Long-term Maintenance of the Influenza-Specific Cross-Reactive Memory CD4+ T-Cell Responses Following Repeated Annual Influenza Vaccination

J Infect Dis. 2017 Mar 1;215(5):740-749. doi: 10.1093/infdis/jiw619.


Background: Annual vaccination for healthcare workers and other high-risk groups is the mainstay of the public health strategy to combat influenza. Inactivated influenza vaccines confer protection by inducing neutralizing antibodies efficiently against homologous and closely matched virus strains. In the absence of neutralizing antibodies, cross-reactive T cells have been shown to limit disease severity. However, animal studies and a study in immunocompromised children suggested that repeated vaccination hampers CD8+ T cells. Yet the impact of repeated annual influenza vaccination on both cross-reactive CD4+ and CD8+ T cells has not been explored, particularly in healthy adults.

Methods: We assembled a unique cohort of healthcare workers who received a single AS03-adjuvanted H1N1pdm09 vaccine in 2009 and subsequently either repeated annual vaccination or no further vaccination during 2010-2013. Blood samples were collected before the influenza season or vaccination to assess antibody and T-cell responses.

Results: Antibody titers to H1N1pdm09 persisted above the protective level in both the repeated- and single-vaccination groups. The interferon γ+ (IFN-γ+) and multifunctional CD4+ T-cell responses were maintained in the repeated group but declined significantly in the single-vaccination group. The IFN-γ+CD8+ T cells remained stable in both groups.

Conclusions: This study provides the immunological evidence base for continuing annual influenza vaccination in adults.

Keywords: CD4; CD8; Influenza vaccination; T-cell; antibody; immune response; healthcare worker.

MeSH terms

  • Adult
  • Antibodies, Neutralizing / blood
  • Antibodies, Viral / blood
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cohort Studies
  • Cross Reactions
  • Female
  • Follow-Up Studies
  • Humans
  • Influenza A Virus, H1N1 Subtype
  • Influenza Vaccines / administration & dosage
  • Influenza Vaccines / therapeutic use*
  • Influenza, Human / immunology
  • Influenza, Human / prevention & control*
  • Male
  • Middle Aged
  • Vaccines, Inactivated / administration & dosage
  • Vaccines, Inactivated / therapeutic use


  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Influenza Vaccines
  • Vaccines, Inactivated