About

The Problem

The 2035 target of the End TB Strategy is a 90% reduction in TB rates and 95% reduction in TB deaths compared with 2015 levels. Although the global TB mortality is falling, 16% of TB patients still die. Most deaths from TB are preventable with early diagnosis and appropriate treatment.

However, more than 4 million patients are not diagnosed or treated due to inadequate tests that either lack sensitivity or require sophisticated laboratory infrastructure which is unavailable in the majority of health care settings. A point-of-care (PoC) triage test is needed in low resource settings to prioritize those with the highest risk for TB disease to higher levels of care. On the other hand, more complex, resource-intensive but highly accurate tests would improve diagnosis of complicated cases in well-developed health care systems and in specialized medical facilities, even in less developed settings. Varied diagnostic capacity may co-exist in different regions of the same country, for instance in the rural and urban areas of Africa, and therefore a comprehensive battery of diagnostic tests that are appropriate for specific settings are needed. Children also pose specific diagnostic challenges and tests suit-able for adults may not always be appropriate.

Meeting the End TB Strategy targets will also require dramatically improved prevention of disease approaches to block transmission. With 1.7 billion people latently infected, it is not cost-effective to provide prophylaxis to all. Hence a test that could predict those most at risk of developing disease would enable targeted therapeutic approaches. Similarly, tests to enable personalized or stratified treatment strategies are urgently needed.

Our Approach

Our hypothesis is that recent molecular and microbiological diagnostic advances have opened the door for new approaches that can target different levels of health care. The new tests address different cut-points in the TB infection and disease spectrum.

We will test a range of new assays for different levels of health care: 1) at PoC: two triage tests, based on detection of host proteins (priority Ia), and host transcripts (priority Ib), both on fingerstick blood, and a high-sensitivity urinary lipoarabinomannan (uLAM) assay (priority Ic); and 2) at central laboratories: multiplex real time quantitative reverse transcriptase PCR (qRT-PCR) test for the top published mRNA signatures and a host 4-protein biosignature in blood measured by Luminex (priorities IIa and IIb, respectively) for progression to TB.

We will evaluate the performance of these tests according to internationally established target product profiles (TPP) for the respective health care levels through the following Specific Aims:

AIM 1: Evaluate tests for active TB disease.

This will include priorities I-IIa and tests and will be evaluated in children and adults (between ages 3 months and 70 years), with and without HIV-coinfection, and in different socio-economic settings. We will perform head-to-head comparisons of our target tests in patient cohorts from Africa (South Africa and Gambia) and SE Asia (Vietnam), presenting with symptoms compatible with active TB in primary healthcare settings.

AIM 2: Evaluate tests to identify those with the highest risk for progression to active TB.

To identify incident TB amongst household contacts of active TB cases, we will follow up close contacts for 12 months and perform predictive assays. Cohorts include children and adults between the ages of 12 and 70 years, with and without HIV infection.'