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Development of a High-Throughput Microfluidics-Enabled Functional Assay for Rapidly Identifying Neutralizing Antibodies

Award Number: R01AI141607
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 Viral pathogenesis kills 100 million people each year. However, broadly neutralizing antibodies (Abs) pro- duced by B lymphocytes in fortunate hosts routinely eliminates the threat of the most lethal viruses. Identifying the antigenic epitopes that can induce such neutralizing Abs (nAbs) via immunization is at best protracted and fraught with technical challenges, if possible at all. We are developing a novel, microfluidic, lab-on-a-chip tech- nology to radically speed the ability to functionally assay the neutralization capability of clonal Ab produced by one human B cell. PRESCIENT (Platform for the Rapid Evaluation of antibody SucCess using Integrated mi- crofluidics ENabled Technology) is a high-throughput, single-cell resolution platform that can measure the neu- tralization capability of the Abs produced by single B lymphocytes through a direct functional assay in a droplet microfluidics format. Thus, it provides an unbiased, single-cell resolution, high-throughput, near-complete anal- ysis of the entire B cell repertoire to identify B cells that neutralize viral infection. As influenza sometimes causes one half million deaths per year and we have a battery of tools and rea- gents already developed for this pathosystem, we have chosen it as the viral model in which to test our central hypothesis that PRESCIENT will deliver a fast and low cost route for discovering neutralizing Abs (nAbs). We will take a tripartite approach with these aims: 1) to optimize the performance of the device with greater reliabil- ity, throughput and efficiency, 2) to quantitatively assess PRESCIENT's ability to recognize hybridomas that make nAbs against H1N1 influenza from progressively more rigorous mixed populations, and 3) to rapidly iden- tify nAbs against H1N1 and H3N2 influenza from EBV-immortalized human peripheral blood B cells. Phage and other display systems commonly used for nAb discovery have inherent bias and protein produc- tion hurdles due to non-mammalian post-translational modifications, thus direct utilization of B cells is ideal. Droplet microfluidic systems, where pico-liter scale water-in-oil emulsion droplets function as independent bio- reactors, can efficiently manipulate cells with unprecedented speed and precision. Droplet microfluidic systems for screening Abs produced from hybridomas that inhibit specific biochemical reactions have been described. However, systems that integrate Ab screening and viral neutralization bioassays have not yet been achieved. The major innovation is the development and utilization of the first high-throughput system for the functional discovery of human nAbs against infectious agents, a truly vertical leap for the fields of vaccinology, immuno- therapeutic design and epitope discovery. With PRESCIENT, immunologists will be able to rapidly identify from a convalescent patient's blood draw the “needle in the haystack” paratope that generates life-saving broadly neutralizing Abs. Ultimately, the unique immunoglobulin heavy and light chain DNA rearrangements will be iso- lated from the PRESCIENT-sorted cell for monoclonal Ab production or structural vaccine epitope engineering. 1


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 = $0 )
2024	2023	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Allergy and Infectious Diseases Research	000	5	3/14/2024	NON-COMPETING CONTINUATION	-$521,618
2024	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Allergy and Infectious Diseases Research	001	6	3/14/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$521,618
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $653,159 )
2023	2023	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Allergy and Infectious Diseases Research	000	5	5/31/2023	NON-COMPETING CONTINUATION	$653,159
														Subtotal = $653,159

Issue Date FY: 2022 ( Subtotal = $653,159 )
2022	2022	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Allergy and Infectious Diseases Research	000	4	6/7/2022	NON-COMPETING CONTINUATION	$653,159
														Subtotal = $653,159

Issue Date FY: 2021 ( Subtotal = $707,436 )
2021	2021	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Allergy and Infectious Diseases Research	000	3	5/27/2021	NON-COMPETING CONTINUATION	$707,436
														Subtotal = $707,436

Issue Date FY: 2020 ( Subtotal = $719,651 )
2020	2020	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Allergy and Infectious Diseases Research	000	2	5/27/2020	NON-COMPETING CONTINUATION	$719,651
														Subtotal = $719,651

Issue Date FY: 2019 ( Subtotal = $702,284 )
2019	2019	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Allergy and Infectious Diseases Research	000	1	6/7/2019	NEW	$702,284
														Subtotal = $702,284

Grand Total All Awards = $3,435,689

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Development of a High-Throughput Microfluidics-Enabled Functional Assay for Rapidly Identifying Neutralizing Antibodies

Award Number: R01AI141607

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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