Safety and persistence of the humoral and cellular immune responses induced by 2 doses of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine administered to infants, children and adolescents: Two open, uncontrolled studies

Abstract

In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6-35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3-17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4(+) T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6-35 months and 3-17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158.

Keywords: AS03 adjuvant; H1N1 pandemic vaccine; cell-mediated immunity; children; haemagglutinin inhibition; microneutralisation; persistence; safety.

Figure 1.

Participant flow. Footnote: TVC = total vaccinated cohort, ATP = according to protocol, HA = haemagglutinin antigen, N = number of children.

Figure 2.

Haemagglutinin inhibition antibody geometric mean titres at pre-vaccination, Day 21, Day 42, and Month 12 in (A) Study A and (B) Study B (according to protocol cohort for persistence at Month 12). Footnote: 3–9 years age group = children in Study B, who received the first vaccine dose at 3–9 years of age, 10–17 years age group = children in Study B, who received the first vaccine dose at 10–17 years of age. Error bars represent 95% confidence intervals.

Figure 3.

Neutralising antibody geometric mean titres at pre-vaccination, Day 21, Day 42, and Month 12 in (A) Study A and (B) Study B (according to protocol cohort for persistence at Month 12). Footnote: 3–9 years age group = children in Study B, who received the first vaccine dose at 3–9 years of age, 10–17 years age group = children in Study B, who received the first vaccine dose at 10–17 years of age. Error bars represent 95% confidence intervals.

Figure 4.

Frequencies of H1N1 split antigen specific CD4⁺ T-cells identified as expressing 2 or more markers among CD40L, IL-2, IFN-γ, TNF-α, and IL-13 per million of CD4⁺ T-cells at pre-vaccination, Day 21, Day 42, and Month 12 in (A) Study A and (B) Study B (sub-cohort of the according to protocol cohort for persistence at Month 12). Footnote: IL-2 = interleukin-2, TNF-α = tumor necrosis factor α, IFN-γ = gamma interferon, IL-13 = interleukin-13.

Figure 5.

Functional characterization of H1N1 split antigen specific CD4⁺ T-cells per million CD4⁺ T-cells at pre-vaccination, Day 21, Day 42, and Month 12 in (A) Study A and (B) Study B (sub-cohort of the according to protocol cohort for persistence at Month 12). Footnote: IL-2 = interleukin-2, TNF-α = tumor necrosis factor α, IFN-γ = gamma interferon, IL-13 = interleukin-13.