Early Clearance of Mycobacterium tuberculosis: The INFECT Case Contact Cohort Study in Indonesia

Abstract

Background Early clearance of Mycobacterium tuberculosis is the eradication of infection before an adaptive immune response develops. We aimed to identify host factors associated with early clearance. Methods Indonesian household contacts patients with smear-positive tuberculosis (TB) had an interferon-γ release assay (IGRA) at baseline and 14 weeks later. Early clearance was defined as a persistently negative IGRA. Contact characteristics, exposure, and disease phenotype were assessed for association with a positive IGRA at each time point. Results Of 1347 contacts of 462 TB cases, 780 (57.9%) were IGRA positive and 490 (36.3%) were IGRA negative. After 14 weeks, 116 of 445 (26.1%) initially negative contacts were IGRA converters; 317 (71.2%) remained persistently negative. BCG vaccination reduced the risk of a positive baseline IGRA (relative risk [RR], 0.89 [95% confidence interval {CI} .83–.97]; P = .01), and strongly reduced the risk of IGRA conversion (RR, 0.56 [95% CI, .40–.77]; P < .001). BCG protection decreased with increasing exposure (P = .05) and increasing age (P = .004). Risk of IGRA conversion was positively associated with hemoglobin concentration (P = .04). Conclusions A quarter of household TB case contacts were early clearers. Protection against M. tuberculosis infection was strongly associated with BCG vaccination. Lower protection from BCG with increasing M. tuberculosis exposure and age can inform vaccine development.

Innate immune memory of tissue-resident macrophages and trained innate immunity: Re-vamping vaccine concept and strategies

“…In so doing, trained AM will be able to overcome the innate immune tolerogenic/suppressive effects of M.tb upon exposure for enhanced innate protection. Indeed, it has been observed that up to 20% of the human house contacts exposed to M.tb could quickly clear infection (early clearers) as judged by lack of conversion in the interferon‐gamma‐release assay and purified protein derivative skin test, 55 and such protection is associated with increased innate immune responses and BCG vaccination 58,59 …”

“…Interrogating the innate immune training effects at local mucosal tissue levels following parenteral BCG vaccination represents a timely quest. It will help understand the innate immune mechanisms underlying the early, adaptive immunity‐independent clearance of M.tb in the lung upon exposure observed among BCG‐vaccinated humans who were in close contact with index TB cases 55,58,59 . The circulating mononuclear cells from these early clearers produced enhanced proinflammatory cytokines in response to heterologous pathogens E. coli and S. pneumoniae .…”

Heterogenous Immune Response to TB is Not a False Negative

“…Third, in a recent study, Verrall et al 5 found that early clearance of M. tuberculosis is associated with increased innate immune responses. Likewise, the clearance of M. tuberculosis may be associated with T-cell responses.…”

Thinking Outside the Box: Innate- and B Cell-Memory Responses as Novel Protective Mechanisms Against Tuberculosis

“…As mentioned before, the study of the mechanisms underlying immunity to Mtb infection has focused on immunological memory mediated by adaptive immune cells, mainly CD4+ T helper lymphocytes. However, human studies have shown that up to a quarter of the individuals that are in close contact with active TB patients remain clear of the infection (16). These individuals test negatively in the purified protein derivative (PPD) skin test and IFN-γ release assays (IGRAs) (16,17), which are two indirect readouts of adaptive responses against immune-dominant Mtb antigens.…”

“…However, human studies have shown that up to a quarter of the individuals that are in close contact with active TB patients remain clear of the infection (16). These individuals test negatively in the purified protein derivative (PPD) skin test and IFN-γ release assays (IGRAs) (16,17), which are two indirect readouts of adaptive responses against immune-dominant Mtb antigens. A positive BCG vaccination history has been associated with this state of immune protection (16).…”