Early clearance versus control: what is the meaning of a negative tuberculin skin test or interferon-gamma release assay following exposure to Mycobacterium tuberculosis?

Abstract

The elimination of tuberculosis (TB) cannot reasonably be achieved by treatment of individual cases and will require an improved vaccine or immunotherapy. A challenge in developing an improved TB vaccine has been the lack of understanding what is needed to generate sterilizing immunity against Mycobacterium tuberculosis (Mtb) infection. Several epidemiological observations support the hypothesis that humans can eradicate Mtb following exposure. This has been termed early clearance and is defined as elimination of Mtb infection prior to the development of an adaptive immune response, as measured by a tuberculin skin test or interferon-gamma release assay. Here, we examine research into the likelihood of and possible mechanisms responsible for early clearance in household contacts of patients with active TB. We explore both innate and adaptive immune responses in the lung. Enhanced understanding of these mechanisms could be harnessed for the development of a preventative vaccine or immunotherapy.

Keywords: Mycobacterium tuberculosis; household contact studies; infection; preventative vaccine.

Figure 1.. Outcomes of exposure to Mycobacterium tuberculosis (Mtb).

Mtb exposure can lead to infection, early clearance, latent tuberculosis infection, or, ultimately, tuberculosis. Early clearance occurs before the development of an adaptive immune response detected by a tuberculin skin test (TST) or interferon-gamma release assay (IGRA). Understanding of the underlying mechanisms dictating the outcomes of exposure to Mtb could greatly facilitate the definition of correlates of protective immunity to Mtb infection and generate targets of a preventative vaccine. Possible mechanisms responsible for early clearance in household contacts of active tuberculosis patients that are explored in this review are listed on the right (orange).