
have improved affinities/avidities for ManLAM, and the sensitivity of these reagents will be compared to those
of existing reagents and lateral flow assays against several cohorts of pediatric urine samples that meet the
requirements of this RFA (<5 years old, >20% HIV+). We will screen memory B cell populations from selected
patients to identify new mabs with high affinities and/or specificities for uLAM, and select yeast display libraries
generated by randomization of the key CDR regions of our lead detection reagent for variants with higher
affinities and specificites than the parental antibody. The binding properties of these new mAbs will be
characterized, and their efficacy in detecting uLAM in the pediatric samples will be tested. Antibody
combinations with demonstrably better sensitivities than existing reagents will be transferred to our commercial
collaborators at Fujifilm and other companies for incorporation and testing in their platforms. The overall goals
of this study are to develop an improved LAM detection assay that meets or exceeds the Target Product Profile
(TPP) proposed by the WHO for high priority biomarker-based, non-sputum-based, POC tests for TB detection.
摘要
项目成果
期刊论文数量(0)
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会议论文数量(0)
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ABRAHAM PINTER其他文献
ABRAHAM PINTER的其他文献
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{{ truncateString('ABRAHAM PINTER', 18)}}的其他基金
Development of a highly-sensitive urine test for tuberculosis (TB) that detects diverse forms of urinary TB lipoarabinomannan (uLAM)
开发一种高灵敏度的结核病尿液检测方法,可检测多种形式的尿液结核菌脂阿拉伯甘露聚糖 (uLAM)
- 批准号:
10667871 - 财政年份:2022
- 资助金额:
$ 74.73万 - 项目类别:
Complementary diagnostic biomarkers of sputum culture-negative TB [R21]
痰培养阴性结核病的补充诊断生物标志物 [R21]
- 批准号:
10557869 - 财政年份:2022
- 资助金额:
$ 74.73万 - 项目类别:
Complementary diagnostic biomarkers of sputum culture-negative TB [R21]
痰培养阴性结核病的补充诊断生物标志物 [R21]
- 批准号:
10433028 - 财政年份:2022
- 资助金额:
$ 74.73万 - 项目类别:
Enhanced POC assay for TB in HIV-infected children based on the ultrasensitive detection of the urinary form of the lipoarabinomannan antigen
基于尿形式阿拉伯脂甘露聚糖抗原的超灵敏检测,增强 HIV 感染儿童结核病的 POC 检测
- 批准号:
10675836 - 财政年份:2020
- 资助金额:
$ 74.73万 - 项目类别:
Enhanced POC assay for TB in HIV-infected children based on the ultrasensitive detection of the urinary form of the lipoarabinomannan antigen
基于尿形式阿拉伯脂甘露聚糖抗原的超灵敏检测,增强 HIV 感染儿童结核病的 POC 检测
- 批准号:
10378761 - 财政年份:2020
- 资助金额:
$ 74.73万 - 项目类别:
Novel epitopes that mediate broad neutralization of clade B and C HIV-1 isolates
介导 B 型和 C 型 HIV-1 分离株广泛中和的新表位
- 批准号:
8701676 - 财政年份:2013
- 资助金额:
$ 74.73万 - 项目类别:
Optimizing protective vaccine targets in the V1/V2 domain of HIV-1 gp120
优化 HIV-1 gp120 V1/V2 结构域中的保护性疫苗靶标
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8501371 - 财政年份:2012
- 资助金额:
$ 74.73万 - 项目类别:
Optimizing protective vaccine targets in the V1/V2 domain of HIV-1 gp120
优化 HIV-1 gp120 V1/V2 结构域中的保护性疫苗靶标
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8410364 - 财政年份:2012
- 资助金额:
$ 74.73万 - 项目类别:
Strategies for Eliciting bnAbs against Conserved HIV-1 Quaternary Epitopes
引发针对保守的 HIV-1 四级表位的 bnAb 的策略
- 批准号:
8429448 - 财政年份:2010
- 资助金额:
$ 74.73万 - 项目类别:
Strategies for Eliciting bnAbs against Conserved HIV-1 Quaternary Epitopes
引发针对保守的 HIV-1 四级表位的 bnAb 的策略
- 批准号:
8035414 - 财政年份:2010
- 资助金额:
$ 74.73万 - 项目类别:
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