BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study

J Infect Dis. 2015 Dec 15;212(12):1930-8. doi: 10.1093/infdis/jiv332. Epub 2015 Jun 12.


Background: Influenza-related morbidity and mortality remain high. Seasonal vaccination is the backbone of influenza management but does not always result in protective antibody titers. Nonspecific effects of BCG vaccination related to enhanced function of myeloid antigen-presenting cells have been reported. We hypothesized that BCG vaccination could also enhance immune responses to influenza vaccination.

Methods: Healthy volunteers received either live attenuated BCG vaccine (n = 20) or placebo (n = 20) in a randomized fashion, followed by intramuscular injection of trivalent influenza vaccine 14 days later. Hemagglutination-inhibiting (HI) antibodies and cellular immunity measured by ex vivo leukocyte responses were assessed.

Results: In BCG-vaccinated subjects, HI antibody responses against the 2009 pandemic influenza A(H1N1) vaccine strain were significantly enhanced, compared with the placebo group, and there was a trend toward more-rapid seroconversion. Additionally, apart from enhanced proinflammatory leukocyte responses following BCG vaccination, nonspecific effects of influenza vaccination were also observed, with modulation of cytokine responses against unrelated pathogens.

Conclusions: BCG vaccination prior to influenza vaccination results in a more pronounced increase and accelerated induction of functional antibody responses against the 2009 pandemic influenza A(H1N1) vaccine strain. These results may have implications for the design of vaccination strategies and could lead to improvement of vaccination efficacy.

Keywords: BCG; heterologous immunity; influenza vaccination; innate immune memory; trained immunity; vaccination strategy.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Viral / blood*
  • BCG Vaccine / administration & dosage*
  • Healthy Volunteers
  • Hemagglutination Inhibition Tests
  • Humans
  • Influenza Vaccines / administration & dosage*
  • Influenza Vaccines / immunology*
  • Injections, Intramuscular
  • Male
  • Pilot Projects
  • Placebos / administration & dosage
  • Vaccination / methods*
  • Young Adult


  • Antibodies, Viral
  • BCG Vaccine
  • Influenza Vaccines
  • Placebos