Lisbeth Marianne Thøstesen1, Thomas Nørrelykke Nissen2, Jesper Kjærgaard3, Gitte Thybo Pihl4, Nina Marie Birk5, Christine Stabell Benn6, Gorm Greisen7, Poul-Erik Kofoed8, Ole Pryds9, Henrik Ravn10, Dorthe Lisbeth Jeppesen11, Peter Aaby12, Lone Graff Stensballe13. 1. Department of Paediatrics, Kolding Hospital, Skovvangen 2-8, DK-6000 Kolding, Denmark. Electronic address: lmje@dadlnet.dk. 2. Department of Paediatrics 460, Copenhagen University Hospital, Hvidovre, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark. Electronic address: tnnissen@gmail.com. 3. 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. 4. Department of Paediatrics, Kolding Hospital, Skovvangen 2-8, DK-6000 Kolding, Denmark. Electronic address: gitte.thybo.pihl@rsyd.dk. 5. Department of Paediatrics 460, Copenhagen University Hospital, Hvidovre, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark. Electronic address: ninabirk@gmail.com. 6. 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. 7. Neonatal Department, Juliane Marie Centret, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. Electronic address: Gorm.Greisen@regionh.dk. 8. 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. 9. Department of Paediatrics 460, Copenhagen University Hospital, Hvidovre, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark. Electronic address: pryds@dadlnet.dk. 10. 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. 11. Department of Paediatrics 460, Copenhagen University Hospital, Hvidovre, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark. Electronic address: Dorthe.Lisbeth.Jeppesen@regionh.dk. 12. Bandim Health Project, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark. Electronic address: p.aaby@bandim.org. 13. 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.
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. DISCUSSION: 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.
RCT Entities:
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. DISCUSSION: 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: T N Nissen; N M Birk; B A Blok; R J W Arts; A Andersen; J Kjærgaard; L M Thøstesen; T Hoffmann; D L Jeppesen; S D Nielsen; P-E Kofoed; L G Stensballe; P Aaby; M Ruhwald; M G Netea; C S Benn; O Pryds Journal: Eur J Clin Microbiol Infect Dis Date: 2017-09-10 Impact factor: 3.267
Authors: Jesper Kjærgaard; Nina M Birk; Thomas N Nissen; Lisbeth M Thøstesen; Gitte T Pihl; Christine S Benn; Dorthe L Jeppesen; Ole Pryds; Poul-Erik Kofoed; Peter Aaby; Gorm Greisen; Lone G Stensballe Journal: Pediatr Res Date: 2016-07-18 Impact factor: 3.756
Authors: Nina Marie Birk; Thomas Nørrelykke Nissen; Jesper Kjærgaard; Hans Jacob Hartling; Lisbeth Marianne Thøstesen; Poul-Erik Kofoed; Lone Graff Stensballe; Andreas Andersen; Ole Pryds; Mihai G Netea; Christine Stabell Benn; Susanne Dam Nielsen; Dorthe Lisbeth Jeppesen Journal: Sci Rep Date: 2017-09-29 Impact factor: 4.379