Our results suggest that capsular serotype, rather than other aspects of a pneumococcal strain’s genetic makeup reflected by ST, was the primary determinant of vaccine effect in this cluster-randomized trial of PCV7. Invasive disease [8
] and NP carriage [6
] of VT pneumococci were reduced in PCV communities compared with MCV communities; however, after accounting for the lesser effect of PCV on serotype 19F than other VTs, there was no evidence that the impact of the vaccine was variable for different STs. Likewise, NVA/NVT pneumococci were more commonly obtained from invasive disease (although not statistically significantly so) [8
] and NP carriage [6
] in PCV than in MCV communities, but there was no evidence that particular STs among the NVA/NVTs expanded in the PCV communities more than others. Capsular switching may have occurred, and indeed 1 serotype 35F variant of ST124 (normally serotype 14) was detected in a PCV community. However, given that 151 NVA/NVT strains from PCV communities were analyzed, we can say that capsular switching made only a minor contribution to the process of serotype replacement during the present clinical trial.
For VATs, there was little evidence for differential representation of STs in PCV versus MCV communities. In this study as in others, serotype 19A tended to be more common in PCV communities (acting like an NVA/NVT, consistent with weak effectiveness of the vaccine against serogroup 19), whereas other VATs tended to be inhibited by cross-reactive immunity. Therefore, we suspect that, with a larger sample of VATs, we would have observed significant differences in ST representation, with serotype 19A–associated STs being overrepresented in PCV communities relative to STs associated with other VATs.
Our findings suggest that PCV7 acts as a “serotype filter”—that is, that the impact of PCV7 on the prevalence of a particular pneumococcal strain is predictable on the basis of the serotype of that strain, without reference to other aspects of the strain’s genetic background as determined by ST. VT strain transmission is inhibited in communities that receive PCV7, and inhibition is similar for all VT strains, with the exception that serotype 19F strains are less inhibited than other VT strains. NVA/NVT strains show an increased prevalence in carriage in PCV7 communities, but this increase is equivalent across all STs, a finding that is robust whether all isolates are considered together or whether carriage, OM, and invasive disease isolates are considered separately.
Mathematical models developed around the time of the introduction of PCV7 predicted that use of such a vaccine could lead to the expansion of existing NVA/NVT pneumococcal populations or to the appearance of novel serotypes or STs. The models suggested that if particular NVA/NVT strains were highly transmissible in the absence of competitors but were strongly inhibited by competition from VT pneumococci in the absence of vaccination, such strains might increase from very low frequencies in an unvaccinated population to much higher frequencies after vaccine introduction [11
]. This theoretical possibility did not occur after the introduction of PCV7 in the context of the present study; rather, many existing STs of NVA/ NVT strains increased in frequency. It was also suggested before the introduction of PCV that capsular switching may play an important role in the pneumococcal population’s response to conjugate vaccination [11
]. If particular clonal characteristics other than capsular serotype (e.g., antimicrobial resistance or other determinants of fitness) accounted for the success of certain STs that expressed VT capsules before vaccination, then capsular switching might provide a ready means for such highly fit types to spread in the presence of vaccination. Novel capsule-switched strains were rare in the present study, consistent with earlier findings that capsular serotype seems to be a primary determinant of the abundance of particular strains of pneumococci [21
Pneumococcal invasive disease has declined dramatically since the licensure of PCV7, despite an increase in disease from NVA/NVTs. A recent study examined clonal compositions of populations of invasive disease isolates from the United States, comparing isolates from 1999 (before PCV7 licensure) to those from 2001 and 2002 (after licensure) [17
]. That study also found that the clonal makeup of each serotype was similar before and after vaccine introduction, although several novel STs were identified in the post licensure samples. Limited evidence of capsular switching was found in that study. Most isolates in the present study came from NP carriage in children in the target age group for the vaccine, although we also considered disease isolates from the same ages in the same communities. Each of our findings was reproduced whether we considered all isolates together or separated carriage isolates from disease isolates. Thus, our findings confirm for NP carriage (as well as disease) what was observed by Beall et al. [17
] in invasive disease.
These findings are cause for cautious optimism about the future impact of PCV. If pneumococcal populations adapt to the selective pressure of conjugate vaccination mainly by increased frequency of STs associated with NVA/NVTs, then the appearance of new, highly transmissible, or highly virulent NVA/NVT STs may be less likely than if (contrary to observations to date) the use of PCV7 had provoked rapid evolution of pneumococci, with frequent capsular switching or rapid spread of previously unobserved STs. This optimistic interpretation should be tempered by the following caveats: (1) the trends observed in the first years of PCV7 use may or may not be maintained, because vaccine uptake increases worldwide over time and pneumococcal populations have the time to adapt to this growing selective pressure; (2) the rising prevalence of antimicrobial resistance in NVA/NVT pneumococci [22
] shows that pneumococcal populations are not evolutionarily static and will continue to adapt to vaccine pressure; and (3) the existence of globally successful, often multidrugresistant pneumococcal STs suggests that some factor other than serotype alone may contribute to the ability of pneumococci to spread efficiently [24
], although recent theoretical work suggests that pneumococcal population structure may be largely explainable by neutral (nonselective) population processes [25
Given these trends, continued surveillance of serotype, STs, and antimicrobial resistance patterns of pneumococci is warranted. Of particular concern is the monitoring of major increases in disease caused by pneumococci of previously minor serotypes and the accumulation of resistance to multiple antimicrobial classes in new serotypes.