Strain characteristics of Streptococcus pneumoniae carriage and invasive disease isolates during a cluster-randomized clinical trial of the 7-valent pneumococcal conjugate vaccine

Abstract

Widespread use of 7-valent pneumococcal conjugate vaccine (PCV7) has led to significant reductions in disease while changing pneumococcal population dynamics via herd immunity and serotype replacement. We performed multilocus sequence typing (MLST) on 590 pneumococcal isolates obtained during the American Indian clinical trial of PCV7, in which communities were randomized for eligible children to receive either PCV7 or a meningococcal conjugate vaccine (MCV). Sequence types (STs) were analyzed to determine the impact of the vaccine on pneumococcal population structure and to assess the possible impact of pneumococcal genetic background on vaccine effects. One hundred forty-three STs were obtained, the most frequent being ST199, the only one that included vaccine serotypes (VTs), non-vaccine-associated nonvaccine serotypes (NVA/NVTs), and vaccine-associated serotypes (VATs). Serotype replacement observed in the PCV communities was due to a diverse population of STs, most of which also existed in the MCV communities. Possible capsular switching to create novel ST associations with NVA/NVTs was detected only once. Reductions in VTs and changes in VATs in PCV communities did not show evidence of variation by ST, after accounting for lower vaccine effectiveness against serotype 19F. These observations suggest the hypothesis that the vaccine acts as a "serotype filter": its effect on a particular strain can be predicted on the basis of the serotype of the strain, with little effect of genetic background (as assessed by MLST) over and above capsule. If sustained, such patterns provide some cause for optimism that rapid evolution of PCV escape strains with drug resistance or high virulence is unlikely.

Figure 1

Representation of the pneumococcal population structure in this study (all 590 isolates from carriage, otitis media, and invasive disease), modified from the output of eBURST (version 3). Each circle represents a single sequence type (ST), with the area proportional to the no. of isolates of that type. The Venn diagram indicates whether a given ST was found in vaccine serotype (VT), vaccine-associated serotype (VAT), or non–vaccine-associated nonvaccine serotype (NVA/NVT) isolates or in >1 of these types (these serotypes refer to the strains in our study, not to all known serotypes associated with the ST). White circles represent STs found only in pneumococcal conjugate vaccine (PCV) communities, black circles represent STs found only in meningococcal conjugate vaccine (MCV) communities, and gray circles represent STs found in both types of communities. Solid lines represent single-locus variants, and dashed lines represent double-locus variants not already connected through single-locus variants.

Figure 2

Analysis of serotype replacement. Serotype replacement (non–vaccine-associated nonvaccine serotype [NVA/NVT] isolates in pneumococcal conjugate vaccine [PCV] communities) was largely due to expansion of sequence types (STs) that already existed in control (meningococcal conjugate vaccine [MCV]) communities. The figure shows the distribution of STs among NVA/NVT isolates in PCV and MCV communities; 80% of NVA/NVT isolates in PCV communities and 88% of NVA/NVT isolates in MCV communities were of STs that were found in both communities.