Standard‐dose seasonal influenza vaccines often produce modest immunogenic responses in adults ≥65 years old. MF59 is intended to elicit a greater magnitude and increased breadth of immune response.

To determine the effectiveness of seasonal MF59‐adjuvanted trivalent/quadrivalent influenza vaccine (aTIV/aQIV) relative to no vaccination or vaccination with standard or high‐dose egg‐based influenza vaccines among people ≥65 years old.

Cochrane methodological standards and PRISMA‐P guidelines were followed. Real‐world evidence from non‐interventional studies published in peer‐reviewed journals and gray literature from 1997 through to July 15, 2020, including cluster‐randomized trials, were eligible. Two reviewers independently extracted data; risk of bias was assessed using the ROBINS‐I tool.

Twenty‐one studies conducted during the 2006/07–2019/20 influenza seasons were included in the qualitative review; 16 in the meta‐analyses. Meta‐analysis of test‐negative studies found that aTIV reduced medical encounters due to lab‐confirmed influenza with pooled estimates of 40.7% (95% CI: 21.9, 54.9; I² = 0%) for non‐emergency outpatient visits and 58.5% (40.7, 70.9; I² = 52.9%) for hospitalized patients. The pooled estimate of VE from case‐control studies was 51.3% (39.1, 61.1; I² = 0%) against influenza‐ or pneumonia‐related hospitalization. The pooled estimates for the relative VE of aTIV for the prevention of influenza‐related medical encounters were 13.9% (4.2, 23.5; I² = 95.9%) compared with TIV, 13.7% (3.1, 24.2; I² = 98.8%) compared with QIV, and 2.8% (−2.9, 8.5; I² = 94.5%) compared with HD‐TIV.

Among adults ≥65 years, aTIV demonstrated significant absolute VE, improved relative VE compared to non‐adjuvanted standard‐dose TIV/QIV, and comparable relative VE to high‐dose TIV.