To the Editors:
We thank Dagan et al for their interest in our study, which was, indeed, initiated by their hypothesis.1 First, we would like to correct some interpretations in their response.
Their first fundamental assumption is that vaccine-type (VT) pneumococcus is the most dominant pathogen in early otitis media (OM) and a minor one in complex OM. The Finnish Otitis Media (FinOM) trial2 provides unique data as the control arm (N = 831 children) is the biggest cohort with prospective follow-up for OM etiology determined by middle-ear fluid cultures between 2 and 24 months of age: the prevalence of the 7 VT + 6A pneumococci was 25% in early OM compared with 21% in OM episodes during subsequent follow-up (unpublished data on file). VT + 6A pneumococci caused roughly 22% of all OM episodes, whether the OM was the first, second, third or any later OM within an individual. Thus, VT pneumococcus remained an important pathogen in recurrent and complex OM. However, proportions may be misleading. Because most OM occurred after the 6 months of age, the “incidence” of VT-OM was actually higher after the early OM period. In their letter, Dagan et al mix number of subjects and episodes and consider culture-positive findings only; the correct numbers are provided above.
Their second fundamental assumption is that pneumococcal conjugate vaccines (PCVs) prevent a large fraction of early OM. However, only minor fractions of VT-OM were prevented between the first and second, and second and third doses (21% and 43%, respectively), but up to 57% afterward.2 Only 9% of all VT-OM episodes prevented occurred during the early acute otitis media period. We fully agree that in large-scale vaccination programs, the effectiveness against VT disease approaches 100% as the indirect effect develops. However, even with full eradication of vaccine serotypes, the projected reduction in “early VT-OM” would be only 13% of all VT-OM episodes. Nevertheless, the FinOM trial long-term findings, on which the hypothesis is partly based on,3 were observed in an era of no PCV vaccination program and no indirect impact.
Their third fundamental problem with the hypothesis is that it fails to consider replacement in full. With the minor reduction in VT-OM, replacement by pneumococcal non-VTs and other bacterial species reduces the net reduction.2 There was no reduction in overall OM during the first 6 months of life in the FinOM trial.
Finally, an optimal study design to test the hypothesis would be a randomized trial with PCVs with different vaccination schedules; we have performed this in the Finnish Invasive Pneumococcal disease trial.4,5 The long-term vaccine effectiveness estimates against OM outcomes were similar, whether the vaccinations were started before 7 months of age (median, 14 weeks) or later (unpublished).
In conclusion, the roles of VT-OM and especially the impact of early OM have been exaggerated in the hypothesis. Science goes forward by developing and testing hypotheses, the current one in question is very interesting, but it needs to be rejected based on the data. Early OM is an indicator, not cause, of OM recurrence, and PCVs offer long-term effectiveness against VT otitis.
Arto A. Palmu, MD, PhD
Department of Public Health Solutions
National Institute for Health and Welfare
1. Dagan R, Pelton S, Bakaletz L, et al. Prevention of early episodes of otitis media by pneumococcal vaccines might reduce progression to complex disease. Lancet Infect Dis. 2016;16:480492.
2. Eskola J, Kilpi T, Palmu A, et al.; Finnish Otitis Media Study Group. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001;344:403409.
3. Sarasoja I, Jokinen J, Lahdenkari M, et al. Long-term effect of pneumococcal conjugate vaccines on tympanostomy tube placements. Pediatr Infect Dis J. 2013;32:517520.
4. Palmu AA, Jokinen J, Nieminen H, et al. Effectiveness of the ten-valent pneumococcal conjugate vaccine against tympanostomy tube placements in a cluster-randomized Trial. Pediatr Infect Dis J. 2015;34:12301235.
5. Palmu AA, Jokinen J, Nieminen H, et al. Effect of pneumococcal Haemophilus influenzae
protein D conjugate vaccine (PHiD-CV10) on outpatient antimicrobial purchases: a double-blind, cluster randomised phase 3-4 trial. Lancet Infect Dis. 2014;14:205212.