title: Early versus late BCG vaccination in HIV-1-exposed infants in Uganda: study protocol for a randomized controlled trial.
abstract: Bacillus Calmette-Guérin (BCG) vaccination may have nonspecific effects, i.e., effects on childhood morbidity and mortality that go beyond its effect on the risk of childhood tuberculosis (TB). Though the available scientific literature is mostly from observational studies, and is fraught with controversy, BCG vaccination at birth may protect infants in high-mortality populations against serious infections other than TB. Yet, other studies indicate that giving BCG later in infancy may modify immune responses to non-TB antigens and potentially enhance immunity, potentially also against tuberculosis (TB). It is unclear whether BCG vaccination very early in life offers adequate protection against TB and other infections among HIV-1-exposed children because even those who remain uninfected with HIV-1 show signs of impaired immunocompetence early in infancy. This study will compare BCG vaccination at birth with BCG vaccination at 14 weeks of age in HIV-1-exposed infants.
  
  
  
  This is an individually randomized controlled trial in 2200 HIV-1-exposed infants. The intervention is BCG vaccination within 24 h of birth while the comparator is BCG given at 14 weeks of age. The study co-primary outcomes are severe illness in the first 14 weeks of life, and production of tumor necrosis factor, interleukin (IL)-1β, IL-6 and interferon-γ in response to mycobacterial and nonmycobacterial antigens. The study is being conducted in three health centers in Uganda.
  
  
  
  A well-timed BCG vaccination could have important nonspecific effects in HIV-1-exposed infants. This trial could inform the development of appropriate timing of BCG vaccination for HIV-1-exposed infants.
  
  
  
  ClinicalTrials.gov, identifier: NCT02606526 . Registered on 12 November 2015.
authors.affiliation: Department of Epidemiology and Biostatics, School of Public Health, College of Health Sciences, Makerere University, Kampala, Uganda. nankabirwav@gmail.com.|Centre for Intervention Science in Maternal and Child Health, Centre for International Health, University of Bergen, . nankabirwav@gmail.com.
authors.forename: Victoria
authors.identifier: http://orcid.org/0000-0002-9952-8942
authors.initials: V
authors.lastname: Nankabirwa
authors.affiliation: Department of Paediatrics and Child Health, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
authors.forename: James K
authors.initials: JK
authors.lastname: Tumwine
authors.affiliation: Centre for Intervention Science in Maternal and Child Health, Centre for International Health, University of Bergen.
authors.forename: Olive
authors.initials: O
authors.lastname: Namugga
authors.affiliation: Centre for Intervention Science in Maternal and Child Health, Centre for International Health, University of Bergen.
authors.forename: Thorkild
authors.initials: T
authors.lastname: Tylleskär
authors.affiliation: Department of Paediatrics and Child Health, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
authors.forename: Grace
authors.initials: G
authors.lastname: Ndeezi
authors.affiliation: Centre for Intervention Science in Maternal and Child Health, Centre for International Health, University of Bergen.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Robberstad
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Centre for Intervention Science in Maternal and Child Health, Centre for International Health, University of Bergen.|Global Women and Children's Health, Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Halvor
authors.initials: H
authors.lastname: Sommerfelt
mesh_terms: D001500:BCG Vaccine / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D002985:Clinical Protocols; D016207:Cytokines / Q000097:blood / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000635:transmission / Q000821:virology; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D064789:Immunity, Heterologous; D007115:Immunization Schedule; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D014454:Uganda; D014611:Vaccination
chemical_list: D001500:BCG Vaccine; D015415:Biomarkers; D016207:Cytokines
keywords: BCG; Infants HIV-1-exposed; Nonspecific effects; Trial; Vaccination