The subsequent AOM incidences were lower if no bacteria were detected in early AOM, and especially if child had no confirmed AOM within the first 6 months of age (Table 1).
We also performed various sensitivity analyses resulting in similar results (Table 2). In these, we evaluated PCV 7 vaccine types only as the exposure (ie, not including 6A), sensoring the follow-up at first tympanostomy tube placement (for AOM analysis), inclusion of the first AOM episode only to define the exposure (not all episodes within 6 months as in the primary analysis), and excluding subjects with otitis media diagnosed outside the study clinics before age of 6 months of age and those with abnormal tympanic membrane findings suggesting otitis media at enrolment to avoid bias in the exposure classification, and finally, the use of the age of 12 months as the cut-point for the definition of exposure and outcome follow-up.
Early vaccine-type pneumococcal AOM was not associated with a higher incidence of subsequent AOM compared with AOM due to other confirmed bacterial etiology. These data do not support any specific role for vaccine-type pneumococcus in this hypothesis, but rather subjects with early AOM due to any bacterial etiology are prone to experience also later disease.
Currently, the PCVs are the only vaccines available to prevent early AOM. Influenza vaccines have been shown to reduce influenza-related AOM,5 but the vaccine is licensed for children 6 months of age and older; therefore, direct protection against early AOM is not possible. Development of vaccines against other otitis pathogens is ongoing.
Although the vaccine efficacy of PncCRM7 against any AOM in clinical trials was low, only 6%–7%,3,6,7 the vaccine efficacy estimates against recurrent AOM (defined as 3 within 6 months or 4 within 12 months) and tympanostomy tube placements have been higher, especially in long-term follow-up.4,8
In our earlier reanalysis on recurrence of AOM, we found high vaccine efficacy for the PncCRM7 vaccine against recurrent vaccine-type AOM, but failed to show efficacy against overall AOM of increasing rank.9 This demonstrates the importance of disease replacement; reduction of vaccine-type AOM leads to an increased disease burden due to other pathogens in AOM resulting in a low net impact in the total population.9 On the contrary, observational before-after PCV introduction data show reduction, not replacement, in AOM due to other pathogens in a selected subgroup of complex disease.10 In this kind of study design, multiple sources of bias should be borne in mind including care-seeking behavior, diagnostic changes (both clinical and laboratory), administrative changes, and so on.
Nevertheless, with large-scale PCV vaccination programs, it is possible to further prevent early vaccine-type AOM, even before the age of first dose of the vaccination, due to the development of the indirect impact and eventual eradication of the vaccine-type circulation in carriage.11 However, the replacement by other pathogens, including nonvaccine pneumococci,12 is also likely to be enhanced during the vaccination programs.
The serotypes for the PCVs were originally selected based on their importance in causing invasive pneumococcal disease. The relative importance was due the common carriage of these serotypes and their relative propensity to cause disease (case-to-carrier ratio) compared with other pneumococcal serotypes. While clear differences in the case-to-carrier ratios have been observed in invasive pneumococcal disease,13 the differences in AOM are more subtle.14 Thus, also pneumococcal serotypes not included in the vaccine are capable of causing otitis media.
The evaluation whether the early AOM is a true risk factor for subsequent disease per se or a mere indicator of a frail subject is difficult when all the risk factors are not known and the incidence shows major variation due to, for example, viral respiratory infection epidemics, seasonality, and age.
PCVs have been shown to elicit long-lasting antibodies, which probably contribute to the long-term protection.15 Thus, the impact of the PCVs does not only rely on prevention of early episodes.
The active prospective follow-up with detection of AOM confirmed by myringotomy underlines the specificity of the pathogen-specific results in our study. The high incidence of AOM observed in the trial, on the other hand, speaks for high sensitivity of the case detection. Our various sensitivity analyses showed that the study findings were robust. The limitations of this study include the low number of pathogen-specific AOM episodes resulting in quite wide CIs and the potentially poor generalizability to other settings with different AOM etiology and risk factors. However, it should be noted that the FinOM trial is the single trial globally that has assessed etiology in all cases of AOM longitudinally in an unselected cohort.
We postulate that the long-term impact of PCVs on otitis media cannot be fully explained by the prevention of early vaccine-type episodes, but also sustained vaccine-type antibody persistence and the development of the indirect impact with eradication of the vaccine-type carriage contribute to the protection against AOM, including complex disease. To fully prevent later otitis media and its sequelae, prevention of early AOM irrespective of etiology is important.
1. Kilpi T, Herva E, Kaijalainen T, et alBacteriology of acute otitis media
in a cohort of Finnish children followed for the first two years of life. Pediatr Infect Dis J. 2001;20:654–662.
2. Dagan R, Pelton S, Bakaletz L, et alPrevention of early episodes of otitis media by pneumococcal vaccines might reduce progression to complex disease. Lancet Infect Dis. 2016;16:480–492.
3. Eskola J, Kilpi T, Palmu A, et alFinnish Otitis Media Study Group. Efficacy of a pneumococcal conjugate vaccine
against acute otitis media
. N Engl J Med. 2001;344:403–409.
4. Sarasoja I, Jokinen J, Lahdenkari M, et alLong-term effect of pneumococcal conjugate vaccines on tympanostomy tube placements. Pediatr Infect Dis J. 2013;32:517–520.
5. Trivedi DCochrane review summary: influenza vaccines for preventing acute otitis media
in infants and children. Prim Health Care Res Dev. 2016;17:105–106.
6. Black S, Shinefield H, Fireman B, et alEfficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine
in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J. 2000;19:187–195.
7. Fireman B, Black SB, Shinefield HR, et alImpact of the pneumococcal conjugate vaccine
on otitis media. Pediatr Infect Dis J. 2003;22:10–16.
8. Palmu AA, Verho J, Jokinen J, et alThe seven-valent pneumococcal conjugate vaccine
reduces tympanostomy tube placement in children. Pediatr Infect Dis J. 2004;23:732–738.
9. Jokinen J, Palmu AA, Kilpi TAcute otitis media replacement and recurrence
in the Finnish otitis media vaccine trial. Clin Infect Dis. 2012;55:1673–1676.
10. Dagan R, Ben-Shimol S, Leibovitz E, et alImplementation of PCV7/PCV13 in Israel Had a Significant Impact on Both Pneumococcal and Non-pneumococcal Complex Otitis Media Rates. 2014.Philadelphia, PA: IDWeek;
11. Huang SS, Hinrichsen VL, Stevenson AE, et alContinued impact of pneumococcal conjugate vaccine
on carriage in young children. Pediatrics. 2009;124:e1–11.
12. Pichichero METen-year study of acute otitis media
in Rochester, NY. Pediatr Infect Dis J. 2016;35:1027–1032.
13. Hanage WP, Kaijalainen TH, Syrjänen RK, et alInvasiveness of serotypes and clones of Streptococcus pneumoniae among children in Finland. Infect Immun. 2005;73:431–435.
14. Hanage WP, Auranen K, Syrjänen R, et alAbility of pneumococcal serotypes and clones to cause acute otitis media
: implications for the prevention of otitis media by conjugate vaccines. Infect Immun. 2004;72:76–81.
15. Ekström N, Ahman H, Palmu A, et alFinOM Study Group. Concentration and high avidity of pneumococcal antibodies persist at least 4 years after immunization with pneumococcal conjugate vaccine
in infancy. Clin Vaccine Immunol. 2013;20:1034–1040.
Keywords:Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
conjugate vaccine; acute otitis media; recurrence; pneumococcus; infant