Impact of the pneumococcal conjugate vaccine on serotype distribution and susceptibility trends of pediatric non-invasive Streptococcus pneumoniae isolates in Tokai,Japan over a 5-year period

Introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in February 2010 markedly reduced the burden of invasive pneumococcal disease (IPD) and changed serotype distribution in Japan. We investigated the serotype distribution and susceptibility trends of non-invasive Streptococcus pneumoniae isolates collected from pediatric patients. A total of 564 pneumococcal isolates were collected over a 5-year period between 2008 and 2012. The coverage of PCV7 significantly decreased throughout the study period, from 49.3% in period 1 (between June 2008 and April 2009) to 23.4% in period 4 (between October 2011 and March 2012). This change was mainly due to a large decrease in the frequency of 19F (from 20.6% to 9.9%) and 6B (from 10.3% to 2.7%) and an increase in serotype 3 (from 5.1% to 13.5%) and serogroup 15 (from 4.4% to 9.0%). According to serotype replacement, the susceptible ratios of S. pneumoniae to β-lactams increased slightly while macrolide resistance remained high. The high frequency of macrolide-resistant pneumococcal isolates may continue because of the high frequency of erm(B) in replace serotypes such as serotype 3 and serogroup 15. The continuous surveillance study is essential following the introduction of a second generation 13-valent pneumococcal conjugate vaccine (PCV13).     

Lower respiratory infections mortality among Brazilians under-five before and after national pneumococcal conjugate vaccine implementation

BackgroundStudies on the impact of pneumococcal conjugate vaccines (PCV) on mortality, especially among preschoolers are scarce. We aimed to assess time trend mortality from lower respiratory infections (LRI), taken as a proxy of pneumonia, from 1990 to 2017.MethodsThis ecological study assessed the mortality rate among Brazilians under-five before and after the national PCV-10 implementation in 2010. Pneumococcal meningitis (PM) and diarrheal diseases (DD) were included as a “positive and negative controls”, respectively. Trend analysis was performed through Global Burden of Disease estimates. Joinpoint regression modeling was used to describe trends in mortality and to identify time points of its statistically significant decreases throughout the study period.ResultsThere was a sustainable reduction in mortality rates for these three diseases, with no relevant changes in the secular trends for LRI and PM after the PCV-10 implementation. For LRI, PM, and DD the higher and statistically significant (p < 0.05) annual percent change reduction occurred between 2000 and 2003, (−8.3%), 1997–2000 (−11.9%), and 1990–1994.(−13.8%), respectively, i.e., several years before the nationwide implementation of PCV-10. Moreover, for LRI the annual percent change (from −5.9 to −8.8) verified from 1990 to 2009, i.e., 20 years before countrywide vaccination, was comparable to that observed during the PCV era, that is, from minus 5.8 to minus 7.8, between 2010 and 2017.ConclusionMortality from LRI, PM, and DD decreased over time, irrespective of national PCV-10 implementation in Brazil. Other factors such as healthcare delivery, socioeconomic status improvement, and health interventions may have impacted this secular trend.     

Increasing non-susceptibility to antibiotics within carried pneumococcal serotypes — Alaska, 2008–2015

BackgroundIn Alaska, while introduction of 13-valent pneumococcal conjugate vaccine led to declines in invasive pneumococcal disease, carriage prevalence remained stable because of replacement with non-vaccine serotypes. We assessed antibiotic non-susceptibility of carried pneumococci during serotype redistribution, determined the contributions of within-serotype shifts, and assessed factors that could explain changes in non-susceptibility.MethodsEach year from 2008 to 2015, at multiple sites in Alaska, we collected nasopharyngeal swabs and completed surveys for a convenience sample of participants. Pneumococcal serotyping and antimicrobial susceptibility testing for penicillin and erythromycin were performed. We described changes in non-susceptibility of isolates from 2008–2011 to 2012–2015, and assessed the contributions of serotype redistribution and within-serotype changes in non-susceptibility by comparing observed data to modeled data removing either factor. We used weighted logistic regression to assess whether reported risk factors could explain changes over time in non-susceptibility within serotypes.ResultsFrom 2008–2011 to 2012–2015, the overall proportion of isolates non-susceptible to penicillin or erythromycin increased by 3%, from 23% (n = 1,183) to 26% (n = 1,589; P < 0.05). However, a decrease of 3% would be expected if serotype redistribution occurred without within-serotype changes in non-susceptibility. Standardization by either factor produced hypothetical data significantly different to observed data. Within serotypes, the average annual increase in odds of non-susceptibility to penicillin or erythromycin was 1.08 (95% CI 1.05–1.11). Recent antibiotic exposure, urban residence and increased household size of participants predicted isolate non-susceptibility but did not explain the increase over time.DiscussionAn overall increase in non-susceptibility of carried pneumococcal isolates to penicillin or erythromycin resulted from increases in non-susceptibility within serotypes, which outweighed a protective effect of serotype redistribution. Characterization of emerging resistant clones within carried non-vaccine serotypes, including risk factors for colonization and disease, would support disease prevention efforts and inform vaccine strategies.     

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.     

Pneumonia prevention: Cost-effectiveness analyses of two vaccines among refugee children aged under two years,Haemophilus influenzae type b-containing and pneumococcal conjugate vaccines,during a humanitarian emergency,Yida camp,South Sudan

By September 2013, war between Sudan and South Sudan resulted in >70,000 Sudanese refugees and high pneumonia incidence among the 20,000 refugees in Yida camp, South Sudan. Using Médecins Sans Frontières (MSF)-provided data and modifying our decision-tree models, we estimated if administering Haemophilus influenzae type b (Hib)-containing (pentavalent vaccine, also with diphtheria pertussis and tetanus [DPT] and hepatitis B) and pneumococcal conjugate (PCV) vaccines were cost-effective against hospitalized pneumonia. Among children <2 years old, compared with no vaccination, one- and two-doses of combined Hib-containing and PCV would avert an estimated 118 and 125 pneumonia cases, and 8.5 and 9.1 deaths, respectively. The cost per Disability-Adjusted-Life-Year averted for administering combined one- and two-doses was US$125 and US$209, respectively. MSF demonstrated that it was possible to administer these vaccines during an emergency and our analysis found it was highly cost-effective, even with just one-dose of either vaccine. Despite unknown etiology, there is strong field and now economic rationale for administering Hib and PCV during at least one humanitarian emergency.     

Cost-effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) in older Australians

BackgroundThe 23-valent pneumococcal polysaccharide vaccine (PPV23) has been funded under the Australia National Immunisation Program (NIP) since January 2005 for those aged >65 years and other risk groups. In 2016, PCV13 was accepted by the Pharmaceutical Benefits Advisory Committee (PBAC) as a replacement for a single dose of PPV23 in older Australian adults.MethodsA single-cohort deterministic multi-compartment (Markov) model was developed describing the transition of the population between different invasive and non-invasive pneumococcal disease related health states. We applied a healthcare system perspective with costs (Australian dollars, A$) and health effects (measured in quality adjusted life-years, QALYs) attached to model states and discounted at 5% annually. We explored replacement of PPV23 with PCV13 at 65 years as well as other age based vaccination strategies. Parameter uncertainty was explored using deterministic and probabilistic sensitivity analysis.ResultsIn a single cohort, we estimated PCV13 vaccination at the age of 65 years to cost ∼A$11,120,000 and prevent 39 hospitalisations and 6 deaths from invasive pneumococcal disease and 180 hospitalisations and 10 deaths from community acquired pneumonia. The PCV13 program had an incremental cost-effectiveness ratio of ∼A$88,100 per QALY gained when compared to a no-vaccination, whereas PPV23 was ∼A$297,200 per QALY gained. To fall under a cost-effectiveness threshold of A$60,000 per QALY, PCV13 would have to be priced below ∼A$46 per dose. The cost-effectiveness of PCV13 in comparison to PPV23 was ∼A$35,300 per QALY gained.ConclusionIn comparison to no-vaccination, we found PCV13 use in those aged 65 years was unlikely to be cost-effective unless the vaccine price was below A$46 or a longer duration of protection can be established. However, we found that in comparison to the PPV23, vaccination with PCV13 was cost-effective. This partly reflects the poor value for money estimated for PPV23 use in Australia.     

Immunogenicity,safety and reactogenicity of the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in 2–17-year-old children with asplenia or splenic dysfunction: A phase 3 study

BackgroundImmunization with pneumococcal vaccines is an important prophylactic strategy for children with asplenia or splenic dysfunction, who are at high risk of bacterial infections (including S. pneumoniae). This study aimed to assess immunogenicity and safety of pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, GSK) in this at-risk population.MethodsThis phase III, multi-centre, open-label, controlled study, in which at-risk children with asplenia or splenic dysfunction were enrolled (age strata: 2–4, 5–10 and 11–17 years), was conducted in Poland and the Russian Federation. For the 2–4 years at-risk group, healthy age-matched children were enrolled as control. Unprimed children (not previously vaccinated with any pneumococcal vaccine) received 2 PHiD-CV doses (≥2 months apart) and pneumococcal vaccine-primed children received 1 dose. Immune responses were assessed pre-vaccination and one month post-each dose. Solicited and unsolicited adverse events (AEs) were recorded for 4 and 31 days post-vaccination, respectively, and serious AEs (SAEs) throughout the study.ResultsOf 52 vaccinated children (18 at-risk primed, 28 at-risk unprimed and 6 control unprimed), 45 (18, 23 and 4, respectively) were included in the according-to-protocol cohort for immunogenicity. Post-vaccination (post-dose 1 in primed and post-dose 2 in unprimed children), for each vaccine pneumococcal serotype and vaccine-related serotype 6A all at-risk children had antibody concentrations ≥0.2 µg/mL, and for vaccine-related serotype 19A at least 94.4%. Increases in antibody geometric mean concentrations were observed. For most serotypes, all at-risk children had post-vaccination opsonophagocytic activity (OPA) titers ≥8 and increases in OPA geometric mean titers were observed. No safety concerns were raised. One non-fatal SAE (respiratory tract infection, considered not vaccine-related) was reported by one at-risk unprimed child.ConclusionPHiD-CV was immunogenic and well tolerated in 2–17-year-old children with asplenia or splenic dysfunction.Clinical Trial Registry: www.clinicaltrials.gov, NCT01746108.     

Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial

Background

Histopathological diagnosis of diffuse gliomas is subject to interobserver variation and correlates modestly with major prognostic and predictive molecular abnormalities. We investigated a series of patients with locally diagnosed anaplastic oligodendroglial tumors included in the EORTC phase III trial 26951 on procarbazine/lomustine/vincristine (PCV) chemotherapy to explore the diagnostic, prognostic, and predictive value of targeted next-generation sequencing (NGS) in diffuse glioma and to assess the prognostic impact of FUBP1 and CIC mutations.

Methods

Mostly formalin-fixed paraffin-embedded samples were tested with targeted NGS for mutations in ATRX, TP53, IDH1, IDH2, CIC, FUBP1, PI3KC, TERT, EGFR, H3F3A, BRAF, PTEN, and NOTCH and for copy number alterations of chromosomes 1p, 19q, 10q, and 7. TERT mutations were also assessed, with PCR.

Results

Material was available from 139 cases, in 6 of which results were uninformative. One hundred twenty-six tumors could be classified: 20 as type II (IDH mutation [mut], “astrocytoma”), 49 as type I (1p/19q codeletion, “oligodendroglioma”), 55 as type III (7+/10q– or TERTmut and 1p/19q intact, “glioblastoma”), and 2 as childhood glioblastoma (H3F3Amut), leaving 7 unclassified (total 91% classified). Molecular classification was of clear prognostic significance and correlated better with outcome than did classical histopathology. In 1p/19q codeleted tumors, outcome was not affected by CIC and FUBP1 mutations. MGMT promoter methylation remained the most predictive factor for survival benefit of PCV chemotherapy.

Conclusion

Targeted NGS allows a clinically relevant classification of diffuse glioma into groups with very different outcomes. The diagnosis of diffuse glioma should be primarily based on a molecular classification, with the histopathological grade added to it. Future discussion should primarily aim at establishing the minimum requirements for molecular classification of diffuse glioma.