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Rabbit InMAD Discovery of Novel Biomarkers for POC Tuberculosis Diagnostic Assay

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI104377-01A1
Agency Tracking Number: R41AI104377
Amount: $592,540.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA12-089
Solicitation Year: 2013
Award Year: 2014
Award Start Date (Proposal Award Date): 2014-04-15
Award End Date (Contract End Date): 2016-03-31
Small Business Information
Norman, OK 73071-1127
United States
DUNS: 099550915
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (405) 253-6004
Business Contact
Phone: (405) 360-4669
Research Institution
FORT COLLINS, CO 80523-1062
United States

 Nonprofit college or university

DESCRIPTION provided by applicant Tuberculosis TB is a chronic infectious disease that infects approximately one third of the worldandapos s population Eighty five percent of the estimated million new cases of TB in occurred in resource limited countries located in Asia and Africa In there were million deaths from TB among HIV negative patients and additional TB deaths among HIV positive patients In some tuberculosis endemic areas fewer than of TB cases are diagnosed due to the lack of accurate and easy to use diagnostic assays Currently diagnosis relies on demonstration of the bacteria Mycobacterium tuberculosis in clinical specimens by serial sputum smear microscopy and culture These methods lack sensitivity are time consuming are expensive and require trained personnel An alternative approach is to develop an efficient immunoassay to detect M tb antigens in bodily fluid such as serum or urine Current commercial immunoassay kits that detect M tb glycan lipoarabinomannan LAM in urine exhibit poor sensitivity perhaps due to low abundance Alternative biomarkers need to be identified to facilitate accurate diagnosis and treatment of tuberculosis Our overall hypothesis is that M tb biomarkers are shed into the urine and or serum during infection and that high affinity monoclonal antibodies can be generated in rabbits to these biomarkers Subsequently we hypothesize that through the use of these mAbs a sensitive and specific immunoassay can be constructed to detect these biomarkers in patients The first specific aim is to identify novel M tb biomarkers shed into serum and urine during infection This will be accomplished by immunizing na ve rabbits with serum and urine from infected rabbits a technique known as InMAD Unlike rabbits immunized with crude antigens such as M tb whole cell lysate or culture filtrate rabbits immunized using this approach will create antibodies to only clinically relevant biomarkers that are shed into the serum or urine The key to this aim is that rabbits will be infected with a highly virulent strain of M tb W Beiing strain sublineage RD that has high transmission rates and represents endemic disease The polyclonal antibodies will be used in proteomic analysis of serum and urine samples of infected rabbits in the second aim which is to validate the identified biomarkers The third specific aim is to produce rabbit monoclonal antibodies to the validated M tb biomarkers While several M tb immunoreactive proteins have been previously described the approach that we will use in all three aims will facilitate the identification of new biomarkers Using the rabbit for both the disease model and immunization will provide relevant disease state serum and urine as well as antibodies that will have higher affinity and greater epitope recognition than
their mouse counter parts If the goals of this Phase I are achieved Phase II will use mAbs from Phase I to construct and evaluate an immunoassay in POC format Our preferred assay platform would be the lateral flow immunochromatographic dipstick assay as it will meet all of the World Health Organizationandapos s A S S U R E D criteria for developing world diagnostic assays If successful this translational research project could dramatically decrease mortality from tuberculosis through accurate diagnosis allowing for appropriate treatment Importantly this can be done at the low cost needed in resource limited countries PUBLIC HEALTH RELEVANCE Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis the bacillus that infects approximately one third of the worldandapos s population Current diagnostic methods either lack effective sensitivity or are too labor and resource intensive for regions where tuberculosis burden is greatest This is a translational research study whose initial goal is to identify biomarkers that are shed into the urine or serum of M tuberculosis infected rabbits with the ultimate goal of developing an immunoassay that will facilitate accurate and timely diagnosis of tuberculosis If successful this project could dramatically decrease the morbidity mortality and health care costs associated with tuberculosis through earlier diagnosis

* Information listed above is at the time of submission. *

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