Effect on cellular and humoral immune responses of the AS03 adjuvant system in an A/H1N1/2009 influenza virus vaccine administered to adults during two randomized controlled trials

Abstract

The influence of AS03(A), a tocopherol oil-in-water emulsion-based adjuvant system, on humoral and cell-mediated responses to A/California/7/2009 H1N1 pandemic vaccine was investigated. In two observer-blind studies, a total of 261 healthy adults aged 18 to 60 years were randomized to receive either AS03(A)-adjuvanted H1N1 vaccine containing 3.75 μg hemagglutinin (HA) or nonadjuvanted H1N1 vaccine containing 15 or 3.75 μg HA on days 0 and 21. Hemagglutination inhibition (HI) antibody and T-cell responses were analyzed up to day 42. A first dose of AS03(A)-adjuvanted vaccine (3.75 μg HA) or nonadjuvanted vaccine (15 μg HA) induced HI responses of similar magnitudes that exceeded licensure criteria (e.g., 94 to 100% with titers of ≥ 40). A lower response following 3.75 μg HA without adjuvant was observed (73% with titers of ≥ 40). Following a second dose, geometric mean HI titers at day 42 were higher for AS03(A)-adjuvanted vaccine (636 and 637) relative to nonadjuvanted vaccine (341 for 15 μg HA and 150 for 3.75 μg HA). Over the 42-day period, the increase in frequency of A/H1N1/2009-specific CD4⁺ T cells was significantly higher in the adjuvanted group than in the nonadjuvanted group. There was no evidence of correlation between baseline CD4⁺ T-cell frequencies and day 21 HI antibody titers, while there was some correlation (R = 0.35) between day 21 CD4⁺ T-cell frequencies and day 42 HI titers. AS03(A) adjuvant enhanced the humoral and CD4⁺ T-cell-mediated responses to A/H1N1/2009 vaccine. Baseline A/H1N1/2009-specific CD4⁺ T-cell frequencies did not predict post-dose 1 antibody responses, but there was some correlation between post-dose 1 CD4⁺ T-cell frequencies and post-dose 2 antibody responses.

Figures

Fig. 1.

(A) Participant flowchart for study A; (B) participant flowchart for study B.

Fig. 2.

Adjusted geometric means of the frequencies of CD4+ T cells specific for A/California/7/2009 H1N1 split antigen or A/California/7/2009 H1 peptide pool (presented with hemagglutination inhibition antibody geometric mean titers at the same time points).

Fig. 3.

Scatter plot of hemagglutination inhibition antibodies at day 21 versus frequency of CD4+ T cells specific for A/California/7/2009 H1N1 split antigen at day 0 (prevaccination) (per protocol cohort for immunogenicity). R, Spearman's partial correlation coefficient adjusted by age, sex, history of vaccination, and prevaccination status (seropositive or seronegative). *, positive for at least two immunological markers among CD40L, IFN-γ, IL-2, and TNF-α.

Fig. 4.

Scatter plot of hemagglutination inhibition antibodies at day 42 versus frequency of CD4+ T cells specific for A/California/7/2009 H1N1 split antigen at day 21 (per protocol cohort for immunogenicity). R, Spearman's partial correlation coefficient adjusted by age, sex, history of vaccination, and prevaccination status (seropositive or seronegative). *, positive for at least two immunological markers among CD40L, IFN-γ, IL-2, and TNF-α.