Oral Presentation Lorne Infection and Immunity 2021

Immunomodulatory effects of neonatal Bacillus Calmette–Guérin vaccination on responses to unrelated pathogens (#50)

Nicole L Messina 1 2 , Bridget Freyne 1 2 , Susie Germano 1 , Nigel Curtis 1 2 3 , Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) Group 4
  1. Infection, Immunity and Global Health theme, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
  2. Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia
  3. Infectious Diseases Unit, The Royal Children’s Hospital Melbourne, Parkville, Victoria, Australia
  4. MIS BAIR Group:, Susan Donath, Kaya Gardiner, Dan Casalaz, Roy M Robins-Browne , Mihai G Netea, Katie L Flanagan, Tobias Kollmann, Anne-Louise Ponsonby, Peter Vuillermin

The live attenuated vaccine Bacillus Calmette–Guérin (BCG) is given to the majority of infants worldwide to protect against tuberculosis (TB). In addition to protecting against TB and other mycobacterial infections, BCG vaccination has beneficial off-target effects associated with an up to 45% reduction in all-cause infant mortality in high-mortality settings. This is proposed to result from BCG-mediated protection against non-mycobacterial infections. Neonatal BCG vaccination may also reduce infant allergy and eczema.

 

We have established a randomised controlled trial, the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR)1, in which 1272 neonates were randomised to receive BCG vaccination or not, to determine if BCG protects against allergic sensitisation, eczema and infections in infancy. Using samples from MIS BAIR participants, we investigated the immunomodulatory effects of neonatal BCG vaccination.

 

Our studies revealed that neonatal BCG vaccination reduces in vitro cytokine and chemokine responses to non-mycobacterial pathogens2. In addition to altering the level of cytokine secretion, we found that in BCG vaccination induced an interferon (IFN)-γ ‘non-responder’ state in infants resulting in failure to produce IFN-γ following in vitro stimulation with a range of pathogens3.  Consistent with BCG’s heterogeneous actions in protecting against TB, we observed heterogeneity in the effect of BCG vaccination on immune responses to mycobacterial and non-mycobacterial pathogens. We identified several modifiable and non-modifiable factors that contributed to this heterogeneity and thus may impact the beneficial off-target effects of BCG.

 

Like BCG, measles containing vaccines (MCV) reduce all-cause infant mortality in high-mortality settings. Using samples taken from MIS BAIR participants, we also investigated the effects of MCV on infant immune responses to unrelated pathogens to determine whether the beneficial off-target effects of BCG and MCV are mediated by similar mechanisms.

  1. Messina NL et al. Study protocol for the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR), a randomised controlled trial. BMJ Open. 9:e032844. doi: 10.1136/bmjopen-2019-032844
  2. Freyne B, et al. Neonatal BCG Vaccination Influences Cytokine Responses to Toll-like Receptor Ligands and Heterologous Antigens. J Infect Dis 2018; 217(11): 1798-808.
  3. Freyne B, et al. Neonatal BCG Vaccination Reduces Interferon-γ Responsiveness to Heterologous Pathogens in Infants From a Randomized Controlled Trial. J Infect Dis. 2020;221(12):1999-2009