The Journal of Infectious Diseases EDITORIAL COMMENTARY

Influenza Vaccine Effectiveness: Mysteries, Enigmas, and a Few Clues Andrew T. Pavia Division of Pediatric Infectious Diseases, University of Utah School of Medicine, Salt Lake City

(See the major article by Gaglani et al on pages 1546–56.)

Keywords.

influenza vaccine; influenza virus; vaccine effectiveness; influenza vaccine effectiveness; case-control studies.

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

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 ([email protected]). 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 [email protected]. DOI: 10.1093/infdis/jiv579

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 studies have provided 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 by Gaglani 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, when A(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 influenza vaccine (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. The ACIP based 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 LAIV was 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 influenza A(H3N2) virus infection, during 2011–2012 and 2012–2013. How can we explain the surprising failure of LAIV against influenza A(H1N1)

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virus during 2013–2014? Gaglani et al suggest that the problem may lie in the thermostability of the A(H1N1)pdm09 vaccine construct. The hemagglutinin and neuraminidase genes for each year’s vaccine are expressed by reverse genetics in the cold-adapted vaccine strain [19], so the resultant virus is a 6:2 reassortant. The hemagglutinin protein from the original A(H1N1)pdm09 strains early in the pandemic contained glutamic acid at position 47 (E47) in the stalk, a critical locus in the fusion domain of hemagglutinin. Later circulating viruses contained lysine at this position (K47). Cotter et al demonstrated that the K47 virus was more infectious than the E47 virus in ferrets, probably reflecting further adaptation to humans. In addition, vaccine constructs with E47 were more heat labile, which would be predicted to affect stability and potency [20]. Indeed, data presented to the ACIP by the manufacturer suggested that lots shipped earlier in the year at higher ambient temperatures were associated with lower effectiveness than those shipped later in the season. There are other possible explanations that cannot be excluded with the available data. Because the influenza A(H1N1) virus in 2013–2014 had circulated with little antigenic change and the H1N1 component of vaccines was unchanged since 2009, it is possible that immune mechanisms limited replication of LAIV in recipients, attenuating the immune response. Immune-mediated limitation of replication has been hypothesized to explain why LAIV is less effective than IIV in older adults [21]. Undetected problems during manufacturing, shipping, or storage could also have contributed to lower effectiveness. The larger problem stems from our incomplete knowledge of correlates of natural and vaccine-induced immunity to influenza. Our understanding of natural immunity to influenza remains incomplete >80 years after the Robert Shope’s isolation of influenza virus. Antibody to hemagglutinin is used for regulatory approval but is, at best, an imperfect correlate 1522



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of effectiveness for IIV. LAIV generally elicits less robust humoral responses but induces long-lived CD4+ T-cell responses, even in some subjects who do not have a humoral response [22, 23]. It is becoming clear that T-cell–mediated responses are critical in long-term and cross-strain protection against influenza [24]. Many have called for new influenza vaccines [1], but, in the meantime, careful studies will help us understand and better use existing vaccines. The characteristics of an optimal vaccine might include rapid and inexpensive production, broad protection against drifted and pandemic strains, and production of T-cell and Bcell memory. This goal is unlikely to be achieved by novel vaccine constructs alone. It will require a deeper understanding of the enigmas and mysteries of influenza pathogenesis and immunity.

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Notes Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant 1R01AI104593-01) and BioFire Diagnostics. Potential conflict of interest. A. T. P. has received grants from BioFire Diagnostics, personal fees and other compensation from Antimicrobial Therapy, and personal fees from WebMD, all outside the submitted work. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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References 1. Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12:36–44. 2. De Serres G, Skowronski DM, Wu XW, Ambrose CS. The test-negative design: validity, accuracy and precision of vaccine efficacy estimates compared to the gold standard of randomised placebo-controlled clinical trials. Euro Surveill 2013; 18:pii:20585. 3. Gilca R, Skowronski DM, Douville-Fradet M, et al. Mid-Season Estimates of Influenza Vaccine Effectiveness against Influenza A(H3N2) Hospitalization in the Elderly in Quebec, Canada, January 2015. PLoS One 2015; 10:e0132195. 4. Flannery B, Clippard J, Zimmerman RK, et al. Early estimates of seasonal influenza vaccine effectiveness United States, January 2015. MMWR Morb Mortal Wkly Rep 2015; 64:10–5. 5. Fry AM, Gubareva L, Garten R, et al. Influenza vaccine effectiveness against drifted versus vaccine-like A/H3N2 viruses during the 2014–15 influenza season—US Flu VE Network [abstract 1350]. In: IDWeek 2015. San Diego, CA, 2015. 6. Holden JP, Lander E, Varmus H. Report to the President on reengineering influenza vaccine production

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to meed the challenges of pandemic influenza. 2010. https://http://www.whitehouse.gov/sites/default/files/ microsites/ostp/PCAST-Influenza-Vaccinology-Report. pdf. Accessed 23 November 2015. McLean HQ, Thompson MG, Sundaram ME, et al. Influenza vaccine effectiveness in the United States during 2012–2013: variable protection by age and virus type. J Infect Dis 2015; 211:1529–40. Skowronski DM, De Serres G, Dickinson J, et al. Component-specific effectiveness of trivalent influenza vaccine as monitored through a sentinel surveillance network in Canada, 2006–2007. J Infect Dis 2009; 199:168–79. Kissling E, Valenciano M, Cohen JM, et al. I-MOVE multi-centre case control study 2010–11: overall and stratified estimates of influenza vaccine effectiveness in Europe. PLoS One 2011; 6:e27622. Ferdinands JM, Shay DK. Magnitude of potential biases in a simulated case-control study of the effectiveness of influenza vaccination. Clin Infect Dis 2012; 54:25–32. Foppa IM, Haber M, Ferdinands JM, Shay DK. The case test-negative design for studies of the effectiveness of influenza vaccine. Vaccine 2013; 31:3104–9. Janjua NZ, Skowronski DM, De Serres G, et al. Estimates of influenza vaccine effectiveness for 2007– 2008 from Canada’s sentinel surveillance system: cross-protection against major and minor variants. J Infect Dis 2012; 205:1858–68. Ohmit SE, Petrie JG, Malosh RE, Fry AM, Thompson MG, Monto AS. Influenza vaccine effectiveness in households with children during the 2012–2013 season: assessments of prior vaccination and serologic susceptibility. J Infect Dis 2015; 211:1519–28. Gaglani M, Pruszynski J, Murthy K, et al. Influenza vaccine effectiveness against the 2009 pandemic A(H1N1) virus differed by vaccine-type during 2013– 14 in the United States. J Infect Dis 2016; 213:1546–56. Belshe RB, Nichol KL, Black SB, et al. Safety, efficacy, and effectiveness of live, attenuated, cold-adapted influenza vaccine in an indicated population aged 5–49 years. Clin Infect Dis 2004; 39:920–7. Coelingh K, Olajide IR, MacDonald P, Yogev R. Efficacy and effectiveness of live attenuated influenza vaccine in school-age children. Expert Rev Vaccines 2015; 14:1331–46. Caspard H, Gaglani M, Clipper L, et al. Effectiveness of live attenuated influenza vaccine and inactivated influenza vaccine in children 2–17 years of age in 2013– 2014 in the United States [abstract 1352]. In: IDWeek 2015, San Diego California, October 7–11, 2015. Cost AA, Hiser MJ, Hu Z, et al. Brief report: mid-season influenza vaccine effectiveness estimates for the 2013–2014 influenza season. MSMR 2014; 21:15–7. Maassab HF. Adaptation and growth characteristics of influenza virus at 25 degrees c. Nature 1967; 213:612–4. Cotter CR, Jin H, Chen Z. A single amino acid in the stalk region of the H1N1pdm influenza virus HA protein affects viral fusion, stability and infectivity. PLoS Pathog 2014; 10:e1003831. Ohmit SE, Victor JC, Rotthoff JR, et al. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med 2006; 355:2513–22. Mohn KG, Bredholt G, Brokstad KA, et al. Longevity of B-cell and T-cell responses after live attenuated influenza vaccination in children. J Infect Dis 2015; 211:1541–9. Talaat KR, Luke CJ, Khurana S, et al. A live attenuated influenza A(H5N1) vaccine induces long-term immunity in the absence of a primary antibody response. J Infect Dis 2014; 209:1860–9. La Gruta NL, Turner SJ. T cell mediated immunity to influenza: mechanisms of viral control. Trends Immunol 2014; 35:396–402.

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

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