title: The effect of neonatal BCG vaccination on atopy and asthma at age 7 to 14 years: an historical cohort study in a community with a very low prevalence of tuberculosis infection and a high prevalence of atopic disease.
abstract: BACKGROUND
  There are conflicting reports on the effect of BCG vaccination on the subsequent development of atopy and asthma. There are no data on the effects of neonatal BCG vaccination on cytokine responses of lymphocytes that are exposed in vitro to allergens.
  
  
  OBJECTIVE
  We sought to test the hypothesis that neonatal BCG vaccination or, alternatively, evidence of an immunologic memory of this vaccination is associated with a reduced prevalence of allergic sensitization, asthma, eczema, and hay fever during childhood.
  
  
  METHODS
  An historical cohort study was conducted among 7- to 14-year-old children who were born in 2 districts in Sydney, Australia, and whose mothers were born in southeast Asia. One district had routinely administered BCG vaccination to infants born to overseas-born mothers and the other had not. Eligible subjects were identified from birth registers. Consenting subjects completed questionnaires, performed spirometric and airway hyperresponsiveness testing, and had allergen skin prick testing and tuberculin skin testing. Blood was collected to measure total serum IgE levels and for in vitro lymphocyte culture in the presence of an extract of house dust mite, the dominant allergen in this region, and purified protein derivative of Mycobacterium tuberculosis (tuberculin). IL-4, IL-5, IL-10, and IFN-gamma were measured in the culture supernatant.
  
  
  RESULTS
  The cohort included 309 BCG-vaccinated subjects and 442 non-BCG-vaccinated subjects. BCG-vaccinated subjects did not have a lower rate of allergic sensitization than nonvaccinated subjects. However, among the subgroup of subjects with a family history of rhinitis or eczema, BCG vaccination was associated with a lower prevalence of current asthma (defined as recent wheezing plus airway hyperresponsiveness; relative risk, 0.46; 95% CI, 0.22-0.95). BCG vaccination was also associated with lower levels of allergen-stimulated IL-10 production in vitro. Among the BCG-vaccinated subjects, the 44 (14.3%) who had tuberculin skin test reaction sizes of 5 mm or greater and the 31 (18.3%) who demonstrated an in vitro IFN-gamma response to purified protein derivative of M tuberculosis did not have lower rates of allergic sensitization and, overall, did not have a lower prevalence of allergic disease than tuberculin skin test or IFN-gamma nonreactors.
  
  
  CONCLUSIONS
  We conclude that neonatal BCG vaccination has an effect on T-cell allergen responsiveness 7 to 14 years after vaccination and that among a subgroup of subjects with an inherited predisposition to allergic disease, this is associated with clinically relevant beneficial effects. The findings of this study encourage the view that external influences on the immune system in the neonatal period have consequences that extend into later childhood and influence the expression of asthma. Genetic factors are likely to modify the effect of those external factors.
authors.affiliation: Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.
authors.forename: Guy B
authors.initials: GB
authors.lastname: Marks
authors.forename: Kitty
authors.initials: K
authors.lastname: Ng
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Brett G
authors.initials: BG
authors.lastname: Toelle
authors.forename: Wei
authors.initials: W
authors.lastname: Xuan
authors.forename: Elena G
authors.initials: EG
authors.lastname: Belousova
authors.forename: Warwick J
authors.initials: WJ
authors.lastname: Britton
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000375:Aging / Q000502:physiology*; D001249:Asthma / Q000517:prevention & control*; D001315:Australia / Q000453:epidemiology; D001500:BCG Vaccine / Q000627:therapeutic use*; D002478:Cells, Cultured; D015331:Cohort Studies; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000453:epidemiology / Q000517:prevention & control*; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D015995:Prevalence; D014373:Tuberculin / Q000494:pharmacology; D014374:Tuberculin Test; D014376:Tuberculosis / Q000453:epidemiology; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D014373:Tuberculin; D007371:Interferon-gamma