This study compared the dynamics of NVT disease in 4 countries before universal PCV7 vaccination. In Spain, Belgium and France, serotype 1, 7F and 19A incidence increased considerably under rising (though moderate) vaccine coverage. In England and Wales, where PCV7 use was negligible, serotype 1 disease increased substantially, 7F disease rose less than in the other countries, and 19A disease increased nonsignificantly. The proportion of IPD caused by serotype 19A remained stable in England and Wales, and the incidence of meningitis caused by 19A and 7F did not change significantly, suggesting that an increase in case detection caused part of the changes in 19A and 7F incidence. Indeed, a study showed that the 21% increase in IPD incidence in southwest England during 1996–
2005 was no longer observed after adjustment for annual blood-culturing rates (24
In Spain, the marked increase in NVT occurred concomitantly with PCV7 use, which led several studies to conclude that vaccine-induced replacement of serotypes had largely contributed to this increase (6,11
). On the basis of our study findings, we suggest that vaccine use contributed to the increase in serotypes 7F and 19A. Both serotypes increased markedly under increasing PCV7 coverage and remained stable or increased less in the countries not using PCV7. Increases in 19A and 7F incidences correlated significantly with increasing vaccine sales in Spain and Belgium and were more pronounced in children <5 years of age, at whom PCV7 was aimed, than in older children. In Belgium and Spain, where both serotypes had already increased before PCV7 introduction, its slope escalated after PCV7 use. Although these data were observed under moderate PCV7 coverage, recent data from Belgium, England and Wales, and France indicate additional increases in the adjusted incidences of serotypes 7F and 19A under universal vaccination (2007–08) and high vaccine coverage (25–27
However, we also suggest that vaccine-induced serotype replacement alone cannot explain the increase in NVT. First, serotype 1 rose well before PCV7 marketing in Belgium and Spain, affected predominantly older age groups, and increased in England and Wales in the absence of vaccine use. Second, serotype 19A increased in Belgium and Spain before PCV7 use. Similarly, serotype 7F or 19A disease also increased in countries not using PCV7 (28–30
). Third, some EU countries with widespread PCV7 use did not experience similar rises (31,32
Other factors most likely contributed to the increases. Cyclical trends of serotype 1 were described in Scandinavian countries before any PCV7 use (3,33,34
). A wave of serotype 1 (and possibly 7F) may have occurred in these 4 neighboring countries. Conversely, the high use of antimicrobial drugs, especially macrolides, allegedly favored the increase of nonsusceptible serotype 19A (14,35
). A modeling study suggested that use of antimicrobial drugs played a larger role than did PCV7 use in the increase of resistant 19A in the United States (36
). In 3 countries in our study where 19A incidence (and resistant strains) increased, use of antimicrobial drugs was higher than in England and Wales where 19A stayed stable. However, incidence of penicillin- and erythromycin-susceptible 19A strains also increased in Spain and Belgium. Macrolide use decreased 37%–
41% during 1998–
2006 in the 3 countries, whereas 19A incidence increased 80%–
253%. Similarly, serotype 19A incidence increased in England and Wales after universal PCV7 vaccination despite stable macrolide use (26
). The role of antimicrobial drugs is thus difficult to delineate and suggests a synergistic effect of antimicrobial drugs and PCV7. Other factors for replacement have been raised (high prevalence of NVT carriage and low vaccine coverage), but they conflict with current knowledge (37
): 7F is a rarely carried serotype, and 19A and 7F increased further under higher PCV7 coverage. These conflicting views suggest that factors leading to replacement disease are still not fully understood; its cause is probably multifactorial and population dependant.
Our study has several limitations. First, enhancement of pediatric IPD surveillance and possible changes in blood culture practices could not be completely controlled by our methods of adjusting for underreporting. This limitation certainly applied to England and Wales, where reconciliation of 2 datasets could not totally adjust for the increase in case reporting and blood culturing, which most likely contributed to the increased incidence in nearly all serotypes studied, probably leading to overestimation of the NVT increase in England and Wales. Increase in blood culturing over time in the other countries is not suggested by the sharp decrease in PCV7-type IPD, the similar trends in serotype-specific meningitis incidence (based on CSF isolation), and data on blood cultures in hospitals in Belgium (+13% from 1999–
2002 to 2005–2006 while NVT IPD increased 210%). Second, missing serotype data (more frequent in the prevaccine period) may have led to imprecision in serotype distributions; however, similar age-specific PCV7-type and NVT distributions and trends were observed in other studies in Belgium, France, Spain, and England (5–8,24
), PCV7 serotype coverage did not vary with the geographic origin of pneumococcal strains in France (7
), and the age and sample distribution of children for whom serotype information was available did not differ from that of other children in the Belgium dataset. Finally, estimation of vaccine coverage assumed that all PCV7 doses were administered at an average schedule of 3 doses for children <2 years of age. This method may overestimate PCV7 coverage because a proportion of children are likely to be incompletely vaccinated given the high cost of PCV7 paid for by parents (38
), but it may also underestimate coverage because many children received fewer doses in catch-up vaccination. However, coverage values were close to those estimated by population surveys (6,7,11,38
Such an ecologic study cannot determine which rise in disease incidence is attributable to vaccine, secular trends, or use of antimicrobial drugs, and other possible factors may have contributed. However, the strength of this study is in the comparison of epidemiologic changes in 4 countries showing variations in serotype dynamics, vaccine use, and antimicrobial drug use.
The increase in incidence of serotypes 1, 7F, and 19A has partly countered the positive impact of PCV7 on overall IPD incidence in the first 2–5 years of nonuniversal vaccine use in Belgium, France, and Spain. The new 10-valent (1 and 7F) or 13-valent (1, 7F, and 19A) conjugate vaccines include these serotypes. However, a better understanding of serotype dynamics and contribution of vaccine and antimicrobial drug use is essential to guide decisions on the implementation of new vaccines and to assess their impact. Multicountry studies are useful for comparing serotype dynamics among population groups that have different levels of vaccine and antimicrobial drug use, but analyses should account for underreporting and prevaccine trends.