We conducted a systematic review and network meta-analysis (NMA). We searched the Cochrane Library Central Register of Controlled Trials, MEDLINE and EMBASE databases, and websites of regulatory agencies, through December 15th, 2020. We included placebo- or no vaccination-controlled, and head-to-head randomized clinical trials (RCTs). Pairs of reviewers independently screened the studies, abstracted the data, and appraised the risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome was laboratory-confirmed
influenza. We also synthesized data for hospitalization, mortality,
influenza-like illness (ILI),
pneumonia or lower
respiratory-tract disease, systemic and local adverse events (AEs). We estimated summary risk ratios (RR) using pairwise and NMA with random effects. This study is registered with PROSPERO, number CRD42018091895.
Findings: We identified 13,439 citations. A total of 231 RCTs were included after screening: 11 studies did not provide useful data for the analysis; 220 RCTs [100,677 children (< 18 years) and 329,127 adults (18-60 years) and elderly (≥ 61 years)] were included in the NMA. In adults and the elderly, all
vaccines, except the trivalent inactivated intradermal
vaccine (3-IIV ID), were more effective than placebo in reducing the risk of laboratory-confirmed
influenza, with a RR between 0.33 (95% credible interval [CrI] 0.21-0.55) for trivalent inactivated high-dose (3-IIV HD) and 0.56 (95% CrI 0.41-0.74) for trivalent live-
attenuated vaccine (3-LAIV). In adults and the elderly, compared with trivalent
inactivated vaccine (3-IIV), no significant differences were found for any, except 3-LAIV, which was less efficacious [RR 1.41 (95% CrI 1.04-1.88)]. In children, compared with placebo, RR ranged between 0.13 (95% CrI 0.03-0.51) for trivalent
inactivated vaccine adjuvanted with
MF59/AS03 and 0.55 (95% CrI 0.36-0.83) for trivalent
inactivated vaccine. Compared with 3-IIV, 3-LAIV and trivalent inactivated adjuvanted with
MF59/AS03 were more efficacious [RR 0.52 (95% CrI 0.32-0.82) and RR 0.23 (95% CrI 0.06-0.87)] in reducing laboratory-confirmed
influenza. With regard to safety, higher systemic AEs rates after vaccination with 3-IIV, 3-IIV HD, 3-IIV ID, 3-IIV
MF59/AS03-adj, quadrivalent inactivated (4-IIV), quadrivalent adjuvanted (4-IIV
MF59/AS03-adj), quadrivalent recombinant (4-RIV), 3-LAIV or quadrivalent live attenuated (4-LAIV)
vaccines were noted in adults and the elderly [RR 1.5 (95% CrI 1.18-1.89) to 1.15 (95% CrI 1.06-1.23)] compared with placebo. In children, the systemic AEs rate after vaccination was not significantly higher than placebo.
Interpretation: The directorate general of welfare, Lombardy region.