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Protection Against Mycobacterial Infection: A Case-Control Study of Pairs of Gambian Children with Discordant Infection Status Despite Matched TB Exposure

Background: Children are particularly susceptible to tuberculosis. However, most children exposed to Mycobacterium tuberculosis are able to control the pathogen without evidence of infection. Correlates of human protective immunity against tuberculosis infection are lacking, and their identification would aid vaccine design. 
 
Methods: We recruited pairs of asymptomatic children with discordant tuberculin skin test status but the same sleeping proximity to the same adult with sputum smear-positive tuberculosis in a matched case-control study in The Gambia. Participants were classified as either Highly Exposed Uninfected [HEU] or Highly Exposed Infected [HEI] children. Serial luminescence measurements using an in vitro functional auto-luminescent Bacillus Calmette–Guerin (BCG) whole blood assay quantified the dynamics of host control of mycobacterial growth. Assay supernatants were analysed with a multiplex cytokine assay to measure associated inflammatory responses. 
 
Findings: 29 pairs of matched HEI and HEU children aged 5 to 15 years old were enrolled. Samples from HEU children had higher levels of mycobacterial luminescence at 96H than HEI children. HEU children also produced less BCG-specific interferon-γ than HEI children at 24 hours and at 96 hours. 
 
Interpretation: HEI children showed superior control of mycobacterial growth compared to HEU children in a functional assay whilst cytokine responses mirrored infection status. 
 
Funding: Clinical Research Training Fellowship jointly funded by UK Medical Research Council (MRC) and UK Department for International Development (DFID) under MRC/DFID Concordat agreement and part of the EDCTP2 programme supported by the European Union (MR/K023446/1). Also enabled by MRC Program Grants (MR/K007602/1, MR/K011944/1, MC_UP_A900/1122). 
 
Declaration of Interests: BK holds a patent for a paediatric TB diagnostic biosignature. The authors do not have any other commercial or other association that might pose a conflict of interest. The data presented here form part of RB’s PhD thesis “Protection from Mycobacterium tuberculosis infection: Learning from exposed but uninfected children” awarded March 2018 by Imperial College London. 
 
Ethics Approval Statement: The study was approved by The Gambia Government/MRC Joint Ethics Committee (SCC1405 and SCC1273) and the Imperial College Healthcare Tissue Bank (R13071).