Early Rise of Blood T Follicular Helper Cell Subsets and Baseline Immunity as Predictors of Persisting Late Functional Antibody Responses to Vaccination in Humans

PLoS One. 2016 Jun 23;11(6):e0157066. doi: 10.1371/journal.pone.0157066. eCollection 2016.


CD4+ T follicular helper cells (T(FH)) have been identified as the T-cell subset specialized in providing help to B cells for optimal activation and production of high affinity antibody. We recently demonstrated that the expansion of peripheral blood influenza-specific CD4(+)IL-21(+)ICOS1(+) T helper (T(H)) cells, three weeks after vaccination, associated with and predicted the rise of protective neutralizing antibodies to avian H5N1. In this study, healthy adults were vaccinated with plain seasonal trivalent inactivated influenza vaccine (TIIV), MF59(®)-adjuvanted TIIV (ATIIV), or saline placebo. Frequencies of circulating CD4(+) T(FH)1 ICOS(+) T(FH) cells and H1N1-specific CD4(+-)IL-21(+)ICOS(+) CXCR5(+) T(FH) and CXCR5(-) T(H) cell subsets were determined at various time points after vaccination and were then correlated with hemagglutination inhibition (HI) titers. All three CD4(+) T cell subsets expanded in response to TIIV and ATIIV, and peaked 7 days after vaccination. To demonstrate that these T(FH) cell subsets correlated with functional antibody titers, we defined an alternative endpoint metric, decorrelated HI (DHI), which removed any correlation between day 28/day 168 and day 0 HI titers, to control for the effect of preexisting immunity to influenza vaccine strains. The numbers of total circulating CD4(+)T(FH)1 ICOS(+) cells and of H1N1-specific CD4(+)IL-21(+)ICOS(+) CXCR5(+), measured at day 7, were significantly associated with day 28, and day 28 and 168 DHI titers, respectively. Altogether, our results show that CD4(+) T(FH) subsets may represent valuable biomarkers of vaccine-induced long-term functional immunity.

Trial registration: ClinicalTrials.gov NCT01771367.

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Viral / blood
  • Antibodies, Viral / immunology
  • Antibody Formation / immunology*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Biomarkers
  • Hemagglutination Inhibition Tests
  • Humans
  • Immunity*
  • Immunophenotyping
  • Inducible T-Cell Co-Stimulator Protein / metabolism
  • Influenza A Virus, H1N1 Subtype / immunology
  • Influenza Vaccines / immunology
  • Lymphocyte Activation / immunology
  • Lymphocyte Count*
  • Prognosis
  • Public Health Surveillance
  • Receptors, CXCR5 / metabolism
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • Time Factors
  • Vaccination*
  • Young Adult


  • Antibodies, Viral
  • Biomarkers
  • Inducible T-Cell Co-Stimulator Protein
  • Influenza Vaccines
  • Receptors, CXCR5

Associated data

  • ClinicalTrials.gov/NCT01771367

Grant support

These studies were funded by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115308, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.