For the 2015–2016 influenza season, influenza vaccines were effective against influenza viruses in general and against A(H1N1)pdm09 in particular. The overall vaccine effectiveness was 48%, a finding consistent with other seasons in which vaccine virus strains were antigenically similar to circulating virus strains,3,8,9 and inactivated vaccines were effective against both A(H1N1)pdm09 viruses and influenza B viruses. However, despite the change to the A(H1N1)pdm09 strain in the quadrivalent live attenuated vaccine,8 we again observed that this vaccine was not effective among children, particularly against A(H1N1)pdm09.

In June 2016, preliminary 2015–2016 vaccine-effectiveness estimates from the Influenza Vaccine Effectiveness Network and from several other observational studies were presented to the ACIP. In each of these studies, estimated vaccine effectiveness against A(H1N1)pdm09 was lower for the live attenuated vaccine than for the inactivated vaccine. Preliminary estimates from the Department of Defense for children 2 to 17 years of age indicated a nonsignificant vaccine effectiveness of 15% for the quadrivalent live attenuated vaccine against A(H1N1)pdm09, as compared with a significant 68% effectiveness for the trivalent or quadrivalent inactivated vaccine.22 The Influenza Clinical Investigation for Children (ICICLE) study (ClinicalTrials.gov number, NCT01997450) estimated vaccine effectiveness among children 2 to 17 years of age at study sites in eight U.S. states. For A(H1N1)pdm09, the interim results of that study showed a nonsignificant vaccine effectiveness of 50% for the quadrivalent live attenuated vaccine and a significant vaccine effectiveness of 71% for the trivalent or quadrivalent inactivated vaccine.23 A Finnish cohort study involving 2-year-old children showed a significant vaccine effectiveness against influenza A — predominantly against A(H1N1)pdm09 — of 48% for the quadrivalent live attenuated vaccine and 80% for the trivalent inactivated vaccine.24 Finally, a U.K. study involving children 2 to 17 years of age showed a nonsignificant vaccine effectiveness of 42% against A(H1N1)pdm09 for the quadrivalent live attenuated vaccine, as compared with an effectiveness of 100% for the trivalent inactivated vaccine.25 In light of these data, the ACIP made an interim recommendation not to use the quadrivalent live attenuated vaccine in the United States for the 2016–2017 influenza season.26

Although these observational studies consistently showed lower effectiveness for the live attenuated vaccine than for the inactivated vaccine, point estimates for the effectiveness of the live attenuated vaccine varied widely among studies. The reasons for this are unclear. The quadrivalent live attenuated vaccines in the United States, Finland, and the United Kingdom were all produced by the same manufacturer at the same plant,24 so it is unlikely that differences in estimated vaccine effectiveness are due to variations in the vaccine product. The observed variations could be due to chance, since the vaccine-effectiveness point estimates for all five studies have relatively wide confidence intervals. Vaccination history among children probably differs between populations in the U.S. and European studies. In the United States, children following the ACIP recommendations would have received at least one dose of inactivated influenza vaccine before 2 years of age and the quadrivalent live attenuated vaccine thereafter.27 In contrast, the Joint Committee on Vaccination and Immunisation in the United Kingdom recommends influenza vaccination beginning at 2 years of age for healthy children, using the quadrivalent live attenuated vaccine, and the Finnish study predominantly included children who had never received an influenza vaccine. Thus, children in the U.S. studies differed from their European counterparts in the number of previous influenza vaccine doses received and in the formulation of their first vaccinations. None of these studies was well-powered to examine differences in vaccine effectiveness according to vaccination history, so it is difficult to explore this in more detail. This is not a complete explanation, since discrepant results were also seen among the U.S. studies, which may have similar populations with regard to previous vaccination.

Other findings from this study merit comment. With the exception of the quadrivalent live attenuated vaccine in children, the 2015–2016 influenza vaccines were effective in persons of all ages and against all circulating virus subtypes and lineages. Some studies have suggested that previous-season vaccination inhibits the effectiveness of the vaccine for the current season. As in previous seasons investigated by the Influenza Vaccine Effectiveness Network, we found that vaccine effectiveness among participants who had been vaccinated in the previous season was lower than that among those who had not been vaccinated in the previous season, although the difference was not significant.3,8,9 We also found that the quadrivalent inactivated vaccine was significantly more effective than the trivalent inactivated vaccine against B/Victoria viruses, which were not included in the 2015–2016 trivalent vaccine. In some previous seasons, the trivalent inactivated vaccine has been seen to protect against both B lineages.3 Our finding of superior vaccine effectiveness of the quadrivalent relative to the trivalent inactivated vaccine against B/Victoria suggests that switching to the quadrivalent inactivated vaccine may indeed prevent more cases of influenza B than the trivalent vaccine during some seasons; this idea needs to be tested.

Several limitations of our study should be considered. As with any observational study, we cannot rule out unmeasured confounding as an explanation for our findings. In addition, the test-negative design is still comparatively new. This design may be subject to biases that are not fully understood,28-31 although it is unlikely that these biases would be differential between the live attenuated vaccine and the inactivated vaccine. Our overall study population was large, but the study lacked power to estimate vaccine effectiveness precisely in certain subgroups of interest, particularly when participants were stratified according to both age and influenza virus subtype or lineage. Strengths of this study include the prospective screening and enrollment of participants meeting predefined clinical criteria, the geographically diverse study sites, and the use of a highly specific test for influenza virus.32 In addition, our findings were robust to a wide range of assumptions regarding study eligibility, choice of variables to include in adjusted vaccine-effectiveness models, and definition of vaccination status.

During the 2015–2016 influenza season, the quadrivalent live attenuated influenza vaccine was found to be ineffective against A(H1N1)pdm09 in children, whereas there was substantial effectiveness of the inactivated influenza vaccine. Potential explanations for the live attenuated vaccine having lower effectiveness than the inactivated vaccine in this group remain unclear but may include poor replicative fitness of its A(H1N1)pdm09 strains or vaccine-virus interference.33 Although the quadrivalent live attenuated vaccine remains licensed in the United States, the ACIP did not recommend this vaccine for the 2016–2017 influenza season.