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Population differences in immune responses following neonatal BCG vaccination in different African settings

Presented at the Neonatal Society 2010 Autumn Meeting.

Fitchett JR1, Lalor MK1, Ben-Smith A1,2, Crampin A2,3, Fine PEM3, Ota MO4, Burl S5, Flanagan KL5, Dockrell HM1

1 Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United Kingdom
2 Karonga Prevention Study, Chilumba, Karonga District, Malawi
3 Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
4 Tuberculosis Immunology, Medical Research Council (UK) The Gambia, Fajara, The Gambia
5 Infant Immunology, Medical Research Council (UK) The Gambia, Fajara, The Gambia

Background: Live-attenuated Mycobacterium bovis Bacille Calmette-Guérin (BCG) is currently the only vaccine available to protect against tuberculosis (TB). Neonatal administration of the vaccine induces a TH1- type immune response and secretion of the cytokine IFN-γ. BCG protects against severe childhood cases of tuberculous meningitis and miliary TB but confers variable protection against pulmonary TB later in life, particularly in TB endemic areas. Earlier studies attempting to study mechanisms behind this discrepancy have shown that Mycobacterium tuberculosis (M.tb) PPD-stimulated IFN-γ concentrations in 6 day diluted whole blood cultures were much higher in UK BCG vaccinated infants compared to age-matched Malawian infants given the BCG vaccine. We have now tested another group of infants and their mothers using identical laboratory protocols in another TB endemic country, The Gambia.

Methods: Neonates were vaccinated with BCG in the first week of life and at three-months-old infants were recruited into the study with their biological mothers. Venous blood samples were taken from infant-mother pairs for the detection of IFN-γ production by enzyme-linked immunosorbent assay (ELISA) following diluted whole blood assay stimulation with an array of tuberculous antigens over 6 days.

Results: 93% of Gambian infants (28 of 30) made a positive IFN-γ response (>62pg/ml) to M.tbPPD stimulation, comparable to previously studied UK infants (93% vs. 100%), and higher than the proportion of responders previously detected in Malawi (93% vs. 53%; Lalor MK et al. JID 2009; 199:795-800). However, the median IFN-γ response from Gambian infants was lower than median IFN-γ responses from UK infants (310pg/ml vs. 1,779pg/ml; p = <0.0001). The median IFN-γ responses in Gambian and Malawian infants were comparable (310pg/ml vs. 289pg/ml; p = 0.7036). The response measured in the Gambian infants was not associated with the response measured in their mothers.

Conclusion: The study findings indicate quantitative differences in cytokine secretion in different African settings in response to M.tb PPD antigen stimulation. The data are consistent with published evidence demonstrating lower infant immune responses post-BCG vaccination by latitude, and the underlying mechanisms influencing cytokine secretion post-vaccination warrant further investigation.

Acknowledgements: Bill and Melinda Gates Foundation Grand Challenge (award 6_74 to S.H.E. Kaufmann, principal investigator; H.M.D., coinvestigator; M.O.O., coinvestigator). The Gambian infants were recruited from a field site funded by MRC (UK). The elective project was kindly supported by a grant from the Neonatal Society to J.R.F.

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