BACKGROUND: When new vaccine components or platforms are developed, they will typically need to demonstrate noninferiority or superiority over existing products, resulting in the assessment of relative vaccine effectiveness (rVE). This review aims to identify how rVE evaluation is being performed in studies of influenza to inform a more standardized approach. METHODS: We conducted a systematic search on PubMed, Google Scholar, and Web of Science for studies reporting rVE comparing vaccine components, dose, or vaccination schedules. We screened titles, abstracts, full texts, and references to identify relevant articles. We extracted information on the study design, relative comparison made, and the definition and statistical approach used to estimate rVE in each study. RESULTS: We identified 63 articles assessing rVE in influenza virus. Studies compared multiple vaccine components (n = 38), two or more doses of the same vaccine (n = 17), or vaccination timing or history (n = 9). One study compared a range of vaccine components and doses. Nearly two-thirds of all studies controlled for age, and nearly half for comorbidities, region, and sex. Assessment of 12 studies presenting both absolute and relative effect estimates suggested proportionality in the effects, resulting in implications for the interpretation of rVE effects. CONCLUSIONS: Approaches to rVE evaluation in practice is highly varied, with improvements in reporting required in many cases. Extensive consideration of methodologic issues relating to rVE is needed, including the stability of estimates and the impact of confounding structure on the validity of rVE estimates.

Influenza viruses are associated with a substantial global burden of morbidity and mortality every year. Estimates of influenza-associated mortality often vary between studies due to differences in study settings, methods, and measurement of outcomes. We reviewed 103 published articles assessing population-based influenza-associated mortality through searches of PubMed and Embase, and we identified considerable variation in the statistical methods used across studies. Studies using regression models with an influenza activity proxy applied 4 approaches to estimate influenza-associated mortality. The estimates increased with age and ranged widely, from -0.3-1.3 and 0.6-8.3 respiratory deaths per 100,000 population for children and adults, respectively, to 4-119 respiratory deaths per 100,000 population for older adults. Meta-regression analysis identified that study design features were associated with the observed variation in estimates. The estimates increased with broader cause-of-death classification and were higher for older adults than for children. The multiplier methods tended to produce lower estimates, while Serfling-type models were associated with higher estimates than other methods. No average estimate of excess mortality could reliably be made due to the substantial variability of the estimates, partially attributable to methodological differences in the studies. Standardization of methodology in estimation of influenza-associated mortality would permit improved comparisons in the future.