We found that, irrespective of a patient’s vaccination status for the prior season, current season vaccination is associated with greater protection against laboratory-confirmed infection by influenza H1N1 and B. This was evident comparing vaccination in both seasons to vaccination in the prior season only. Furthermore, compared to no vaccination for either season, individuals who received the current season’s vaccine had greater protection against all three influenza types/subtypes. Therefore, vaccination in the current season is generally the best option for the patient. Recent studies have raised questions about the impact of repeated vaccination [6,7,8], which is of concern to policymakers with regard to annual influenza vaccination recommendations. Of relevance to the policymaker (but not the patient, who cannot alter their vaccination history), we observed no differences in VE between vaccination in both seasons and vaccination in the current season only for any influenza type/subtype, providing no overall evidence of harm from repeated vaccination. The 2014–2015 influenza season was an exception, where pooled VE across three studies was lower for those vaccinated in both the current and prior season compared to those vaccinated in the current season alone. Based on the NOS, we assessed that the studies included in this review had a low risk of bias. However, the theoretical underpinnings of the test-negative design are still in the process of explication [40,41,42], and there has not yet been a theoretical assessment of the potential biases in evaluation of repeated vaccine effects using the test-negative design.

The results of this review are similar to those found by Beyer et al. in 1999 [5]; their meta-analysis of seven field studies and 12 serologic studies found no significant difference between the single and multiple vaccination groups. However, our study represents an advance by including studies that feature contemporary laboratory testing methods and study designs with consistent vaccination comparison groups. A recently published meta-analysis reported pooled VE estimates for the same vaccination status groups as our study (prior only, current only, both seasons) [43]. Similar to the present results, that study found VE to be consistently lowest among those vaccinated during the prior season only. Additionally, for the 2014–2015 season, VE against H3N2 was found to be higher for those vaccinated in the current season only compared to those vaccinated during both seasons. However, that study did not examine the differences in VE as presented in this study.

In our review, the comparison groups used in the meta-analysis provided a more refined calculation of VE that accounted for recent vaccination history. Standard VE calculations (those that do not account for prior vaccination history of the vaccinated group) compare those vaccinated in the study season (a mixture of subjects vaccinated in the current season only and those with current and prior vaccination) to a reference group of those not vaccinated in the study season (which includes both those vaccinated in neither season and those vaccinated in the prior season only). Our study allowed for these vaccination groups to be analyzed separately to understand the impact of prior season vaccination on current season VE.

Our study was further strengthened by aligning the VE comparisons with patient and policy perspectives in order to aid decision-making by patients, practitioners, and policymakers. Additionally, by calculating the differences in VE between the various vaccination groups within each study, we controlled for any methodological biases unique to a particular study, since these biases would apply equally to each vaccination group. Thus, rather than first pooling the VE estimates from each vaccination group across studies and subsequently taking the difference, we pooled the differences obtained from VE estimates within each study. Finally, because VE can vary by age group and influenza type/subtype, this study was strengthened by the detailed stratification of results by type/subtype, as well as by using VE estimates for the most specific patient groups (e.g., age-stratified groups rather than ‘all ages’).

This study also has some limitations. First, the analysis accounts only for vaccination status in one prior season. Results might differ when considering a patient’s vaccination history over a greater number of seasons, which is particularly significant when considering the importance of influenza VE in older adults who have potentially received many years of consecutive vaccinations. McLean et al. [6] found no difference when exploring VE over two consecutive seasons, but when they used a reference group with no vaccination over six seasons, those vaccinated in the current season only and not in the previous five seasons had the highest VE against influenza H3N2 and B, with progressively lower VE with increasing vaccines received over the previous five seasons. Few studies reported on vaccination history beyond prior and current seasons, and they did not group history consistently; therefore, further analysis incorporating the effects of serial vaccination from these studies was not possible, but is an important analysis to conduct in the future when more data are available. Second, our study did not account for past influenza infection, which may have provided some protective effect against laboratory-confirmed influenza in subsequent seasons [44]. A patient’s first exposure to influenza vaccination or infection can impact subsequent responses to vaccination or infection (referred to as original antigenic sin or back-boosting), which was not accounted for in this study [45]. Third, this study did not differentiate between the types of influenza vaccines used (e.g., live attenuated or inactivated; quadrivalent or trivalent; adjuvanted or unadjuvanted; high dose or standard dose). Given the differing types of immune response induced by these various products, different impacts of prior vaccination on current season VE may ensue. Fourth, we evaluated the absolute difference in VE instead of assessing a ratio; the latter could be considered more appropriate given the scale on which VE is calculated. However, the reporting of ratios introduces other challenges such as accommodating negative values and estimating confidence intervals. Since deriving practical conclusions for annual vaccine decision-making was the goal, we reported more intuitive differences in VE, as others have done previously [14, 46]. Finally, based on the limited available information in each study, we could not adjust for the match between the current season’s vaccine and the circulating strains, the prior season’s vaccine and the current season’s circulating strains, nor changes in vaccine strains from one season to another, all of which may affect VE from one year to the next, as noted by Smith et al.’s [47] antigenic distance hypothesis. Skowronski et al. [48] recently examined VE for influenza H3N2 in Canada using this framework, and concluded that the effects of repeated vaccination were consistent with the antigenic distance hypothesis. We attempted to assess VE based on antigenic distance in the included articles by considering the vaccine strain and circulating strain match where possible, but not all studies provided detailed strain information. In the articles with sufficient information, the variation of vaccine and circulating strain matches were too few and were grouped by season, and as seasonal analysis was already included in our meta-analysis, no further information was gained. However, consistent with Skowronski et al.’s findings [48], we observed a significant negative interference in the 2014–2015 influenza season, supporting the antigenic distance hypothesis which predicts that this would occur when vaccine strains are homologous from one year to the next but the prior season’s vaccine does not match the current circulating strain. Future VE studies should continue to incorporate vaccination status in prior seasons and provide as much detail as possible to allow assessment of the match between vaccine and circulating strains and the changes in vaccine strains over time. Future studies should also assess the impact of vaccination over multiple past seasons.