Evaluation of non-inferiority of intradermal versus adjuvanted seasonal influenza vaccine using two serological techniques: a randomised comparative study

Pierre Van Damme, Robert Arnou, Froukje Kafeja, Anne Fiquet, Patrick Richard, Stéphane Thomas, Gilles Meghlaoui, Sandrine Isabelle Samson, Emilio Ledesma, Pierre Van Damme, Robert Arnou, Froukje Kafeja, Anne Fiquet, Patrick Richard, Stéphane Thomas, Gilles Meghlaoui, Sandrine Isabelle Samson, Emilio Ledesma

Abstract

Background: Although seasonal influenza vaccine is effective in the elderly, immune responses to vaccination are lower in the elderly than in younger adults. Strategies to optimise responses to vaccination in the elderly include using an adjuvanted vaccine or using an intradermal vaccination route. The immunogenicity of an intradermal seasonal influenza vaccine was compared with that of an adjuvanted vaccine in the elderly.

Methods: Elderly volunteers (age > or = 65 years) were randomised to receive a single dose of trivalent seasonal influenza vaccine: either a split-virion vaccine containing 15 microg haemagglutinin [HA]/strain/0.1-ml dose administered intradermally, or a subunit vaccine (15 microg HA/strain/0.5-ml dose) adjuvanted with MF59C.1 and administered intramuscularly. Blood samples were taken before and 21 +/- 3 days post-vaccination. Anti-HA antibody titres were assessed using haemagglutination inhibition (HI) and single radial haemolysis (SRH) methods. We aimed to show that the intradermal vaccine was non-inferior to the adjuvanted vaccine.

Results: A total of 795 participants were enrolled (intradermal vaccine n = 398; adjuvanted vaccine n = 397). Non-inferiority of the intradermal vaccine was demonstrated for the A/H1N1 and B strains, but not for the A/H3N2 strain (upper bound of the 95% CI = 1.53) using the HI method, and for all three strains by the SRH method. A post-hoc analysis of covariance to adjust for baseline antibody titres demonstrated the non-inferiority of the intradermal vaccine by HI and SRH methods for all three strains. Both vaccines were, in general, well tolerated; the incidence of injection-site reactions was higher for the intradermal (70.1%) than the adjuvanted vaccine (33.8%) but these reactions were mild and of short duration.

Conclusions: The immunogenicity and safety of the intradermal seasonal influenza vaccine in the elderly was comparable with that of the adjuvanted vaccine. Intradermal vaccination to target the immune properties of the skin appears to be an appropriate strategy to address the challenge of declining immune responses in the elderly.

Trial registration: ClinicalTrials.gov: NCT00554333.

Figures

Figure 1
Figure 1
Comparison of European Medicines Agency (EMA) immunogenicity variables for the intradermal and adjuvanted influenza vaccines assessed by haemagglutinin inhibition (HI; left-hand column) and single radial haemolysis (SRH; right-hand column) methods. Analyses were carried out with the other immunogenicity analysis set (participants who received a study vaccine and for whom pre-and post-vaccination titres on days 0 and 21 were available for each strain). The horizontal line indicates the EMA threshold for each variable. (a) Ratio of individual post-and pre-vaccination geometric mean titres (GMTR); (b) Post-vaccination seroprotection rate1 (%); (c) Seroconversion/significant increase rate2 (%). *: statistically significantly difference between the groups (adjuvanted vaccine -intradermal vaccine) was observed for the A/Solomon (HINI) strain using the full analysis set: 5.8% (95% CI: 1.1-10.5). 1Seroprotection: percentage of participants with anti-HA titre ≥ 40 [1/dil] or ≥ 25 mm2 for HI and SRH methods, respectively. 2Seroconversion: anti-HA post-vaccination titre ≥ 40 (1/dil; HI method) or ≥ 25 mm2 (SRH method) for participants with a pre-vaccination anti-HA individual titre < 10 (1/dil; HI method) or ≥ 4 mm2 (SRH method). Significant increase: ≥ fourfold increase (HI method) or ≥ 1.5-fold increase (SRH method) from pre-to post-vaccination anti-HA individual titre for participants with a pre-vaccination anti-HA individual titre ≥ 10 (1/dil - HI method) or > 4 mm2 (SRH method).
Figure 2
Figure 2
Summary of safety assessments with the intradermal and adjuvanted vaccines on days 0-7 post-vaccination. (a) Incidence of all and of severe solicited injection-site reactions. (b) Incidence of solicited systemic reactions

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