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Enhanced POC assay for TB in HIV-infected children based on the ultrasensitive detection of the urinary form of the lipoarabinomannan antigen

Award Number: R01AI152157
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $733,212 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	000	5	4/15/2024	NON-COMPETING CONTINUATION	$733,212
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	002	4	4/18/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$716,968
2024	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	001	3	4/18/2024	NON-COMPETING CONTINUATION	-$716,968
														Subtotal = $733,212

Issue Date FY: 2023 ( Subtotal = $747,342 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	002	4	3/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$747,342
2023	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	001	3	3/21/2023	NON-COMPETING CONTINUATION	$0
2023	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	3	2/22/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $747,342

Issue Date FY: 2022 ( Subtotal = $967,330 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	3	4/19/2022	NON-COMPETING CONTINUATION	$747,342
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	001	3	8/30/2022	SUPPLEMENT FOR EXPANSION	$219,988
														Subtotal = $967,330

Issue Date FY: 2021 ( Subtotal = $747,759 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	2	3/26/2021	NON-COMPETING CONTINUATION	$747,759
														Subtotal = $747,759

Issue Date FY: 2020 ( Subtotal = $729,737 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	1	4/14/2020	NEW	$729,737
														Subtotal = $729,737

Grand Total All Awards = $3,925,380

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Enhanced POC assay for TB in HIV-infected children based on the ultrasensitive detection of the urinary form of the lipoarabinomannan antigen

Award Number: R01AI152157

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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