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

Bridget Freyne; Nicole L Messina; Susan Donath; Susie Germano; Rhian Bonnici; Kaya Gardiner; Dan Casalaz; Roy M Robins-Browne; Mihai G Netea; Katie L Flanagan; Toby Kollmann; Nigel Curtis; Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) Group

doi:10.1093/infdis/jiaa030

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

J Infect Dis. 2020 Jun 11;221(12):1999-2009. doi: 10.1093/infdis/jiaa030.

Authors

Bridget Freyne^{1

2

3}, Nicole L Messina^{1

2}, Susan Donath^{2

4}, Susie Germano¹, Rhian Bonnici¹, Kaya Gardiner¹, Dan Casalaz⁵, Roy M Robins-Browne^{1

6}, Mihai G Netea^{7

8}, Katie L Flanagan^{9

10}, Toby Kollmann^{11

12}, Nigel Curtis^{1

2}; Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) Group

Collaborators

Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) Group:
Veronica Abruzzo, Katie Allen, Clare Morrison, Anne-Louise Ponsonby, Peter Vuillermin

Affiliations

¹ Infectious Diseases and Microbiology Group, Murdoch Children's Research Institute, Royal Children's Hospital Melbourne, Parkville, Australia.
² Department of Paediatrics, The University of Melbourne, Parkville, Australia.
³ Institute of Infection and Global Health, The University of Liverpool and The Malawi-Liverpool Wellcome Trust Research Programme, Blantyre, Malawi.
⁴ Clinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, Parkville, Australia.
⁵ Department of Paediatrics, Mercy Hospital for Women, Heidelberg, Australia.
⁶ Department of Microbiology and Immunology, The University of Melbourne, Parkville, Australia.
⁷ Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
⁸ Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
⁹ University of Tasmania, Launceston, Australia.
¹⁰ Monash University, Clayton, Australia.
¹¹ Department of Experimental Medicine, University of British Columbia, Vancouver, Canada.
¹² Department of Pediatrics, University of British Columbia, Vancouver, Canada.

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.

Keywords: BCG; heterologous; immunization; infants; innate immunity; nonspecific effects.

Publication types

Clinical Trial, Phase III
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Age Factors
Australia
BCG Vaccine / administration & dosage
BCG Vaccine / immunology*
Bacterial Infections / immunology
Bacterial Infections / microbiology
Bacterial Infections / prevention & control*
Female
Follow-Up Studies
Host Microbial Interactions / immunology
Humans
Immunity, Heterologous*
Immunization Schedule
Immunogenicity, Vaccine*
Infant
Infant, Newborn
Interferon-gamma / blood
Interferon-gamma / immunology
Interferon-gamma / metabolism*
Male
Mass Vaccination / methods
Treatment Outcome

Substances

BCG Vaccine
IFNG protein, human
Interferon-gamma