Evaluating the non-specific effects of BCG vaccination on the immune system and serological response to influenza vaccination in the elderly: A randomised controlled trial.

OBJECTIVES: The Bacillus Calmette-Guerin (BCG) vaccine has beneficial effects on the immune system, which may lead to non-specific protection against non-tuberculous infections and increase the response to subsequent vaccinations. Seasonal influenza vaccination is used to protect senior citizens against influenza, but the serological response to the inactivated influenza vaccine (IIV) decreases in the elderly due to immunosenescence. The aim of this study was to test the capacity of BCG to boost the specific immune response to IIV and explore the effect of BCG on the innate immune system and health of senior citizens.

METHODS: A randomised controlled trial with a nested immunological study including 273 Danish citizens >65 years. Participants were randomised into four equally sized groups combining BCG with IIV in different sequences compared with IIV alone. The primary outcome was change in influenza antibody hemagglutination inhibition (HI) titre four weeks after vaccination. Secondary outcomes were infection rate during six months follow-up, and association between influenza antibody titre and infection rate. In subgroup analyses, we explored the effect of BCG on lymphocyte populations seven days after IIV and on cytokine production after stimulation of mononuclear cells in vitro.

RESULTS: Four weeks after influenza vaccination, the mean fold change in HI titre over all serotypes was 2.3-2.5 with no significant differences between the treatment groups. Seroconversion rate was comparable between treatment groups, and in strata of age and sex. There was no difference in the rate of infection between the groups and there was no association with influenza antibody level. We found no difference in distribution of lymphocytes. Combining BCG with IIV had modest impact on in vitro cytokine production compared with IIV alone.

CONCLUSION: BCG vaccination did not increase serological response to seasonal influenza vaccination or reduce the incidence of infection in this population of Danish senior citizens.

TRIAL REGISTRATION: EU Clinical Trials Register (EudraCT number 2019-002781-12).

SUMMARY: In this randomised clinical trial of Danish senior citizens, BCG vaccination did not influence serological response to influenza vaccination or reduce the risk of infection compared with placebo. There was no clear indication of induction of trained immunity.

Copyright © 2026 The Authors. Published by Elsevier Ltd.. All rights reserved.

PMID: 41650670