Influenza is a major public health concern that annually causes illness in a substantial proportion of the U.S. population, and may result in serious complications, including hospitalization and death. Vaccination is the single best way to prevent influenza.
FluMist (manufactured by MedImmune, LLC) is a live attenuated influenza vaccine administered intranasally, and was originally licensed (approved) as a trivalent vaccine on June 17, 2003, for use in individuals ages 5 through 49 years for the prevention of influenza disease caused by Influenza A subtype viruses and the type B virus contained in the vaccine. On September 19, 2007, FDA approved expanding the population for use of FluMist to include children between the ages of 2 and 5 years. FDA granted approval for use in individuals 2 through 49 years of age based, in part, on its evaluation of randomized, controlled clinical trials demonstrating the efficacy of FluMist in the prevention of virus culture-confirmed influenza illness. Pre-licensure clinical data as well as clinical data obtained soon after licensure indicated that FluMist was as effective as inactivated influenza vaccine. On February 29, 2012, FDA approved FluMist Quadrivalent, a formulation containing two Influenza A subtype viruses and two type B viruses for use in persons 2 through 49 years of age. The effectiveness of FluMist Quadrivalent was based on an evaluation of immune responses in vaccinated persons, as well as the demonstrated effectiveness of the trivalent formulation. With FDA approval of FluMist Quadrivalent, MedImmune committed to conduct an observational postmarketing study of the effectiveness of FluMist Quadrivalent in children 2 through 17 years of age over four influenza seasons. Completion of this study is expected by December 2017.
Based on data from observational studies showing lower than expected effectiveness of FluMist Quadrivalent from 2013 through 2016, on June 22, 2016, the Advisory Committee on Immunization Practices (ACIP), an advisory committee to the Centers for Disease Control and Prevention (CDC), voted to recommend that FluMist Quadrivalent should not be used during the 2016-2017 influenza season. FDA’s considerations regarding this vaccine are noted and explained below.
FDA continues to find that the benefits of FluMist Quadrivalent outweigh any potential risks. As such, the agency has determined that specific regulatory action is not warranted at this time. This determination is based on FDA’s review of manufacturing and clinical data supporting licensure noted above, the totality of the evidence presented at the ACIP meeting, taking into account the inherent limitations of observational studies conducted to evaluate influenza vaccine effectiveness, as well as the well-known variability of influenza vaccine effectiveness across influenza seasons. FDA continues to work closely with MedImmune to determine the cause of the lower than expected effectiveness of FluMist Quadrivalent observed in recent years.
Summary of Scientific Studies
At the June 22, 2016, ACIP meeting, data were presented on influenza vaccine effectiveness from four observational studies conducted in subgroups of the pediatric population during the 2015-2016 influenza season. Two of the studies were conducted in the United States – one by MedImmune as part of its postmarketing commitment to FDA and one by CDC. A third study was conducted in the United Kingdom by Public Health England in collaboration with other partners. The fourth study was conducted in Finland by the Finland National Institute for Health and Welfare. Based on presentations at the ACIP meeting, for Influenza A (H1N1), both U.S. studies showed lower effectiveness of FluMist Quadrivalent compared to inactivated influenza vaccines (i.e., injectable vaccines), and neither U.S. study showed statistically significant effectiveness of FluMist Quadrivalent against Influenza A (H1N1). However, three of the studies (MedImmune’s U.S. study, the U.K. study, and the Finland study) showed statistically significant effectiveness of FluMist Quadrivalent against all influenza strains combined, ranging from 46% to 58% effectiveness. This level of overall effectiveness is comparable to vaccine effectiveness against vaccine-similar strains obtained from observational studies in children for both FluMist and inactivated influenza vaccines in prior seasons. In contrast, CDC’s U.S. study did not show statistically significant effectiveness of FluMist Quadrivalent for all influenza strains combined. Reasons for discordant results among the studies, particularly between the two U.S. studies, are not clear but may include limitations inherent in observational study designs.
About Influenza Vaccine Effectiveness
Influenza viruses continually undergo changes in their genetic makeup. These changes can occur from one season to the next; they can also occur over the course of a single influenza season. Unlike other vaccines, the composition of influenza vaccines must be periodically updated so that they are effective against what are anticipated to be the predominant circulating viruses in the upcoming influenza season.
The effectiveness of influenza vaccines varies from year to year. There is always the possibility of a less-than-optimal match between the influenza virus strains that end up predominating during the influenza season and those covered by the vaccines. This occurred during the 2014-2015 influenza season when all seasonal influenza vaccines, including inactivated vaccines and FluMist Quadrivalent, performed unusually poorly overall. The vaccines’ lower than expected effectiveness that season has been attributed primarily to the spread of a "drifted" strain of influenza A (H3N2) that did not match well with the H3N2 strain used in the vaccines. In the U.S., overall effectiveness for all influenza vaccines for the season was estimated at 23%.
Influenza vaccine effectiveness can also be affected by the age and health of the person being vaccinated and prior exposure to influenza disease or influenza vaccines.
Addressing Lower than Expected Effectiveness of FluMist Quadrivalent
In the 2013-2014 influenza season, when lower than expected effectiveness of FluMist Quadrivalent was first observed, Influenza A (H1N1) was the predominant circulating influenza virus strain. When the data showing lower than expected vaccine effectiveness became available, FDA began working with MedImmune to investigate potential reasons for this finding. Identification of possible problems with thermostability of the Influenza A (H1N1) vaccine strain led to a manufacturing change that could be implemented in time for the 2015-2016 influenza season. Available data from observational studies of influenza vaccine effectiveness for the 2015-2016 influenza season suggest that this change led to improved FluMist Quadrivalent effectiveness against Influenza A (H1N1) compared to that previously observed in the 2013-2014 influenza season. However, these data also suggest that factors other than thermostability may be contributing to the lower than expected effectiveness of FluMist Quadrivalent observed in recent years. FDA is continuing to work with MedImmune to better understand these findings.
Additional information about the vaccine is available on FDA’s web site.