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

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- adjuvantedH5N1 pandemic vaccine (3.75 μg hemagglutininof 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- adjuvantedvaccine (1xH5N1-AS) or the non- adjuvantedvaccine (1xH5N1), or two double doses of the AS03A- adjuvantedvaccine (2xH5N1-AS) or the non- adjuvantedvaccine (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 antibodieswere assessed in a subset of the adjuvantedgroups. 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 meantitres 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 + Tc ells per 10 6 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 meantitres 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 meantitres for haemagglutination inhibition antibodies, and CD4 + T-cell responses tended to be higher in the AS03A- adjuvantedgroups. There was no clear benefit, in terms of long-term persistence of the immune response, of doubling the dose of the adjuvantedvaccine. No safety concern was observed up to 24 months post-primary vaccination.