Immune correlates of early clearance of <i>Mycobacterium tuberculosis</i> among tuberculosis household contacts in Indonesia

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’.