This is the first multistudy analysis to assess the impact of LAIV on all-cause AOM. For AOM associated with culture-confirmed influenza, LAIV has demonstrated an 85% reduction compared with placebo and a 54% reduction compared with IIV.17 However, to understand the full public health impact of this reduction in influenza-associated AOM, an evaluation of the vaccine’s effect on annual all-cause AOM was necessary. The estimated 7.5% reduction in the annual burden of AOM by LAIV is comparable with the 6–7% reduction demonstrated in randomized clinical trials of PCV7.1,5 The present evidence for an effect against all-cause AOM also demonstrates that reductions in influenza-associated AOM are not offset by increased rates of AOM due to other pathogens.
Although 2 previous placebo-controlled studies of LAIV 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. Statistically significant efficacy was observed in year 1 of placebo-controlled studies. Although there was a trend for an effect also in year 2 of the placebo-controlled studies, no statistically significant difference was observed; this might be due to the smaller sample 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% reductions in all-cause AOM during the peak influenza activity in young children attending day care.9,14 By contrast, the study by Hoberman et al15 failed to demonstrate an effect during 2 mild influenza seasons in a general population of young children, although there was a trend for an effect among children aged 19–24 months. As demonstrated also in the current analysis, the level of influenza vaccine effectiveness against all-cause AOM is significantly influenced by the incidence of influenza and the proportion of AOM caused by other pathogens during the surveillance period. Because influenza vaccines should not be able to prevent AOM cases associated with other viral infections in the months after vaccination, the estimates of influenza vaccine effectiveness against all-cause AOM are always lower with longer surveillance periods that exceed the period of major influenza activity in any area.
The projected annual rate of AOM in unvaccinated US and European children in the current analysis was 0.94 episodes per person-year, which is comparable to but slightly lower than the 1.24 episodes per person-year observed by Eskola et al5 who used a similar definition for AOM. The most likely explanation for the difference is that the participants in the study by Eskola et al were substantially younger than those in the present studies and therefore more susceptible to the development of AOM. The difference could also be partially due to seasonal variation, but it is also possible that not all AOM cases were detected in the LAIV studies, especially in the 2 Asian studies in which the observed rates of AOM were lower than elsewhere.18,21 However, even if some AOM cases were missed in the LAIV studies, both treatment groups should have been similarly affected due to randomization and blinding, and thus the relative efficacy estimates would remain unaffected.
AOM is frequently associated with a concomitant or immediately preceding upper respiratory viral illness.3 Virus-induced inflammation leads to Eustachian tube dysfunction, which facilitates pathogen entry into the middle ear.30 Even in the era of widespread PCV7 vaccination, influenza-associated AOM is commonly caused by Streptococcus pneumoniae, but in most cases of AOM other bacterial pathogens can be found in the middle ear fluid, most frequently together with viruses.10,31–33 Because influenza virus and S. pneumoniae often act as copathogens in AOM,10,34 one would expect some degree of overlap between the all-cause AOM efficacies of PCV7 and LAIV. In the study by Eskola et al,5 the observed 6% overall reduction associated with PCV7 was driven by a 34% reduction in pneumococcal AOM. The efficacy against AOM caused by vaccine and cross-reactive serotypes was partially offset by an increased number of AOM cases due to other pneumococcal serotypes and other bacterial species. In the current analysis, US subjects in the IIV-controlled study by Belshe et al26 were widely vaccinated with the PCV7 vaccine before enrollment. The statistically significant 15.5% reduction in all-cause AOM in these subjects demonstrates that LAIV can significantly reduce all-cause AOM even in the setting of PCV7 vaccination.
An important limitation of the ability of LAIV to impact the burden of AOM in young children is that LAIV is only approved for children aged ≥2 years. The incidence of AOM is highest in younger children, but the burden of AOM is significant also in children aged ≥2 years. For example, in a prospective cohort study among outpatient children, 20% of children aged 3–6 years developed AOM as a complication of influenza.12 Fireman et al1 reported approximately 10 medical visits for otitis per 100 children per month among children aged 24–42 months. Moreover, they estimated that PCV7 efficacy against all-cause otitis visits in children aged 24–42 months was 3.7%, lower than the efficacy observed in younger children.
The strengths of this study include the large sample size derived from all randomized trials conducted in a diverse population. Additionally, 5 of the 6 placebo-controlled studies used similar diagnostic criteria for defining AOM. However, the placebo-controlled study by Belshe et al23 used a different definition and used the term otitis media rather than AOM, which may have allowed inclusion of children with both AOM and otitis media with effusion. Another limitation was the requirement for fever as part of the diagnosis of AOM in the IIV-controlled studies, as AOM can frequently occur in the absence of fever. Validation of the investigators in the clinical diagnosis of AOM was also not performed in these studies; however, on the contrary, this reflects the true situation in everyday clinical practice for the diagnosis and management of AOM. Finally, the annualized efficacy of LAIV against all-cause AOM required the use of extrapolated data, as no data were collected in the trials for June through October. However, it is reassuring that the modeled rates for these months were similar to the actual trial data for months with generally low influenza activity (eg, April and May). Additionally, the projected annual effectiveness represents a conservative estimate as no LAIV effect was assumed in these months. The annual effectiveness estimate is essentially a scaled dilution of the statistically significant effectiveness observed during the study influenza seasons.
LAIV reduced the rate of all-cause AOM compared with placebo in young children. The estimated 12-month efficacy of LAIV against all-cause AOM in young children was comparable with that of PCV7. As PCV7 has been shown to only prevent approximately one-third of all pneumococcal AOM cases, and influenza-associated AOM can be caused by S. pneumoniae and other bacterial pathogens as well as influenza virus alone, the use of LAIV in addition to PCVs would help further reduce the incidence of AOM in young children.
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acute otitis media; live attenuated influenza vaccine; trivalent inactivated influenza vaccine