title: BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies.
abstract: BACKGROUND
  The efficacy of BCG vaccines against pulmonary tuberculosis varies between populations, showing no protection in Malawi but 50-80% protection in the UK. To investigate the mechanism underlying these differences, randomised controlled studies were set up to measure vaccine-induced immune responsiveness to mycobacterial antigens in both populations.
  
  
  METHODS
  483 adolescents and young adults in Malawi and 180 adolescents in the UK were tested for interferon-gamma (IFN-gamma) response to M tuberculosis purified protein derivative (PPD) in a whole blood assay, and for delayed type hypersensitivity (DTH) skin test response to tuberculin PPD, before and 1 year after receiving BCG (Glaxo 1077) vaccination or placebo or no vaccine.
  
  
  RESULTS
  The percentages of the randomised individuals who showed IFN-gamma and DTH responses were higher in Malawi than in the UK pre-vaccination-ie, 61% (331/546) versus 22% (47/213) for IFN-gamma and 46% (236/517) versus 13% (27/211) for DTH. IFN-gamma responses increased more in the UK than in Malawi, with 83% (101/122) and 78% (251/321) respectively of the vaccinated groups responding, with similar distributions in the two populations 1 year post-vaccination. The DTH response increased following vaccination in both locations, but to a greater extent in the UK than Malawi. The IFN-gamma and DTH responses were strongly associated, except among vaccinees in Malawi.
  
  
  CONCLUSIONS
  The magnitude of the BCG-attributable increase in IFN-gamma responsiveness to M tuberculosis PPD, from before to 1 year post-vaccination, correlates better with the known levels of protection induced by immunisation with BCG than does the absolute value of the IFN-gamma or DTH response after vaccination. It is likely that differential sensitisation due to exposure to environmental mycobacteria is the most important determinant of the observed differences in protection by BCG between populations.
authors.affiliation: Karonga Prevention Study, Chilumba, Malawi.
authors.forename: Gillian F
authors.initials: GF
authors.lastname: Black
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Weir
authors.forename: Sian
authors.initials: S
authors.lastname: Floyd
authors.forename: Lyn
authors.initials: L
authors.lastname: Bliss
authors.forename: David K
authors.initials: DK
authors.lastname: Warndorff
authors.forename: Amelia C
authors.initials: AC
authors.lastname: Crampin
authors.forename: Bagrey
authors.initials: B
authors.lastname: Ngwira
authors.forename: Lifted
authors.initials: L
authors.lastname: Sichali
authors.forename: Bernadette
authors.initials: B
authors.lastname: Nazareth
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
authors.forename: Keith
authors.initials: K
authors.lastname: Branson
authors.forename: Steven D
authors.initials: SD
authors.lastname: Chaguluka
authors.forename: Linda
authors.initials: L
authors.lastname: Donovan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jarman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: King
authors.forename: Paul E M
authors.initials: PE
authors.lastname: Fine
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Dockrell
mesh_terms: D000293:Adolescent; D000328:Adult; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008295:Malawi; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D014373:Tuberculin / Q000276:immunology*; D014374:Tuberculin Test; D014376:Tuberculosis / Q000517:prevention & control*; D006113:United Kingdom
chemical_list: D001500:BCG Vaccine; D014373:Tuberculin; D007371:Interferon-gamma