Effectiveness of Intranasal Live Attenuated Influenza Vaccine Against All-Cause Acute Otitis Media in Children Heikkinen Et Al Terho Heikkinen, MD, Phd,* Stan L

Mary

INF Vaccine Reports 203098

LAIV and Acute Otitis Media Effectiveness of Intranasal Live Attenuated Influenza Vaccine Against All-cause Acute Otitis Media in Children Heikkinen et al Terho Heikkinen, MD, PhD,* Stan L. Block, MD,† Seth L. Toback, MD,‡ Xionghua Wu, PhD,‡ and Christopher S. Ambrose, MD‡

cute otitis media (AOM) remains the most common bacterial Background: Acute otitis media (AOM) is a frequent complication of influ- infection and the most frequent reason for antibiotic treatment enza in children, and influenza vaccination helps protect against influenza- A Pediatr Infect Dis J in infants and young children. Although the incidence of AOM associated AOM. A live attenuated influenza vaccine (LAIV) approved for peaks around the age of 1 year, the rates of AOM are substantial eligible children aged ≥2 years for the prevention of influenza also effec- in older children.1,2 The high prevalence of antimicrobial resistance tively reduces influenza-associated AOM. However, the annual effective- among common bacteria causing AOM has substantially compli- Lippincott Williams & Wilkins ness of LAIV against all-cause AOM is unknown. cated the management of AOM, and efforts to reduce the use of Methods: AOM rates in children aged 6–83 months from 6 randomized, antibiotics for this disease are being assessed. As a consequence, placebo-controlled trials and 2 randomized, inactivated influenza vaccine- prevention of AOM through vaccination is an important area of controlled trials were pooled and analyzed. To enable comparison with Hagerstown, MD research.3,4 studies of AOM prevention by pneumococcal conjugate vaccines, 12-month Pneumococcal conjugate vaccines (PCVs) are currently effectiveness was calculated assuming that LAIV had no effect outside of used in most developed countries to prevent severe invasive pneu- influenza seasons. XXX mococcal illnesses in children. Although these 7- to 13-valent vac- Results: During influenza seasons, LAIV efficacy compared with placebo cines are very effective against invasive pneumococcal infections, against all-cause AOM in children aged 6–71 months (N = 9497) was they have also shown some efficacy against pneumococcal AOM. 12.4% (95% confidence interval [CI]: 2.0%, 21.6%) in year 1. In year 2, In a large clinical trial in Finland, the efficacy of the 7-valent PCV the efficacy in children aged 18–83 months (N = 4142) was 6.2% (95% CI: (PCV7) was 34% against AOM caused by any pneumococci in chil- −12.4%, 21.7%). Compared with inactivated influenza vaccine, the efficacy dren followed up to 24 months of age.5 However, because other bac- of LAIV in children aged 6–71 months (N = 9901) against febrile all-cause teria and viruses account for the majority of all AOM cases, PCV7 AOM was 9.7% (95% CI: −2.1%, 20.1%). The estimated 12-month effec- was able to reduce the annual incidence of all-cause AOM by 6%. tiveness of LAIV compared with placebo against all-cause AOM was 7.5% Similar results were obtained in the United States, where PCV7 was (95% CI: −2.4%, 16.2%). shown to reduce the rates of all-cause AOM episodes by 6.6% and Conclusions: LAIV reduced the incidence of all-cause AOM compared office visits by 7.8% in children aged 3–42 months.1 Higher reduc- with placebo in children. The estimated 12-month effectiveness of LAIV 2013 tions in all-cause AOM due to PCV7 have been reported6,7 in non- was comparable with 7-valent pneumococcal conjugate vaccine. The effects randomized studies that are influenced by herd protection, potential of the vaccines will overlap somewhat; however, because pneumococcal temporal confounding from more stringent criteria for diagnosing conjugate vaccines only prevent a fraction of all pneumococcal AOM and AOM and increasing use of influenza vaccines in US children. influenza-associated AOM can be caused by other pathogens, LAIV could The key role of respiratory viruses in the etiology and patho- further reduce the incidence of AOM in children. genesis of AOM is well established.3 Influenza viruses are known Key Words: acute otitis media, live attenuated influenza vaccine, trivalent to predispose a child to AOM.2,8–13 In a large prospective study of Copyright © 2013 by Lippincott Williams & Wilkins inactivated influenza vaccine respiratory infections in children, AOM developed as a complication of influenza in 40% of children aged <3 years and in 20% (Pediatr Infect Dis J 2013;32: 669–674) of children aged 3–6 years.12 Several clinical studies have demon- 00 strated that influenza-associated AOM can be effectively prevented by influenza vaccination.9,14–16 However, because influenza vaccine cannot exert its effect outside of the influenza season, the public health impact of influenza vaccination in reducing the overall 00 Accepted for publication December 19, 2012. annual incidence of AOM remains unknown. From the *Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; †Kentucky Pediatric and Adult Research, Bard- An intranasally administered, Ann Arbor strain live attenu- 0891-3668 stown, KY; and ‡MedImmune, Gaithersburg, MD. ated influenza vaccine (LAIV) is approved for eligible children Seth L. Toback, MD is currently at Gilead Sciences, Inc. Seattle, WA. aged ≥2 years. We have previously shown that the efficacy of LAIV TH and SLB have served as consultants for MedImmune, LLC (Gaithersburg, against influenza-associated AOM was 85% compared with pla- MD). SLT was an employee of MedImmune at the time of study and draft- cebo and 54% compared with inactivated influenza vaccine (IIV).17 10.1097/INF.0b013e3182840fe7 ing of the manuscript. XW and CSA are employees of MedImmune. This research was funded by MedImmune. Employees of MedImmune worked The aim of this study was to determine the effectiveness of LAIV collaboratively with the investigators in the design of the study, in analysis against all-cause AOM in children during influenza seasons, total and interpretation of the data, and reviewed and approved the manuscript. study surveillance periods and throughout an entire year. The Pediatric Infectious Disease Journal TH and SLB were not paid for their work on this manuscript. Editorial assis- tance in formatting the manuscript for submission was provided by Susan E. Myers, MSc, and Gerard P. Johnson, PhD, of Complete Healthcare Commu- MATERIALS AND METHODS nications, Inc. (Chadds Ford, PA) and funded by MedImmune. The authors 32 have no other funding or conflicts of interest to disclose. Eight randomized studies were identified in which LAIV Address for correspondence: Terho Heikkinen, MD, PhD, Department of Pedi- efficacy against AOM was a prespecified secondary endpoint. atrics, Turku University Hospital, FI-20520 Turku, Finland. E-mail: terho. These studies were conducted in the United States, Europe and [email protected]. Asia (Table 1). These studies have been described previously as 6 Copyright © 2012 by Lippincott Williams & Wilkins ISSN: 0891-3668/13/3206-669 individual studies and in an integrated analysis of influenza- DOI: 10.1097/INF.0b013e3182840fe7 associated AOM incidence.17–26 Six trials compared LAIV with June The Pediatric Infectious Disease Journal • Volume 32, Number 6, June 2013 www.pidj.com | 669 2013 Heikkinen et al The Pediatric Infectious Disease Journal • Volume 32, Number 6, June 2013

TABLE 1. Live Attenuated Influenza Vaccine Studies Measuring Efficacy Against AOM

Study Number Age Range, mo LAIV, N Control, N Location

Placebo-controlled studies Study 1, year 118 12–35 1653 1111 Asia Study 1, year 218 24–47 771 494 Asia Study 2, year 119 6–35 951 665 Europe Study 2, year 219 18–47 640 450 Europe Study 3, year 120 6–35 944 942 Multinational Study 3, year 220 18–47 338 342 Multinational Study 421 6–35 525 516 Asia Study 522 11–23 765 385 Multinational Study 6, year 123 15–71 854 417 United States Study 6, year 224 27–83 747 362 United States IIV-controlled studies Study 725 6–71 1050 1035 Europe Study 826 6–59 3916 3935 Multinational placebo, and 2 trials compared LAIV with IIV. Data on episodes of analysis. Therefore, pooled analyses were performed separately for AOM due to any cause were extracted by treatment group from all years 1 and 2. An estimate of efficacy against all-cause AOM epi- studies for the per-protocol population. The analyses included only sodes was calculated using the Andersen-Gill method with robust those children who were fully vaccinated (2 doses if previously sandwich covariance estimate of Cox proportional hazards model unvaccinated, 1 dose if previously vaccinated). If multiple potencies with treatment as the only effect. The efficacy was calculated as (1 of LAIV were studied,21 only data from the approved dose potency – hazard ratio) × 100. (106.5–7.5 fluorescent focus units/mL) were included in the analysis. All-cause AOM was defined as AOM due to any cause in Projected 12-Month Effectiveness Estimate study subjects, regardless of viral culture results. As in the study To estimate the annual impact of LAIV on all-cause AOM, of PCV7 by Eskola et al,5 an AOM episode was considered as a AOM rates were projected for months outside of the study surveil- new episode if it occurred at least 30 days after the previous AOM lance periods. To make comparisons with the randomized, placebo- episode. In 5 of the 6 placebo-controlled studies and in the IIV- controlled studies of PCV7 that were conducted in the United controlled study by Ashkenazi et al,25 AOM was defined using the States1,27 and Europe,5 only data from subjects in the United States criteria used by Eskola et al5: by the demonstration of a visually and Europe in placebo-controlled studies were used. Actual study abnormal tympanic membrane (with regard to color, position and/ data were used for AOM rates for months during the study surveil- or mobility) suggesting effusion in the middle ear, concomitantly lance periods. For other months, AOM rates were extrapolated by with ≥1 of the following signs and/or symptoms of acute infection: multiplying the average AOM rate in placebo recipients during the fever (≥38°C rectal or oral or 37.5°C axillary), earache, irritability, study surveillance periods by the published ratio of AOM rates in diarrhea, vomiting, acute otorrhea not caused by external otitis or the United States for May to October versus November to April.1 To other symptoms of respiratory infection. In the placebo-controlled assume no effect of LAIV outside of the influenza season, the same study by Belshe et al,23 otitis media was defined as a clinical diag- extrapolated AOM rate was applied to LAIV and placebo recipi- nosis made by a healthcare provider without further criteria. The ents for the months of June to October. The effectiveness of LAIV IIV-controlled study by Belshe et al26 also defined otitis media as against all-cause AOM during the 12-month period was calculated a clinical diagnosis made by a healthcare provider, but required using Poisson regression. fever as part of the diagnosis. Thus, in the current analysis, for both 25,26 IIV-controlled studies, fever (≥100°F oral or ≥100.6°F rectal/ RESULTS tympanic or 99.6°F axillary) was a requirement for the diagnosis ≥ In the placebo-controlled trials, data for pooled analyses of AOM. were available for 9497 children aged 6–71 months for year 1 and for 4142 children aged 18–83 months for year 2 (Tables 2 and 3). Efficacy Estimates During Influenza Seasons and In IIV-controlled trials, data were available for 9901 children aged Study Surveillance Periods 6–71 months. Of all 23,540 study subjects, 84% were healthy AOM rates were calculated by dividing the number of AOM children without additional qualifications; 11% were enrolled in a episodes by the total population in each treatment group. Surveil- placebo-controlled study that required all participants to attend ≥12 lance for AOM was conducted throughout each study using regular, hours of daycare per week;19 9% were enrolled in an IIV-controlled weekly telephone contacts, clinic visits or home visits with the sub- study that required a history of 2 or more respiratory tract infec- ject and their parent(s)/legal guardian(s). Efficacy estimates were tions (eg, common cold, AOM, bronchitis, pneumonia and bron- calculated for the study-specific influenza seasons (as defined for chiolitis) in the previous 12 months;25 and 47% were younger than each study country based on the weekly numbers of episodes of 24 months. culture-confirmed influenza) as well as for the entire study surveillance periods. To examine the potential impact of PCV7 use on Efficacy of LAIV Against All-cause AOM During AOM rates and LAIV efficacy, a separate analysis was conducted Influenza Seasons that excluded seasons and areas in which there was published evi- The mean durations of the study influenza seasons were 21.3 dence of significant PCV7 use. weeks in year 1 and 18.2 weeks in year 2 of the placebo-controlled Because all subjects in year 2 of the placebo-controlled stud- studies (Table 2) and 14.3 weeks in the IIV-controlled studies (Table ies had also been subjects in year 1, the data from these 2 years were 3). AOM rates varied considerably by study, with especially low not independent from each other and thus not suitable for a pooled rates reported in Asian studies (studies 1 and 4); placebo recipients

TABLE 2. Live Attenuated Influenza Vaccine Efficacy Against All-cause AOM in Placebo-controlled Studies During the Influenza Seasons and Total Surveillance Periods

Influenza Season Total Surveillance Period

Mean Study Mean Total Influenza LAIV n*/N Placebo n*/N VE, % LAIV n*/N Placebo n*/N VE, % Surveillance Season (Rate per 100) (Rate per 100) (95% CI) (Rate per 100) (Rate per 100) (95% CI) Period (weeks) (weeks)

Study 1, 32.8 61/1649 (3.7) 41/1105 (3.7) 1.6 (–58.7, 39.0) 49.1 77/1653 (4.7) 59/1111 (5.3) 12.6 (–32.4, 42.3) year 118 Study 1, 25.5 16/770 (2.1) 12/494 (2.4) 13.4 (–91.1, 60.8) 46.8 23/771 (3.0) 20/494 (4.0) 26.5 (–43.4, 62.3) year 218 Study 2, 14.8 274/951 (28.8) 199/664 (30.0) 4.5 (–14.5, 20.3) 23.6 387/951 (40.7) 278/665 (41.8) 3.4 (–14.7, 18.7) year 119 Study 2, 13.2 90/639 (14.1) 60/450 (13.3) –6.1 (–49.7, 24.7) 22.1 128/640 (20.0) 85/450 (18.9) –5.9 (–43.3, 21.7) year219 Study 3, 18.3 190/944 (20.1) 233/941 (24.8) 19.3 (–0.4, 35.1) 26.3 237/944 (25.1) 284/942 (30.1) 17.3 (–0.9, 32.2) year120 Study 3, 20.0 80/338 (23.7) 81/342 (23.7) –0.1 (–41.9, 29.4) 28.9 103/338 (30.5) 101/342 (29.5) –2.6 (–40.1, 24.9) year220 Study 421 22.9 23/521 (4.4) 33/515 (6.4) 31.5 (–26.7, 62.9) 31.4 30/525 (5.7) 38/516 (7.4) 22.0 (–38.6, 56.1) Study 522 9.0 45/624 (7.2) 35/312 (11.2) 37.0 (–1.0, 60.7) 26.2 123/765 (16.1) 80/385 (20.8) 23.4 (–8.9, 46.1) Study 6, 16.8 265/854 (31.0) 160/417 (38.4) 20.0 (0.6, 35.6) 17.3 271/854 (31.7) 161/417 (38.6) 18.6 (–1.0, 34.4) year123 Study 6 13.8 143/747 (19.1) 84/362 (23.2) 18.3 (–8.6, 38.6) 24.9 224/747 (30.0) 114/362 (31.5) 5.3 (–22.3, 26.7) Year 224 Year 1 21.3 858/5543 (15.5) 701/3954 (17.7) 12.4 (2.0, 21.6) 31.7 1125/5692 (19.8) 900/4036 (22.3) 10.9 (1.3, 19.7) pooled Year 2 18.2 329/2494 (13.2) 237/1648 (14.4) 6.2 (–12.4, 21.7) 31.5 478/2496 (19.2) 320/1648 (19.4) 1.3 (–16.2, 16.1) pooled

*Numerators may contain more than 1 AOM episode per subject. VE indicates vaccine efficacy.

TABLE 3. Live Attenuated Influenza Vaccine Efficacy Against All-cause AOM in IIV-controlled Studies During the Influenza Seasons and Total Surveillance Periods

Influenza Season Total Surveillance Period

Study Mean Mean Total LAIV n*/N IIV n*/N RE, % LAIV n*/N IIV n*/N RE, % Influenza Surveillance (Rate per 100) (Rate per 100) (95% CI) (Rate per 100) (Rate per 100) (95% CI) Season (wk) Period (wk)

Study 725 8.1 50/1048 (4.8) 50/1034 (4.8) 1.8 (–47.7, 34.7) 26.4 138/1050 (13.1) 136/1035 (13.1) 0.0 (–29.5, 22.8) Study 826 16.0 503/3900 (12.9) 558/3919 (14.2) 10.3 (–2.0, 21.2) 24.9 720/3916 (18.4) 803/3935 (20.4) 10.6 (0.1, 20.0) Pooled 14.3 553/4948 (11.2) 608/4953 (12.3) 9.7 (–2.1, 20.1) 25.3 858/4966 (17.3) 939/4970 (18.9) 9.1 (–0.7, 17.9)

IIV-controlled studies required fever (≥100°F oral or ≥100.6°F rectal/tympanic or ≥99.6°F axillary) as part of the AOM diagnosis. *Numerators may contain more than 1 AOM episode per subject. RE indicates relative efficacy. in these studies had AOM rates of 2.4–6.4 per 100, whereas the In the IIV-controlled studies, the pooled febrile all-cause mean rates in other studies were 27.0 and 19.5 per 100 in years 1 AOM rates were 12.3 per 100 among IIV recipients and 11.2 per and 2, respectively. 100 among LAIV recipients, yielding a 9.7% (95% CI: –2.1%, In the placebo-controlled studies, the pooled rates of AOM 20.1%) efficacy of LAIV relative with IIV (Table 3). In these in year 1 were 17.7 per 100 among placebo recipients and 15.5 studies, among IIV recipients, the rates of febrile all-cause AOM per 100 among LAIV recipients, for an efficacy of 12.4% (95% were 18.8 and 7.6 per 100 for subjects aged <24 and ≥24 months, confidence interval [CI]: 2.0%, 21.6%) against all-cause AOM respectively, whereas among LAIV recipients, the corresponding (Table 2). A similar trend was observed in year 2, but the difference rates were 16.2 and 7.5 per 100. The relative efficacy of LAIV was did not reach statistical significance. In year 1, AOM rates were 15.2% (95% CI: 0.8%, 27.4%) in children aged <24 months (N similar in subjects <24 months versus those aged ≥24 months: = 4151) and 1.2% (95% CI: –20.4%, 18.8%) in those aged ≥24 among placebo recipients, the rates in these age groups were 17.9 months (N = 5750). and 17.5 per 100, respectively, and among LAIV recipients, the All placebo-controlled studies and all IIV-controlled studies corresponding rates were 15.1 and 15.9 per 100. The small numbers outside the United States were conducted before the widespread uti- of children aged <24 months in year 2 prevented a meaningful lization of PCV7 or in countries with no PCV7 availability.28 How- comparison between the age groups. In year 1, LAIV efficacy ever, in the IIV-controlled study conducted in 2004 to 2005,26 PCV7 against all-cause AOM was 13.4% (95% CI: –0.8%, 25.6%) in use was already widespread in the United States; by 2003, 70% of subjects aged <24 months (N = 5217) and 10.5% (95% CI: –5.5%, eligible US children had received at least 3 doses of PCV7.29 In that 24.0%) in subjects aged ≥24 months (N = 4280). particular study, LAIV efficacy compared with IIV in US subjects

(N = 3819) was 15.5% (95% CI: 0.3%, 28.4%), whereas the corresponding efficacy in subjects in European countries (N = 3494) was 4.2% (95% CI: –17.9%, 22.2%). Efficacy of LAIV Against All-cause AOM During Total Study Surveillance Periods Overall, the mean total study surveillance periods were 31.7 weeks in year 1 and 31.5 weeks in year 2 of the placebo-controlled studies (Table 2) and 25.3 weeks in the IIV-controlled studies (Table 3). As expected, LAIV efficacy estimates for the longer total surveillance periods were generally lower than the estimates for the study-specific influenza seasons. However, despite the total surveillance periods substantially exceeding the influenza seasons, the efficacy of LAIV against all-cause AOM in year 1 of the placebo- controlled studies was 10.9% (95% CI: 1.3%, 19.7%). Projected 12-Month Effectiveness of LAIV Against All-cause AOM The rates of all-cause AOM in US and European subjects in the placebo-controlled studies were available for November through May (Table 4). The efficacy of LAIV against all-cause AOM in these subjects during the actual influenza seasons was 14.9% (95% CI: 1.6%, 26.5%). During the total study surveillance periods that FIGURE 1. Projected annual all-cause AOM incidence rate exceeded the influenza seasons (November through May), the cor- from US and European placebo-controlled studies. responding efficacy was 11.6% (95% CI: –1.4%, 23.0%). The mean rate of AOM among placebo recipients during the study surveillance periods was 9.05 per 100 person-months. According to the However, to understand the full public health impact of this reduc- report by Fireman et al,1 otitis media in US children occurred at tion in influenza-associated AOM, an evaluation of the vaccine’s a rate 1.5-fold higher in November through April relative to May effect on annual all-cause AOM was necessary. The estimated through October. Using this ratio, the rate of AOM in LAIV and 7.5% reduction in the annual burden of AOM by LAIV is comparable with the 6–7% reduction demonstrated in randomized clini- placebo subjects for the months outside of the study surveillance 1,5 periods was estimated at 6.03 events per 100 person-months. With cal trials of PCV7. The present evidence for an effect against this assumption, the cumulative 12-month AOM rates for LAIV all-cause AOM also demonstrates that reductions in influenza- and placebo recipients were estimated to be 7.21 and 7.80 per 100 associated AOM are not offset by increased rates of AOM due to person-months, respectively, yielding a projected 12-month effec- other pathogens. tiveness of LAIV against all-cause AOM of 7.5% (95% CI: −2.4%, Although 2 previous placebo-controlled studies of LAIV 16.2%) (Fig. 1). demonstrated a 21% reduction in all-cause AOM incidence and 30–32% reductions in all-cause febrile otitis media,20,23 the current analysis provides a more robust estimate across multiple studies. DISCUSSION Statistically significant efficacy was observed in year 1 of placebo- This is the first multistudy analysis to assess the impact controlled studies. Although there was a trend for an effect also in of LAIV on all-cause AOM. For AOM associated with culture- year 2 of the placebo-controlled studies, no statistically significant confirmed influenza, LAIV has demonstrated an 85% reduction difference was observed; this might be due to the smaller sample compared with placebo and a 54% reduction compared with IIV.17 size and thus reduced statistical power to observe an effect. The efficacy of IIV against all-cause AOM has also been demonstrated in some previous studies that have shown 30–36% TABLE 4. Monthly All-cause AOM Incidence Rate reductions in all-cause AOM during the peak influenza activity in young children attending day care.9,14 By contrast, the study by for LAIV and Placebo Recipients in US and European Hoberman et al15 failed to demonstrate an effect during 2 mild influ- Placebo-controlled Studies enza seasons in a general population of young children, although there was a trend for an effect among children aged 19–24 months. Monthly All-cause AOM Incidence (Rate per 100 As demonstrated also in the current analysis, the level of influenza Person-Months) vaccine effectiveness against all-cause AOM is significantly influenced by the incidence of influenza and the proportion of AOM Month* LAIV Placebo caused by other pathogens during the surveillance period. Because November 9.50 13.80 influenza vaccines should not be able to prevent AOM cases associ- December 8.62 10.50 ated with other viral infections in the months after vaccination, the January 8.57 7.90 estimates of influenza vaccine effectiveness against all-cause AOM February 9.16 11.40 are always lower with longer surveillance periods that exceed the March 8.86 10.20 period of major influenza activity in any area. April 5.62 6.27 May 5.47 6.27 The projected annual rate of AOM in unvaccinated US and June through October 6.03 6.03 European children in the current analysis was 0.94 episodes per Total 7.21 7.80 person-year, which is comparable to but slightly lower than the 5 *Study data used for November through May; projected data used for June through 1.24 episodes per person-year observed by Eskola et al who used October. a similar definition for AOM. The most likely explanation for the

difference is that the participants in the study by Eskola et al were essentially a scaled dilution of the statistically significant effective- substantially younger than those in the present studies and therefore ness observed during the study influenza seasons. more susceptible to the development of AOM. The difference could also be partially due to seasonal variation, but it is also possible that Conclusions not all AOM cases were detected in the LAIV studies, especially in LAIV reduced the rate of all-cause AOM compared with pla- the 2 Asian studies in which the observed rates of AOM were lower cebo in young children. The estimated 12-month efficacy of LAIV than elsewhere.18,21 However, even if some AOM cases were missed against all-cause AOM in young children was comparable with that in the LAIV studies, both treatment groups should have been simi- of PCV7. As PCV7 has been shown to only prevent approximately larly affected due to randomization and blinding, and thus the rela- one-third of all pneumococcal AOM cases, and influenza-asso- tive efficacy estimates would remain unaffected. ciated AOM can be caused by S. pneumoniae and other bacterial AOM is frequently associated with a concomitant or imme- pathogens as well as influenza virus alone, the use of LAIV in addi- diately preceding upper respiratory viral illness.3 Virus-induced tion to PCVs would help further reduce the incidence of AOM in inflammation leads to Eustachian tube dysfunction, which facili- young children. tates pathogen entry into the middle ear.30 Even in the era of widespread PCV7 vaccination, influenza-associated AOM is commonly ACKNOWLEDGMENTS caused by Streptococcus pneumoniae, but in most cases of AOM Contributors: TH, SLB, SLT, XW and CSA contributed to other bacterial pathogens can be found in the middle ear fluid, the study concept and design. SLT, XW and CSA contributed to most frequently together with viruses.10,31–33 Because influenza 10,34 the acquisition of data. All authors contributed to the analysis and virus and S. pneumoniae often act as copathogens in AOM, one interpretation of data, drafting of the manuscript and critical revi- would expect some degree of overlap between the all-cause AOM 5 sion of the manuscript for important intellectual content. XW con- efficacies of PCV7 and LAIV. In the study by Eskola et al, the tributed to statistical analysis. All authors have seen and approved observed 6% overall reduction associated with PCV7 was driven the final manuscript for submission. by a 34% reduction in pneumococcal AOM. The efficacy against AOM caused by vaccine and cross-reactive serotypes was partially REFERENCES offset by an increased number of AOM cases due to other pneumo- 1. Fireman B, Black SB, Shinefield HR, et al. Impact of the pneumococcal coccal serotypes and other bacterial species. 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Moreover, they esti- media and pressure-equalizing tube insertions in children after introduction of pneumococcal conjugate vaccine. Pediatrics. 2007;119:707–715. mated that PCV7 efficacy against all-cause otitis visits in children 8. Ruuskanen O, Arola M, Putto-Laurila A, et al. Acute otitis media and res- aged 24–42 months was 3.7%, lower than the efficacy observed in piratory virus infections. Pediatr Infect Dis J. 1989;8:94–99. younger children. 9. Heikkinen T, Ruuskanen O, Waris M, et al. Influenza vaccination in the pre- The strengths of this study include the large sample size vention of acute otitis media in children. Am J Dis Child. 1991;145:445–448. derived from all randomized trials conducted in a diverse popu- 10. Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respira- lation. Additionally, 5 of the 6 placebo-controlled studies used tory viruses in the middle ear during acute otitis media. N Engl J Med. similar diagnostic criteria for defining AOM. However, the pla- 1999;340:260–264. cebo-controlled study by Belshe et al23 used a different definition 11. Neuzil KM, Zhu Y, Griffin MR, et al. Burden of interpandemic influenza and used the term otitis media rather than AOM, which may have in children younger than 5 years: a 25-year prospective study. J Infect Dis. allowed inclusion of children with both AOM and otitis media with 2002;185:147–152. effusion. Another limitation was the requirement for fever as part 12. Heikkinen T, Silvennoinen H, Peltola V, et al. Burden of influenza in children in the community. J Infect Dis. 2004;190:1369–1373. of the diagnosis of AOM in the IIV-controlled studies, as AOM can 13. Poehling KA, Edwards KM, Weinberg GA, et al.; New Vaccine Surveillance frequently occur in the absence of fever. Validation of the investi- Network. The underrecognized burden of influenza in young children. N gators in the clinical diagnosis of AOM was also not performed in Engl J Med. 2006;355:31–40. these studies; however, on the contrary, this reflects the true situ- 14. Clements DA, Langdon L, Bland C, et al. Influenza A vaccine decreases the ation in everyday clinical practice for the diagnosis and manage- incidence of otitis media in 6- to 30-month-old children in day care. Arch ment of AOM. Finally, the annualized efficacy of LAIV against Pediatr Adolesc Med. 1995;149:1113–1117. all-cause AOM required the use of extrapolated data, as no data 15. Hoberman A, Greenberg DP, Paradise JL, et al. Effectiveness of inactivated were collected in the trials for June through October. However, it influenza vaccine in preventing acute otitis media in young children: a randomized controlled trial. JAMA. 2003;290:1608–1616. is reassuring that the modeled rates for these months were simi- 16. Heikkinen T, Ruuskanen O. Effectiveness of influenza vaccine to prevent lar to the actual trial data for months with generally low influenza acute otitis media. JAMA. 2004;291:692–693; author reply 693. activity (eg, April and May). Additionally, the projected annual 17. Block SL, Heikkinen T, Toback SL, et al. The efficacy of live attenuated effectiveness represents a conservative estimate as no LAIV effect influenza vaccine against influenza-associated acute otitis media in children. was assumed in these months. The annual effectiveness estimate is Pediatr Infect Dis J. 2011;30:203–207.

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