{
  "abstract": "Introduction Young children and children living with HIV are at high risk of progressing to tuberculosis (TB) disease following Mycobacterium tuberculosis (Mtb) exposure and infection, and also of developing severe forms of disease and TB-related mortality. Identifying children who have very early (sub-clinical) TB disease, prior to progression to clinically apparent TB, would mean that TB preventive treatment (TPT) could be more efficiently targeted to this group. Identifying biomarker changes on drug therapy in children with Mtb infection or very early disease could pave the way for the development of tests that can identify which children have viable bacilli and are therefore at increased risk of disease progression.Methods and analysis The INTREPID study will use already collected samples taken from well-phenotyped paediatric cohorts in three clinical studies conducted in South Africa in children <5 years, including a drug-resistant TPT trial (TB-CHAMP), an observational household contact study (interferon-gamma release assay studies) and a prospective diagnostic study (Umoya), all conducted in a setting with a high burden of TB and HIV. We will employ transcriptomic, proteomic, metabolomic and serology approaches to analyse changes in host blood profiles at every stage along the TB continuum, from Mtb exposure to disease and from children treated for Mtb infection and early TB disease, as well as targeted Mtb antibody analysis. Data on viral co-infections and relevant clinical and epidemiological parameters will be integrated and evaluated to identify the optimal biosignatures that can predict future progression to clinically overt disease in children below 5 years of age, including those living with HIV.Ethics and dissemination The study protocol received ethical approval from the Stellenbosch University Health Research Ethics Committee (N23/03/025). The study findings will be disseminated through peer-reviewed publications, scientific conferences and formal presentations to healthcare professionals and to local communities, in collaboration with the Desmond Tutu TB Centre Community Advisory Board.",
  "authors": [
    {
      "affiliations": [
        "Department of Infectious Disease, Imperial College London, London, England, UK",
        "Centre for Paediatrics and Child Health, Imperial College London, London, England, UK"
      ],
      "name": "Melissa Shea Hamilton"
    },
    {
      "affiliations": [
        "Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University Faculty of Medicine and Health Sciences, Cape Town, South Africa"
      ],
      "name": "Iena P Derks"
    },
    {
      "affiliations": [
        "Department of Infectious Disease, Imperial College London, London, England, UK",
        "Centre for Paediatrics and Child Health, Imperial College London, London, England, UK"
      ],
      "name": "Myrsini Kaforou"
    },
    {
      "affiliations": [
        "Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University Faculty of Medicine and Health Sciences, Cape Town, South Africa"
      ],
      "name": "Rory Dunbar"
    },
    {
      "affiliations": [
        "Ragon Institute of Massachusetts General Brigham, MIT and Harvard, Cambridge, Massachusetts, USA",
        "Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, Massachusetts, USA"
      ],
      "name": "Ryan P McNamara"
    },
    {
      "affiliations": [
        "Ragon Institute of Massachusetts General Brigham, MIT and Harvard, Cambridge, Massachusetts, USA",
        "Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, Massachusetts, USA"
      ],
      "name": "Sarah M Fortune"
    },
    {
      "affiliations": [
        "Centre for Genomics and Child Health, Queen Mary University of London, London, UK"
      ],
      "name": "Robin Basu-Roy"
    },
    {
      "affiliations": [
        "Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University Faculty of Medicine and Health Sciences, Cape Town, South Africa"
      ],
      "name": "Anneen van Deventer"
    },
    {
      "affiliations": [
        "Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University Faculty of Medicine and Health Sciences, Cape Town, South Africa"
      ],
      "name": "Corne Bosch"
    },
    {
      "affiliations": [
        "Department of Infectious Disease, Imperial College London, London, England, UK",
        "Centre for Paediatrics and Child Health, Imperial College London, London, England, UK"
      ],
      "name": "Claire Dunican"
    },
    {
      "affiliations": [
        "Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University Faculty of Medicine and Health Sciences, Cape Town, South Africa"
      ],
      "name": "Marieke M van der Zalm"
    },
    {
      "affiliations": [
        "Department of Infectious Disease, Imperial College London, London, England, UK",
        "Centre for Paediatrics and Child Health, Imperial College London, London, England, UK"
      ],
      "name": "Michael Levin"
    },
    {
      "affiliations": [
        "Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University Faculty of Medicine and Health Sciences, Cape Town, South Africa"
      ],
      "name": "H Simon Schaaf"
    },
    {
      "affiliations": [
        "Translational Genomics Research Institute, Arizona State University, Tempe, Arizona, USA"
      ],
      "name": "John A Altin"
    },
    {
      "affiliations": [
        "Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University Faculty of Medicine and Health Sciences, Cape Town, South Africa"
      ],
      "name": "Anneke C Hesseling"
    },
    {
      "affiliations": [
        "Department of Infectious Disease, Imperial College London, London, England, UK",
        "Centre for Paediatrics and Child Health, Imperial College London, London, England, UK",
        "Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University Faculty of Medicine and Health Sciences, Cape Town, South Africa"
      ],
      "name": "James A Seddon"
    }
  ],
  "title": "Protocol for a biomarker discovery study to identify correlates of risk for future tuberculosis disease progression in South African children (INTREPID)",
  "uid": "fdc326f2-0378-5ed5-8c5a-764fb4e8cc25"
}