title: Bacillus Calmette-Guérin immunisation at birth and morbidity among Danish children: A prospective, randomised, clinical trial.
abstract: BACKGROUND
  Studies from low-income countries report positive non-specific effects of early Bacillus Calmette-Guérin (BCG) immunisation on childhood health and survival. Neonatal immunisation with BCG may prime the immune system and offer partial protection against other infectious and possibly allergic diseases. The potential clinical value of these non-specific effects has not yet been examined in a large randomised trial in high-income countries.
  
  
  METHODS
  The Danish Calmette Study is a multicentre randomised clinical trial conducted between October 2012 and November 2015. Within the first 7 days of life, infants were randomly assigned to intra-dermal vaccination with BCG or no intervention. At 3 and 13 months of age structured telephone interviews and clinical examinations of the children were conducted. In a subgroup of children blood samples were drawn and stool samples collected at age 4 days, 3 and 13 months. Thymus index was assessed by ultrasound in a subgroup at randomisation and at 3 months. The primary study outcome is hospitalisation within the first 15 months of life as assessed in Danish health registers. Secondary outcomes include infectious disease hospitalisations, wheezing, eczema, use of prescribed medication, growth, development, thymus index, T- and B-cell subpopulations assessed by flow cytometry, in vitro cytokine responses and specific antibody responses to other vaccines. Adverse reactions were registered.
  
  
  CONCLUSIONS
  With participation of 4184 families and more than 93% adherence to clinical follow-up at 3 and 13 months, this randomised clinical trial has the potential to create evidence regarding non-specific effects of BCG vaccination in a high-income setting.
authors.affiliation: Department of Paediatrics, Kolding Hospital, Skovvangen 2-8, DK-6000 Kolding, Denmark. Electronic address: lmje@dadlnet.dk.
authors.forename: Lisbeth Marianne
authors.initials: LM
authors.lastname: Thøstesen
authors.affiliation: Department of Paediatrics 460, Copenhagen University Hospital, Hvidovre, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark. Electronic address: tnnissen@gmail.com.
authors.forename: Thomas Nørrelykke
authors.initials: TN
authors.lastname: Nissen
authors.affiliation: The Child and Adolescent Clinic 4072, Juliane Marie Centret, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. Electronic address: jekjaergaard@gmail.com.
authors.forename: Jesper
authors.initials: J
authors.lastname: Kjærgaard
authors.affiliation: Department of Paediatrics, Kolding Hospital, Skovvangen 2-8, DK-6000 Kolding, Denmark. Electronic address: gitte.thybo.pihl@rsyd.dk.
authors.forename: Gitte Thybo
authors.initials: GT
authors.lastname: Pihl
authors.affiliation: Department of Paediatrics 460, Copenhagen University Hospital, Hvidovre, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark. Electronic address: ninabirk@gmail.com.
authors.forename: Nina Marie
authors.initials: NM
authors.lastname: Birk
authors.affiliation: Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark; OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, DK-5000 Odense, Denmark. Electronic address: cb@ssi.dk.
authors.forename: Christine Stabell
authors.initials: CS
authors.lastname: Benn
authors.affiliation: Neonatal Department, Juliane Marie Centret, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. Electronic address: Gorm.Greisen@regionh.dk.
authors.forename: Gorm
authors.initials: G
authors.lastname: Greisen
authors.affiliation: Department of Paediatrics, Kolding Hospital, Skovvangen 2-8, DK-6000 Kolding, Denmark; Institute of Regional Health Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark. Electronic address: Poul.Erik.Kofoed@rsyd.dk.
authors.forename: Poul-Erik
authors.initials: PE
authors.lastname: Kofoed
authors.affiliation: Department of Paediatrics 460, Copenhagen University Hospital, Hvidovre, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark. Electronic address: pryds@dadlnet.dk.
authors.forename: Ole
authors.initials: O
authors.lastname: Pryds
authors.affiliation: Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark; OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, DK-5000 Odense, Denmark. Electronic address: hjn@ssi.dk.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ravn
authors.affiliation: Department of Paediatrics 460, Copenhagen University Hospital, Hvidovre, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark. Electronic address: Dorthe.Lisbeth.Jeppesen@regionh.dk.
authors.forename: Dorthe Lisbeth
authors.initials: DL
authors.lastname: Jeppesen
authors.affiliation: Bandim Health Project, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark. Electronic address: p.aaby@bandim.org.
authors.forename: Peter
authors.initials: P
authors.lastname: Aaby
authors.affiliation: The Child and Adolescent Clinic 4072, Juliane Marie Centret, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark; Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark. Electronic address: lone.graff.stensballe@regionh.dk.
authors.forename: Lone Graff
authors.initials: LG
authors.lastname: Stensballe
mesh_terms: D001500:BCG Vaccine / Q000008:administration & dosage* / Q000009:adverse effects; D016207:Cytokines / Q000276:immunology; D003718:Denmark; D019049:Developed Countries; D005260:Female; D006304:Health Status; D006801:Humans; D006967:Hypersensitivity / Q000517:prevention & control*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011446:Prospective Studies; D012107:Research Design
chemical_list: D001500:BCG Vaccine; D016207:Cytokines
keywords: BCG vaccination; Bacillus Calmette-Guérin; Children; Heterologous immunity; Non-specific effects of vaccines; Randomised clinical trial