| Summary: | The imperfect effectiveness of seasonal influenza vaccines is often blamed on antigenic mismatch, but even when the match appears good, effectiveness can be surprisingly low. Seasonal influenza vaccines also stand out for their variable effectiveness by age group from year to year and by recent vaccination status. These patterns suggest a role for immune history in influenza vaccine effectiveness, but inference is complicated by uncertainty about the contributions of bias to the estimates themselves. In this review, we describe unexpected patterns in the effectiveness of seasonal influenza vaccination and explain how these patterns might arise as consequences of study design, the dynamics of immune memory, or both. Resolving this uncertainty could lead to improvements in vaccination strategy, including the use of universal vaccines in experienced populations, and the evaluation of vaccine efficacy against influenza and other antigenically variable pathogens.
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