Neonatal BCG Vaccination Reduces Interferon-γ Responsiveness to Heterologous Pathogens in Infants From a Randomized Controlled Trial

• Published in: The Journal of infectious diseases Vol. 221; no. 12; pp. 1999 - 2009
• Main Authors: Freyne, Bridget, Messina, Nicole L, Donath, Susan, Germano, Susie, Bonnici, Rhian, Gardiner, Kaya, Casalaz, Dan, Robins-Browne, Roy M, Netea, Mihai G, Flanagan, Katie L, Kollmann, Toby, Curtis, Nigel
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 11.06.2020
• Subjects: Age Factors; Australia; Bacillus Calmette-Guerin vaccine; Bacterial Infections - immunology; Bacterial Infections - microbiology; Bacterial Infections - prevention & control; BCG; BCG Vaccine - administration & dosage; BCG Vaccine - immunology; Cytokines; Female; Follow-Up Studies; Host Microbial Interactions - immunology; Humans; Immunity, Heterologous; Immunization; Immunization Schedule; Immunogenicity, Vaccine; Infant; Infant, Newborn; Infants; Inflammation; Interferon; Interferon-gamma - blood; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin 1 receptor antagonist; Interleukin 1 receptors; Interleukin 10; Interleukin 8; Ligands; Macrophage inflammatory protein; Major and Brief Reports; Male; Mass Vaccination - methods; Neonates; Newborn babies; Pathogens; Stimulants; TLR1 protein; Toll-like receptors; Treatment Outcome; Vaccination; γ-Interferon; Australia; heterologous; infants; innate immunity; immunization; BCG; nonspecific effects
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiaa030

Abstract 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. Neonatal BCG vaccination results in a decreased proportion of infants mounting an IFN-γ response to heterologous stimulation at 7 months of age. Both sex and maternal BCG vaccination status influenced the effect of BCG vaccination on heterologous cytokine responses.