title: BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study.
abstract: 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.
authors.affiliation: Department of Internal Medicine Department of Intensive Care Medicine, Radboud Institute for Health Sciences.
authors.forename: Jenneke
authors.initials: J
authors.lastname: Leentjens
authors.affiliation: Department of Intensive Care Medicine, Radboud Institute for Health Sciences.
authors.forename: Matthijs
authors.initials: M
authors.lastname: Kox
authors.affiliation: Department of Intensive Care Medicine, Radboud Institute for Health Sciences.
authors.forename: Robin
authors.initials: R
authors.lastname: Stokman
authors.affiliation: Department of Intensive Care Medicine, Radboud Institute for Health Sciences.
authors.forename: Jelle
authors.initials: J
authors.lastname: Gerretsen
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Radboud Institute for Molecular Life Sciences, Nijmegen.
authors.forename: Dimitri A
authors.initials: DA
authors.lastname: Diavatopoulos
authors.affiliation: Department of Internal Medicine.
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.affiliation: Erasmus MC Department of Viroscience, Rotterdam, The Netherlands.
authors.forename: Guus F
authors.initials: GF
authors.lastname: Rimmelzwaan
authors.affiliation: Department of Intensive Care Medicine, Radboud Institute for Health Sciences.
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.affiliation: Department of Internal Medicine.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000097:blood*; D001500:BCG Vaccine / Q000008:administration & dosage*; D064368:Healthy Volunteers; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D007273:Injections, Intramuscular; D008297:Male; D010865:Pilot Projects; D010919:Placebos / Q000008:administration & dosage; D014611:Vaccination / Q000379:methods*; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D001500:BCG Vaccine; D007252:Influenza Vaccines; D010919:Placebos
keywords: BCG; heterologous immunity; influenza vaccination; innate immune memory; trained immunity; vaccination strategy