Superior antigen-specific CD4+ T-cell response with AS03-adjuvantation of a trivalent influenza vaccine in a randomised trial of adults aged 65 and older

Abstract

Background: The effectiveness of trivalent influenza vaccines may be reduced in older versus younger adults because of age-related immunosenescence. The use of an adjuvant in such a vaccine is one strategy that may combat immunosenescence, potentially by bolstering T-cell mediated responses.

Methods: This observer-blind study, conducted in the United States (US) and Spain during the 2008-2009 influenza season, evaluated the effect of Adjuvant System AS03 on specific T-cell responses to a seasonal trivalent influenza vaccine (TIV) in ≥65 year-old adults.Medically-stable adults aged ≥65 years were randomly allocated to receive a single dose of AS03-adjuvanted TIV (TIV/AS03) or TIV. Healthy adults aged 18-40 years received only TIV. Blood samples were collected on Day 0, Day 21, Day 42 and Day 180. Influenza-specific CD4+ T cells, defined by the induction of the immune markers CD40L, IL-2, IFN-γ, or TNF-α, were measured in ex vivo cultures of antigen-stimulated peripheral blood mononuclear cells.

Results: A total of 192 adults were vaccinated: sixty nine and seventy three ≥65 year olds received TIV/AS03 and TIV, respectively; and fifty 18 - 40 year olds received TIV. In the ≥65 year-old group on Day 21, the frequency of CD4+ T cells specific to the three vaccine strains was superior in the TIV/AS03 recipients to the frequency in TIV (p < 0.001). On Days 42 and 180, the adjusted-geometric mean specific CD4+ T-cell frequencies were also higher in the TIV/AS03 recipients than in the TIV recipients (p < 0.001). Furthermore, the adjusted-geometric mean specific CD4+ T-cell frequencies were higher in the ≥65 year-old recipients of TIV/AS03 than in the18 - 40 year old recipients of TIV on Days 21 (p = 0.006) and 42 (p = 0.011).

Conclusion: This positive effect of AS03 Adjuvant System on the CD4+ T-cell response to influenza vaccine strains in older adults could confer benefit in protection against clinical influenza disease in this population.

Trial registration: (Clinicaltrials.gov.). NCT00765076.

Figures

Figure 1

The allocation and elimination of subjects during the course of the study. The reasons for elimination from the Total Vaccinated cohort (TVC) to give the per protocol immunogenicity cohorts are described to the left of each box. Safety was assessed in the TVC.

Figure 2

Influenza-specific CD4+T-cell responses to vaccination in the immunogenicity cohort. Box and whisker plots describing the frequency of CD4+ T cells (A) specific for the three (pooled) influenza vaccine strains and identified as expressing two or more immune markers among CD40L, IL-2, TNF-α and IFN-γ after a short term in vitro stimulation; (B-left) specific for each of the individual influenza vaccine strains and induced to express at least two immune markers; and (B-right) specific for the three (pooled) influenza vaccine strains and induced to express one defined immune marker (x-axis) and at least one other. The whiskers extend to the lowest (Min) and highest (Max) values; the box extends to the 1st quartile (Q1) and 3rd quartiles (Q3) in which the median is marked by a horizontal line.

Figure 3

Influenza-specific CD8+T-cell responses to vaccination in the per protocol immunogenicity cohort. Box and whisker plots describing the frequency of CD8+ T cells specific for the three (pooled) influenza vaccine strains and induced to express at least two immune markers. The whiskers extend to the lowest (Min) and highest (Max) values; the box extends to the 1st quartile (Q1) and 3rd quartiles (Q3) in which the median is marked by a horizontal line.

Figure 4

Influenza-specific cytotoxic CD4+and CD8+T-cell responses to vaccination in the per protocol immunogenicity cohort. Box and whisker plots describing the frequency of CD4+ or CD8+ T cells specific for the three (pooled) influenza vaccine strains and induced to express Granzyme B and IFN-γ and/or IL-2 (Spanish subjects only). For the TIV/AS03(≥65), TIV(≥65) and TIV(18–40) groups, N = 30–32, 35–36 and 24–25, respectively. The whiskers extend to the lowest (Min) and highest (Max) values; the box extends to the 1st quartile (Q1) and 3rd quartiles (Q3) in which the median is marked by a horizontal line.

Figure 5

Influenza-specific antibody responses to vaccination in the per protocol immunogenicity cohort. Histograms describing geometric mean titres (GMT) for haemagglutinin inhibition, percentage seroprotection rates, and neutralisation GMTs at Day 0, Day 21, Day 42 and Day 180.

Figure 6

Scatter plot comparisons of log-transformed values of fold-changes (Day 21 versus Day 0) of HI titres and frequencies of CD4+T cells expressing at least two immune markers specific for the three vaccine strains, in samples from all three groups of the Per Protocol cohort (N = 120, 120 and 118; upper, middle and lower graphs, respectively). Pearson correlation coefficients (r) and related trend line are shown for each comparison.

Pre-publication history