Our findings show that 4 years after introduction of PCV7 in the Netherlands, the overall annual incidence of IPD decreased by 60% (from 35.0 to 14.1 cases/100,000 persons) among children <2 years of age, the age group targeted for vaccination; the decrease was a result of virtually complete eradication of PCV7 serotypes. In children 2–4 years of age, a 48% reduction was seen in IPD cases overall. A significant decline of 13% was also observed in persons >65 years of age. No significant decline in overall IPD was seen in persons 5–64 years of age because the decline in PCV7-serotype IPD was offset by a similar increase in non–PCV7 serotype IPD. The proportion of immunocompromised patients within PCV7-serotype IPD also increased. Despite these findings, the length of hospital stay and case-fatality rates declined over the last years. Our findings indicate that use of PCV7 in the Netherlands resulted in a major decrease in PCV7-serotype IPD among all age groups.
Our results for children are in line with those in England and Wales (4
). However, among persons 5–65 years of age, the effect of herd immunity was less pronounced in the Netherlands than in England and Wales (4
), where PCV7 was introduced around the same time as in the Netherlands (summer 2006), or in the United States 4 years after the introduction of PCV7 in 2000 (14
). This difference can be partly explained by the absence of a catch-up campaign for children <2 years of age in the Netherlands. Young children are a primary reservoir for carriage and transmission of pneumococci because of prolonged colonization episodes related to their immature immune systems. Vaccination of toddlers in addition to newborns has a major effect on the speed of onset of herd immunity in the population. Therefore, by continuing surveillance in the Netherlands, we will likely see more reduction of PCV7-serotype IPD in the years after 2010. A major issue will be the rise in non–PCV7 serotypes, which is estimated by Choi et al. (19
) to be ≈90% in England and Wales. Despite this large increase in non–PCV7 serotype IPD, it is expected that this will not offset the decrease in PCV7-serotype IPD in infants and elderly persons.
The decline of IPD cases among persons with immunocompromising conditions was limited compared with the decline among nonimmunocompromised persons. This result may be biased because the number of PCV7-serotype IPD cases in this group was relatively small before introduction of PCV7. However, the case-fatality rate for non–PCV7 serotype IPD in the post-implementation period declined among otherwise healthy persons and among those with comorbid conditions, suggesting a less severe course of disease, even in patients with serious immunocompromising conditions. Thus, even if the incidence of IPD decreased less in immunocompromised persons than in the general population, persons with immunocompromising conditions still appear to benefit from the vaccination program because of a reduction in case-fatality rates.
The reduced case-fatality rate for non–PCV7 serotype IPD since the introduction of PCV7 can be partly explained by a large increase in serotype 1 IPD. This invasive serotype is associated with a low case-fatality rate (12
), which remained low (6%–8%) in the Netherlands during the study period. Case-fatality rates for the other individual serotypes also did not change significantly after introduction of PCV7. In line with a lower case-fatality rate, we also found a reduced length of hospital stay for patients with PCV7-serotype IPD and those with non–PCV7 serotype IPD. However, in the Netherlands, there has been a tendency toward shorter hospital stays, which along with other factors (e.g., improved hospital efficiency) may affect the finding of a reduced length of hospital stay for patients with IPD (21
). For example, in 2006 a new financial system was introduced in the Netherlands that encourages shortening of the length of hospital stay.
In children, the increase in non–PCV7 serotype disease was most pronounced among patients with meningitis. Although the numbers were too small to yield significant differences, these data indicate that surveillance should be continued and special attention should be paid to patient characteristics and the evolution of serotype circulation over time.
The incidence of IPD caused by nonvaccine– S. pneumoniae
serotypes 1, 19A, 22F, and 23B increased significantly after introduction of PCV7 in the Netherlands. The increase in serotype 19A has been consistently reported worldwide, especially increased carriage among children (22
) and increased cases of serotype 19A–associated invasive disease (24
) and otitis media (25
). The role of PCV7 in promoting serotype 19A carriage in vaccinated children compared with unvaccinated controls has been shown (22
). In many countries, the increase in serotype 19A disease is associated with high levels of penicillin resistance (24
). In the Netherlands, only 1.8% of pneumococcal strains are reported to be resistant (29
). The increase in serotype 22F was also seen in the United States and in England and Wales (3
). The occurrence of serotype 1 was also shown to fluctuate and decline in presence of PCV7 (4
). We did not see an increase in IPD caused by serotypes 6C and 15B/C, although increases have been reported elsewhere (3
). On May 1, 2011, the Dutch government switched from the 7-valent to the 10-valent pneumococcal conjugate vaccine, which includes serotypes 1, 5, and 7F in addition to those in PCV7 (30
). The 13-valent pneumococcal conjugate vaccine, which has not been introduced in the Netherlands, adds protection against serotypes 3, 6A, and 19A.
Surveillance artifacts resulting from enhanced surveillance and increased awareness after the introduction of the vaccine should be considered when evaluating the effects of the PCV7 vaccination program (4
). However, adjustments for these artifacts can introduce new biases leading to over- and underestimation of the true effects of the vaccine. We believe there are no indications for enhanced surveillance and increased awareness in our study. The laboratory-based surveillance system remained unchanged during the study period, 2004–2010. Unlike the situation in England and Wales (4
), the number of pneumococcal isolates obtained from CSF samples in the Netherlands remained stable during the years before PCV7 was introduced (Technical Appendix Figure 1
). Moreover, the incidences of IPD caused by a great majority of non–PCV7 serotypes remained stable during the entire study period; the exceptions were for IPD caused by serotypes 1, 19A, 22F, and 23B (Technical Appendix Figure 2
). If enhanced surveillance had taken place, one would expect an increase in the reported number of IPD cases caused by any of these serotypes. Thus, we made no corrections for increased case ascertainment or awareness in this study.
Our study does have limitations. First, the study periods before and after implementation of the vaccine program were relatively short; this may have caused an overestimation or underestimation of our results. To account for a proper transition period, we did not include June 2006–May 2008 in our comparisons because no clear conclusions could be drawn from this period. Second, changes in IPD epidemiology could have been influenced by variations in the seasonal influenza and the influenza A(H1N1)pdm09 virus epidemics in 2009 (31
). Last, no data were available on the national prevalence of comorbidities/diseases. Thus, we could not evaluate IPD incidence rate ratios for the 3 patient groups in our study: otherwise healthy persons, persons with any comorbidity, and persons with immunocompromising conditions.
The results of this study show that PCV7 use has reduced the number of IPD cases and deaths in children <2 years of age (the age group targeted for vaccination) and in persons >65 years of age. However, after introduction of PCV7, cases of IPD caused by non–PCV7 serotypes increased significantly among elderly persons, and the proportion of immunocompromised persons with IPD increased. Despite these increases, the overall IPD case-fatality rate among patients >65 years of age decreased, which seems to be a positive consequence of shifts in circulating serotypes after introduction of a pneumococcal conjugate vaccine for infants.