Dynamics and immune mechanisms of QFT response in close contacts of TB cases

Rationale: A vaccine that prevents infection with Mycobacterium tuberculosis (Mtb) (POI vaccine) is an ideal approach to TB control.  As Mtb infection (MTBI) is measured indirectly (positive tuberculin skin test (TST) or interferon gamma release assay (IGRA), prevention of IGRA conversion is the primary endpoint for POI trials.  A recent trial showed that revaccination of adolescents with BCG failed to prevent IGRA conversion but was 45.4% effective in preventing sustained IGRA conversion. This observation provides impetus for the study of protective immune mechanisms in the context of the dynamics of IGRA conversion and reversion. The HHC model has substantial advantages over the adolescent cohorts used in the vaccine trial as the nature, timing and intensity of exposure to TB is known. In the research design, we will prioritize elucidating mechanisms associated with QFT-con, QFT-rev and risk of progression to TB. Although unsustained IGRA conversion has been taken as an efficacy endpoint in POI trials, published initial findings indicate that they may be at substantial risk of progression, comparable, in fact, to the IGRA converters. Having all 4 groups, the proposed study will allow us to clarify this issue.

Aims:

1. Determine the clinical implications of dynamic changes in the QFT response in 12 months following close contact with a TB patient.
2. Examine if dynamic changes in the QFT response are associated with activation of phenotypically and functionally distinct subsets of T cells.
3. Examine if the dynamic changes in the QFT response are associated with     altered macrophage anti-mycobacterial effector responses.