THWART-TB : Testing Health Workers At Risk to advance our understanding of TB infection

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PROJECT SUMMARY Tuberculosis (TB) remains a leading infectious cause of death globally. 1.7 billion people worldwide are estimated to have been infected with TB (LTBI); yet TB infection remains poorly understood. Current LTBI tests cannot distinguish between current infection versus a persistent immune response to a cleared infection and have a low predictive value to identify which people are at risk of developing incident active TB disease. We propose to establish a prospective longitudinal cohort study of health workers (HWs) in Cape Town, South Africa, where our preliminary data reveals HWs have a high annual TB infection risk (34%). This cohort, who will undergo frequent serial evaluation (every 3 months) with a combination of novel assays never previously evaluated together, presents a unique opportunity to evaluate immune responses at the time of initial infection and to characterize the dynamic profile of these immune responses over time in a high-risk population. This interdisciplinary study addresses three knowledge gaps: 1) We will evaluate serial interferon gamma release assay (IGRA) responses to identify early TB infection and characterize the dynamics of IGRA conversion and reversion, which will contribute to understanding of transient versus persistent infection. Furthermore we will elicit HW preferences regarding serial LTBI testing strategies and decision making that will inform the implementation of HW TB screening, which is urgently needed given their occupational TB risk. 2) We will evaluate the temporal dynamics of immune responses to TB by measuring serial RNA biosignatures, C-reactive protein, and Mycobacterium tuberculosis (Mtb)-antibody responses. We will determine whether biosignature results are persistently elevated or wane over time and how these correlate with other measures of immune response. We will be able to comprehensively profile changes in Mtb-antibody responses by not only quantifying IgG levels but by evaluating all isotypes, subclasses and Fc-receptor binding profiles. 3) We will evaluate serial blood samples for detectable Mtb, based on testing of CD34-positive PBMCs and a phage-based assay (Actiphage). Comparing novel Mtb DNA detection approaches could enhance understanding and risk stratification for incident TB in high-risk populations. Our novel data on Mtb immune responses and Mtb quantification in people with LTBI will improve understanding of the correlates of TB immune clearance versus persistence and could help to identify individuals at a higher risk of progression. This study is aligned with the NIAID mission to ‘advance the understanding and diagnosis of re-emerging diseases such as TB’ and to ‘develop international research capacity to respond appropriately to re-emerging disease threats’.