The bacterium Streptococcus pneumoniae can lead to life-threatening illnesses including invasive pneumonia, meningitis and bloodstream infection (BSI), often referred to as invasive pneumococcal disease (IPD). Severe illness and increased mortality are predominantly associated with young children and older adults. The first 7 valent pneumococcal conjugate vaccine (PCV7) was developed to protect against predominant serotypes at the time of development; these 7 serotypes were responsible for up to 82% infections in children <5 years of age worldwide at the time of vaccine introduction.1 Subsequently, additional 10- and 13-valent vaccines were introduced into national programs in most countries to provide additional protection against the emergence of vaccine replacement serotypes.2–6 A recent global analysis of pediatric invasive disease indicates that the mortality rate from pneumococcal disease has decreased by 51% (range 7%–74%) in children <5 years after the introduction of conjugate vaccines.7
While the introduction of PCVs reduced the burden of IPD in young children through direct protection and older children and adults through herd-protection, there has been some variation in the extent of reduction most likely due to the variation in vaccine schedule, vaccine uptake and the level of vaccine replacement observed.8–13 It was recently suggested that the emergence of vaccine replacement serotypes in children and adults in England and Wales may compromise the benefits of the conjugate vaccination schedule.12 This is in contrast to the United States which has not observed a similar increase in non-PCV13 serotypes in children or adults despite having similar vaccine uptake in children albeit a difference in number of doses.13 Given the variation in vaccine replacement and overall disease decline, it is essential to monitor prevalent serotypes responsible for invasive disease to detect emerging trends in pneumococcal disease.
PCV7 was introduced to the Irish childhood immunization schedule in September 2008 with 1 vaccine dose recommended for children at 2, 6 and 12 months of age (2 + 1 campaign) and a catch-up campaign for all children <2 years of age. In December 2010, PCV13 replaced PCV7 with the vaccine offered to children at 2, 6 and 12 months of age, without a catch-up campaign. In December 2016, the vaccine schedule was changed to 1 dose of PCV13 at 2, 6 and 13 months to accommodate the introduction of the Neisseria meningitis type B vaccine at 12 months. Vaccine uptake of the recommended number of doses of PCV was approximately 89% at the time of vaccine introduction and has remained high during this surveillance period (90%–92% for all 3 doses).14
Here, we describe specific changes in serotypes associated with IPD in children from all culture-confirmed cases available from children <16 years of age from July 2007 to June 2018 which includes pre- and post-PCV7/13 introduction periods. We also review vaccine breakthrough/failures, susceptibility to antimicrobials, predominant serotypes and the implications for future vaccination approaches in a country where a very high proportion of invasive isolates is characterized.
MATERIALS AND METHODS
Case Definition and disease surveillance
Confirmed IPD cases include isolation of S. pneumoniae by culture or the detection of S. pneumoniae nucleic acid or antigens from a normally sterile site.15 Clinicians and laboratories have been legally obliged to notify the Departments of Public Health (DPH) of IPD infections in Ireland since 2004. Statutory notification data of infectious diseases are collated using the Computerised Infectious Diseases Reporting system. Public and private clinical laboratories are requested to refer all culture-positive IPD isolates to the Irish Pneumococcal Reference Laboratory housed in the Irish Meningitis and Sepsis Reference Laboratory. The serotype results are then linked with the individual notifications and monitored through the DPH and at a national level each quarter at the Health Protection Surveillance Centre. Laboratories with incomplete typing data based on notifiable cases are contacted directly and invited to refer available isolates to the Irish Pneumococcal Reference Laboratory for typing. Enhanced surveillance of IPD notifications (including vaccination history, underlying risk factors for disease and patient outcome) is undertaken by DPH for all pediatric cases. Through this surveillance network, potential vaccine breakthrough/failures that have been legally notified are identified. An invasive PCV-serotype case in a child that has been immunized with at least 2 doses of PCV before 12 months of age (ie, missing the booster dose) or IPD caused by a PCV-serotype in a child who had received at least 1 dose after 12 months of age (with either 0 or 1 doses in the first 12 months) is considered a postprimary vaccine failure (vaccine breakthrough) if the onset of infection is at least 14 days after immunization. Based on the expected immune response, a postbooster vaccine failure refers to a PCV-serotype in a child with at least 2 doses in the first year of life and a booster dose after 12 months of age, with onset at least 7 days after the booster dose.16,17 The cases associated with the verified vaccine breakthrough/failures were identified in our dataset in a protocol submission approved by the National Computerised Infectious Diseases Reporting Peer Review Group (July 19, 2016). Ethical approval for the research was granted via Children’s Health Ireland at Temple Street, Dublin (Reference 17.060).
Serotyping was performed on all culture-positive invasive pneumococcal isolates available using serum samples from the Staten Serum Institut (SSI Diagnostica, Hillerød, Denmark) and a multiplex polymerase chain reaction (PCR) as previously described.18 Antimicrobial susceptibility was assessed using the E-test method (Biomerieux, Marcy l’Etoile, France), and results interpreted using the European Committee on Antimicrobial Susceptibility Testing meningitis breakpoints. Penicillin-, cefotaxime- and erythromycin-nonsusceptible pneumococci were defined as a minimum inhibitory concentration of >0.06, >0.5 and >0.25 mg/L, respectively.
Incidence rates (IR) were calculated based on the annual population estimates from the most recent census in 2016 provided by the Central Statistics Office (http://www.cso.ie) and expressed as the number of serotyped isolates from cases per 100,000 population (/100,000). The population of children <16 years of age ranged from 942,071 to 1,069,960 during this period. The isolates were also categorized according to vaccine-associated serotypes: PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, 23F); the additional serotypes included in PCV13 but not in PCV7, ie, PCV13-7 serotypes (1, 3, 5, 6A, 7F, 19A) and non-PCV13 serotypes, non–vaccine-associated serotypes and nontypeable/noncapsulated isolates which were confirmed as S. pneumoniae species using PCR. The distribution of typed IPD isolates was categorized by serotype, vaccine-related groups, patient age and epidemiologic year (July to June). Data analysis was performed using online software (https://www.medcalc.org) for calculating incidence rate ratios (IRR) and 95% confidence intervals (CI). Two-tailed P value ≤0.05 was considered statistically significant. Simpson’s index of diversity (D) was used to calculate the diversity of non-PCV13 serotypes associated with IPD. The formula used is D = Σ n (n − 1)/N (N − 1), where N = total number of non-PCV13 isolates in the collection in a year and n = total number of isolates of each non-PCV13 serotype that year.
A total of 456 IPD cases were typed from pediatric cases from 2007–2008 to 2017–2018. When the typing data were merged with clinical notification data, 91% of culture-positive isolates were typed during this 11-year surveillance period. PCR-positive cases (culture-negative) were not included in this study as there were no isolates available for conventional serotyping.
Half of all IPD cultures were from children <2 years of age (n = 227, 49.7%). The overall disease IR decreased rapidly after the introduction of PCV7 and went from 38.48/100,000 in 2007–2008 to 13.47/100,000 by 2017–2018 (IRR: 0.35, 95% CI: 0.20–0.61, P = 0.0002, Fig. 1A and Table 1, Supplemental Digital Content, http://links.lww.com/INF/D717). The most significant decline was in PCV7 serotypes which decreased by 97% in 2017–2018 (IRR: 0.03, 95% CI: 0.00–0.21; P = 0.0005). The incidence of PCV13-7 serotypes also declined from 7.07/100,000 in 2007–2008 to 1.58/100,000 by 2017–2018 (IRR: 0.22, 95% CI: 0.05–1.04; P = 0.0558). However, the non-PCV13 types have continually increased annually from an IR of 3.93/100,000 in 2007–2008 to 11.09/100,000 by 2017–2018 (IRR: 2.82, 95% CI: 1.02–7.84; P = 0.0463). The predominant serotype in children <2 years of age included PCV7 serotype 14, which fell rapidly from n = 14 in 2007–2008 to 0 since 2011–2012. Serotype 19A was the only PCV13-7 serotype identified since 2012–2013 and was responsible for 1–4 IPD cases annually in children <2 years of age. There were 21 different non-PCV13 serotypes associated with IPD in this age group over the 11 years, with no consistent trend in replacement serotypes over the surveillance period. Fourteen non-PCV13 serotypes in 2017–2018 included 10A (n = 3), 22F (n = 3), 15B/C (n = 2) and 1 each of serotypes 8, 12F, 15A, 24F, 33F, 35B.
Children between 2 and 4 years of age accounted for 30% (n = 138/456) of all pediatric IPD cases during this period. By 2010–2011 onward, most children 2–4 years of age should have been vaccinated with either PCV7 or PCV13. Consequently, a trend of a rapid decline in PCV7 and PCV13-7 serotypes was observed in this age group (Fig. 1B and Table 1, Supplemental Digital Content, http://links.lww.com/INF/D717). There was however a sharp increase in non-PCV13 serotypes in this group from 0 in 2007–2008 to n = 11 in 2017–2018. The non-PCV13 serotypes included 9N, 11A, 12F, 17F, 23B, 24B and 23B, with 1–3 cases per serotype with varied annual frequency.
Twenty percent of the IPD infections were from older children, 5–16 years of age (n = 91), which reflects reduced risk of IPD in older children. There was a smaller decline in PCV7 and PCV13-7 serotypes in this age group (Fig. 1C and Table 1, Supplemental Digital Content, http://links.lww.com/INF/D717). Serotypes 19F (covered in PCV7 and PCV13), 19A and 7F (covered in PCV13) were still responsible for 1–2 infections annually in this cohort, indicating that these vaccine serotypes are still circulating in this older population, some of whom would have not received PCV vaccination based on age at the time of vaccine introduction. In contrast to younger children, the number of non-PCV13 types did not increase in older children 5–15 years of age in 2007–2008 in comparison to 2017–2018 (n = 4, in both years) but was higher in 2014–2015 to 2016–2017 (n = 7–10). The overall IPD numbers were lower in this age group than the younger pediatric cohorts.
Overall, the introduction of PCV7 and PCV13 reduced the burden of IPD and PCV13-serotype cases in children, particularly in younger children who were directly vaccinated. However, within all 3 age groups, there was no consistent trend for any specific predominant non-PCV13 serotypes emerging in the pediatric population (Table 2, Supplemental Digital Content, http://links.lww.com/INF/D718 and Table 3, Supplemental Digital Content, http://links.lww.com/INF/D719); instead a diverse collection of different non-PCV13 serotypes was responsible for IPD in children in the post-PCV13 era. In 2007–2008, 7 different non-PCV13 serotypes were associated with disease (Simpson's diversity index of D = 0.840, this increased to 15 different non-PCV13 serotypes by 2017–2018 (diversity index D = 0.948). The predominant serotypes (in order of numbers received) include serotypes 23B, 15B/C, 22F, 33F, 12F, 8, 24F, 38, 10A, 15A, 9N, 11A and 35B, with variability in the predominant serotypes within each age group and epidemiologic year. For each of the 3 age groups, the incidence of non-PCV13 serotypes doubled in the years after PCV13 introduction (by 2013–2014 and 2015–2016) but plateaued at this level in the subsequent years, which may suggest that the vaccine replacement reached a natural equilibrium. Continued surveillance would be required to confirm this finding.
Susceptibility to Antimicrobials
As indicated in Figure 2, the number of penicillin-nonsusceptible pneumococci (PNSP) decreased from 19.7% in 2007–2008 to 13.5% in 2017–2018. Although the annual number of nonsusceptible isolates was small, a similar trend was observed for cefotaxime-nonsusceptible pneumococci (CNSP) and erythromycin-nonsusceptible pneumococci (ENSP). The rate of CNSP isolates decreased from 15.8% in 2007–2008 to 5.4% in 2017–2018 and the rate of ENSP decreased from 29.8% to 13.5%, respectively. The changes in antimicrobial susceptibility were mainly due to a decline in PCV7 types (particularly, serotypes 14 and 19F) and PCV13-7 serotypes (serotypes 6A and 19A) that were more likely to display reduced susceptibility to penicillin than other non-PCV serotypes. However, there was an increase in non-PCV13 serotypes associated with PNSP including serotypes 15A, 23B and 35B that have emerged in more recent years in the pediatric population.
Vaccine Breakthrough/Failures in Children
As outlined in Table 1, during the 11-year surveillance period, there were 16 vaccine breakthrough/failures recorded, of which 10 were serotype 19A (62.5%), followed by serotype 19F (n = 2, 12.5%) and 1 each of serotype 3, 7F, 6B and 14. There were 6 postprimary failures (vaccine breakthrough) cases in children partially vaccinated or those with mixed schedules. Most cases (n = 10/16) were postbooster vaccine failures where the children received all 3 doses at appropriate intervals. The strains associated with vaccine breakthrough/failure cases also displayed reduced susceptibility to antimicrobials with 69% PNSP, 56% CNSP and 75% ENSP. The cases presented clinically with BSIs (9/16), BSI with pneumonia (4/16) and meningitis (1/16) and almost all cases recovered from IPD illness (15/16, 93%). Surveillance data indicated 3 of the patients had comorbidities and received treatment through a Hickman line catheter (n = 2) and a lumen intravenous line (n = 1). Other risk factors reported included diagnosis with a neurologic syndrome, asthma and tonsillitis in 3 other patients.
The most significant change observed during this study was the sharp decline in the number of PCV7 and PCV13-7 serotypes in children <2 years. These findings were similar to a European multicenter study reporting a decline of 72%–79% in PCV13 serotypes (IRR: 0.40–0.41) in children <5 years 4 years postvaccine introduction.8 Similarly, the United States reported a decline in PCV13-7 serotypes in children <5 years (93%) in the postvaccine era.19
However, our findings and those from the multicenter European study contrast with those from the United States with regard to vaccine replacement. We observed a significant increase in the incidence of non-PCV13 serotypes, including among children <2 years (IRR: 2.82). These findings were similar to what was recently reported in England and Wales, with a significant increase in non-PCV13 serotypes in children <2 years of age (IRR: 1.59) and 2–4 years of age (IR: 1.66) by 2016–2017.12 Similar to our study, Ladhani et al12 reported that while the pediatric population <15 years still benefits greatly from PCV13 (72%–81% decline in IPD), the rapid increase of non-PCV13 serotypes is eroding the benefits of the current vaccines with the number of IPD infections in adults now similar to the baseline period, similar to that reported previously in adults in Ireland.20,21
The main challenge to vaccine replacement is that instead of a limited number of predominant serotypes responsible for the majority of infections at the time of PCV13 introduction, there is now a more diverse range of serotypes associated with invasive disease. In a recent review of global post-PCV data, Balsells et al22 reported that the predominant serotypes included 9 additional serotypes not covered in the current vaccine and the predominant types varied depending on region. Likewise, a study from England and Wales noted an increase in over 13 non-PCV13 serotypes in the postvaccine era, with similar predominant serotypes across all age categories.12 Our surveillance of pediatric IPD indicates that non-PCV13 serotypes now account for 78% of IPD cases and that 15 different serotypes were associated with IPD in 2017–2018, including serotype 23B (11%), 22F, 12F, 10A (8% each) and serotype 8 (5%), with 24 different non-PCV13 serotypes associated with IPD over the 11-year period. Some of these non-PCV13 serotypes including 8, 12F, 24F and 33F that are now reported to have a greater disease potential and more likely to be associated with invasive disease than carriage in comparison to most PCV13 serotypes that have declined in the postvaccine era.23 It is likely that higher valency vaccines, which include some of these serotypes, would assist in reducing the incidence of IPD. The results of a clinical trial published in 2018 reported that a 15-valent vaccine induced a sufficient immune response in healthy infants against PCV13 types and two additional serotypes, 22F and 33F.24 The additional serotypes covered in PCV15 accounted for four cases of non-PCV13 types in 2017–2018 (n = 4/29, 14%) in our study, therefore, this vaccine may be of limited impact in Ireland. A 20-valent conjugate vaccine is currently going through accelerated the food and drug administration clinical trials and aims to provide additional protection against 22F, 33F, 10A, 15B, 8, 11A and 12F in adults as well as PCV13 serotypes.25 The additional serotypes in PCV20 accounted for 52% (n = 15/29) of non-PCV13 infections in 2017–2018 in Ireland and thus may potentially have an impact on IPD. However, there is still some uncertainty as to when this will be available for children.
Of the 16 vaccine failures/breakthroughs, two cases were only eligible for the booster dose, two cases had mixed PCV7 and PCV13 schedule based on vaccination schedule change, while two patients were too young for final booster dose and therefore considered vaccine breakthrough cases. There were 10 cases in children fully vaccinated which were considered vaccine failures. The majority of the vaccine failures and breakthroughs in Ireland were due to serotype 19A, in contrast to other countries which have a similar vaccination schedule who have reported serotype 3 as the predominant serotype associated with vaccine failures.26–28 Previous studies have indicated that serotype 3 elicits a lower antibody response in vaccinated children than all other PCV13 serotypes and is therefore more likely to be associated with vaccine failures.29 However, a study in England and Wales reported that while the majority of PCV13 vaccine failures in fully vaccinated children were serotype 3 (n = 12/14, 85%), there was a cluster of serotype 19A infections in vaccinated children approximately 12 months of age. This may be indicative of waning immunity after the two infant priming doses of PCV13, which demonstrates the importance of the booster dose.30 Similarly, van der Linden et al31 also noted that serotype 19A was also the most frequent serotype associated with those missing the booster dose of PCV13 and that missed or delayed doses of PCV was likely to lead to IPD events. These findings highlight the essential need for children to receive priming and booster doses to provide sufficient protection. Most vaccine failures in the Irish cohort were reported in older children (median 37 months at the time of illness), which may be suggestive of waning immunity.30 However, it is important to note that five of the patients with vaccine-type infections had comorbidities or underlying illnesses that increase the risk of infection and may have altered the immune response to infection. Considering children with comorbidities are twice as likely to be hospitalized with an IPD event and have a 3 times higher case-fatality ratio than children without comorbidities, vaccination remains an important priority to protect this vulnerable population.32
While the number of 19A cases in children <16 years in Ireland has decreased by 25% from 2007–2008 to 2017–2018 (IRR: 0.66, 95% CI: 0.15–2.95), it remains a predominant serotype among children. Similarly, the United States also reported a number of vaccine failures associated with 19A, but their numbers decreased significantly after a short period after the introduction of PCV13.33 Similar to our findings, Godot et al34 reported that 19A was the main serotype associated with vaccine failures in France up to 2013, but more recent findings from France have indicated that serotype 3 was associated with more fully vaccinated failures while serotype 19A was associated with more partially vaccinated/vaccine-breakthrough cases,35 which is similar to the England and Wales.30
There were limitations in our study due to the retrospective nature of surveillance. First, we were only able to report on cases that were referred to the national reference laboratory for serotyping. Matching our typing data with those from the legally notifiable national infectious disease database indicates that we have serotyped a high proportion of pediatric IPD cases, that is, 91% that were culture-positive during this period. We therefore believe our analysis is representative of disease incidence in Ireland. Second, given the population in Ireland and the number of cases, it can be difficult to infer statistical significance on the trends observed. However, given the high percentage of cases typed, we believe these data are reflective of the national data and may be of interest to other countries when assessing the changes in serotype epidemiology from a country with a well-established PCV13 vaccine schedule. Third, we did not assess the immune response after vaccination to determine if each child associated with vaccine failure was able to elicit expected immunologic response. While this assessment may have been performed as part of clinical follow-up, such results were beyond the scope of this project.
The introduction of PCV7 and PCV13 has significantly reduced the incidence of disease in the pediatric population in Ireland. Further reducing the burden of IPD has become more complex as the number of non-PCV13 serotypes associated with IPD has doubled in the postvaccine era. Our data also found non-PCV13 serotypes are now more likely to be associated with reduced susceptibility to antimicrobials. Consequently, timely introduction of higher valency vaccines to include PCV13 serotypes and newly emerging serotypes or more universal target vaccines need to be introduced to limit the increase of non-PCV13 invasive disease in children. The PCVs have significantly reduced the incidence of disease in children in Ireland but we cannot become complacent in the wake of emerging replacement serotypes. Unlike in many other countries, most vaccine failures in Ireland were not due to serotype 3 but serotype 19A and the isolates were highly resistant to antimicrobials, highlighting the importance of continued surveillance.
We thank the clinical laboratories for submitting isolates for typing and Departments of Public Health for ongoing surveillance. We thank Dr. Mary Ward, Specialist in Public Health Medicine, for reviewing the manuscript.
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