Pneumococcal Conjugated Vaccines Decreased Acute Otitis Media Burden: A Population-Based Study in Israel.

OBJECTIVE: To study time trends in all-cause acute otitis media (AOM) burden by calculating incidence rates of AOM episodes and recurrent acute otitis media (rAOM) cases in highly immunized pediatric population during the pre- and post-pneumococcal conjugated vaccine (PCV) years. STUDY DESIGN: In this population-based study, AOM episodes and rAOM cases were identified in Clalit Health Services-insured Israeli children aged 0-10 years between 2005 and 2018 by using a data-sharing platform. Because a near-sequential implementation of PCV-7/PCV-13 occurred within a 1-year period (2009/2010), we compared AOM visits before (2005-July 2009) and after (August 2009-2018) the introduction of PCVs. We focused on children younger than 2 years of age, who are the target population of PCVs and are at AOM peak age. RESULTS: We identified 805 389 AOM episodes contributed by 270 137 children. The median number of AOM episodes was 2 (IQR 1-4). A downward trend of incidence rates of AOM episodes was observed during the post-PCV years in children younger than age 9 years (P < .001). The largest decrease (21%) was observed in children younger than 1 year, from 807/1000 children during the pre-PCV years to 640/1000 during the post-PCV years (P < .001). An average annual decrease of ∼14/1000 AOM episodes was calculated in children younger than 1 year old (ß = -13.39, 95% CI -16.25 to -10.53, P < .001). Of rAOM cases, documented in 84 237 (31.2%) children, 74% were in children younger than 2 years, and 55% were in boys. The risk to develop rAOM significantly decreased during the post-PCV years in children younger than 2 years (hazard ratio 0.893, 95% CI 0.878-0.908; P < .001). CONCLUSIONS: AOM burden significantly decreased following PCVs introduction in highly immunized children.

The impact of serotype-specific vaccination on phylodynamic parameters of Streptococcus pneumoniae and the pneumococcal pan-genome.

In the United States, the introduction of the heptavalent pneumococcal conjugate vaccine (PCV) largely eliminated vaccine serotypes (VT); non-vaccine serotypes (NVT) subsequently increased in carriage and disease. Vaccination also disrupts the composition of the pneumococcal pangenome, which includes mobile genetic elements and polymorphic non-capsular antigens important for virulence, transmission, and pneumococcal ecology. Antigenic proteins are of interest for future vaccines; yet, little is known about how the they are affected by PCV use. To investigate the evolutionary impact of vaccination, we assessed recombination, evolution, and pathogen demographic history of 937 pneumococci collected from 1998-2012 among Navajo and White Mountain Apache Native American communities. We analyzed changes in the pneumococcal pangenome, focusing on metabolic loci and 19 polymorphic protein antigens. We found the impact of PCV on the pneumococcal population could be observed in reduced diversity, a smaller pangenome, and changing frequencies of accessory clusters of orthologous groups (COGs). Post-PCV7, diversity rebounded through clonal expansion of NVT lineages and inferred in-migration of two previously unobserved lineages. Accessory COGs frequencies trended toward pre-PCV7 values with increasing time since vaccine introduction. Contemporary frequencies of protein antigen variants are better predicted by pre-PCV7 values (1998-2000) than the preceding period (2006-2008), suggesting balancing selection may have acted in maintaining variant frequencies in this population. Overall, we present the largest genomic analysis of pneumococcal carriage in the United States to date, which includes a snapshot of a true vaccine-naïve community prior to the introduction of PCV7. These data improve our understanding of pneumococcal evolution and emphasize the need to consider pangenome composition when inferring the impact of vaccination and developing future protein-based pneumococcal vaccines.

Differences in the Impact of Pneumococcal Serotype Replacement in Individuals With and Without Underlying Medical Conditions.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have had a well-documented impact on the incidence of invasive pneumococcal disease (IPD). However, declines in IPD due to vaccine-targeted serotypes have been partially offset by increases in IPD due to nonvaccine serotypes (NVTs). The goal of this study was to quantify serotype-specific changes in the incidence of IPD that occurred in different age groups, with or without certain comorbidities, following the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) and 13-valent pneumococcal conjugate vaccine (PCV13) in the childhood vaccination program in Denmark. METHODS: We used nationwide surveillance data for IPD and a hierarchical Bayesian regression framework to estimate changes in the incidence of IPD associated with the introduction of PCV7 (2007) and PCV13 (2010) while controlling for serotype-specific epidemic cycles and unrelated secular trends. RESULTS: Following the introduction of PCV7 and PCV13 in children, the net impact of serotype replacement varied considerably by age group and comorbidities. Differences in the magnitude of serotype replacement were due to variations in the incidence of NVTs in the different risk groups before the introduction of PCVs. The relative increases in the incidence of IPD caused by specific NVTs did not differ appreciably between risk groups in the postvaccination period. Serotype replacement offset a greater proportion of the benefit of PCVs in strata in which the NVTs comprised a larger proportion of cases prior to the introduction of the vaccines. CONCLUSIONS: These findings could help to predict the impact of next-generation PCVs in specific risk groups.

Decline in Pneumococcal Disease Attenuated in Older Adults and Those With Comorbidities Following Universal Childhood PCV13 Immunization.

BACKGROUND: Following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in the United States, epidemiology of pneumococcal disease shifted such that disease incidence in the elderly exceeded that in children. We evaluated the impact of replacing PCV7 with PCV13 on disease burden in adults and identified age/risk-specific subgroups with the highest remaining disease burden. METHODS: A retrospective design and data from two US healthcare claims repositories were used. Study population included adults aged ≥18 years and was stratified by age (18-49, 50-64, 65-74, ≥75) and risk profile (healthy, at-risk, high-risk). Rate ratios comparing invasive pneumococcal disease (IPD), all-cause hospitalized pneumonia (ACHP), and pneumococcal pneumonia requiring hospitalization among at-risk and high-risk adults vs healthy counterparts were estimated for 2007-2010 (pre-PCV13), 2011-2012 (peri-PCV13), and 2013-2015 (post-PCV13). RESULTS: Across study periods, IPD and ACHP rates increased with age (2-27 times higher in persons ≥75 vs 18-49) and comorbidity (4-20 times higher in high-risk vs healthy). From pre- to post-PCV13 period, IPD rates declined 5%-48% and ACHP rates declined 4%-19% across age and risk groups (ACHP did not decline in persons ≥75). Decline in IPD and ACHP was attenuated among older adults and those with comorbidities. Accordingly, rate ratios among at-risk and high-risk persons (vs healthy counterparts) increased during the peri- and post-PCV13 periods compared with the pre-PCV13 period. CONCLUSIONS: The switch to PCV13 was associated with large declines in pneumococcal disease among US adults. However, the decline was attenuated with increasing age (and, for ACHP, was absent in persons ≥75) and in those with comorbidities.

Effect of Pneumococcal Conjugate Vaccines on Pneumococcal Meningitis, England and Wales, July 1, 2000-June 30, 2016.

We describe the effects of the 7-valent (PCV7) and 13-valent (PCV13) pneumococcal conjugate vaccines on pneumococcal meningitis in England and Wales during July 1, 2000-June 30, 2016. Overall, 84,473 laboratory-confirmed invasive pneumococcal disease cases, including 4,160 (4.9%) cases with meningitis, occurred. PCV7 implementation in 2006 did not lower overall pneumococcal meningitis incidence because of replacement with non-PCV7-type meningitis incidence. Replacement with PCV13 in 2010, however, led to a 48% reduction in pneumococcal meningitis incidence by 2015-16. The overall case-fatality rate was 17.5%: 10.7% among patients <5 years of age, 17.3% among patients 5-64 years of age, and 31.9% among patients >65 years of age. Serotype 8 was associated with increased odds of death (adjusted odds ratio 2.9, 95% CI 1.8-4.7). In England and Wales, an effect on pneumococcal meningitis was observed only after PCV13 implementation. Further studies are needed to assess pneumococcal meningitis caused by the replacing serotypes.

Estimated impact of revising the 13-valent pneumococcal conjugate vaccine schedule from 2+1 to 1+1 in England and Wales: A modelling study.

BACKGROUND: In October 2017, the United Kingdom Joint Committee on Vaccination and Immunisation (JCVI) recommended removal of one primary dose of the 13-valent pneumococcal conjugate vaccine (PCV13) from the existing 2+1 schedule (2, 4, 12 months). We conducted a mathematical modelling study to investigate the potential impact of a 1+1 (3, 12 month) schedule on invasive pneumococcal disease (IPD) and pneumococcal community-acquired pneumonia (CAP). Our results and those from a 1+1 immunogenicity study formed the key evidence reviewed by JCVI. METHODS AND FINDINGS: We developed age-structured, dynamic, deterministic models of pneumococcal transmission in England and Wales to describe the impact on IPD of 7-valent PCV (PCV7; introduced in 2006) and PCV13 (introduced in 2010). Key transmission and vaccine parameters were estimated by fitting to carriage data from 2001/2002 and post-PCV IPD data to 2015, using vaccine coverage, mixing patterns between ages, and population data. We considered various models to investigate potential reasons for the rapid increase in non-PCV13 (non-vaccine serotype [NVT]) IPD cases since 2014. After searching a large parameter space, 500 parameter sets were identified with a likelihood statistically close to the maximum and these used to predict future cases (median, prediction range from 500 parameter sets). Our findings indicated that the emergence of individual NVTs with higher virulence resulting from ongoing replacement was likely responsible; the NVT increase was predicted to plateau from 2020. Long-term simulation results suggest that changing to a 1+1 schedule would have little overall impact, as the small increase in vaccine-type IPD would be offset by a reduction in NVT IPD. Our results were robust to changes in vaccine assumptions in a sensitivity analysis. Under the base case scenario, a change to a 1+1 schedule in 2018 was predicted to produce 31 (6, 76) additional IPD cases over five years and 83 (-10, 242) additional pneumococcal-CAP cases, with together 8 (-2, 24) additional deaths, none in children under 15 years. Long-term continuation with the 2+1 schedule, or changing to a 1+1, was predicted to sustain current reductions in IPD cases in under-64-year-olds, but cases in 65+-year-olds would continue to increase because of the effects of an aging population. Limitations of our model include difficulty in fitting to past trends in NVT IPD in some age groups and inherent uncertainty about future NVT behaviour, sparse data for defining the mixing matrix in 65+-year-olds, and the methodological challenge of defining uncertainty on predictions. CONCLUSIONS: Our findings suggest that, with the current mature status of the PCV programme in England and Wales, removing one primary dose in the first year of life would have little impact on IPD or pneumococcal CAP cases or associated deaths at any age. A reduction in the number of priming doses would improve programmatic efficiency and facilitate the introduction of new vaccines by reducing the number of coadministered vaccines given at 2 and 4 months of age in the current UK schedule. Our findings should not be applied to other settings with different pneumococcal epidemiology or with immature programmes and poor herd immunity.

Association of Pneumococcal Conjugate Vaccine Coverage With Pneumococcal Meningitis: An Analysis of French Administrative Areas, 2001-2016.

Geographic variations of invasive pneumococcal disease incidence and serotype distributions were observed after pneumococcal conjugate vaccine introduction at regional levels and among French administrative areas. The variations could be related to regional vaccine coverage (VC) variations that might have direct consequences for vaccination-policy impact on invasive pneumococcal disease, particularly pneumococcal meningitis (PM) incidence. We assessed vaccine impact from 2001 to 2016 in France by estimating the contribution of regional VC differences to variations of annual local PM incidence. Using a mixed-effect Poisson model, we showed that, despite some variations of VC among administrative areas, vaccine impact on vaccine-serotype PM was homogeneously confirmed among administrative areas. Compared with the prevaccine era, the cumulative VC impact on vaccine serotypes led, in 2016, to PM reductions ranging among regions from 87% (25th percentile) to 91% (75th percentile) for 7-valent pneumococcal conjugate vaccine serotypes and from 58% to 63% for the 6 additional 13-valent pneumococcal conjugate vaccine serotypes. Nonvaccine-serotype PM increases from the prevaccine era ranged among areas from 98% to 127%. By taking into account the cumulative impact of growing VC and VC differences, our analyses confirmed high vaccine impact on vaccine-serotype PM case rates and suggest that VC variations cannot explain PM administrative area differences.

Association Between the Decline in Pneumococcal Disease in Unimmunized Adults and Vaccine-Derived Protection Against Colonization in Toddlers and Preschool-Aged Children.

Vaccinating children with pneumococcal conjugate vaccine (PCV) disrupts transmission, reducing disease rates in unvaccinated adults. When considering changes in vaccine dosing strategies (e.g., removing doses), it is critical to understand which groups of children contribute most to transmission to adults. We used data from Israel (2009-2016) to evaluate how the buildup of vaccine-associated immunity in children was associated with declines in invasive pneumococcal disease (IPD) due to vaccine-targeted serotypes in unimmunized adults. Data on vaccine uptake and prevalence of colonization with PCV-targeted serotypes were obtained from children visiting an emergency department in southern Israel and from surveys of colonization from central Israel. Data on IPD in adults were obtained from a nationwide surveillance study carried out in Israel. We compared the trajectory of decline of IPD due to PCV-targeted serotypes in adults with the decline of colonization prevalence and increase in vaccine-derived protection against pneumococcal carriage among different age groupings of children. The declines in IPD in adults were most closely associated with the declines in colonization and increased vaccination coverage among children in the age range of 36-59 months. This suggests that preschool-aged children, rather than infants, are responsible for maintaining the indirect benefits of PCVs.

Effectiveness of 7- and 13-Valent Pneumococcal Conjugate Vaccines in a Schedule Without a Booster Dose: A 10-Year Observational Study.

Background: Unique among high-income countries, Australia has used a 3 + 0 schedule (3 primary doses, no booster) for infant pneumococcal conjugate vaccine (PCV) since January 2005, initially 7 valent (PCV7) then 13 valent (PCV13) from July 2011. We measured vaccine effectiveness (VE) of both PCVs against invasive pneumococcal disease (IPD) using 2 methods. Methods: Cases were IPD notifications to the national surveillance system of children eligible for respective PCVs. For case-control method, up to 10 age-matched controls were derived from the Australian Childhood Immunisation Register. For indirect cohort method, controls were IPD cases due to serotypes not in PCVs. VE was calculated as (1 - odds ratio [OR]) × 100 by logistic regression. VE waning was estimated as odds of vaccine type (VT) IPD in consecutive 12-month periods post-dose 3. Results: Between 2005 and 2014, there were 1209 and 308 IPD cases in PCV7-eligible and PCV13-eligible cohorts, respectively. Both methods gave comparable VE estimates. In infants, VE for 3 doses against VT IPD was 92.9% (95% confidence interval [CI], 27.7% to 99.3%) for PCV7 and 86.5% (95% CI, 11.7% to 97.9%) for PCV13. From 12 months post-dose 3, the odds of VT IPD by 24-36 months increased significantly for PCV7 (5.6, 95% CI, 1.2-25.4) and PCV13 (5.9, 95% CI, 1.0-35.2). Conclusions: For both PCVs in a 3 + 0 schedule, despite similar VE, progressive increase in breakthrough cases only occurred post-PCV13. This supports the importance of a booster dose of PCV13 in the second year of life to maintain protection.

Trends in Invasive Pneumococcal Disease in Cancer Patients After the Introduction of 7-valent Pneumococcal Conjugate Vaccine: A 20-year Longitudinal Study at a Major Urban Cancer Center.

Background: Rates of invasive pneumococcal disease (IPD) declined since routine childhood immunization with the 7-valent pneumococcal conjugate vaccine (PCV7) in 2000. We studied the impact of PCV7 on the incidence of IPD in cancer patients. Methods: This was a retrospective analysis of adult and pediatric patients treated at Memorial Sloan Kettering Cancer Center from 1992 to 2012. Recovery of Streptococcus pneumoniae from a sterile site defined IPD. IPD incidence was calculated as cases per 1,000 unique patient-visits per year (UPV). IPD incidence was calculated for the periods: "before PCV7" (1992-2000), "after PCV7" (2001-2010) and "after PCV13" (2011-2012). Results: Of 343 IPD cases, 165, 155, and 23 cases occurred "before PCV7," "after PCV7" and "after PCV13" respectively. The IPD incidence declined from 0.43 "before PCV7" to 0.17 "after PCV7" (95% confidence interval [CI]: 0.33-0.46, P < .001) and 0.11 "after PCV13" (95% CI: 0.42-0.96, P = .004). Adults with hematologic malignancies and children had the highest incidence. In patients 1-4 years old, the incidence declined from 11.2 "before PCV7" to 2.38 "after PCV7" (79% decrease, 95% CI: 0.1-0.4, P < .001). In patients with hematologic malignancies, the incidence declined from 2.55 "before PCV7" to 0.92 "after PCV7" (64% decrease, 95% CI: 0.27-0.47, P < .001). Conclusions: The incidence of IPD among cancer patients sharply declined after introduction of PCV7; especially in high risk groups. The decline in adults suggests an indirect effect from PCV7 childhood vaccination.

Laboratory surveillance of antimicrobial resistance and multidrug resistance among Streptococcus pneumoniae isolated in the Kinki region of Japan, 2001-2015.

The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced among children in Japan in 2010. There are no long-term multicenter surveillance studies of antimicrobial resistance in S. pneumoniae before and after the introduction of PCV7. Therefore, we examined chronological trends in antimicrobial resistance among 4534 strains of S. pneumoniae isolated from both children and adults in the Kinki region of Japan during 2001-2015. High-level penicillin and third-generation cephalosporin resistance in S. pneumoniae increased among both children and adults during the period before the introduction of PCV7 (2001-2010). Besides penicillin and cephalosporin, pneumococcal carbapenem and macrolide resistance increased among children. The rate of resistance to these antibiotics was higher among children than among adults. The introduction of PCV7 decreased the rate of non-susceptibility to ß-lactam antibiotics and the rate of multidrug resistant S. pneumoniae among children, but not among adults.

Long-term Impact of a "3 + 0" Schedule for 7- and 13-Valent Pneumococcal Conjugate Vaccines on Invasive Pneumococcal Disease in Australia, 2002-2014.

BACKGROUND: Australia introduced universal 7-valent pneumococcal conjugate vaccine (PCV7) from 2005, replaced by 13-valent PCV (PCV13) in 2011, uniquely among high-income countries giving doses at 2, 4, and 6 months (3 + 0 schedule). Data on impact of a timely 3 + 0 PCV schedule with high coverage are sparse, with none for PCV13. METHODS: We used national surveillance of invasive pneumococcal disease (IPD) from 2002 for baseline and appropriate later comparison periods to calculate incidence rate ratios (IRRs) by serotype and age using a Poisson model. PCV coverage was assessed from the Australian Childhood Immunisation Register. RESULTS: After 9 years of timely 3-dose PCV coverage of >92%, all-age IPD in Australia almost halved (IRR, 0.53; 95% confidence interval [CI], .50-.57), but differed by PCV era. Reductions in IPD due to vaccine serotypes from PCV7 (IRR, 0.20; CI, .17-.22) were about 2-fold greater than for IPD due to extra serotypes in PCV13 (13v-non7v) in a similar period (IRR, 0.58; CI, .51-.66). Post-PCV13 declines in serotype 19A IPD in persons aged <2 years (IRR, 0.23; CI, .13-.35) and ≥2 years (IRR, 0.35; CI, .28-.44) differed from other 13v-non7v IPD (IRR, 0.73; CI, .35-1.48 for those aged <2 years and IRR, 0.96; CI, .81-1.15 for those ≥2 years). Meningitis due to vaccine serotypes nearly disappeared in children eligible for 3 PCV13 doses. IPD due to non-PCV13 serotypes increased by 30% compared with 76% for non-PCV7 serotypes in equivalent period of vaccine use. CONCLUSIONS: Reductions in vaccine-type IPD post-PCV13 were inferior to Australian experience with PCV7 and reports from high-income countries giving a PCV booster dose. Applicability of findings to other settings would depend on age of IPD onset, serotype profile, and timeliness of vaccination.

Pan-serotype Reduction in Progression of Streptococcus pneumoniae to Otitis Media After Rollout of Pneumococcal Conjugate Vaccines.

BACKGROUND: Reductions in otitis media (OM) burden following rollout of pneumococcal conjugate vaccines (PCVs) have exceeded predictions of vaccine impact. In settings with active surveillance, reductions in OM caused by vaccine-targeted pneumococcal serotypes have co-occurred with reductions in OM caused by other pathogens carried in the upper-respiratory tract of children. To understand these changes, we investigated the progression of vaccine-targeted and non-vaccine pneumococcal serotypes from carriage to OM before and after vaccine rollout. METHODS: Nasopharyngeal carriage prevalence of pneumococcus was monitored in prospective studies of Bedouin and Jewish children <3 years old in southern Israel between 2004 and 2016. Incidence of OM necessitating middle-ear fluid culture (predominantly complex OM including recurrent, spontaneously-draining, non-responsive, and chronic cases) was monitored via prospective, population-based active surveillance. We estimated rates of pneumococcal serotype-specific progression from carriage to disease before and after rollout of PCV7/13, measured as OM incidence per carrier. We pooled serotype-specific estimates using Bayesian random-effects models. RESULTS: On average, rates of progression declined 92% (95% credible interval: 79-97%) and 80% (46-93%) for PCV7/13 serotypes among Bedouin and Jewish children <12 months old, respectively, and 32% (-58-71%) and 61% (-5-86%) among children aged 12-35m. For non-vaccine serotypes, rates of progression among Bedouin and Jewish children aged <12m declined 74% (55-85%) and 43% (4-68%), respectively. CONCLUSIONS: Vaccine-targeted and non-vaccine pneumococcal serotypes showed lower rates of progression to complex OM after rollout of PCV7/13. Early-life OM episodes historically associated with vaccine-serotype pneumococci may impact the susceptibility of children to OM progression.

Imputing the Direct and Indirect Effectiveness of Childhood Pneumococcal Conjugate Vaccine Against Invasive Pneumococcal Disease by Surveying Temporal Changes in Nasopharyngeal Pneumococcal Colonization.

The limited capability in most low- to middle-income countries to study the benefit of pneumococcal conjugate vaccine (PCV) in protecting against invasive pneumococcal disease (IPD) calls for alternate strategies to assess this. We used a mathematical model to predict the direct and indirect effectiveness of PCV by analyzing serotype-specific colonization prevalence and IPD incidence prior to and following childhood PCV immunization in South Africa. We analyzed IPD incidence from 2005 to 2012 and colonization studies undertaken in human immunodeficiency virus (HIV)-uninfected and HIV-infected child-mother dyads from 2007 to 2009 (pre-PCV era), in 2010 (7-valent PCV era), and in 2012 (13-valent PCV era). We compared the model-predicted changes in IPD incidence with observed changes in IPD incidence, according to HIV status, in children aged 3 months-5 years and in women aged 18-45 years. We observed reductions in vaccine-serotype colonization and IPD due to vaccine serotypes among children and women after PCV introduction. Using the changes in vaccine-serotype colonization data, the model-predicted changes in vaccine-serotype IPD incidence rates were similar to the observed changes in PCV-unvaccinated children and adults, but not among children under age 24 months. Surveillance of colonization prior to and following PCV use can be used to impute the indirect protection afforded by PCV in unvaccinated age groups, including those in high-HIV-prevalence settings.

Changes in the pneumococcal disease-related hospitalisations in Spain after the replacement of 7-valent by 13-valent conjugate vaccine.

In Spain, anti-pneumococcal vaccination is recommended for all children under 2 years old, high-risk groups and adults ≥65 years old. However, it is not funded in most autonomous communities. This study aims to compare pneumococcal disease hospitalisation rates between Period 1 (2007-2009), when 7-valent (PCV7) vaccine was available, and Period 2 (2011-2013), after the change to 13-valent (PCV13) vaccine in Spain. Data on hospitalisations were obtained from the National Registry of Hospitalisations. We calculated hospitalisation rates (HRs) and hospitalisation rate ratios (HRRs) among periods by age group and autonomous community, for all and by clinical presentation. From 138,361 patients hospitalised, 83,528 (60.4 %) were males. The median age was 73.8 years. The most common clinical presentation was pneumonia (133,204 hospitalisations; 96.3 %), followed by septicaemia (7053 hospitalisations; 5.1 %) and meningitis (3182 hospitalisations; 2.3 %). In Period 2, hospitalisations among children <5 years old decreased for pneumonia [HRR: 0.37; 95 % confidence interval (95 % CI): 0.35 to 0.39] and meningitis (HRR: 0.53; 95 % CI: 0.44 to 0.65). For adults ≥65 years old, pneumonia (HRR: 0.49; 95 % CI: 0.49 to 0.50) and peritonitis (HRR: 0.34; 95 % CI: 0.19 to 0.63) hospitalisations decreased and septicaemia hospitalisations (HRR: 1.27; 95 % CI: 1.18 to 1.36) increased. Significant changes in HRs for pneumococcal disease were observed even without an integrated and continuous vaccination programme after the introduction of PCV13, especially in children <5 years old and for pneumonia. The impact of the PCV13 adult vaccination new recommendations on the septicaemia increase reported should be evaluated in the future.

How valid are IMS DA summary statistics of children's vaccination status?

PURPOSE: Accurate recording of immunization status is essential for the evaluation of any immunization programme. In September 2006, 7-valent pneumococcal conjugate vaccination (PCV7) was introduced into the UK's routine childhood immunization programme. This study validated the PCV7 immunization status of children aged 2 years recorded in the IMS Disease Analyses (DA) database. METHODS: The PCV7 vaccination uptake rate for children born in 2008 in the IMS DA database was calculated. A sample of 173 of the 2497 children not recorded as vaccinated was identified, and a questionnaire was sent to each of their general practitioners to ascertain the child's true PCV7 vaccination status. RESULTS: In the IMS DA data of 15 237 children born in 2008, 12 740 (83.6%) had a vaccination record of PCV7. One-hundred and eleven of the 167 questionnaires sent to the child's general practitioners were returned, giving an adjusted response rate of 111/167 (66.5%). Based on the general practitioners' responses, 71 (64%) of these children were fully vaccinated according to their general practitioner's records making the revised estimated vaccination rate for this cohort 94.1% CONCLUSION: This validation study has shown that caution is needed if using historical IMS patient-level data to analyse the effectiveness of PCV7 as there is a potential under-recording of immunization leading to under representation of vaccination rates by approximately 10%. Copyright © 2016 John Wiley & Sons, Ltd.

An infant with concurrent serotype 6C invasive pneumococcal disease and infectious mononucleosis.

Streptococcus pneumoniae is a main causative agent of serious invasive bacterial infections. However, concurrent infection with invasive pneumococcal disease (IPD) and viral infectious mononucleosis (IM) is rare. We report an infant with serotype 6C infection causing IPD occurring simultaneously with IM. A previously healthy 11-month-old girl referred to our hospital because of fever, leukopenia, and elevated C-reactive protein presented to us with disturbance of consciousness, tachycardia, tachypnea and agranulocytosis. Other findings included tonsillitis with purulent exudates and white spots, bilateral cervical adenopathy, and hepatosplenomegaly. We diagnosed her illness as sepsis and administered a broad-spectrum antibiotic, an antiviral agent, and granulocyte transfusions. After treatment was initiated, fever gradually decreased and general condition improved. IPD was diagnosed based upon isolation of S. pneumoniae of serotype 6C from blood cultures obtained on admission. Concurrently the girl had IM, based upon quantitation of Epstein-Barr viral DNA copies in blood and fluctuating serum antibody titers. Although simultaneous IPD and IM is a rare occurrence, this possibility is important to keep in mind.

Sex differences in invasive pneumococcal disease and the impact of pneumococcal conjugate vaccination in the Netherlands, 2004 to 2015.

Implementation of pneumococcal conjugate vaccines in the Netherlands (PCV7 in 2006 and PCV10 in 2011) for infants caused a shift in serotypes in invasive pneumococcal disease (IPD). We explored sex differences in serotype-specific IPD incidence before and after vaccine introduction. Incidences in the pre-PCV7 (June 2004-May 2006), post-PCV7 (June 2008-May 2011) and post-PCV10 period (June 2013-May 2015), stratified by age, were compared. Incidence was higher in men for all age groups (overall in men: 16.7, 15.5 and 14.4/100,000 and women: 15.4, 13.6 and 13.9/100,000 pre-PCV7, post-PCV7 and post-PCV10, respectively), except for 20-39 year-olds after PCV7 and 40-64 year-olds after PCV10 introduction. After PCV7 and PCV10 introduction, the overall IPD incidence decreased in men aged 20-39 years (from 5.3 pre-PCV7 to 4.7 and 2.6/100,000 post-PCV7 and post-PCV10, respectively), whereas it showed a temporary increase in women (from 3.9/100,000 pre-PCV7 to 5.0/100,000 post-PCV7 and back to 4.0/100,000 post-PCV10) due to replacement disease. PCV10 herd effects were observed throughout, but in women older than 40 years, a significant increase in non-PCV10 serotype offset a decrease in overall IPD incidence. Ongoing surveillance of IPD incidence by sex is important to evaluate the long-term effects of PCV implementation.

No long-term evidence of hyporesponsiveness after use of pneumococcal conjugate vaccine in children previously immunized with pneumococcal polysaccharide vaccine.

BACKGROUND: A randomized controlled trial in Fiji examined the immunogenicity and effect on nasopharyngeal carriage after 0, 1, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) in infancy followed by 23-valent pneumococcal polysaccharide vaccine (23vPPV; Pneumovax) at 12 months of age. At 18 months of age, children given 23vPPV exhibited immune hyporesponsiveness to a micro-23vPPV (20%) challenge dose in terms of serotype-specific IgG and opsonophagocytosis, while 23vPPV had no effect on vaccine-type carriage. OBJECTIVE: This follow-up study examined the long-term effect of the 12-month 23vPPV dose by evaluating the immune response to 13-valent pneumococcal conjugate vaccine (PCV13) administration 4 to 5 years later. METHODS: Blood samples from 194 children (now 5-7 years old) were taken before and 28 days after PCV13 booster immunization. Nasopharyngeal swabs were taken before PCV13 immunization. We measured levels of serotype-specific IgG to all 13 vaccine serotypes, opsonophagocytosis for 8 vaccine serotypes, and memory B-cell responses for 18 serotypes before and after PCV13 immunization. RESULTS: Paired samples were obtained from 185 children. There were no significant differences in the serotype-specific IgG, opsonophagocytosis, or memory B-cell response at either time point between children who did or did not receive 23vPPV at 12 months of age. Nasopharyngeal carriage of PCV7 and 23vPPV serotypes was similar among the groups. Priming with 1, 2, or 3 PCV7 doses during infancy did not affect serotype-specific immunity or carriage. CONCLUSION: Immune hyporesponsiveness induced by 23vPPV in toddlers does not appear to be sustained among preschool children in this context and does not affect the pneumococcal carriage rate in this age group.

Pneumococcal Conjugate Vaccine and Pneumonia Prevention in Children with Congenital Heart Disease.

BACKGROUND: A successful strategy to prevent Streptococcus pneumoniae infections is the administration of pneumococcal conjugate vaccines (PCVs). OBJECTIVE: To analyze the effectiveness of the 7- and 13-valent PCV for the prevention of all-cause pneumonia. MATERIALS AND METHODS: A retrospective cohort of children younger than 5 years of age, with congenital heart disease (CHD) and different vaccination schedules, was analyzed. History of vaccination was confirmed with verifiable records. The outcome measure was all-cause pneumonia or bronchopneumonia. Protocol was approved by the Institutional Review Board. For comparisons, we used inferential statistics with Chi-square and Fisher's exact test; a p ≤ 0.5 was considered statistically significant. Relative and absolute risks reduction and number needed to treat were also calculated. RESULTS: A total of 348 patients were included: 196 with two or more doses of PCV (considered the vaccinated group), and 152 in the unvaccinated group. There was a statistically significant difference for pneumonia events (p < 0.001) between the vaccinated (26/196) and unvaccinated (51/152) groups. The relative risk reduction was 60.5%, and the absolute risk reduction, 20.3%. There were no differences between patients who received two, three or four doses. The number needed to vaccinate to prevent one event of pneumonia was 5 children. CONCLUSIONS: At least two doses of PCV in children with CHD reduced the risk of all-cause pneumonia.