Objectives: To compare the efficacy of influenza vaccines of any valency for adults 60 years and older. Methods: Design: Systematic review with network meta-analysis (NMA) Information sources: MEDLINE, EMBASE, JBI Evidence-Based Practice (EBP) Database, PsycINFO, and Cochrane Evidence Based Medicine database from inception to June 20, 2022. Eligibility criteria: Randomized controlled trials (RCTs) including older adults (≥60 years old) receiving an influenza vaccine licensed in Canada or the United States (versus placebo, no vaccine, or any other licensed vaccine), at any dose. Outcome measures: Primary outcomes: Laboratory-confirmed influenza (LCI) and influenza-like illness (ILI). Secondary outcomes: number of vascular adverse events, hospitalization for acute respiratory infection (ARI) and ILI, inpatient hospitalization, emergency room (ER) visit for ILI, outpatient visit, and mortality, among others. Data extraction, risk of bias (ROB), and certainty of evidence assessment: Two reviewers screened, abstracted, and appraised articles (Cochrane ROB 2 tool) independently. We assessed certainty of findings using CINeMA and GRADE approaches. Data synthesis: We performed random-effects meta-analysis and NMA, and estimated odds ratios (ORs) for dichotomous outcomes and incidence rate ratios (IRRs) for count outcomes along with corresponding 95% confidence intervals (95%CI) and prediction intervals. Results: We included 41 RCTs and 15 companion reports comprising eight vaccine types and 206,032 participants. Vaccines prevented LCI compared with placebo, with high-dose trivalent (IIV3-HD) (NMA, nine RCTs, 52,202 participants, OR 0.23, 95%CI [0.11 to 0.51], low certainty of evidence) and RIV (OR 0.25, 95%CI [0.08 to 0.73], low certainty of evidence) among the most efficacious vaccines. Standard dose trivalent inactivated influenza vaccine (IIV3-SD) prevented ILI compared with placebo, but the result was imprecise (meta-analysis, two RCTs, 854 participants, OR 0.39, 95%CI [0.15 to 1.02], low certainty of evidence). Any high dose (HD) prevented ILI compared with placebo (NMA, nine RCTs, 65,658 participants, OR 0.38, 95%CI [0.15 to 0.93]). Adjuvanted quadrivalent inactivated influenza vaccine (IIV4-Adj) was associated with the least vascular adverse events (NMA: eight RCTs, 57,677 participants, IRR 0.18, 95%CI [0.07 to 0.43], very low certainty of evidence). RIV on all-cause mortality was comparable to placebo (NMA: 20 RCTs, 140,577 participants, OR 1.01, 95%CI [0.23 to 4.49], low certainty of evidence). Conclusions: This systematic review demonstrated high efficacy associated with IIV3-HD and RIV vaccines in protecting elderly persons against LCI, and RIV vaccine minimizing all-cause mortality when compared with other vaccines. However, differences in efficacy between these vaccines remain uncertain with very low to moderate certainty of evidence.

The authors have declared no competing interest.

This work was funded by a Canadian Institutes of Health Research Drug Safety and Effectiveness Network (No. DMC – 166263). SES is funded by a Tier 1 Canada Research Chair in Knowledge Translation and Quality of Care, the Mary Trimmer Chair in Geriatric Medicine, and a Foundation Grant (Canadian Institutes of Health Research). ACT holds a Tier 2 Canada Research Chair in Knowledge Synthesis. MC was part supported by the Health Research Board (Ireland) and the HSC Public Health Agency (Grant number CBES-2018-001) through Evidence Synthesis Ireland/Cochrane Ireland.

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The full dataset and statistical code are available from the corresponding author upon reasonable request.