Abstract Some individuals, even when heavily exposed to an infectious tuberculosis patient, do not develop a specific T-cell response as measured by interferon-gamma release assay (IGRA). This could be explained by an IFN-γ-independent adaptive immune response, or an effective innate host response clearing Mycobacterium tuberculosis (Mtb) without adaptive immunity. In heavily exposed Indonesian tuberculosis household contacts (n=1347), a persistently IGRA negative status was associated with presence of a BCG scar, and - especially among BCG-vaccinated individuals - with altered innate immune cells dynamics, higher heterologous ( Escherichia coli -induced) proinflammatory cytokine production, and higher inflammatory proteins in the IGRA mitogen tube. Neither circulating concentrations of Mtb -specific antibodies nor functional antibody activity associated with IGRA status at baseline or follow-up. In a cohort of adults in a low tuberculosis incidence setting, BCG vaccination induced heterologous innate cytokine production, but only marginally affected Mtb- specific antibody profiles. Our findings suggest that a more efficient host innate immune response, rather than a humoral response, mediates early clearance of Mtb . The protective effect of BCG vaccination against Mtb infection may be linked to innate immune priming, also termed ‘trained immunity’.

Immune correlates of early clearance of Mycobacterium tuberculosis among tuberculosis household contacts in Indonesia