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Neonatal BCG vaccination reduces interferon-γ responsiveness to heterologous pathogens in infants from a randomized controlled trial


Freyne, B and Messina, NL and Donath, S and Germano, S and Bonnici, R and Gardiner, K and Casalaz, D and Robins-Browne, RM and Netea, MG and Flanagan, K and Kollmann, T and Curtis, N, Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) Group, Neonatal BCG vaccination reduces interferon-γ responsiveness to heterologous pathogens in infants from a randomized controlled trial, Journal of Infectious Diseases, 221, (12) pp. 1999-2009. ISSN 0022-1899 (2020) [Refereed Article]

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Copyright Statement

The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: doi:10.1093/infdis/jiaa030


Background: BCG vaccination has beneficial nonspecific (heterologous) effects that protect against nonmycobacterial infections. We have previously reported that BCG vaccination at birth alters in vitro cytokine responses to heterologous stimulants in the neonatal period. This study investigated heterologous responses in 167 infants in the same trial 7 months after randomization.

Methods: A whole-blood assay was used to interrogate in vitro cytokine responses to heterologous stimulants (killed pathogens) and Toll-like receptor (TLR) ligands.

Results: Compared to BCG-naive infants, BCG-vaccinated infants had increased production of interferon gamma (IFN-γ) and monokine induced by gamma interferon (MIG) (CXCL9) in response to mycobacterial stimulation and decreased production of IFN-γ in response to heterologous stimulation and TLR ligands. Reduced IFN-γ responses were attributable to a decrease in the proportion of infants who mounted a detectable IFN-γ response. BCG-vaccinated infants also had increased production of MIG (CXCL9) and interleukin-8 (IL-8), and decreased production of IL-10, macrophage inflammatory protein-1α (MIP-1α), and MIP-1β, the pattern of which varied by stimulant. IL-1Ra responses following TLR1/2 (Pam3CYSK4) stimulation were increased in BCG-vaccinated infants. Both sex and maternal BCG vaccination status influenced the effect of neonatal BCG vaccination.

Conclusions: BCG vaccination leads to changes in IFN-γ responsiveness to heterologous stimulation. BCG-induced changes in other cytokine responses to heterologous stimulation vary by pathogen.

Item Details

Item Type:Refereed Article
Keywords:BCG, heterologous, immunization, infants, innate immunity, nonspecific effects
Research Division:Biomedical and Clinical Sciences
Research Group:Paediatrics
Research Field:Neonatology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Prevention of human diseases and conditions
UTAS Author:Flanagan, K (Dr Katie Flanagan)
ID Code:152348
Year Published:2020
Web of Science® Times Cited:15
Deposited By:Health Sciences
Deposited On:2022-08-17
Last Modified:2022-09-15
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