title: The immunological effect of revaccination with Bacille Calmette-Guérin vaccine at 19 months of age.
abstract: BACKGROUND
  Bacille Calmette-Guérin (BCG) vaccination has important non-specific immune effects. In a randomized trial in Guinea-Bissau, BCG revaccination was associated with significantly increased survival in children who received diphtheria-tetanus-pertussis (DTP)-booster vaccine before enrolment and in children who did not receive micronutrient supplementation (MN). Within the trial we assessed the immunological effects of BCG revaccination.
  
  
  METHODS
  Children were randomized to BCG or nothing. Blood was sampled 6-11 weeks after randomization (early sample group) or 5-9 months later (late sample group). In vitro cytokine responses (interferon (IFN)-γ, interleukin (IL)-13, tumor-necrosis-factor (TNF)-α, and IL-10) were assessed in whole blood cultures stimulated with lipopolysaccharide (LPS), purified protein derivative (PPD) or phytohaemagglutinin (PHA). Effect-modification by sex, DTP-booster vaccination and MN was studied.
  
  
  RESULTS
  Cytokines were measured in 345 infants. BCG was associated with significantly increased IFN-γ (geometric mean ratio (GMR)=4.54 (95% confidence interval: 3.13-6.58)) and IL-13 (GMR=1.43 (1.00-2.05)) PPD responses, the effect being strongest in the early sample group. Across all three conditions BCG tended to increase IL-10 (LPS, PHA, PPD: GMR=1.20, 1.12, 1.20), most pronounced in the late sample group. BCG reduced the TNF-α/IL-10 ratio in boys with DTP-booster at bleeding and increased it in those without (interaction test: p=0.03). In children without MN, BCG was associated with reduced TNF-α response in the early sample group (p=0.006), and increased IL-10 in the late sample group (p=0.03).
  
  
  CONCLUSIONS
  BCG revaccination resulted in a strong IFN-γ response to PPD, which waned slightly over time. BCG also affected the pro-/anti-inflammatory balance, with reduced TNF-α and increased IL-10 responses to LPS, PHA and PPD. This effect depended on sex, DTP-booster vaccination and micronutrient supplementation, being most pronounced in children who had received DTP-booster before enrolment and children who had not received MN, i.e. the group of children which also had lower mortality after BCG revaccination.
authors.affiliation: Research Center for Vitamins & Vaccines, Bandim Health Project, Statens Serum Institute, Artillerivej 5, 2300 Copenhagen S, Denmark. a.andersen@bandim.org
authors.forename: Andreas
authors.initials: A
authors.lastname: Andersen
authors.forename: Adam
authors.initials: A
authors.lastname: Roth
authors.forename: Kristoffer Jarlov
authors.initials: KJ
authors.lastname: Jensen
authors.forename: Christian
authors.initials: C
authors.lastname: Erikstrup
authors.forename: Ida Marie
authors.initials: IM
authors.lastname: Lisse
authors.forename: Hilton
authors.initials: H
authors.lastname: Whittle
authors.forename: Erliyani
authors.initials: E
authors.lastname: Sartono
authors.forename: Maria
authors.initials: M
authors.lastname: Yazdanbakhsh
authors.forename: Peter
authors.initials: P
authors.lastname: Aaby
authors.forename: Christine Stabell
authors.initials: CS
authors.lastname: Benn
mesh_terms: D001500:BCG Vaccine / Q000008:administration & dosage* / Q000276:immunology*; D016001:Confidence Intervals; D019587:Dietary Supplements; D015721:Diphtheria-Tetanus-Pertussis Vaccine / Q000008:administration & dosage; D005260:Female; D006169:Guinea-Bissau; D006801:Humans; D007117:Immunization, Secondary; D007223:Infant; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000097:blood; D018793:Interleukin-13 / Q000097:blood; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D018977:Micronutrients / Q000008:administration & dosage / Q000276:immunology; D009163:Mycobacterium bovis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014611:Vaccination
chemical_list: D001500:BCG Vaccine; D015721:Diphtheria-Tetanus-Pertussis Vaccine; D018793:Interleukin-13; D008070:Lipopolysaccharides; D018977:Micronutrients; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma