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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.

Gillard P, Giet D, Heijmans S, Dramé M, Walravens K, Roman F - Trials (2014)

Bottom Line: Serious adverse events and adverse events of specific interest were recorded.There was no clear benefit, in terms of long-term persistence of the immune response, of doubling the dose of the adjuvanted vaccine.NCT00397215 (7 November 2006).

View Article: PubMed Central - PubMed

Affiliation: GSK Vaccines, Wavre, Belgium. paul.gillard@gsk.com.

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).

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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.
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Fig2: 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.

Mentions: At month 12, the percentages of participants who remained seropositive for HI antibodies against A/Vietnam/1194/2004 were 62.8% (95% CI 51.7% to 73.0%) and 77.8% (95% CI 67.2% to 86.3%) in the adjuvanted 1xH5N1-AS and 2xH5N1-AS groups, respectively, compared to 48.6% (95% CI 31.9% to 65.6%) and 39.1% (95% CI 19.7% to 61.5%) in the non-adjuvanted 1xH5N1 and 2xH5N1 groups, respectively. At month 24, seropositivity rates were in a similar range to those at month 12; 62.8% (95% CI 51.7% to 73.0%) in the 1xH5N1-AS group, 70.4% (95% CI 59.2% to 80.0%) in the 2xH5N1-AS group, 54.1% (95% CI 36.9% to 70.5%) in the non-adjuvanted 1xH5N1 group, and 45.8% (95% CI 25.6% to 67.2%) in the non-adjuvanted 2xH5N1 group.GMTs for HI antibodies against A/Vietnam/1194/2004 waned considerably as time elapsed after the last primary dose. At month 12, HI antibody GMTs were 22.2 (95% CI 16.5 to 29.9) in the 1xH5N1-AS group, 25.7 (95% CI 19.3 to 34.3) in the 2xH5N1-AS group, 13.6 (95% CI 8.9 to 20.8) in the 1xH5N1 group and 10.0 (95% CI 6.5 to 15.5) in the 2xH5N1 group (Figure 2A). At month 24, GMTs 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 (Figure 2A). In comparison, pre-vaccination GMTs were 11.5 (95% CI 8.7 to 15.1) for 1xH5N1-AS, 9.7 (95% CI 7.4 to 12.5) for 2xH5N1-AS, 9.3 (95% CI 6.3 to 13.6) for 1xH5N1 and 6.8 (95% CI 5.4 to 8.7) for 2xH5N1.For SCR and SPR, CHMP criteria were no longer fulfilled at both month 12 and month 24 for the HI immune response against any of the two strains tested (Figure 2B,C and Figure 3B,C). At month 24, HI antibody seroprotection rates were 37.2% (95% CI 27.0% to 48.3%) in the 1xH5N1-AS group, 30.9% (95% CI 21.1% to 42.1%) in the 2xH5N1-AS group, 16.2% (95% CI 6.2% to 32.0%) in the non-adjuvanted 1xH5N1 group, and 8.3% (95% CI 1.0% to 27.0%) in the non-adjuvanted 2xH5N1 group.The heterologous HI immune response against the A/Indonesia/05/2005 strain was lower than against the A/Vietnam/1194/2004 strain in all groups (Figure 3A-C), with a GMT of 7.0 (95% CI 6.1 to 8.1) for 1xH5N1-AS, 7.3 (95% CI 6.2 to 8.6) for 2xH5N1-AS, 5.6 (95% CI 4.9 to 6.4) for 1xH5N1 and 5.0 (95% CI 5.0 to 5.0) for 2xH5N1 at month 24; these values were below the cut-off of 10. GMTs remained higher than baseline for the adjuvanted groups while those of the non-adjuvanted groups were in the same range as baseline values; pre-vaccination GMTs were 5.1 (95% CI 5.0 to 5.2) for 1xH5N1-AS, 5.1 (95% CI 5.0 to 5.3) for 2xH5N1-AS, 5.1 (95% CI 4.9 to 5.3) for 1xH5N1, and 5.0 (95% CI 5.0 to 5.0) for 2xH5N1.Figure 2


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.

Gillard P, Giet D, Heijmans S, Dramé M, Walravens K, Roman F - Trials (2014)

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.
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Fig2: 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.
Mentions: At month 12, the percentages of participants who remained seropositive for HI antibodies against A/Vietnam/1194/2004 were 62.8% (95% CI 51.7% to 73.0%) and 77.8% (95% CI 67.2% to 86.3%) in the adjuvanted 1xH5N1-AS and 2xH5N1-AS groups, respectively, compared to 48.6% (95% CI 31.9% to 65.6%) and 39.1% (95% CI 19.7% to 61.5%) in the non-adjuvanted 1xH5N1 and 2xH5N1 groups, respectively. At month 24, seropositivity rates were in a similar range to those at month 12; 62.8% (95% CI 51.7% to 73.0%) in the 1xH5N1-AS group, 70.4% (95% CI 59.2% to 80.0%) in the 2xH5N1-AS group, 54.1% (95% CI 36.9% to 70.5%) in the non-adjuvanted 1xH5N1 group, and 45.8% (95% CI 25.6% to 67.2%) in the non-adjuvanted 2xH5N1 group.GMTs for HI antibodies against A/Vietnam/1194/2004 waned considerably as time elapsed after the last primary dose. At month 12, HI antibody GMTs were 22.2 (95% CI 16.5 to 29.9) in the 1xH5N1-AS group, 25.7 (95% CI 19.3 to 34.3) in the 2xH5N1-AS group, 13.6 (95% CI 8.9 to 20.8) in the 1xH5N1 group and 10.0 (95% CI 6.5 to 15.5) in the 2xH5N1 group (Figure 2A). At month 24, GMTs 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 (Figure 2A). In comparison, pre-vaccination GMTs were 11.5 (95% CI 8.7 to 15.1) for 1xH5N1-AS, 9.7 (95% CI 7.4 to 12.5) for 2xH5N1-AS, 9.3 (95% CI 6.3 to 13.6) for 1xH5N1 and 6.8 (95% CI 5.4 to 8.7) for 2xH5N1.For SCR and SPR, CHMP criteria were no longer fulfilled at both month 12 and month 24 for the HI immune response against any of the two strains tested (Figure 2B,C and Figure 3B,C). At month 24, HI antibody seroprotection rates were 37.2% (95% CI 27.0% to 48.3%) in the 1xH5N1-AS group, 30.9% (95% CI 21.1% to 42.1%) in the 2xH5N1-AS group, 16.2% (95% CI 6.2% to 32.0%) in the non-adjuvanted 1xH5N1 group, and 8.3% (95% CI 1.0% to 27.0%) in the non-adjuvanted 2xH5N1 group.The heterologous HI immune response against the A/Indonesia/05/2005 strain was lower than against the A/Vietnam/1194/2004 strain in all groups (Figure 3A-C), with a GMT of 7.0 (95% CI 6.1 to 8.1) for 1xH5N1-AS, 7.3 (95% CI 6.2 to 8.6) for 2xH5N1-AS, 5.6 (95% CI 4.9 to 6.4) for 1xH5N1 and 5.0 (95% CI 5.0 to 5.0) for 2xH5N1 at month 24; these values were below the cut-off of 10. GMTs remained higher than baseline for the adjuvanted groups while those of the non-adjuvanted groups were in the same range as baseline values; pre-vaccination GMTs were 5.1 (95% CI 5.0 to 5.2) for 1xH5N1-AS, 5.1 (95% CI 5.0 to 5.3) for 2xH5N1-AS, 5.1 (95% CI 4.9 to 5.3) for 1xH5N1, and 5.0 (95% CI 5.0 to 5.0) for 2xH5N1.Figure 2

Bottom Line: Serious adverse events and adverse events of specific interest were recorded.There was no clear benefit, in terms of long-term persistence of the immune response, of doubling the dose of the adjuvanted vaccine.NCT00397215 (7 November 2006).

View Article: PubMed Central - PubMed

Affiliation: GSK Vaccines, Wavre, Belgium. paul.gillard@gsk.com.

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).

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Related in: MedlinePlus