Immunogenicity of AS03-adjuvanted and non-adjuvanted trivalent inactivated influenza vaccines in elderly adults: A Phase 3, randomized trial and post-hoc correlate of protection analysis

Guillermo M Ruiz-Palacios, Geert Leroux-Roels, Jiri Beran, Jeanne-Marie Devaster, Meral Esen, Odile Launay, Janet E McElhaney, Gerrit A van Essen, Anne Benoit, Carine Claeys, Walthère Dewé, Christelle Durand, Xavier Duval, Ann R Falsey, Gregory Feldman, Florence Galtier, Pierre Gervais, Shinn-Jang Hwang, Shelly McNeil, Jan Hendrik Richardus, Andrew Trofa, Lidia Oostvogels, Influence65 study group, Guillermo M Ruiz-Palacios, Geert Leroux-Roels, Jiri Beran, Jeanne-Marie Devaster, Meral Esen, Odile Launay, Janet E McElhaney, Gerrit A van Essen, Anne Benoit, Carine Claeys, Walthère Dewé, Christelle Durand, Xavier Duval, Ann R Falsey, Gregory Feldman, Florence Galtier, Pierre Gervais, Shinn-Jang Hwang, Shelly McNeil, Jan Hendrik Richardus, Andrew Trofa, Lidia Oostvogels, Influence65 study group

Abstract

In this study we describe the immunogenicity results from a subset of older people (N = 5187) who participated in a Phase 3 randomized, observer-blinded trial of AS03-TIV versus TIV (Fluarix™) (ClinicalTrials.gov, NCT00753272). Participants received one dose of AS03-TIV or TIV in each study year and antibody titers against the vaccine strains were assessed using hemagglutination-inhibition (HI) assay at 21 d and 180 d post-vaccination in each vaccine group in the 2008/09 (Year 1) and 2009/10 (Year 2) influenza seasons. Manufacturing consistency of 3 lots of AS03-TIV for HI antibody responses in Year 1 was a co-primary objective. In a post-hoc analysis, a statistical regression model included 4830 subjects in whom immunogenicity and laboratory-confirmed attack rate data were available; the analysis was performed to assess HI antibody titers against A/H3N2 as a correlate of protection for laboratory-confirmed A/H3N2 influenza. AS03-TIV and TIV elicited strong HI antibody responses against each vaccine strain 21 d post-vaccination in both years. The manufacturing consistency of 3 lots of AS03-TIV was demonstrated. In both years and each vaccine group, HI antibody responses were lower for A/H1N1 than the other vaccine strains. Day 180 seroconversion rates (proportion with ≥4-fold increase in titer compared with pre-vaccination titer) in Year 1 in the AS03-TIV and TIV groups, respectively, were 87.7% and 74.1% for A/H3N2, 69.7% and 59.6% for influenza B, and 58.3% and 47.4% for A/H1N1. The post-hoc statistical model based on A/H3N2 attack rates and HI antibody titers estimated that a 4-fold increase in post-vaccination titers against A/H3N2 was associated with a 2-fold decrease in the odds of A/H3N2 infection.

Keywords: AS03; correlates of protection; immunogenicity; older; seasonal influenza; vaccine.

Figures

Figure 1.
Figure 1.
Participant flow chart. Note: AS03, tocopherol, oil-in-water emulsion-based Adjuvant System; CI, confidence intervals; TIV, inactivated trivalent influenza vaccine; Year 1, 2008/09; Year 2, 2009/10.
Figure 2.
Figure 2.
Day 21 hemagglutination-inhibition-based GMTs in the per-protocol immunogenicity cohort in Year 1 (A) and Year 2 (B). Note: AS03, tocopherol, oil-in-water emulsion-based Adjuvant System; CI, confidence intervals; TIV, inactivated trivalent influenza vaccine; GMT, geometric mean titer; N, number of subjects in the cohort with data available at time-point; Year 1, 2008/09; Year 2, 2009/10; Influenza A strains were A/Brisbane/59/2007 (H1N1 strain) and A/Uruguay/716/2007 (H3N2 strain); Influenza B strains were B/Brisbane/3/2007 (Victoria lineage) in Year 1 and B/Brisbane/60/2008 (Yamagata lineage) in Year 2.
Figure 3.
Figure 3.
Day 21 and 180 hemagglutination-inhibition-based GMTs in the per-protocol immunogenicity persistence cohorts in Year 1 (A) and Year 2 (B). Note: AS03, tocopherol, oil-in-water emulsion-based Adjuvant System; CI, confidence intervals; TIV, inactivated trivalent influenza vaccine; N, number of subjects in the cohort with data available at time-point; GMT, geometric mean titer; Year 1, 2008/09; Year 2, 2009/10; Influenza A strains were A/Brisbane/59/2007 (H1N1 strain) and A/Uruguay/716/2007 (H3N2 strain); Influenza B strains were B/Brisbane/3/2007 (Victoria lineage) in Year 1 and B/Brisbane/60/2008 (Yamagata lineage) in Year 2.
Figure 4.
Figure 4.
Day 21 and 180 hemagglutination-inhibition-based SCRs in the per-protocol immunogenicity persistence cohorts in Year 1 (A) and Year 2 (B). Note: AS03, tocopherol, oil-in-water emulsion-based Adjuvant System; CI, confidence intervals; TIV, inactivated trivalent influenza vaccine; N, number of subjects in the cohort with data available at time-point; Year 1, 2008/09; Year 2, 2009/10; Influenza A strains were A/Brisbane/59/2007 (H1N1 strain) and A/Uruguay/716/2007 (H3N2 strain); Influenza B strains were B/Brisbane/3/2007 (Victoria lineage) in Year 1 and B/Brisbane/60/2008 (Yamagata lineage) in Year 2; SCR, seroconversion rate defined as the proportion of seronegative subjects at baseline with post-vaccination titer of ≥1:40, or pre-vaccination titer of ≥1:10 and ≥4-fold increase post-vaccination.
Figure 5.
Figure 5.
Number of subjects in each titer category and number of A/H3N2 cases (A) and proportion of subjects in each titer category with PCR-confirmed A/H3N2 infection (B) in the immunogenicity subset.
Figure 6.
Figure 6.
A/H3N2 HI antibody titer and estimated risk of A/H3N2 influenza infection overall (A), in a low/moderate season (B) and in a high season (C) in the immunogenicity subset. Note: Points represent the observed proportions of cases and the dotted curve show 95% confidence interval; HI, hemagglutination-inhibition.

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