The 583 isolates belonged to 28 serotypes. Twenty-five isolates [4% (3–7)] were PCV7-serotypes (19F, 18C), and 40 isolates [7% (4–11)] had a serotype included in PCV13 but not in PCV7 (19A, 3, 7F, 6A). The overall prevalence of PCV13 serotypes was 7 of 100 children (5–10). The 5 most prevalent serotypes were 15B/C, 21, 35F, 23B and 23A (Fig. 2); 49% of isolates belonged to these non-PCV13 serotypes.
In 2013, 93 ST were identified, of which 10 constituted 50% of the isolates. Twenty ST (22% of ST; 7% of isolates) were novel to the MLST database. Fifty-eight ST belonged to 19 CC, and there were 35 singletons. The dominating CC were CC439, CC199 and CC177/international CC193; see (Supplemental Digital Content 1, http://links.lww.com/INF/C139) for an overview of all serotypes, ST and CC found in the 3 samples. Multiple capsular serotypes were expressed by ST162, ST62, ST177 and ST199; the ST/serotype combinations ST162/31, ST62/23A and ST177/24F had not yet been reported in the online MLST database. In addition, 5 other novel ST/serotype combinations were observed: ST1609/23A, ST945/23B, ST2154/15BC, ST4310/6C and ST2958/11A. These novel ST/serotype combinations accounted for 17 isolates in total; none of the combinations exceeded 7 isolates.
Decreased susceptibility (intermediate or full resistance) to at least 1 antimicrobial agent was found in 90 isolates [15% (11–21) of isolates]; Table 3. Thirty-nine isolates [7% (4–11)] were intermediate resistant to penicillin (MIC > 0.064 mg/L, the meningitis breakpoint for penicillin resistance); 36% of these were serotype 23B and belonged to CC1349/international CC156. Twenty-two isolates [4% (2–6)] were resistant to erythromycin. Coresistance to erythromycin, clindamycin and tetracycline was found in 18 isolates [3% (2–6)]. These coresistant isolates belonged to ST/serotypes ST179/19F, ST63/15A, ST344/NT and ST4310/6C. Resistance to trimethoprim/sulfamethoxazole only was found in 29 isolates [5% (3–8)], mainly among ST162/24F and ST193/21. Strains with decreased susceptibility were recovered from 70% of the DCC.
Comparing the PCV13 Sample with the Prevaccination and PCV7 Samples
The 2013 sample did not differ from the 2006 and 2008 samples regarding the main demographics and potential risk factors for carriage (Table 1). By design, the vaccine uptake differed between samples. The uptake of the “new vaccine” did not differ between 2008 and 2013: 40% (35–44) for PCV7 versus 42% (38–46) for at least 1 immunization with PCV13. In 2013, children were reported to have suffered from upper respiratory tract infections in the past 3 months slightly more often than in 2008 [2013: 9% (7–12); 2008: 6% (4–8)], and recent antimicrobial use was higher [2013: 10% (8–12); 2008: 5% (4–8)].
While the overall carriage prevalence remained constant around 80% between 2006 and 2008 [PR: 1.03 (0.97–1.11)], the prevalence in 2013 was significantly lower [PR: 0.77 (0.72–0.84); Fig. 1]. Identification of multiple serotypes within individual children was less frequent in 2013 than in 2006 and 2008 (Table 4). The percentage of carriers among DCC varied more in 2013 than in earlier years (P = 0.028; Table 4). The prevalence of each PCV13 serotype was more than halved from 2008 to 2013, except for serotype 19A (Fig. 2). Five of the PCV7 serotypes were absent in 2013. The decrease of overall carriage and of carriage of PCV13 serotypes was observed for all age groups (Table 2). While carriage of non-PCV13 serotypes increased substantially from 2006 to 2008 [PR 1.73 (1.40–2.15)], no further increase was seen in 2013 [PR = 0.99 (0.88–1.12)]. The prevalence of non-PCV13 serotypes 21, 22F, 23A and 23B increased significantly compared with earlier years (called: the expanding NVT), with serotype 23B not being observed in 2006 or 2008. The prevalence of serotypes 21 and 22F already had increased before PCV13 introduction, whereas non-PCV13 serotypes 8, 15B/C, 16F, 33F, 35B and NT had significantly decreased.
Decreased susceptibility to any of the tested antimicrobial agents did not significantly differ over the years [2006: 16% (10–24); 2008: 13% (8–19); 2013: 15% (11–21)], but in 2013 a larger percentage of isolates was intermediate resistant to penicillin [2006: 2% (1–4); 2008: 2% (0–5); 2013: 7% (4–11)]. None of the isolates were penicillin resistant (MIC > 2 mg/L). The percentage of isolates with intermediate resistance to penicillin was higher among the expanding NVT [11% (5–22)] than among other isolates [5% (2–9); χ2P value = 0.009]. Eighty-two percent of isolates that were intermediate resistant to penicillin in 2013 belonged to ST that had not been observed in 2006 or 2008.
Serotype and Genetic Diversity
As the pneumococcal population increased in diversity after PCV7 introduction coinciding serotype replacement,18 we investigated the diversity after the switch to PCV13. The number of serotypes decreased to 28 in 2013, from 32 in 2006 and 34 in 2008, and the D-index for the 2013 sample was lowest (though not significantly different from the 2006 level; Table 4). Furthermore, serotypes clustered more within DCC in 2013, as indicated by the lower median D-index per DCC, but the diversity was only slightly lower than in 2006. The number of ST in 2013 was the same as in 2008, but a smaller number of ST constituted 50% of isolates. Also for ST, the D-index was lowest for the 2013 sample.
Of the 197 ST identified overall in the 3 samples, only 28 ST (14%) were found in all 3 samples (Fig. 3A); these constituted 53% of all isolates (Fig. 3B).
Changes in Genotypic Composition of Expanding NVTs and Persisting VTs
To disentangle underlying mechanisms leading to the increase of certain non-PCV13 serotypes and persistence of some PCV13 serotypes, changes in ST distribution were analyzed. The increases in non-PCV13 serotypes were mainly caused by clonal expansion (48% of the expanding NVT isolates) and introduction of clones not previously identified in the Norwegian carriage samples (47%). Five percent of expanding NVT isolates expressed a new ST/serotype combination. For all other serotypes found in 2013, 69% were clones existing in Norway, 29% were not previously identified in Norway and 2% presented a new ST/serotype combination. Serotype 21 increased through expansion of ST1877, the introduction of ST432 and appearance of 3 novel ST (ST9413, ST9414 and ST9522). The increase of serotypes 23A and 23B was caused mainly by introduction of clones; 77% of serotype 23A isolates in 2013 belonged to ST that were not observed in previous samples, including 2 novel ST belonging to CC439. The 23B isolates mainly belonged to the CC439 and the penicillin-intermediate resistant CC1349 (part of the international CC156). Interestingly, ST439 was observed in 2006 and 2008 with a 23A capsule and in 2013 with a 23B capsule. The serotype 22F increase resulted mainly from expansion of 1 clone, ST433.
Six PCV13 serotypes persisted in 2013. Among these, fewer ST per serotype were found, indicating decreased genetic diversity. Serotype 19F was dominated by isolates belonging to CC177/international CC193, mainly ST177 and ST179. The ST179/19F isolates were coresistant to erythromycin, clindamycin and tetracycline, with an increased prevalence in 2013, following a decrease from 2006 to 2008. The prevalence of ST177/19F decreased, while 2 ST177 isolates with a 24F capsule were observed in 2013. Only a single clone of serotype 3 (ST180) persisted in 2013, but with decreased prevalence. The nonsignificant increase in serotype 19A was mainly because of an increase in the antimicrobial susceptible ST199. PCV13 serotypes 18C, 6A and 7F persisted in 2013 with only a few isolates, but introduction of ST not previously identified in Norway was observed for these serotypes. ST162, associated with serotype 9V in 2006, appeared in 2013 with other capsules; 24F (majority), 15BC and 31.
Our study revealed a decreased carriage prevalence of PCV13 serotypes after switching from PCV7 to PCV13 in the childhood immunization program, confirming its preventive effect on VT carriage.11,30–32 This decrease has already been reflected in direct and indirect protection against VT IPD in Norway.19 In contrast to what happened after PCV7 introduction,24 this decrease occurred without a coinciding increase in the overall prevalence of non-PCV13 carriage. Still, serotype and genetic shifts occurred among non-PCV13 serotypes. Decreased diversity and increased clustering of carriage and of clones within DCC were observed, indicating that a new equilibrium within the pneumococcal population might not yet have been reached, and that serotype replacement in carriage may be delayed instead of absent.
An overall decreased prevalence of pneumococcal carriage after switching to PCV13 has not been described in other settings,11,30–32 except Canada.33 The percentage of carriers found in our study was still higher compared with what has been found elsewhere. We serotyped from enrichment broth using a latex agglutination kit and the capsular reaction test, which permits higher detection of carriage and cocolonization with multiple serotypes compared with studies using conventional culture methods. The high carriage prevalence may, furthermore, be related to the low antibiotic use in Norway, as well as to the fact that the study was performed among children in DCC, where acquisition of pneumococci is frequent.34,35 With a high prevalence, a decrease might be easier to detect. Although the study was performed in and around the capital, we expect the results to be representative for Norway, as the majority of Norwegian children attend DCC and vaccine uptake is high in the entire country. We compared cross-sectional samples to investigate vaccine-related changes over time using samples obtained from a population with similar age distribution, in the same season, with similar sampling and laboratory techniques. The decreased carriage (observed after switching to PCV13) is, therefore, unlikely the result of our study design. A lower acquisition frequency, shorter duration of carriage episodes and/or lower pneumococcal density might have caused the decreased carriage prevalence. The decreased number of serotypes and the lower number of children carrying multiple serotypes indicate decreased frequency of pneumococcal acquisition, also because the currently dominant serotypes are known to be carried for relatively long periods of time.36
The unchanged prevalence of non-PCV13 carriage after switching to PCV13 indicates much more limited serotype replacement compared with what was seen after PCV7 introduction.3,14,24,37 A carriage study in Massachusetts performed shortly after switching to PCV13 did not either find indication for serotype replacement.38 It needs to be determined whether the absence of serotype replacement is permanent or simply delayed. The slight increase in clustering of serotypes and ST within DCC and the larger range of percentage of carriers per DCC may indicate that replacement occurs at a slower pace, as more similar pneumococcal populations in different DCC would be expected at equilibrium. Furthermore, there was a trend of lower serotype and genetic diversity in 2013. After universal vaccine implementation, the diversity in the pneumococcal population shortly decreases, as vaccination removes VT. When vacated niches become colonized, the diversity temporarily increases, until a new equilibrium has been reached.18 The slightly decreased diversity after switching to PCV13 may, therefore, indicate that all niches vacated by PCV13 have not yet been colonized, and that the redistribution of serotypes is delayed. Such delayed response may be explained by different properties of the PCV7 serotypes compared with the additional serotypes in PCV13, with serotypes 1 and 5 being rarely carried. Replacing serotypes might, by definition, be worse colonizers; they would otherwise have been the dominant carried serotypes already.
Despite the unchanged prevalence of non-PCV13 carriage, some non-PCV13 serotypes increased, especially serotype 23B. Increase of serotypes 23B and 22F among IPD cases aged 5 years or older in Norway was observed immediately after shifting to PCV13.19 In Canada33 and UK,22 increases in serotype 23B carriage have been observed among children. Interestingly, the main 23B clone found in this study was a ST that, in Norway, previously only carried 23A capsule. ST439/23B has been described before in the MLST database, suggesting introduction of an existing clone rather than serotype switching in Norway. The same probably accounts for ST162, which previously expressed the 9V capsule, but in 2013 mainly expressed the 24F capsule. Of the 8 novel ST/serotype combinations, ST1609/23A, ST945/23B, ST2154/15BC, ST4310/6C, ST177/24F and possibly ST162/31 went from a VT to a NVT, which may reflect vaccine escape through serotype switching. As the prevalence of these ST was low (≤0.8 of 100 children), the selective advantage seems to be limited. In 2008, only 1 ST was found with a novel ST/serotype combination, which had changed from a VT to a NVT (ST200/15BC24). ST200/15BC was not found in 2013. Overall, increases in carriage of non-PCV13 serotypes resulted from expansion of existing clones and introduction of clones that had not previously been identified in Norway, with limited serotype switching. This resembles what was observed the first years after PCV7 introduction.39,40 Approximately half of the isolates of the expanding NVTs was constituted of clones previously not identified in Norway, compared with less than one third of isolates of all other serotypes.
PCV13 carriage drastically decreased, but PCV13 serotypes 19F, 19A and 3 were still present. Worldwide, serotype 19A has been reported as a main replacing serotype after PCV7 introduction,13,15 and ST199 was the main replacing clone in Norway.41 As no carriage data from just before the switch to PCV13 are available, we do not know whether 19A carriage continued to increase after 2008 and started to decrease after switching to PCV13, as seen for IPD,19 or whether the 19A prevalence has remained stable. Several studies suggest that the effectiveness of PCV13 for serotype 3 is lower compared with other serotypes.42–47 Although serotype 3 was still present in 2013, we observed a decrease in its prevalence and its genetic diversity, suggesting some effectiveness of PCV13 on preventing carriage of serotype 3. The persistence of 19F may be because of advantages caused by antimicrobial resistance, as the antimicrobial susceptible ST177 decreased in prevalence while the resistant ST179 increased.
Overall antimicrobial resistance is limited among pneumococci in Norway. Still, the increase of intermediate resistance to penicillin (specifically among the expanding NVT) and presence of coresistant strains are worrying and warrants further monitoring. Carriage of resistant strains was not associated with the use of antimicrobials (data not shown), and although the percentage of children with reported use of antimicrobials in the 3 months preceding sampling had increased in 2013, no country-wide increase in use of penicillin or erythromycin has been registered in the Norwegian prescription database.48 In Canada, a similar initial decrease in antimicrobial usage after PCV7 introduction was followed by a small increase after switching to PCV13.33
In conclusion, overall pneumococcal carriage among children decreased after switching to PCV13, as a result of decreased VT carriage without a coinciding increase of non-PCV13 carriage. However, the observed serotype and genetic shifts among non-PCV13 serotypes suggest that a new equilibrium has not yet been reached, and increases in NVT carriage may still occur. Fortunately, as the few non-PCV13 serotypes that increased have generally a lower invasive capacity than VT, except for serotype 22F,10–12 direct and indirect effects of PCV13 on IPD can be expected to continue. Serotype switching, which could indicate escape of the vaccine-induced immune response, rarely occurred.
We are grateful to the children and their parents that participated in this study and thank the DCC workers for their support. We are thankful to Ingvild Essén and Line Tyskø for the collection of nasopharyngeal swabs. We acknowledge Anne Ramstad Alme, Gunnhild Rødal, Lene Haakensen and Torill Alvestad for the laboratory analyses and Hang Thi Ngoc Le for making all agar plates. We thank Richard White for statistical advice.
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