Approaches to Comparing Influenza Vaccine Effectiveness to Guide Potential Preferential Product Recommendations

New influenza vaccine products might be licensed in coming years. Ideally, these vaccines would generate more broadly cross-reactive and longer-lasting protection than those currently licensed. Recommendations for the use of and potential preference for new influenza vaccines should be informed by absolute and comparative effectiveness evaluations. Absolute vaccine effects are commonly evaluated pre- and post-licensure, but more complex comparative evaluations have special considerations discussed in this Viewpoint. Relative vaccine effectiveness (rVE) can be assessed in clinical trials, cluster-randomized trials, and a variety of observational designs. Cluster-randomized trials have reduced potential for bias compared to observational studies, but operational barriers may limit feasibility. Observational rVE studies may utilize prospectively collected data or real-world evidence from large healthcare databases. Advantages of observational rVE studies include timeliness and lower cost, but uptake of novel influenza vaccines that is low and variable by age, health status, and other characteristics is a major challenge.