Long-term outcome of the humoral and cellular immune response of an H5N1 adjuvanted influenza vaccine in elderly persons: 2-year follow-up of a randomised open-label study

Paul Gillard, Didier Giet, Stéphane Heijmans, Mamadou Dramé, Karl Walravens, François Roman, Paul Gillard, Didier Giet, Stéphane Heijmans, Mamadou Dramé, Karl Walravens, François Roman

Abstract

Background: Older individuals often have a reduced immune response to influenza vaccination, which might be improved by administering a higher vaccine dose. We compared the immune response to two single doses of the AS03A-adjuvanted H5N1 pandemic vaccine (3.75 μg hemagglutinin of A/Vietnam/1194/2004) with that of two double vaccine doses (7.5 μg hemagglutinin) in adults aged ≥61 years. Here we report the 2-year persistence of the humoral and cellular immune response.

Methods: In this phase II, open-label study, healthy participants aged 61 to 88 years (median 68 years) were randomised (3:1:3:1) to receive two single doses of the AS03A-adjuvanted vaccine (1xH5N1-AS) or the non-adjuvanted vaccine (1xH5N1), or two double doses of the AS03A-adjuvanted vaccine (2xH5N1-AS) or the non-adjuvanted vaccine (2xH5N1), 21 days apart. Serum haemagglutination inhibition antibodies and cellular immune responses against A/Vietnam/1194/2004 were measured in all groups at months 12 and 24; neutralising antibodies were assessed in a subset of the adjuvanted groups. Serious adverse events and adverse events of specific interest were recorded.

Results: At month 24, haemagglutination inhibition antibody seroprotection rates were 37.2% (95% CI 27.0% to 48.3%) for 1xH5N1-AS, 30.9% (95% CI 21.1% to 42.1%) for 2xH5N1-AS, 16.2% (95% CI 6.2% to 32.0%) for 1xH5N1, and 8.3% (95% CI 1.0% to 27.0%) for 2xH5N1. Haemagglutination inhibition antibody geometric mean titres were 17.6 (95% CI 13.7 to 22.5) for 1xH5N1-AS, 18.4 (95% CI 14.2 to 23.8) for 2xH5N1-AS, 12.3 (95% CI 8.9 to 16.9) for 1xH5N1 and 9.8 (95% CI 6.7 to 14.4) for 2xH5N1. The median frequency of antigen-specific CD4+ T cells per 106 T cells (25th quartile; 75th quartile) was 852 (482; 1477) for 1xH5N1-AS, 1147 (662; 1698) for 2xH5N1-AS, 556 (343; 749) for 1x-H5N1 and 673 (465; 1497) for 2xH5N1. Neutralising antibody geometric mean titres were 391.0 (95% CI 295.5 to 517.5) in the 1xH5N1-AS group and 382.8 (95% CI 317.4 to 461.6) in the 2xH5N1-AS group.

Conclusions: Antibody levels declined substantially in all groups. Seroprotection rates, geometric mean titres for haemagglutination inhibition antibodies, and CD4+ T-cell responses tended to be higher in the AS03A-adjuvanted groups. There was no clear benefit, in terms of long-term persistence of the immune response, of doubling the dose of the adjuvanted vaccine. No safety concern was observed up to 24 months post-primary vaccination.

Trial registration: NCT00397215 (7 November 2006).

Figures

Figure 1
Figure 1
Participant flow diagram. Vaccination groups are: 1xH5N1-AS, single dose of the AS03A-adjuvanted vaccine; 1xH5N1, single dose of the non-adjuvanted vaccine; 2xH5N1-AS, double dose of the AS03A-adjuvanted vaccine; 2xH5N1, double dose of the non-adjuvanted vaccine. ATP, according-to-protocol; M, month; N, number of participants in the specified group; n, number of participants with the specified reason for elimination.
Figure 2
Figure 2
H5N1 haemagglutination inhibition antibody response against A/Vietnam/1194/2004. Vaccination groups are: 1xH5N1-AS, single dose of the AS03A-adjuvanted vaccine; 1xH5N1, single dose of the non-adjuvanted vaccine; 2xH5N1-AS, double dose of the AS03A-adjuvanted vaccine; 2xH5N1, double dose of the non-adjuvanted vaccine. Seroconversion rate (SCR) was defined as the percentage of participants with either a pre-vaccination titre <1:10 and a post-vaccination titre ≥1:40, or a pre-vaccination titre ≥1:10 and a ≥4-fold increase in post-vaccination titre; and seroprotection rate (SPR) was defined as the percentage of participants with a haemagglutination inhibition titre ≥1:40. GMT, geometric mean titre. Error bars indicate the 95% confidence intervals. Post-vaccination = day 42 (data also shown in [13]). Post-vaccination results are shown for the according-to-protocol immunogenicity cohort (1xH5N1-AS: N =152, 1xH5N1: N =54, 2xH5N1-AS: N =145, 2xH5N1: N = 44); month 12 and month 24 results for the month 24 according-to-protocol persistence cohort (1xH5N1-AS: N = 86, 1xH5N1: N = 37, 2xH5N1-AS: N =81, 2xH5N1: N = 24); N = maximum number of participants with available results.
Figure 3
Figure 3
H5N1 haemagglutination inhibition antibody response against the heterologous A/Indonesia/05/2005 strain. Vaccination groups are: 1xH5N1-AS, single dose of the AS03A-adjuvanted vaccine; 1xH5N1, single dose of the non-adjuvanted vaccine; 2xH5N1-AS, double dose of the AS03A-adjuvanted vaccine; 2xH5N1, double dose of the non-adjuvanted vaccine. Seroconversion rate (SCR) was defined as the percentage of participants with either a pre-vaccination titre <1:10 and a post-vaccination titre ≥1:40, or a pre-vaccination titre ≥1:10 and a ≥4-fold increase in post-vaccination titre; and seroprotection rate (SPR) was defined as the percentage of participants with a haemagglutination inhibition titre ≥1:40. GMT, geometric mean titre. Error bars indicate the 95% confidence intervals. Post-vaccination = day 42. Post-vaccination results are shown for the according-to-protocol immunogenicity cohort (1xH5N1-AS: N =152, 1xH5N1: N = 54, 2xH5N1-AS: N = 145, 2xH5N1: N = 44); month 12 and month 24 results for the month 24 according-to-protocol persistence cohort (1xH5N1-AS: N = 86, 1xH5N1: N = 37, 2xH5N1-AS: N = 81, 2xH5N1: N =24); N = maximum number of participants with available results.
Figure 4
Figure 4
Neutralising antibody response against A/Vietnam/1194/2004 in the AS03A-adjuvanted groups. Vaccination groups are: 1xH5N1-AS, single dose of the AS03A-adjuvanted vaccine; 1xH5N1, single dose of the non-adjuvanted vaccine; 2xH5N1-AS, double dose of the AS03A-adjuvanted vaccine; 2xH5N1, double dose of the non-adjuvanted vaccine. Seroconversion rate (SCR) was defined as the percentage of vaccinees with a ≥4-fold increase in neutralising antibody titre at post-vaccination. GMT, geometric mean titre. Error bars indicate the 95% confidence intervals. Post-vaccination = day 42 (data also shown in [13]). Post-vaccination results are shown for a subset of the according-to-protocol immunogenicity cohort (1xH5N1-AS: N =87, 2xH5N1-AS: N =82), month 12 and month 24 results for a subset of the month 24 according-to-protocol persistence cohort (1xH5N1-AS: N =51, 2xH5N1-AS: N =54); N = maximum number of participants with available results.
Figure 5
Figure 5
Neutralising antibody response against the heterologous A/Indonesia/05/2005 strain in the AS03A-adjuvanted groups. Vaccination groups are: 1xH5N1-AS, single dose of the AS03A-adjuvanted vaccine; 1xH5N1, single dose of the non-adjuvanted vaccine; 2xH5N1-AS, double dose of the AS03A-adjuvanted vaccine; 2xH5N1, double dose of the non-adjuvanted vaccine. Seroconversion rate (SCR) was defined as the percentage of vaccinees with a ≥4-fold increase in neutralising antibody titre at post-vaccination. GMT, geometric mean titre. Error bars indicate the 95% confidence intervals. Post-vaccination = day 42. Post-vaccination results are shown for a subset of the according-to-protocol immunogenicity cohort (1xH5N1-AS: N =87, 2xH5N1-AS: N =82), month 12 and month 24 results for a subset of the month 24 according-to-protocol persistence cohort (1xH5N1-AS: N =51, 2xH5N1-AS: N =54); N = maximum number of participants with available results.
Figure 6
Figure 6
CD4+T cells specific for A/Vietnam/1194/2004 split-virus antigen, positive for ≥2 immunological markers. Antigen-specific CD4+ T cells expressing ≥2 of the following immunological markers: CD40L, interleukin-2, tumour necrosis factor alpha, or interferon-gamma. Line inside the box, median value; top line of box, third quartile; bottom line of box, first quartile; lower limit of error bar, minimum value; upper limit of error bar, maximum value. Vaccination groups are: 1xH5N1-AS, single dose of the AS03A-adjuvanted vaccine; 1xH5N1, single dose of the non-adjuvanted vaccine; 2xH5N1-AS, double dose of the AS03A-adjuvanted vaccine; 2xH5N1, double dose of the non-adjuvanted vaccine. Post-vaccination = day 42 (data also shown in [13]). Post-vaccination results are shown for the according-to-protocol immunogenicity cohort (1xH5N1-AS: N =120, 1xH5N1: N =43, 2xH5N1-AS: N =118, 2xH5N1: N =30), month 12 results for the month 12 according-to-protocol persistence cohort (1xH5N1-AS: N =90, 1xH5N1: N =41, 2xH5N1-AS: N =91, 2xH5N1: N =30) and month 24 results for the month 24 according-to-protocol persistence cohort (1xH5N1-AS: N =73, 1xH5N1: N =34, 2xH5N1-AS: N =72, 2xH5N1: N =22); N = number of participants with available results.

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