Background: Bacille Calmette-Guérin (BCG) vaccine, primarily used against tuberculosis, has off-target (non-specific) immunomodulatory effects, including potential protection against recurrences of latent herpes simplex virus (HSV) infections. Recurrent episodes of HSV herpes labialis (oral 'cold sores') affect a substantial proportion of the population, including young children, and there is currently no effective preventive intervention.

Methods: This pilot study, nested within the MIS BAIR randomised controlled trial (RCT), explored whether neonatal BCG vaccination, compared with no BCG vaccination, reduces the incidence and recurrence of herpes labialis during the first five years of life.

Findings: Among the 563 children (44% of 1272 randomised) who completed the 5-year follow-up, children in the BCG group were less likely to develop herpes labialis, compared with the control group (5% vs 8%; 38% relative risk reduction, p = 0.1). Risk of recurrence was significantly lower in the BCG group (33% vs. 71%; 53% relative risk reduction, p = 0.02). BCG-vaccinated children also reported a later onset of symptoms and a reduced impact on fluid intake during episodes.

Interpretation: This exploratory study suggests a protective role for neonatal BCG against HSV in children. However, its limitations, including its sample size, incomplete follow up and lack of virological confirmation, mean further studies are needed to confirm these findings.

Funding: National Health and Medical Research Council (NHMRC) of Australia and others, as detailed in the acknowledgements.