Twelve articles of thirteen trials, with 9,723 patients, were included. These analysed 58 treatment groups, of which 52 reported data on haemagglutination inhibition and 57 reported data on micro-neutralisation. The Jadad scores in 11 trials were between three and five out of five, indicating fair-to-good quality. One trial scored one on the Jadad scale and one was assigned a Jadad score of two.
Compared with a baseline dose of 6μg or less of non-enhanced vaccine, the meta-analysis found that immunogenicity increased with the use of non-aluminium-enhanced vaccines, using haemagglutination inhibition, from 6μg or less (OR 78.06, 95% CI 13.2 to 574) to 30μg or more of haemagglutinin antigen (OR 93.70, 95% CI 16.0 to 692). Using micro-neutralisation, it also increased from 6μg or less (OR 16.19, 95% CI 3.94 to 66.8) to 30μg or more of haemagglutinin antigen (OR 28.05, 95% CI 6.63 to 129).
Immunogenicity increased with increasing haemagglutinin antigen dose, but 70% was not attained with aluminium-enhanced or non-enhanced formulations at any dose.
There were no serious adverse events reported in any of the trials. There were significantly higher risks of myalgia with enhanced vaccines compared with non-enhanced formulations at a dose of 15μg of haemagglutinin antigen (RR 2.44, 95% CI 1.80 to 3.31). The non-aluminium-enhanced vaccines were found to have significantly higher risks of headache (RR 1.57, 95% CI 1.04 to 2.36), malaise (RR 1.54, 95% CI 1.04 to 2.28), myalgia (RR 3.50, 95% CI 1.74 to 7.01), and local pain (RR 2.37, 95% CI 1.73 to 3.25), but not fever and erythema. There was no evidence to suggest that higher doses of haemagglutinin antigen increased the risk of adverse events, except for local pain with higher risks observed with 30μg compared with the 15μg dose (RR 1.40, 95% CI 1.14 to 1.71).