Changes in empyema among U.S. children in the pneumococcal conjugate vaccine era

BackgroundParapneumonic empyema, a serious complication of pneumonia, started increasing among U.S. children before the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in 2000, and continued afterwards. This increase was due in part to pneumococcal serotypes not included in PCV7 that were included in the new 13-valent (PCV13) vaccine introduced in 2010. We assessed changes in the incidence of empyema hospitalizations among U.S. children after PCV13 introduction.MethodsWe calculated annualized empyema hospitalization rates among U.S. children <18 years using Nationwide Inpatient Sample and Census data (1997–2013) for four periods based on PCV7 and PCV13 introductions. Relative rates (RR) and 95% confidence intervals (CI) were calculated by age group and sex, comparing PCV7 [early-PCV7 (2001–2005) and late-PCV7 (2006–2009)] and PCV13 (2011–2013) periods with the pre-PCV7 period (1997–1999). Secondary analyses examined changes in pneumococcal, streptococcal, staphylococcal and unspecified empyema.ResultsAmong children <18 years of age, annualized empyema hospitalization rates peaked at 3.6 per 100,000 in the late-PCV7 period compared with 2.1 per 100,000 in the pre-PCV7 period [RR: 1.70 (95% CI: 1.11–2.60)]. However, annualized rates in the post-PCV13 period declined to 2.0 per 100,000, similar to rates in the pre-PCV7 period. Empyema rates among children <2 years were lower in the post-PCV13 period compared to the pre-PCV7 period [RR: 0.77 (95% CI: 0.61–0.96)], but rates in the two periods among children 2–4 and 5–17 years were similar. Most empyema were of unspecified etiology. Pneumococcal and unspecified empyema declined after PCV13 introduction.ConclusionsAlthough empyema hospitalization rates among U.S. children peaked after PCV7 introduction, rates decreased substantially following the introduction of PCV13.     

Comparative incidence dynamics and serotypes of meningitis,bacteremic pneumonia and other-IPD in young children in the PCV era: Insights from Israeli surveillance studies

IntroductionWidespread introduction of pneumococcal conjugated vaccines (PCVs) impacted on invasive pneumococcal disease (IPD). However, IPD reduction may not be similar in all outcomes within IPD.We assessed PCV7/PCV13 impact on pneumococcal meningitis, bacteremic pneumonia (BP) and other (non-meningitis, non-pneumonia) IPD episodes in children <5 years in Israel.MethodsA prospective, population-based, active nationwide surveillance.All pneumococcal invasive episodes with positive blood/CSF cultures, July 2000 through June 2016, were included. Three sub-periods were defined: pre-PCV (2000–2008), PCV7 (2009–2011) and PCV13 (2014–2016). Incidence rate ratios (IRRs) were calculated.ResultsOverall, 4321 episodes were recorded; 456 (10.6%) meningitis, 1478 (34.2%) pneumonia and 2387 (55.2%) other-IPD.In the pre-PCV period, proportion of serotypes in PCV13, but not in PCV7 (mainly serotypes 1, 5 and 19A) was higher in BP (43.3%) compared with other-IPD episodes (32.8%, p < 0.001) and similar to that of meningitis (37.6%, p = 0.1). The proportion of episodes in children <12 months was higher in meningitis (52.1%) compared with pneumonia (23.2%) and other-IPD episodes (39.5%; p < 0.001 for both).The declines of the 3 entities were not similar; Meningitis rate non-significantly declined by 24% (IRR = 0.76; 95% CI 0.57–1.01), while BP and other-IPD rates significantly declined by 57% and 70%, respectively. In contrast to other entities, BP did not decline significantly after PCV7 introduction but started to decline only after PCV13 introduction.Rates of meningitis, pneumonia and other-IPD caused by PCV13-serotypes (VT13) substantially declined by 88%, 95% and 97%, respectively, comparing PCV13 and the pre-PCV periods. However, diseases caused by non-VT13 increased by 256%, 302% in meningitis and pneumonia, respectively, but only 116% in other-IPD.ConclusionsFollowing PCV7/PCV13 introduction, rates of episodes caused by VT13 were substantially reduced in all 3 groups. However, differences in age distribution, serotype replacement and specific serotype decrease suggest different pathogenesis and host susceptibility between the 3 entities.     

Early impact of sequential introduction of 7-valent and 13-valent pneumococcal conjugate vaccine on IPD in Israeli children <5 years: An active prospective nationwide surveillance

BackgroundThe 7-valent pneumococcal conjugated vaccine (PCV7) was introduced to the Israeli national immunization plan (NIP) in July 2009 (administered at age 2, 4 and 12 months), with a fast reduction of invasive pneumococcal disease (IPD) caused by PCV7 serotypes. Starting in November 2010, PCV13 gradually replaced PCV7.AimTo report the impact of PCV7/PCV13 sequential introduction on IPD in Israeli children <5 years.MethodsAn ongoing nationwide, prospective, population-based, active surveillance. All IPD episodes (Streptococcus pneumoniae isolated from blood and/or cerebrospinal fluid) from July 2004 through June 2013 were included.ResultsOverall, 2670 IPD episodes were recorded. Incidence of IPD caused by PCV7 + 6A serotypes during the PCV13 period vs. pre-PCV period decreased by 95% (Incidence Rate Ratio [IRR] = 0.05; 95% CI = 0.03–0.09). This reduction was observed in a two-step manner: 90% in the PCV7-period and further 5% in the PCV13-period. The rates of IPD caused by the 5 additional PCV13-serotypes (1, 3, 5, 7F, 19A; 5VT) increased initially by 47%, but subsequently decreased by 79%, resulting in an overall 70% reduction during the entire study period (IRR = 0.30; 0.21–0.44). A two-fold increase in non-PCV13 serotypes IPD was observed (IRR = 2.43; 1.73–3.66). In total, a 63% reduction of all-serotype IPD episodes was observed in children <5 years (69% and 48% in children <2 and 2–4 years old, respectively).ConclusionsAfter initiation of PCV NIP, a rapid and substantial 2-step IPD reduction was observed in children <5 years. The serotype-specific rate reduction reflected the sequential introduction of PCV7/PCV13.     

PCV13 serotype decrease in Italian adolescents and adults in the post-PCV13 era: Herd protection from children or secular trend?

Background and aim of the workIn 2010 PCV13 replaced PCV7 in the pediatric vaccination schedule for Italian children. While a strong herd effect was demonstrated for PCV7, a possible herd effect due to PCV13 is still under debate. Our aim was to evaluate differences in the distribution of pneumococcal serotypes between the pre and post-PCV13 eras in unvaccinated Italian adolescents and adults with laboratory-confirmed pneumococcal infection from 3 Italian Regions with a high rate of PCV13 vaccination of children.Patients and methodsAdolescents and adults admitted with laboratory-confirmed pneumococcal infection in the hospitals of 3 Italian Regions (Friuli-Venezia Giulia, Emilia Romagna, and Tuscany) between April 2006 and June 2016 were included in the study. Diagnosis of pneumococcal infection and serotyping were performed with Real Time PCR directly on normally sterile fluids or on culture isolates.Results523 patients with laboratory-confirmed pneumococcal infection were enrolled (Male/Female ratio was 300/223, 1.3; median age 67.1, IQR 53.4–74.9). None of the patients had been vaccinated with any pneumococcal vaccine; 96.4% were serotyped. Overall, the most frequent serotypes were 3 (67/504, 13.3%), 8 (43/504, 8.5%), and 19A (38/504, 7.5%). Serotype distribution differed among age classes and clinical presentations.Overall, PCV13 serotypes accounted for 47.6% of cases: 62.3% in the pre-PCV13 era and 45.0% in the post-PCV13 era; (p = 0.005 OR = 2.03; CL 95%: 1.2–3.3). Serotype 7F accounted for 12/77 (15.6%) of all serotypes in the pre-PCV13 period and for 12/427 (2.8%) in the post-PCV13 period and was the only serotype significantly contributing to the difference in percentage between pre and post-PCV13 eras.ConclusionOur study demonstrated a difference in percentage in serotype distribution in adolescents and adults laboratory-confirmed pneumococcal infection between the pre and post-PCV13 eras. This difference is mainly due to the decrease of serotype 7F. Thus, in order to decrease disease burden, adults and in particular the elderly should be offered a specific vaccination program.     

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.     

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 18–49 years of age,naive to 23-valent pneumococcal polysaccharide vaccine

BackgroundBased on the success of vaccination with pneumococcal conjugate vaccines (PCVs) in children, recent studies have focused on PCVs in adults. Data from a randomized, double-blind study comparing the immunogenicity, tolerability, and safety of the 13-valent PCV (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in PPSV23-naive adults 60–64 years of age have been published. The same study also included a cohort of adults aged 18–49 years that received open-label PCV13. The purpose of this cohort was to examine the immunogenicity, safety, and tolerability of PCV13 in adult subjects 18–49 years of age compared with adults 60–64 years of age for whom PCV13 is approved.MethodsAdults naive to PPSV23 were grouped by age into 2 cohorts: 18–49 years (n = 899; further stratified by age into 3 subgroups 18–29, 30–39, and 40–49 years) and 60–64 years (n = 417). All subjects received 1 dose of PCV13. In both age groups, immunogenicity was assessed by antipneumococcal opsonophagocytic activity (OPA) geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) 1 month after vaccination. Safety and tolerability were evaluated.ResultsIn adults aged 18–49 years, OPA GMTs and IgG GMCs were noninferior for all 13 serotypes and statistically significantly higher for all except 1 serotype (OPA GMT) and 5 serotypes (IgG GMCs) compared with adults 60–64 years. Immune responses were highest in the youngest age subgroup (18–29 years). Local reactions and systemic events were more common in adults 18–49 years compared with 60–64 years and were self-limited.ConclusionImmune responses to PCV13 are robust in adults ≥18 years of age, with highest responses observed in the youngest subgroup. Based on its safety and immunologic profile, PCV13 may serve an important therapeutic role in younger adults, particularly those with underlying medical conditions who have an increased risk of serious pneumococcal infections.     

Impact of the 13-valent pneumococcal conjugate vaccine (pcv13) on invasive pneumococcal disease and carriage in Alaska

BackgroundAlaska Native (AN) children have experienced high rates of invasive pneumococcal disease (IPD). In March 2010, PCV13 was introduced statewide in Alaska. We evaluated the impact of PCV13 on IPD in children and adults, 45 months after introduction.MethodsPneumococcal sterile site isolates, reported through state-wide surveillance, were serotyped using standard methods. We defined a pre-PCV13 time period 2005–2008 and post-PCV13 time period April 2010–December 2013; excluding Jan 2009–March 2010 because PCV13 was introduced pre-licensure in one high-risk region in 2009.ResultsAmong Alaska children <5 years, PCV13 serotypes comprised 65% of IPD in the pre-PCV13 period and 26% in the PCV13 period. Among all Alaska children <5 years, IPD rates decreased from 60.9 (pre) to 25.4 (post) per 100,000/year (P<0.001); PCV13 serotype IPD decreased from 37.7 to 6.4 (P<0.001). Among AN children <5 years, IPD rates decreased from 149.2 to 60.8 (P<0.001); PCV13 serotype IPD decreased from 87.0 to 17.4 (P<0.001); non-PCV13 serotype IPD did not change significantly. Among persons 5–17 and ≥45 years, the post-vaccine IPD rate was similar to the baseline period, but declined in persons 18–44 years (39%, P < 0.001); this decline was similar in AN and non-AN persons (38%, P = 0.016, 43%, P = 0.014, respectively).ConclusionsForty-five months after PCV13 introduction, overall IPD and PCV13-serotype IPD rates had decreased 58% and 83%, respectively, in Alaska children <5 years of age when compared with 2005–2008. We observed evidence of indirect effect among adults with a 39% reduction in IPD among persons 18–44 years.     

Early Streptococcus pneumoniae serotype changes in Utah adults after the introduction of PCV13 in children

IntroductionPneumococcal conjugate vaccines (PCV) have indirect effects due to decreased Streptococcus pneumoniae colonization in vaccine recipients. We sought to determine whether the introduction of PCV13 in children led to changes in the epidemiology and clinical manifestations of invasive pneumococcal disease (IPD) in adults.MethodsWe described demographics, comorbidities, clinical manifestations, and serotypes of IPD in Utah adults before (November 2009−February 2010) and after (March 2010−March 2012) the introduction of PCV13 in children. We also compare serotypes causing IPD in Utah adults and children.ResultsAfter the introduction of PCV13 in the childhood vaccine program, the proportion of IPD due to PCV13 exclusive serotypes decreased significantly in Utah adults (64−40%, p = 0.009), primarily due to a decline in serotype 7F (36−15%, p = 0.008). There were non-significant increases in IPD due to Pneumococcal polysaccharide 23 (PPV23) unique serotypes and non-vaccine serotypes, most notably serotype 22F. Changes in the proportions of vaccine and non-vaccine serotypes were similar in adults and children. Meningitis was more commonly due to non-vaccine serotypes relative to non-meningitis cases (47% vs. 18%, p = 0.007). When stratified by sex, decreases in PCV13 serotype IPD were only noted in men (76−33%, p = 0.001).ConclusionsSerotype epidemiology of IPD in adults closely follows that of children in the PCV13 era. Continued surveillance is needed to confirm whether replacement serotypes will lead to increases in pneumococcal meningitis and whether there are sex differences in the indirect effects of PCV vaccination in children.     

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.     

Comparative impact of pneumococcal conjugate vaccines on pneumococcal meningitis according to underlying conditions

BackgroundSeveral underlying conditions increase the risk of pneumococcal meningitis (PM) in childhood. Patients with these diseases are initially considered as an important target of pneumococcal conjugate vaccines (PCVs). Limited data are available for PM in children with underlying conditions. To understand the benefits of PCV7 followed by PCV13 in this vulnerable population, we analyzed the data for a large cohort of pediatric patients with PM in France from 2001 to 2014.MethodsWe conducted hospital-based active surveillance with 227 pediatric wards working with 168 microbiology departments throughout France. Standardized inclusion criteria for PM were used and data were analyzed by a pre-PCV7, post-PCV7 and post-PCV13 period.ResultsFrom 2001 to 2014, among the 1582 cases of PM, 62.5% were reported in children less than 2 years old. Underlying conditions (n = 255, 16.1%) accounted for 7.3% of the cases in these young children versus 30.8% for children ⩾2–18 years old (p < 0.001). After PCV13 implementation, PM cases decreased by 44.0% from 2009 to 2014, mainly in children without underlying conditions. Though the number of children with underlying conditions remained stable, their proportion among overall PM cases increased by 79.1%. Among children with underlying conditions, PCV7 serotypes, 6 additional PCV13 serotypes, additional 11 serotypes in PPV23 and other serotypes accounted for 24.5%, 14.7%, 25.0% and 35.8%, respectively (p < 0.001). After PCV13 implementation, 50.0% of PM cases with underlying conditions and 37.9% without underlying conditions were caused by serotypes included in neither PCV13 nor PPV23.ConclusionBesides the reduced numbers of PM, its profile has changed, with an increase in cases in proportion of children with underlying conditions accompanied by a striking change in serotype distribution. This underlines the importance of detecting underlying conditions in children with PM in the PCV13 era.     

Impact of PCV7/PCV13 introduction on community-acquired alveolar pneumonia in children <5 years

BackgroundAlveolar community-acquired pneumonia (A-CAP) is mostly considered a bacterial disease, mainly pneumococcal. This study was conducted to document the impact of sequential 7-valent and the 13-valent pneumococcal conjugate vaccines (PCV7; PCV13) on emergency room and hospitalization for A-CAP among children <5 years of age.MethodsThis is an ongoing prospective population-based study in southern Israel. The current analysis spans over the period July 2002 through June 2013. A-CAP was defined using the World Health Organization (WHO)’s criteria for radiologically-confirmed pneumonia. PCV7 was introduced in Israel in July 2009 and gradually replaced by PCV13 in November 2010. Pneumococcal conjugate vaccine (PCV) impact was calculated by comparing incidences during 3 pre-defined periods: pre-PCV (2002–2008), PCV7 (2010–2011) and PCV13 (2012–2013).ResultsOverall, 10,142 A-CAP episodes occurred. The annual incidences (per 1,000 inhabitants) in children <5 years old declined from a mean (±standard deviation) of 13.8 ± 0.9 in the pre-PCV period to 11.2 ± 2.7 in the PCV7 period and 7.4 in the PCV13 period, representing a reduction of 13% and 47%, respectively. The overall decrease was significantly faster among outpatients than among hospitalized children (42% and −8%, respectively in the PCV7 period; 68% vs. 32% in hospitalized children in the PCV13 period). While in children 12–23 months a significant decline was observed during the PCV7 and PCV13 periods, significant declines in A-CAP rates were observed only during the PCV13 period in the <12 months and 24–59 months age groups (44% and 46%, respectively).ConclusionsA moderate decline in hospital A-CAP visits in children <5 years old was observed after PCV7 introduction. In contrast, after PCV13 introduction a substantial reduction in all visits was evident.     

Impact of PCV7/PCV13 introduction on invasive pneumococcal disease (IPD) in young children: Comparison between meningitis and non-meningitis IPD

BackgroundThe worldwide introduction of pneumococcal conjugate vaccines (PCV) into National Immunization Programs resulted in rapid and substantial reduction of invasive pneumococcal disease (IPD) rates in children. However, the reduction of meningitis vs. non-meningitis IPD (nm-IPD) was not yet fully elucidated. We compared 7-valent and 13-valent PCV (PCV7 and PCV13) impact on pneumococcal-meningitis vs. nm-IPD in Israeli children <5 years.MethodsWe conducted an ongoing nationwide, prospective, population-based, active surveillance. PCV7 and PCV13 were implemented in Israel in July 2009 and November 2010, respectively. All pneumococcal isolates (blood and/or CSF) from IPD episodes in children <5 years from July 2000 through June 2015 were included. Extrapolation for missing serotypes (34.7% of all isolates) was conducted.Results4163 IPD cases were identified; 3739 nm-IPD (89.8%) and 424 meningitis (10.2%). During the pre-PCV period (2000–2008), children <12 months constituted 52.1% and 33.7% of meningitis and nm-IPD, respectively (p < 0.001). The respective proportions of non-PCV13 serotypes (non-VT) were 18.2% vs. 10.1%, (p < 0.001).Comparing the last study year (2014–2015) to the mean of pre-PCV period, meningitis incidence in children <5 years decreased non-significantly by 27%, while nm-IPD decreased significantly by 69%. Dynamic rates of meningitis and nm-IPD caused by PCV13 serotypes were similar, with 93% and 95% overall reductions, respectively. However, non-VT increased in meningitis relatively to nm-IPD, mainly in children <24 months. Serotype 12F rose sharply and significantly since 2009–2010 through 2014–2015 (28.6% of all non-VT meningitis in children <24 m).ConclusionsThe overall impact of PCV7/PCV13 in children <5 years in Israel was less prominent in meningitis than in nm-IPD. This could be attributed to the younger age of children with meningitis and differences in causative serotypes between the two groups, as the decline of the incidence of meningitis and nm-IPD caused by vaccine-serotypes is similar. Continuous monitoring of meningitis and nm-IPD is warranted.     

Exploratory efficacy endpoints in the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA)

BackgroundThe Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) assessed vaccine-type community-acquired pneumonia (VT-CAP) and vaccine-type invasive pneumococcal disease (VT-IPD) prevention with 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ⩾65 years. We report vaccine efficacy (VE) of PCV13 for the remaining 23 exploratory endpoints and serotype distributions for pneumococcal CAP and IPD.MethodsThis was a parallel-group, randomised, placebo-controlled, double-blind trial comparing single-dose PCV13 with placebo. Exploratory CAP endpoints included first episode of confirmed non-VT (NVT) pneumococcal CAP; all confirmed episodes of NVT pneumococcal CAP, pneumococcal CAP, nonbacteraemic/noninvasive (NB/NI) VT pneumococcal CAP, and NB/NI pneumococcal CAP; and first and all episodes of culture-confirmed VT pneumococcal CAP, culture-confirmed pneumococcal CAP, culture-confirmed NVT pneumococcal CAP, probable VT pneumococcal CAP, probable NVT pneumococcal CAP, and probable and possible pneumococcal CAP. Exploratory IPD endpoints included all episodes of VT-IPD and IPD, and first and all episodes of NVT-IPD. The per-protocol and modified intent-to-treat (mITT) populations were evaluated.ResultsIn total, 84,496 participants were enrolled. Eight of 23 exploratory CAP and IPD endpoints were statistically significant in both populations. In the per-protocol population, these included VE of 29% for all episodes of confirmed pneumococcal CAP, 43% for all NB/NI episodes of VT pneumococcal CAP, 52% for all episodes of culture-confirmed pneumococcal CAP, and 53% for all episodes of IPD. Comparable VE estimates were observed in the mITT population. The most common VT serotypes were 1 (10 first episodes of confirmed pneumococcal CAP; 2 first episodes of IPD) and 7F (22; 7) among PCV13 and placebo recipients, respectively.ConclusionsThe results of this analysis yielded statistically significant PCV13 VE for all episodes of confirmed pneumococcal CAP (including NB/NI and culture-confirmed episodes) and for all episodes of IPD in adults aged ⩾65 years. These findings are consistent with the primary efficacy analysis. ClinicalTrials.gov identifier: NCT00744263.     

Effectiveness of three pneumococcal conjugate vaccines to prevent invasive pneumococcal disease in Quebec,Canada

BackgroundIn Quebec, a pneumococcal conjugate vaccine (PCV) program was implemented in December 2004. The recommended schedule is 2 + 1 doses for low-risk infants. PCV-7 was first used (including catch-up for children <5 years of age), replaced by PCV10 in June 2009, and by PCV13 in January 2011 (no catch-up in both instances). From the beginning, >90% of children received the recommended number of doses.ObjectiveTo assess the effectiveness of the three PCVs sequentially used to prevent invasive infectious disease (IPD).MethodsIPD cases in children 2–59 months during the years 2005–2013 were eligible. Controls were randomly identified in the provincial health insurance registry. Parents were interviewed and immunization records reviewed. Vaccine effectiveness (VE) was computed using multivariate logistic regression models.ResultsOut of 889 IPD cases reported, full participation was obtained for 516 cases (58%) and for 1767 controls. Against vaccine-type IPD, VE (≥1 dose) was 90% (82–95%) for PCV7, 97% (84–99%) for PCV10 and 86% (62–95%) for PCV13. Against 19A IPD, VE was, respectively, 42% (−9% to 69%), 71% (24–89%), and 74% (11–92%). VE (≥2 doses) against PCV13-type IPD was 85% for PCV10 (66–94%), 85% for PCV13 (55–94%), and 89% (58–97%) for a mixed PCV10 + PCV13 schedule.ConclusionsAll three PCV vaccines showed high level of protection against IPD caused by serotypes included in their formulation and there was a high level of cross-protection against 19A for PCV10. No substantial difference was seen between PCV10, PCV13, or a mixed PCV10 + PCV13 schedule.     

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.     

Rethinking number-needed-to-vaccinate for pneumococcal conjugate vaccines in older adults: Current and future implications

BackgroundNumber-needed-to-vaccinate (NNV) is increasingly used to inform decisions about vaccine use, but it is not calculated uniformly across studies. This study compared two methodologies for calculating NNV with 13-valent pneumococcal conjugate vaccine (PCV13) to prevent one case of community-acquired pneumonia (CAP) among US adults aged ≥65 years: (i) using one-year absolute rate differences as was originally performed by the Centers for Disease Control and Prevention (CDC) and (ii) using absolute risk reduction over 5 years.MethodsWe constructed a hypothetical fixed cohort of 200,000 adults aged ≥65 years equally separated into PCV13-vaccinated and PCV13-unvaccinated groups. We incorporated the same conservative assumptions used by CDC in 2014 regarding annual incidence of hospitalized (1375 per 100,000) and outpatient (2010 per 100,000) CAP, the initial (2014) proportion of adult PCV13-type CAP (10%), and PCV13 efficacy against vaccine-type CAP (45%). To model PCV13 impact over time, we assumed annual mortality was 5% for both groups, the percentage of adult PCV13-type CAP declined annually due to pediatric herd effects, and PCV13 efficacy did not wane over 5 years.ResultsAmong adults aged ≥65 years, NNV with PCV13 to prevent one hospitalized and one outpatient case of CAP as originally calculated by CDC in 2014 were 1620 and 1110, respectively. Accounting for 5-year cumulative effects, NNV with PCV13 to prevent one hospitalized and one outpatient case of CAP over 5 years were 576 and 394, respectively. These revised NNV estimates are roughly one third of initial estimates in which cumulative effects were ignored. NNV to prevent any CAP (inpatient or outpatient) over 5 years with one PCV13 dose was 234.ConclusionAccounting for cumulative preventive effects of PCV13 vaccination over time is critical. Failing to do so, even when using conservative disease burden parameters, can grossly underestimate the public health impact of adult PCV13 use.     

Acquisition of Streptococcus pneumoniae in South African children vaccinated with 7-valent pneumococcal conjugate vaccine at 6, 14 and 40 weeks of age

BackgroundSeven-valent pneumococcal conjugate vaccine (PCV7) was introduced into the South African immunization program using 6, 14 and 40 weeks dosing schedule (2 + 1), with no catch-up in older children since April 2009. We investigated pneumococcal colonization acquisition in children who received this schedule and also compared it to historical cohorts of PCV-naïve children (n = 123 in 2007) and children who received a 3 + 1 PCV7 schedule (n = 124 in 2005/06).MethodsTwo hundred and fifty children aged 6–12 weeks were enrolled from December 2009 to April 2010. Participants had nasopharyngeal swabs collected on eight occasions between enrolment and 2-years of age. Standard methods were undertaken for bacterial culture and Streptococcus pneumoniae were serotyped using the Quellung method. Pneumococcal and Staphylococcus aureus colonization in the present study was compared to colonization in two historical longitudinal cohorts.ResultsS. pneumoniae was identified in 1081 (61.4%) of 1761 swabs collected in the current cohort. Pneumococcal colonization peaked at 41-weeks of age (76.8%) and decreased to 62.8% by 2-years of age (p = 0.002); PCV7-serotype colonization decreased during the same period from 28.6% to 15.6% (p = 0.001). Children from the current cohort compared to PCV-naïve children were less likely to be colonized by PCV7-serotypes from 40-weeks to 2-years of age and acquired PCV7-serotypes less frequently. No differences in overall pneumococcal, PCV7-serotype and non-PCV7-serotype colonization or new serotype acquisitions were detected comparing the current cohort to the historical cohort who received the 3 + 1 PCV7 schedule. Staphylococcus aureus colonization was similar in all three cohorts.ConclusionA 2 + 1 PCV7 schedule implemented in South Africa was temporally associated with reduced risk of vaccine-serotype colonization compared to historically unvaccinated children. Also, vaccine-serotype acquisition rate using the 2 + 1 schedule was similar to that in the 3 + 1 dosing cohort, suggesting that similar indirect protection against pneumococcal disease could be derived from either schedule in South Africa.     

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.     

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.     

Long-term mortality after IPD and bacteremic versus non-bacteremic pneumococcal pneumonia

BackgroundShort-term mortality after invasive pneumococcal disease (IPD) and pneumococcal pneumonia is high but data on long-term mortality (including the comparison between bacteremic and non-invasive/non-bacteremic pneumococcal pneumonia) within the first years after diagnosis are scarce.MethodsAdult patients with ‘non-pneumonia’ IPD and ‘invasive pneumonia’ (from 2004 to 2012) and with ‘bacteremic’ vs ‘non-invasive/non-bacteremic (NI/NB)’ pneumococcal pneumonia (from 2008 to 2012) diagnosed by negative blood culture but a positive urinary antigen test (UAT) were identified in a Dutch hospital. Mortality of patients up to 10 years after diagnosis was compared with age- and sex-matched life-expectancy data of the general population. Multivariable Cox regression analysis was used to study predictors for mortality in invasive pneumonia patients and to adjust for confounders comparing mortality between bacteremic and NI/NB/UAT-positive pneumonia patients.ResultsOf 228 invasive pneumonia patients 17% died within 30 days and in 30-day survivors cumulative long-term mortality at 1 and 5 years were 16% and 39% as compared with 3% and 15% in age- and sex-matched persons. High mortality was largely dependent on pre-existent comorbidities. In invasive pneumonia patients who survived the first 30 days, age, male gender, chronic cardiovascular disease, malignancy and PCV7 serotype disease were independent predictors for higher long-term mortality. For bacteremic pneumonia patients (n = 128) 30-day mortality was 16% and almost similar to 14% in NI/NB/UAT-positive pneumococcal pneumonia patients (n = 170). In 30-day survivors of bacteremic pneumonia (n = 108, median age 66 years), cumulative mortality at 1 and 3 years were 13% and 29% as compared with 18% and 40% in NI/NB/UAT-positive pneumococcal pneumonia patients (n = 146, median age 67 years) without a significant difference in mortality.ConclusionsApproximately 40% of all patients, who survived the first 30 days after presentation with non-pneumonia IPD and pneumococcal pneumonia died within the following 5 years. High long-term mortality was largely dependent on pre-existent comorbidity.