Nasopharyngeal carriage of Streptococcus pneumoniae and other bacteria in the 7th year after implementation of the pneumococcal conjugate vaccine in the Netherlands

After introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the infant national immunization program (NIP) in the Netherlands in 2006, Streptococcus pneumoniae strains of the non-vaccine serotype 19A emerged and became the dominant serotype in carriage in children and their parents. Similar patterns were observed in other European countries and the United States. Increases in carriage rates of Staphylococcus aureus and non-typeable (NT) Haemophilus influenzae were also observed. After switching of PCV7 to 10-valent vaccine (PCV10) in 2011, a new carriage surveillance study was performed in the winter of 2012/2013. Nasopharyngeal carriage of S. pneumoniae, H. influenzae, S. aureus, and Moraxella catarrhalis was determined by conventional culture in 330 PCV10-vaccinated 11-month-old children, 330 PCV7-vaccinated 24-month-old children, and their parents. Carriage prevalence was compared with similar carriage studies conducted in 2005, 2009, and 2010/2011. Although serotype 19A remained the most frequently carried pneumococcal serotype in children, prevalence of 19A significantly declined in PCV7-vaccinated 24-month-old children (14% to 8%, p = 0.01), but less in PCV10-vaccinated 11-month-old children (12% to 9%, p = 0.31). Carriage of H. influenzae remained stable at an elevated level (65% in 11-month-olds and 69% in 24-month-olds), while the carriage of S. aureus returned to pre-PCV7 levels in 11-month-old children (14% in 2010/2011 to 7% in 2012/2013), but not in 24-month-olds (remained at 7%). Our results might indicate a new balance between replacing non-vaccine pneumococcal serotypes and other potential pathogenic bacteria in nasopharyngeal carriage. Carriage studies are valuable tools in assessing vaccine effects on pathogens circulating in the population, for evaluation of PCV impact, and in predicting changes in respiratory and invasive disease.     

A 13-year survey of pneumococcal nasopharyngeal carriage in children with acute otitis media following PCV7 and PCV13 implementation

BackgroundThis nasopharyngeal (NP) carriage surveillance study was requested by the European Agency for the Evaluation of Medicinal Products as a post-licensing commitment to determine whether the use of the pneumococcal conjugate vaccines (PCVs) including 7 then 13 valents (introduced in 2001 and 2010, respectively) caused a shift in the distribution of Streptococcus pneumoniae serotypes in children with acute otitis media and modified the resistance of this bacterial species to antibiotics.MethodsBetween 2001 and 2014, 121 pediatricians obtained nasopharyngeal swabs from children with acute otitis media aged 6–24 months. The swabs were analyzed by the French National Reference Centre for Pneumococci. Demographics, medical history and physical examination findings were recorded.ResultsOver the 13 years, among the 7991 enrolled patients, the proportion of PCV-vaccinated children (≥1 dose) increased (54.3–99.7%, p < 0.001). Overall, pneumococcal carriage was reduced from 71.2% to 56.2% from 2001 to 2014 (p < 0.001) and carriage of PCV7 serotypes (STs) from 44.5% to 1.2% (p < 0.001). The carriage of 6 additional STs plus 6C increased from 17.2% to 24.3% from 2001 to 2010 (p < 0.001) and decreased after PCV13 implementation (21.4–3.5%, p < 0.001). The proportion of ST 19A carriage increased from 8.6% to 15.8% from 2001 to 2010 (p < 0.001) and decreased to 1.2% in 2014. After PCV13 implementation, the most frequently carried non-PCV13 STs were ST 15B/C, 11A, 15A, and 35B. Penicillin non-susceptible pneumococcal strains decreased from 67.1% in 2001 to 33.1% in 2014 (p < 0.001).ConclusionsBy the number of patients enrolled and the duration, this study is the largest performed to date. It allows to demonstrate a strong impact of PCVs and to describe the complex dynamics of pneumococcal carriage during AOM. As pneumococcal carriage decreased during AOM, a reduction in the incidence of pneumococcal AOM could be expected.     

Measuring the effects of pneumococcal conjugate vaccine (PCV7) on Streptococcus pneumoniae carriage and antibiotic resistance: The Palestinian-Israeli Collaborative Research (PICR)

BackgroundThe Palestinian-Israeli Collaborative Research (PICR) cross-conflict setting provided a unique opportunity to study overall and indirect effects of pneumococcal conjugate vaccine (PCV7), in two closely related Palestinian populations governed by two distinct health authorities with distinct vaccination policies. Here, PCV7 effects on pneumococcal carriage, serotype distribution and antibiotic resistance are reported.MethodsAnnual cross-sectional surveys of pneumococcal carriage were performed during 2009–2011 among Palestinian children (≤5 years) (a) under Palestinian-Authority (PA) health policy (Ramallah, Nablus and Bethlehem), where PCV7 was unlicensed (b) under Israeli health policy (East-Jerusalem (EJ)) where PCV7 was rapidly implemented from July 2009. Clinical data were collected, pneumococci identified and characterized for antibiotic susceptibilities and serotype. Analyses included multivariate logistic models with an interaction term for PCV7-effect.ResultsAltogether, 2755 children from PA (n = 1772) and EJ (n = 983) were enrolled, of which ∼30% were pneumococcal carriers. While overall carriage was not affected by vaccination policy, carriage of vaccine-type (VT7) strains decreased from 52% to 22% (p < 0.001) in EJ, where PCV was implemented, but not in PA. This was accompanied by an increase in non-VT13 strains from 34% to 65% (p < 0.001) in EJ, but not in PA. Furthermore, within two years post-PCV7 introduction, proportion of multi-drug resistant strains, which was initially 23% in both populations, decreased significantly in EJ, to 10%, while simultaneously it increased in PA to 33% (p < 0.001). Similar trends were observed for resistance to most antibiotic groups. The proportion of resistant isolates among non-VT13 strains did not change during the study period.ConclusionsThe unique study design distinguishes secular and seasonal effects from true vaccine effects. While PCV7 did not affect overall pneumococcal carriage rate, VT7 strains, many of which were antibiotic resistant decreased and were replaced by non-VT13 strains, which were mostly not antibiotic resistant, resulting in a net decrease in antibiotic resistance.     

Impact of the 13-valent pneumococcal conjugate vaccine on Streptococcus pneumoniae multiple serotype carriage

IntroductionPneumococcal multiple serotype carriage is important for evolution of the species and to understand how the pneumococcal population is changing with vaccination. We aimed to determine the impact of the 13-valent pneumococcal conjugate vaccine (PCV13) on multiple serotype carriage.Methods and materialsNasopharyngeal samples from fully vaccinated pneumococcal carriers (4 doses of PCV13, n = 141, aged 18–72 months) or from non-vaccinated pneumococcal carriers (0 doses of any PCV, n = 140, same age group) were analyzed. Multiple serotype carriage was evaluated by DNA hybridization with a molecular serotyping microarray that detects all known serotypes.ResultsVaccinated children had a lower prevalence of multiple serotype carriage than the non-vaccinated group (20.6% vs 29.3%, p = 0.097), and a significantly lower proportion of PCV13 serotypes (6.4% vs 38.5%, p = 0.0001). PCV13 serotypes found among vaccinated children were mostly detected as a minor serotype in co-colonization with a more abundant non-vaccine serotype. Vaccinated children were colonized by a significantly higher proportion of commensal non-pneumococcal Streptococcus spp. (58.2% vs 42.8%, p = 0.012). In vaccinated children there were significantly less non-vaccine type (NVT) co-colonization events than expected based on the distribution of these serotypes in non-vaccinated children.ConclusionsThe results suggest that vaccinated children have lower pneumococcal multiple serotype carriage prevalence due to higher competitive abilities of non-vaccine serotypes expanding after PCV13 use. This might represent an additional benefit of PCV13, as decreased co-colonization rates translate into decreased opportunities for horizontal gene transfer and might have implications for the evolution and virulence of pneumococci.     

Carriage of Haemophilus influenzae is associated with pneumococcal vaccination in Italian children

BackgroundThe pneumococcal population changes observed after the implementation of children immunization with pneumococcal conjugative vaccines (PCV) might have affected the composition of the microbial flora inhabiting the same ecological niche of Streptococcus pneumoniae. The aim of this study was to investigate the effect of PCV immunization, (PCV7 or PCV13), on S. pneumoniae and Haemophilus influenzae colonization in young children in Italy.MethodsNasopharyngeal swabs were obtained from 301 children under 6 years of age (vaccinated or unvaccinated with PCV) during the period January–April 2012. Presence of S. pneumoniae and H. influenzae was investigated using conventional cultural methods. S. pneumoniae isolates were serotyped by the Quellung reaction; capsular type of H. influenzae isolates was determined by PCR. The pattern of associations between the two species and potential risk factors were investigated by a Structural Equation Modelling (SEM) analysis.ResultsThe prevalence of carriage was 31.56% and 43.18% for S. pneumoniae and H. influenzae, respectively. The majority of S. pneumoniae isolates belonged to non vaccine serotypes (non PCV13-types 81.1%) while H. influenzae isolates were all non-typeable. SEM analysis revealed a synergistic association between S. pneumoniae and H. influenzae colonization (rho: 0.27; 95%CI: 0.09–0.46; p = 0.004). In addition, children vaccinated with PCV, either with PCV7 (coef 0.43; 95%CI: 0.07–0.79; p = 0.021) or with PCV13 (coef: 0.45; 95%CI: 0.08–0.82; p = 0.018), were more likely to be colonized by H. influenzae.ConclusionsPneumococcal vaccination increased H. influenzae nasopharyngeal carriage in children. This result highlights that an indirect effect of PCV vaccination can be perturbation of the nasopharyngeal flora. In the era of higher-valent pneumococcal vaccines, surveillance of carriage is crucial to monitor alterations in the bacterial ecosystem, thus preventing possible clinical problems.     

The impact of a pneumococcal conjugate vaccination program on the nasopharyngeal carriage,serotype distribution and antimicrobial resistance of Streptococcus pneumoniae among healthy children in Turkey

BackgroundThe 7-valent conjugate pneumococcal vaccine (PCV7) was introduced by the Turkey National Immunization Program in 2008 and replaced by the PCV13 in 2011. We assessed the impact of PCV vaccination on the nasopharyngeal (NP) carriage, serotype distribution and antimicrobial resistance of Streptococcus pneumoniae (SP) among healthy Turkish children.MethodsA prospective surveillance study was performed between September 2011 and September 2013 in Istanbul, Turkey. NP swabs, demographic data, and vaccination statuses were obtained from 2165 healthy children aged 0–18 years. Pneumococcal carriage was defined by a positive culture; serotyping was performed via multiplex conventional PCR, and the antibiotic susceptibilities of the isolates were determined based on the minimum inhibitory concentration (MIC) values of the Clinical Laboratory Standards Institute (CLSI).ResultsThe prevalence of pneumococcal carriage was 6.4%. The carriage rates were 8%, 7%, and 5% in the following age groups: 0–24 months, 25–60 months, and >60 months, respectively. The carriage rate was significantly higher in the 0–24 month age group than in the >60 months age group (p = 0.03). Sixty percent of the children were not vaccinated with any PCV; 4%, 2%, and 4% received at least 1, 2 or 3 doses and 30% children received the full schedule (4 doses) of either PCV7 or PCV13. Among the isolated S. pneumoniae strains, 45% were of the non-vaccine type (NVT) and 55% were of the vaccine type (VT). The children who received at least a single PCV dose had significantly lower odds of colonization via VT serotypes than the non-vaccinated children [odds ratio: 0.61 (95% confidence interval = 0.41–0.91), p = 0.01]. The percentages of the serotypes covered by PCV7 and PCV13 were 51% and 56%, respectively. The most frequently isolated serotypes were 6A/B/C (n = 22, 16.5%), 19F (n = 18, 13.5%), 23F (n = 15, 11.2%), serotype 9V/A (n = 10, 7.5%), 12F (n = 5, 4.5%), 15A/F (n = 7, 4.5%) and 22 A/F (n = 6, 4.5%). Using the meningitis criteria and the MIC, 62% of the isolates were resistant to penicillin and 13% were non-sensitive to ceftriaxone. Erythromycin and clindamycin resistance were 43% and 31%, respectively.ConclusionWe shown that following nation-wide PCV vaccination, S. pneumoniae NP carriage was decreased.     

Effect on nasopharyngeal pneumococcal carriage of replacing PCV7 with PCV13 in the Expanded Programme of Immunization in The Gambia

IntroductionIn 2011, two years after the introduction of 7-valent Pneumococcal conjugate vaccine (PCV7), the Gambian immunization programme replaced PVC7 with PCV13 (13-valent). Our objective was to assess the additional impact of PCV13 on prevalence of pneumococcal nasopharyngeal carriage.MethodsWe recruited healthy Gambian infants who had received three PCV doses. Nasopharyngeal swabs were collected from infants and their mothers during two cross-sectional surveys (CSS) conducted in infants vaccinated with PCV7 (CSS1) and vaccinated with PCV13 (CSS2). Pneumococci were isolated and serotyped following standardized methods. Whole genome sequencing was performed on non-typable pneumococcus isolated in CSS1 and CSS2.Results339 and 350 infants and their mothers were recruited in CSS1 and CSS2, respectively. Overall prevalence of pneumococcal carriage was 85.4% in infants. Among infants, prevalence of vaccine type (VT) carriage was lower in CSS2 [9.4% versus 4.9% (p = 0.025) for PCV7-VT; 33.3% versus 18.3% (p < 0.001) for PCV13-VT and 23.9% versus 13.7% (p = 0.001) for the 6 additional serotypes included in PCV13]. At CSS2, there was a decrease of serotypes 6A (from 15.3% to 5.7%, p < 0.001) and 19F (from 5.6% to 1.7%, p = 0.007), and an increase of non-typable pneumococci (0.3–6.0%, p < 0.001), most of which (82.4%) were from typable serotype backgrounds that had lost the ability to express a capsule. Prevalence of overall and VT carriage in mothers was similar in CSS1 and CSS2.ConclusionsReplacing PCV7 for PCV13 rapidly decreased prevalence of VT carriage among vaccinated Gambian infants. An indirect effect in mothers was not observed yet. Vaccine-driven selection pressure may have been responsible for the increase of non-typable isolates.     

Pneumococcal carriage among children after four years of routine 10-valent pneumococcal conjugate vaccine use in Brazil: The emergence of multidrug resistant serotype 6C

BackgroundIn 2010, the 10-valent pneumococcal conjugate vaccine (PCV10) was introduced free of charge in Brazil as part of the public immunization program. Here we investigated the carriage prevalence, colonization risk factors, capsular types, and antimicrobial resistance among pneumococcal isolates obtained from children in Brazil four years after routine PCV10 use.MethodsBetween September and December 2014, we conducted a cross-sectional study among children < 6 years old who attended one public and two private clinics in Niterói, RJ, Brazil to evaluate pneumococcal nasopharyngeal carriage. Antimicrobial susceptibility and capsular types were determined for all isolates.ResultsOf 522 children, 118 (22.6%) were pneumococcal carriers. Being ≥ 2 years old, attending childcare center, presenting with any symptoms, having acute or chronic respiratory disease, and residing in a slum were associated with pneumococcal carriage. The most prevalent capsular types were 6C (14.5%), 15B/C (11.5%), 11A/D (9.2%), and 6A (7.6%). PCV10 serotypes represented 2.5%. All isolates were susceptible to levofloxacin, rifampicin, and vancomycin. Penicillin non-susceptible pneumococci (PNSP) comprised 39%, with penicillin and ceftriaxone MICs ranging from 0.12–8.0 μg/ml and 0.012–1.0 μg/ml, respectively. The 33 (28%) erythromycin-resistant isolates (MICs of 1.5 to >256 μg/ml) displayed the cMLS_B (72.7%) or M (27.3%) phenotypes, harboring the erm(B) and/or mef(A/E) genes. High non-susceptibility rates (>20%) to clindamycin, erythromycin, penicillin, and tetracycline were largely explained by the prevalence of multidrug resistant (MDR) serotype 6C isolates.ConclusionsEffects of universal childhood PCV10 use on carriage were evident, with the near elimination of PCV10 serotypes. The emergence of MDR serotype 6C isolates, however, is a concern. Ongoing surveillance to monitor serotype 6C increase in invasive diseases is warranted.     

Five winters of pneumococcal serotype replacement in UK carriage following PCV introduction

The seven-valent pneumococcal conjugate vaccine (PCV7) was added to the UK national immunisation programme in September 2006. PCV13 replaced PCV7 in April 2010. As carriage precedes disease cases this study collected carried pneumococci from children each winter from 2006/7 to 2010/11 over PCV introduction. Conventional microbiology and whole genome sequencing were utilised to characterise pneumococcal strains.Overall prevalence of pneumococcal carriage remained stable. Vaccine serotypes (VT) decreased (p < 0.0001) with concomitant increases in non-vaccine serotypes (NVT). In winter 2010/11 only one isolate of PCV7 VT was observed (6B). PCV13 unique VTs decreased between winters immediately preceding and following PCV13 introduction (p = 0.04). Significant decreases for VTs 6B, 19F, 23F (PCV7) and 6A (PCV13) and increases for NVT 21, 23B, 33F and 35F were detected. The serotype replacement was accompanied by parallel changes in genotype prevalence for associated sequence types with clonal expansion contributing to replacement. By winter 2010/11, serotype coverage of PCV7 and PCV13 was 1% and 11% respectively.VT replacement was observed for PCV7 and PCV13 serotypes. Conjugate vaccine design and use requires continuous monitoring and revision.     

Carriage prevalence and serotype distribution of Streptococcus pneumoniae prior to 10-valent pneumococcal vaccine introduction: A population-based cross-sectional study in South Western Uganda, 2014

BackgroundInformation on Streptococcus pneumoniae nasopharyngeal (NP) carriage before the pneumococcal conjugate vaccine (PCV) introduction is essential to monitor impact. The 10-valent PCV (PCV10) was officially introduced throughout Ugandan national childhood immunization programs in 2013 and rolled-out countrywide during 2014. We aimed to measure the age-specific Streptococcus pneumoniae carriage and serotype distribution across all population age groups in the pre-PCV10 era in South Western Uganda.MethodsWe conducted a two-stage cluster, age-stratified, cross-sectional community-based study in Sheema North sub-district between January and March 2014. One NP swab was collected and analyzed for each participant in accordance with World Health Organization guidelines.ResultsNP carriage of any pneumococcal serotype was higher among children <2 years old (77%; n = 387) than among participants aged ≥15 years (8.5%; n = 325) (chi² p < 0.001).Of the 623 positive cultures, we identified 49 serotypes among 610 (97.9%) isolates; thirteen (2.1%) isolates were non-typeable. Among <2 years old, serotypes 6A, 6B, 14, 15B, 19F and 23F accounted for half of all carriers. Carriage prevalence with PCV10 serotypes was 29.4% among individuals aged <2 years (n = 387), 23.4% in children aged 2–4 years (n = 217), 11.4% in 5–14 years (n = 417), and 0.4% among individuals ≥15 years of age (n = 325). The proportion of carried pneumococci serotypes contained in PCV10 was 38.1% (n = 291), 32.8% (n = 154), 29.4% (n = 156), and 4.4% (n = 22) among carriers aged <2 years, 2–4 years, 5–14 years and ≥15 years, respectively.DiscussionIn Sheema district, the proportion of PCV10 serotypes was low (<40%), across all age groups, especially among individuals aged 15 years or older (<5%). PCV10 introduction is likely to impact transmission among children and to older individuals, but less likely to substantially modify pneumococcal NP ecology among individuals aged 15 years or older.     

Effect of 10-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae among children in São Paulo,Brazil

In March 2010, Brazil introduced the 10-valent pneumococcal conjugate vaccine (PCV10) in the routine infant immunization program using a 4-dose schedule and catch-up for children <23 months. We investigated PCV10 effect on nasopharyngeal carriage with vaccine-type Streptococcus pneumoniae (Spn) and non-typeable Haemophilus influenzae (NTHi) among children in São Paulo city. Cross-sectional surveys were conducted in 2010 (baseline) and 2013 (post-PCV10). Healthy PCV-naïve children aged 12–23 months were recruited from primary health centers during immunization campaigns. Nasopharyngeal swabs were collected and tested for Hi; for Spn, all baseline and a stratified random sample of 400 post-PCV10 swabs were tested. We compared vaccine-type Spn and NTHi carriage prevalence pre-/post-PCV10, and used logistic regression to estimate PCV10 effectiveness (1-adjusted odds ratio × 100%). Overall 501 children were included in the baseline and 1167 in the post-PCV10 survey (including 400 tested for Spn). Spn was detected in 40.3% of children at baseline and 48.8% post-PCV10; PCV10 serotypes were found in 19.8% and 1.8% respectively, representing a decline of 90.9% (p < 0.0001). Carriage of vaccine-related serotypes increased (10.8–21.0%, p < 0.0001), driven primarily by a rise in serotype 6C (1.8–11.2%, p < 0.0001); carriage of serotypes 6A and 19A did not significantly change. PCV10 effectiveness (4 doses) against vaccine-type carriage was 97.3% (95% confidence interval 88.7–99.3). NTHi prevalence increased from 26.0% (130/501) to 43.6% (509/1167, p < 0.0001); PCV10 vaccination seemed significantly associated with NTHi carriage, even after adjusting for other known risk factors. Carriage with PCV10 serotypes among toddlers declined dramatically following PCV10 introduction in São Paulo, Brazil. No protection of PCV10 against NTHi was observed. Our findings contribute to a growing body of evidence of PCV10 impact on vaccine-type carriage and highlight the importance of PCV10 as a tool to reduce the burden of pneumococcal disease in Brazil and globally.     

Impact of the introduction of the pneumococcal conjugate vaccine in the Brazilian routine childhood national immunization program

Brazil introduced the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, Synflorix™, GSK Vaccines) in the routine childhood immunization program in 2010 with a 3 + 1 schedule (with catch-up for children <2 years-old). This review represents the first analysis of the overall impact of a second-generation pneumococcal conjugate vaccine on nasopharyngeal carriage and all the major pneumococcal disease manifestations in a single, pneumococcal conjugate vaccine-naïve, developing country. A total of 15 published articles and 13 congress abstracts were included in the analysis. In children <5 years-old, studies showed a positive impact of PHiD-CV on the incidence of vaccine-type and any-type invasive pneumococcal disease (including decreases in pneumococcal meningitis morbidity and mortality), on pneumonia incidence and mortality, and on otitis media. Nasopharyngeal carriage of vaccine-type and any-type pneumococci decreased after the primary doses, with no early signs of replacement with other pathogens. Finally, herd protection against vaccine-type invasive pneumococcal disease and pneumonia in unvaccinated subjects was shown in some studies for some age groups. In conclusion, pneumococcal disease decreased after the introduction of PHiD-CV into the Brazilian national immunization program. Further follow-up is needed to evaluate the long-term overall impact of PHiD-CV in the Brazilian population.     

Changes in pathogens and pneumococcal serotypes causing community-acquired pneumonia in The Netherlands

BackgroundIn 2006 a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in the immunisation programme for infants in The Netherlands and replaced by PCV10 in 2011. Limited data exist about the impact of PCV on the aetiology of CAP as a whole. The aim of the present study is to describe the overall changes in microbial aetiology, pneumococcal burden (including non-bacteraemic pneumococcal pneumonia) and its serotypes in adult community-acquired pneumonia (CAP) after the introduction of these PCVs.MethodsHospitalised adult CAP patients who participated in three consecutive trials were studied (2004–2006 (n = 201), 2007–2009 (n = 304) and 2012–2016 (n = 300) and considered as pre-PCV7, PCV7 and PCV10 period). Extensive conventional microbiological testing was applied for all patients. In addition, patients with a serotype-specific pneumococcal antibody response were diagnosed with pneumococcal CAP. Changes in proportions of causative pathogens and distributions of pneumococcal serotypes were calculated.ResultsThe proportion of pneumococcal CAP decreased from 37% (n = 74/201) to 26% (n = 77/300) comparing the pre-PCV7 period with the PCV10 period (p = 0.01). For other pathogens, including Legionella spp., Mycoplasma pneumoniae, S. aureus, H. influenzae, and respiratory viruses, no sustained shifts were observed in their relative contribution to the aetiology of CAP. Within the pneumococcal CAP patients, we observed a decrease in PCV7 and an increase in non-PCV10 serotype disease. PCV10-extra type disease did not decrease significantly comparing the PCV10 period with the pre-PCV7 and PCV7 period, respectively. Notably, PCV7 type disease decreased both in bacteraemic and non-bacteraemic patients.ConclusionsOur findings confirm that PCV introduction in infants impact the microbial aetiology of adult CAP and suggest herd effects in adults with CAP after introduction of PCVs in children.     

The rise and fall of pneumococcal serotypes carried in the PCV era

Streptococcus pneumoniae is a major cause of meningitis, sepsis and pneumonia worldwide. Vaccination using pneumococcal conjugate vaccines (PCV) has therefore been part of the UK’s childhood immunisation programme since 2006. Here we describe pneumococcal carriage rates in children under five years of age attending the paediatric department of a large UK hospital in response to vaccine implementation over seven winter seasons from 2006 to 2013. S. pneumoniae (n = 696) were isolated from nasopharyngeal swabs (n = 2267) collected during seven consecutive winters, October to March, 2006/7 to 2012/13. This includes the period immediately following the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7) in 2006 in addition to pre- and post-PCV13 introduction in 2010. We show a decrease in PCV13 vaccine serotypes (VT) in the three years following PCV13 vaccine implementation (2010/11 to 2012/13). Serotype 6A represented the only observed VT following PCV13 implementation with all others (including PCV7 serotypes) absent from carriage. Overall pneumococcal carriage, attributable to non-VT (NVT), was consistent across all sampling years with a mean of 31·1%. The ten most frequently isolated NVTs were 6C, 11A, 15B, 23B, 15A, 21, 22F, 35F, 23A and 15C. Fluctuations in the prevalence of each were however noted. Comparing prevalence at 2006/07 with 2012/13 only 15A was shown to have increased significantly (p value of 0·003) during the course of PCV implementation. These data support the increasing evidence that the primary effect of PCVs is due to population immunity by reducing or eliminating the carriage of invasive VT serotypes. With IPD being increasingly attributed to non-vaccine serotypes, surveillance of carriage data continues to act as an early warning system for vaccine design and public health policy that require continual data of both carried pneumococcal serotypes and IPD attributed serotype data.     

Vaccine escape of piliated Streptococcus pneumoniae strains

IntroductionType1-pilus proteins were suggested as targets of future protein-based vaccines. Here we studied the effect of pneumococcal-conjugate vaccine (PCV7) implementation on the prevalence of piliated strains in a unique study setting which controls for typical confounders; the Palestinian-Israeli Collaborative Research (PICR).MethodsAnnual cross-sectional surveys of pneumococcal carriage were performed during 2009–2011 among two closely related population that live under different health policies (a) Palestinian-Authority (PA) (n = 1773), where PCV7 was not yet introduced (b) East-Jerusalem (EJ) (n = 983) where PCV7 was rapidly implemented. Clinical data were collected, pneumococci identified and characterized and the presence of Type1-pilus genes was determined by rrgC PCR.ResultsFollowing PCV7 implementation in EJ, overall carriage prevalence did not change (∼30%), but VT7 strains decreased from 61.5% to 33.8%. While prevalence of non-piliated-VT7 isolates decreased from 37% to 10%, p < 0.001, the prevalence of piliated-VT7 strains persisted ∼25%. Additionally, piliated non-VT13 strains emerged (1–15%, p < 0.001). These changes were not observed in PA. These dynamics were independent of the bacteria's resistance pattern.ConclusionsA differential effect of PCV7 was observed with a relative resistance of piliated strains to the vaccine. This suggests that Type1-pilus confers an intrinsic advantage for colonization and may be an attractive vaccine target.     

Pneumococcal vaccination: Direct and herd effect on carriage of vaccine types and antibiotic resistance in Icelandic children

BackgroundSince the introduction of pneumococcal conjugate vaccines, vaccine type pneumococcal carriage and disease has decreased world-wide. The aim was to monitor changes in the nasopharyngeal carriage of pneumococci, the distribution of serotypes and antimicrobial resistance in children before and after initiation of the 10-valent pneumococcal vaccination in 2011, in a previously unvaccinated population.MethodsRepeated cross-sectional study at 15 day-care centres in greater Reykjavik area. Nasopharyngeal swabs were collected yearly in March from 2009 to 2015. The swabs were selectively cultured for pneumococci, which were serotyped using latex agglutination and/or PCR and antimicrobial susceptibility determined. Two independent studies were conducted.In study 1, on total impact, isolates from children aged <4 years were included. The vaccine-eligible-cohort (birth-years: 2011–2013, sampled in 2013–2015) was compared with children at the same age born in 2005–2010 and sampled in 2009–2012. In study 2 on herd effect, isolates from older non-vaccine-eligible children (3.5–6.3 years) were compared for the periods before and after the vaccination (2009–2011 vs 2013–2015. Vaccine impact was determined using 1-odds-ratio.ResultsFollowing vaccination, the vaccine impact on vaccine type acquisition was 94% (95% CI: 91–96%) in study 1 and 56% (95% CI: 44–65%) in study 2. The impact on serotype 6 A was 33% (95% CI: −9%; 59%) in study 1 and 42% (95% CI: 10–63%) in study 2 with minimal effect on 19A. The non-vaccine serotypes/groups 6C, 11, 15 and 23B were the most common serotypes/groups after vaccination. Isolates from the vaccine-eligible-cohort had lower penicillin MICs, less resistance to erythromycin and co-trimoxazole and less multi resistance than isolates from the control-group.ConclusionsThe efficacy of the vaccination on vaccine serotypes was high, and a milder effect on vaccine-associated-serotype 6A was observed for the vaccine-eligible-cohort. There was a significant herd effect on vaccine types in older non-vaccine-eligible children. Overall antimicrobial non-susceptibility was reduced.     

Pneumococcal conjugate vaccination response in patients after community-acquired pneumonia,differences in patients with S. pneumoniae versus other pathogens

ObjectivesThe goal of this study is to investigate the immune response to the 13-valent pneumococcal conjugate vaccine (PCV13) in former pneumococcal CAP patients. We hypothesize that an impaired or suboptimal humoral immune response against (specific) pneumococcal serotypes might explain the vulnerability for pneumococcal disease.MethodsHospitalised adult CAP patients who participated in two trials (2004–2006 (n = 201) and, 2007–2009 (n = 304)) were screened. Patients eligible for inclusion had CAP caused by either S. pneumoniae (pneuCAP) or due to another well-defined pathogen (otherCAP). Serotype-specific pneumococcal antibody concentrations (total IgG and IgG2/IgG1) before and 3–4 weeks after PCV13 administration were measured (Luminex) and compared between pneuCAP and otherCAP patients.ResultsWe vaccinated 60 patients:i.e. 34 pneuCAP and 26 otherCAP patients. In the pneuCAP group, 74% of patients were categorized as good responders (≥9/13 serotypes with concentration ≥ 1300 ng/ml), versus 77% in the otherCAP group. Significantly fewer full responders (i.e. 13/13 serotypes with a concentration ≥ 1300 ng/mL) were identified in the pneuCAP group (15% vs 42% respectively, p = 0.02). For serotype 1, total IgG and IgG2/IgG1 subset post-vaccination concentrations were significantly lower among pneuCAP patients. Our additional case-series showed that of 16 pneuCAP patients who were infected by a serotype included in PCV13 three patients did not respond against the serotype originally responsible for their CAP episode, including one former bacteraemic pneumococcal CAP patient who also failed to show a response against the serotype responsible for CAP during infection. Thirteen patients did respond to the previously infecting serotype following PCV13 including three patients who had bacteraemic pneumococcal pneumonia and did not show a response during infection against the serotype responsible for CAP.ConclusionsOur results confirm the immunogenic properties of PCV13 in former pneumococcal CAP patients including patients previously regarded as potential hyporesponders. A slightly diminished overall humoral response to polysaccharides characterizes the former pneumococcal CAP patients.ClinicalTrials.gov Identifier: NCT02141009.     

The short-term impact of each primary dose of pneumococcal conjugate vaccine on nasopharyngeal carriage: Systematic review and meta-analyses of randomised controlled trials

BackgroundEarly onset of persistent otitis media is a priority issue for Australian Indigenous populations. The objective is to determine the direct and short-term impact of one, two and three doses of any pneumococcal conjugate vaccine (PCV) formulation on nasopharyngeal (NP) carriage of Streptococcus pneumoniae (Spn) and non-typeable Haemophilus influenzae (NTHi), the otopathogens targeted by current PCVs.MethodsWe searched MEDLINE (PubMed) and CENTRAL (Cochrane Library) to 29 September 2015. We also scanned reference lists of recent reviews and contacted authors. We included randomised controlled trials (RCTs) with a PCV schedule commencing ≤3 months of age that reported controlled non-cumulative group-specific prevalence data for carriage of Spn or NTHi at age < 12 months. We performed a standard risk of bias assessment. We estimated the pooled relative risk (RR) and 95% confidence interval (95%CI) for each vaccine dose on NP carriage by meta-analysis.ResultsWe included 16 RCTs involving 14,776 participants. The PCVs were conjugated to diphtheria toxin CRM₁₉₇, diphtheria toxoid, tetanus toxoid or NTHi protein D and varied in valency (4–13). Controls were non-PCVs, placebo or no vaccine. The earliest carriage outcome was from 2 to 9 months of age. Compared to controls, there were no significant differences between one or two doses of PCV on vaccine-type (VT) pneumococcal carriage at ∼4 and ∼6 months respectively. However, VT carriage was significantly lower at ∼7 months RR 0.67 95%CI 0.56–0.81 from 9 studies and 7613 infants and non-vaccine type (NVT) carriage was higher RR 1.23 95%CI 1.09–1.40 from 8 studies and 5861 infants. No impact on overall pneumococcal or NTHi carriage was found.ConclusionsThe primary PCV schedule had no significant short-term impact on overall pneumococcal or NTHi NP carriage and a limited impact on VT pneumococcal carriage before the third dose.     

Emergence of antibiotic-resistant non-vaccine serotype pneumococci in nasopharyngeal carriage in children after the use of extended-valency pneumococcal conjugate vaccines in Korea

BackgroundThis study was performed to assess the serotype distribution and antibiotic nonsusceptibility of pneumococcal carriage isolates from children in Korea following the introduction of extended-valency pneumococcal conjugate vaccines (PCVs).MethodsFrom April to June 2014, nasopharyngeal swabs were collected from children who were attending daycare centers in Korea. The collection was conducted in accordance with the World Health Organization Pneumococcal Carriage Working Group standards. Isolates were identified based on colony morphology, the presence of alpha-hemolysis, and inhibition by optochin test. Serotype was determined by Quellung reaction and sequencing analysis (for serogroup 6). The E-test was performed to determine antibiotic susceptibility.ResultsA total of 267 pneumococcal isolates were collected from 734 children. Non-PCV13 serotypes accounted for 88.3% and 23A (12.6%), 15B (10.4%), and 15C (9.5%) were most common. Younger age was associated with higher carriage (65.6% vs. 31.2%, P < 0.001), while completion of PCV vaccination was associated with lower carriage caused by PCV13 serotypes (7.4% vs. 20.8%, P = 0.007). Overall, nonsusceptibility rates were 86.0% to penicillin and 90.5% to erythromycin, with a multidrug resistance rate of 81.5%. Among penicillin-nonsusceptible isolates, those caused by PCV13 serotypes were 11% and non-PCV13 serotypes were 89%. Frequent non-PCV13 serotypes (23A, 15B, and 15C) were all nonsusceptible to both penicillin and erythromycin except one.ConclusionHigh rates of carriage caused by non-PCV13 serotypes such as 23A, 15B, and 15C that show nonsusceptibilities to penicillin and erythromycin were noted following the introduction of extended-valency PCVs in Korea.