The immunogenicity benefit of inactivated
influenza vaccine (IIV) adjuvanted by
squalene over non-adjuvanted aqueous IIV was explored in a meta-analysis involving 49 randomised trials published between 1999 and 2017, and 22,470 eligible persons of all age classes. Most
vaccines contained 15 μg viral haemagglutinin per strain. Adjuvanted IIV mostly contained 9.75 mg
squalene per dose. Homologous pre- and post-vaccination geometric mean titres (GMTs) of haemagglutination-inhibition (HI) antibody were recorded for 290 single
influenza (sub-)type arms. The adjuvant effect was expressed as the ratio of post-vaccination GMTs between
squalene-IIV and aqueous IIV (GMTR, 145 estimates). GMTRs > 1.0 favoured
squalene-IIV over aqueous IIV. For all
influenza (sub-)types, the adjuvant effect proved negatively associated with pre-vaccination GMT and mean age. The adjuvant effect appeared most pronounced in young children (mean age < 2.5 years) showing an average GMTR of 3.7 (95% CI: 2.5 to 5.5). With increasing age, GMTR values gradually decreased towards 1.4 (95% CI: 1.0 to 1.9) in older adults. Heterologous antibody titrations simulating mismatch between
vaccine and circulating virus (30 GMTR estimates) again showed a larger adjuvant effect at young age. GMT values and their variances were converted to antibody-predicted protection rates using an evidence-based clinical protection curve. The adjuvant effect was expressed as the protection rate differences, which showed similar age patterns as corresponding GMTR values. However for
influenza B, the adjuvant effect lasted longer than for
influenza A, possibly due to a generally later influenza B virus exposure. Collectively, this meta-analysis indicates the highest benefit of
squalene-IIV over aqueous IIV in young children and decreasing benefit with progressing age. This trend is similar for seasonal
influenza (sub-)types and the 2009 pandemic strain, by both homologous and heterologous titration. The impact of pre-seasonal immunity on
vaccine effectiveness, and its implications for age-specific vaccination recommendations, are discussed.