Bridget Freyne1,2, Susan Donath3,2, Susan Germano1, Kaya Gardiner1, Dan Casalaz4, Roy M Robins-Browne1,5, Nelly Amenyogbe6,7, Nicole L Messina1,2, Mihai G Netea8,9, Katie L Flanagan10,11, Tobias Kollmann6,7, Nigel Curtis1,2,12. 1. Infectious Diseases and Microbiology Group, Parkville, Australia. 2. Department of Paediatrics, Parkville, Australia. 3. Clinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, Parkville, Australia. 4. Department of Paediatrics, Mercy Hospital for Women, Heidelberg, Australia. 5. Department of Microbiology and Immunology, The University of Melbourne, Parkville, Australia. 6. Department of Experimental Medicine, University of British Columbia, Vancouver, Canada. 7. Division of Infectious Diseases, Department of Pediatrics, University of British Columbia, Vancouver, Canada. 8. Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. 9. Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. 10. School of Medicine, University of Tasmania, Launceston Australia. 11. Department of Immunology and Pathology, Monash University, Clayton, Australia. 12. Infectious Diseases Unit, The Royal Children's Hospital Melbourne, Parkville, Australia.
Abstract
Background: BCG vaccination is associated with a reduction in all-cause infant mortality in high-mortality settings. The underlying mechanisms remain uncertain, but long-term modulation of the innate immune response (trained immunity) may be involved. Methods: Whole-blood specimens, collected 7 days after randomization from 212 neonates enrolled in a randomized trial of neonatal BCG vaccination, were stimulated with killed pathogens and Toll-like receptor (TLR) ligands to interrogate cytokine responses. Results: BCG-vaccinated infants had increased production of interleukin 6 (IL-6) in unstimulated samples and decreased production of interleukin 1 receptor antagonist, IL-6, and IL-10 and the chemokines macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and monocytechemoattractant protein 1 (MCP-1) following stimulation with peptidoglycan (TLR2) and R848 (TLR7/8). BCG-vaccinated infants also had decreased MCP-1 responses following stimulation with heterologous pathogens. Sex and maternal BCG vaccination status interacted with neonatal BCG vaccination. Conclusions: Neonatal BCG vaccination influences cytokine responses to TLR ligands and heterologous pathogens. This effect is characterized by decreased antiinflammatory cytokine and chemokine responses in the context of higher levels of IL-6 in unstimulated samples. This supports the hypothesis that BCG vaccination modulates the innate immune system. Further research is warranted to determine whether there is an association between these findings and the beneficial nonspecific (heterologous) effects of BCG vaccine on all-cause mortality.
RCT Entities:
Background: BCG vaccination is associated with a reduction in all-cause infant mortality in high-mortality settings. The underlying mechanisms remain uncertain, but long-term modulation of the innate immune response (trained immunity) may be involved. Methods: Whole-blood specimens, collected 7 days after randomization from 212 neonates enrolled in a randomized trial of neonatal BCG vaccination, were stimulated with killed pathogens and Toll-like receptor (TLR) ligands to interrogate cytokine responses. Results: BCG-vaccinated infants had increased production of interleukin 6 (IL-6) in unstimulated samples and decreased production of interleukin 1 receptor antagonist, IL-6, and IL-10 and the chemokines macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and monocyte chemoattractant protein 1 (MCP-1) following stimulation with peptidoglycan (TLR2) and R848 (TLR7/8). BCG-vaccinated infants also had decreased MCP-1 responses following stimulation with heterologous pathogens. Sex and maternal BCG vaccination status interacted with neonatal BCG vaccination. Conclusions: Neonatal BCG vaccination influences cytokine responses to TLR ligands and heterologous pathogens. This effect is characterized by decreased antiinflammatory cytokine and chemokine responses in the context of higher levels of IL-6 in unstimulated samples. This supports the hypothesis that BCG vaccination modulates the innate immune system. Further research is warranted to determine whether there is an association between these findings and the beneficial nonspecific (heterologous) effects of BCG vaccine on all-cause mortality.
Authors: Sarah Prentice; Beatrice Nassanga; Emily L Webb; Florence Akello; Fred Kiwudhu; Hellen Akurut; Alison M Elliott; Rob J W Arts; Mihai G Netea; Hazel M Dockrell; Stephen Cose Journal: Lancet Infect Dis Date: 2021-02-17 Impact factor: 71.421
Authors: Renate Richardus; Anouk van Hooij; Susan J F van den Eeden; Louis Wilson; Korshed Alam; Jan Hendrik Richardus; Annemieke Geluk Journal: Front Immunol Date: 2018-04-04 Impact factor: 7.561
Authors: 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 Journal: J Infect Dis Date: 2020-06-11 Impact factor: 5.226
Authors: Mihai G Netea; Jorge Domínguez-Andrés; Luis B Barreiro; Triantafyllos Chavakis; Maziar Divangahi; Elaine Fuchs; Leo A B Joosten; Jos W M van der Meer; Musa M Mhlanga; Willem J M Mulder; Niels P Riksen; Andreas Schlitzer; Joachim L Schultze; Christine Stabell Benn; Joseph C Sun; Ramnik J Xavier; Eicke Latz Journal: Nat Rev Immunol Date: 2020-03-04 Impact factor: 53.106