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Influenza Vaccine Effectiveness: Mysteries, Enigmas, and a Few Clues.

Winston Churchill famously said: “I cannot forecast to you the action of Russia. It is a riddle, wrapped in a mystery, inside an enigma; but perhaps there is a key.” He could have been referring to forecasting influenza epidemics and the effectiveness of influenza vaccines. Currently available influenza vaccines have moderate efficacy, established by placebo-controlled clinical trials, and moderate effectiveness, demonstrated in observational studies [1, 2]. However, there is variation in vaccine effectiveness by age and vaccine type, as well as substantial year-to-year variation. Some of this variation is well understood. With current technology, vaccine strains are selected many months in advance, leading to periodic major antigenic mismatches between the strains used for vaccine and the predominant circulating virus. Such a mismatch occurred in the 2014– 2015 influenza season between the influenza A(H3N2) virus strain in the vaccine (A/Texas/50/2012) and the strain that circulated in North America (A/Switzerland/ 9715293/2013-like), resulting in minimal vaccine effectiveness [3–5]. The need to express the antigens of the selected virus in egg-adapted seed strains can lead to unexpected low yields and delays in vaccine availability. Strain optimization and low yield contributed to the delay in production of vaccine to respond to the 2009 pandemic caused by influenza A(H1N1) virus (A[H1N1]pdm09) [6]. To monitor vaccine effectiveness, annual observational studies are conducted in the United States [7], Canada [8], and Europe [9].These studies use the test-negative case-control study design. This method involves enrollment of patients with medically attended respiratory illness and testing them with sensitive and specific assays for influenza virus. The odds ratio is calculated from the rate of influenza vaccination among those with influenza, compared with those who have a negative test result. Multivariate logistic regression is used to control for potential confounders such as age, presence of high-risk conditions, and calendar time. Effectiveness is calculated as [1− odds ratio] × 100. When the sample size is large enough, effectiveness can be calculated for specific age groups, virus type, and vaccine type. Preliminary results can be available early in the influenza season, to help guide policy [4]. The design has been validated using data from randomized trials [2], but it is still susceptible to potential bias, particularly from differential testing of vaccinated and unvaccinated patients [10, 11]. Annual effectiveness studieshaveprovided some insights. Correlating strain-specific data with effectiveness has helped explore how effectiveness is related to age and the degree of antigenic drift [7,12].Such studies have also provided surprises, including a suggestion that, in some settings, receipt of vaccine in the previous years was associated with lower effectiveness [13]. The article byGaglani et al in this issue of The Journal of Infectious Diseases provides another result that could not have been forecasted [14]. The authors used test-negative case-control data from the US Flu Vaccine Effectiveness Network for the 2013–2014 season,whenA(H1N1)pdm09—essentially the same virus that caused the 2009 pandemic—was the predominant strain. They compared the effectiveness of inactivated influenza vaccine (IIV) and live attenuated influenzavaccine (LAIV). This analysis was timely because, in June 2013, the Advisory Committee on Immunization Practices (ACIP) recommended that LAIV be the preferred vaccine for healthy children aged 2–8 years. TheACIPbased this preference on data from randomized trials [15] and observational studies [16] that showed higher relative efficacy and effectiveness of LAIV, compared with IIV, in children aged 2–8 years. Surprisingly, Gaglani et al found that, during the 2013–2014 season, quadrivalent LAIVwas not effective in children (adjusted vaccine effectiveness, 17%; 95% confidence interval, 39% to −51%). In contrast, IIV was effective with an adjusted vaccine effectiveness of 60% (95% confidence interval, 36%–64%). A similar lack of effectiveness of LAIV was observed in a separate test-negative study among children, funded by the manufacturer [17], and in data from the Armed Forces Surveillance Network [18]. In contrast, LAIV was effective in children against influenza B virus infection, during 2013–2014, and against influenzaA(H3N2) virus infection, during 2011–2012 and 2012–2013. How can we explain the surprising failure of LAIV against influenza A(H1N1) Received and accepted 25 November 2015; published online 6 January 2016. Correspondence: A. T. Pavia, Division of Pediatric Infectious Diseases, University of Utah, 295 Chipeta Way, Salt Lake City, UT 84108 (andy.pavia@hsc.utah.edu). The Journal of Infectious Diseases 2016;213:1521–2 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com. DOI: 10.1093/infdis/jiv579