Invasive pneumococcal pneumonia caused by 13-valent pneumococcal conjugate vaccine types in children with different schedules

Background

In Taiwan, the age group with the greatest incidence of invasive pneumococcal disease is 2–5 years of age, which is different from other countries. This study was conducted to identify risk factors and different 13-valent pneumococcal conjugate vaccine (PCV13) schedules associated with vaccine-type invasive pneumococcal pneumonia (IPP) despite prior vaccination.

Changes in serotypes causing invasive pneumococcal disease (2005–2007 vs. 1997–1999) in children under 2 years of age in a population with intermediate coverage of the 7-valent pneumococcal conjugated vaccine

Serotypes causing invasive pneumococcal disease (IPD) in children aged <2 years in Catalonia (Spain) before and after licensing of the 7-valent pneumococcal conjugated vaccine (7vPCV) were assessed, using samples taken during 1997–1999 and 2005–2007 respectively. The distribution of serotypes causing IPD within these groups was obtained by serotyping strains sent by 22 Catalan hospitals to the Carlos III Health Institute, Madrid. Between 1997–99 and 2005–2007, the proportion of vaccine serotypes causing IPD in Catalonia fell from 70.54% to 31.67% (p <0.0001). The proportion of vaccine-related serotypes, mainly serotype 19A, increased from 9.82% to 32.50% (p <0.0001). The proportion of non-vaccine, non-related serotypes (serotypes not related to vaccine serotypes) rose from 19.64% to 35.83% (p <0.05). Within this group, the proportions of serotype 24F increased significantly. There has been a change in the distribution of serotypes isolated from cases of IPD in children <2 years old in Catalonia, comprising a reduction in the proportion of 7-valent vaccine serotypes, a rise in vaccine-related serotypes, especially 19A, and a smaller rise in non-vaccine, non-related serotypes, especially serotype 24F. A new 13-valent vaccine will cover 77.91% of the serotypes causing IPD in children <2 years old in Catalonia from 2005 to 2007.     

Routine infant immunization with the 7- and 13-valent pneumococcal conjugate vaccines: current perspective on reduced-dosage regimens

The 7 and 13-valent pneumococcal conjugate vaccines are mostly used in routine infant immunizations to prevent the development of pneumococcal disease. Currently, the dosing schedule approved and recommended for PCV7 and PCV13 in infants is 3 primary doses followed by a booster dose in the second year of life. However, a number of countries use a 2-dose only primary series with a booster dose in the second year of life. This review is aimed at providing the reader with a broad perspective on the currently available evidence which supports the clinical use of such reduced dosing schedules for the PCV7 and PCV13 vaccines. Recent evidence has been able to promulgate the immunogenicity and in some cases the effectiveness of the reduced dosing schedule for these vaccines. These findings may reduce costs as well as minimize supply and administration problems relating to the provision of the pneumococcal conjugated vaccines (PCVs). However, some caution is warranted since some inferior data have emerged with regards to the antibody immune response to certain pneumococcal serotypes following the implementation of such reduced dosing regimens. In addition, it is proposed that prospective surveillance be undertaken in all countries which have adopted the reduced-dosage immunization programs. This review may go some way in educating healthcare practitioners and healthcare policy decision makers at large.     

The impact of 13-valent pneumococcal conjugate vaccination on virus-associated community-acquired pneumonia in elderly: Exploratory analysis of the CAPiTA trial

ObjectivesOur objective was to evaluate whether vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) prevents the incidence of community-acquired pneumonia (CAP) caused by influenza (influenza-associated CAP, IA-CAP) or other respiratory viruses in the elderly.MethodsThis analysis was part of the Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA); a double blind, randomized, placebo-controlled trial in 84 496 immunocompetent individuals aged ≥65 years. CAP was defined by clinical and radiological criteria, and oropharyngeal swabs were collected from all individuals referred to a sentinel centre with a clinical suspicion of pneumonia. Presence of influenza A and B, parainfluenza 1, 2, 3 and 4, human adeno-, boca-, corona-, metapneumo-, rhino- and respiratory syncytial viruses was determined by real-time PCR.ResultsOf 3209 episodes of suspected pneumonia, viral aetiology was tested in 2917 and proportions with influenza virus, human metapneumovirus and respiratory syncytial virus were 4.6%, 2.5% and 3.1%, respectively. There were 1653 oropharyngeal swabs for PCR testing available from 1814 episodes that fulfilled criteria for CAP, yielding 23 first episodes of IA-CAP in the PCV13 and 35 in the in placebo group—vaccine efficacy for IA-CAP of 34.4% (95% CI –11.1% to 61.2%; p 0.117). Annual influenza vaccination was received by 672 (87.2%) in the PCV13 group and 719 (87.7%) in the placebo group of the confirmed CAP cases.ConclusionIn a randomized study of 84 496 elderly individuals with a high uptake of influenza vaccination, PCV13 was not associated with a statistically significant reduction of influenza or virus-associated CAP. Overall incidence of non-influenza viral pneumonia was low.     

Changing epidemiology of invasive pneumococcal disease following increased coverage with the heptavalent conjugate vaccine in Navarre, Spain

The present study evaluated changes in the incidence of invasive pneumococcal disease (IPD) and the pattern of serotypes isolated in Navarre, Spain, after the introduction and increased coverage of the heptavalent pneumococcal conjugate vaccine (PCV7). All cases with isolation of pneumococcus from normally sterile bodily fluids were included. The incidence of IPD in children and adults was compared for the periods 2001–2002 and 2006–2007. By the end of 2002, only 11% of children aged <5 years had received any dose of PCV7, whereas, beginning in 2007, the proportion exceeded 50%. Among the cases of IPD aged <5 years, the percentage of those vaccinated increased from 7% during 2001–2002 to 53% during 2006–2007 (p <0.001). The incidence of IPD from PCV7-serotypes decreased by 85% in children <5 years (p <0.001), by 45% in the population aged 5–64 years (p 0.10) and by 68% in those ≥65 years (p 0.004). By contrast, the incidence of IPD from non-PCV7 serotypes increased by 40% overall (p 0.006). The incidence of IPD from all serotypes did not change significantly in children <5 years (from 83 to 72 per 100 000) or in the total population (from 15.8 to 16.3 per 100 000). The percentage of cases as a result of serotypes 7 and 19A increased significantly in both children and adults. No significant changes were seen in the clinical forms of IPD. The pattern of serotypes causing IPD has changed, in both children and adults, following the increased coverage of PCV7, although the incidence has been reduced only slightly.     

Impact of the emergence of non-vaccine pneumococcal serotypes on the clinical presentation and outcome of adults with invasive pneumococcal pneumonia

The introduction of the 7-valent pneumococcal conjugate vaccine in children has led to a change in the pattern of pneumococcal serotypes causing pneumococcal disease. The aim of this study was to compare the clinical presentation and outcome of invasive pneumococcal pneumonia (IPP) in adults between the pre and post-vaccine era. We have conducted an observational study of all adults hospitalized with IPP, from 1996 to 2001 (pre-vaccine period), and from 2005 to 2009 (post-vaccine period). Incidence, serotype distribution and clinical data were compared between both periods. A total of 653 episodes of IPP were diagnosed. The overall incidence of IPP increased from 14.2 to 17.9 cases per 100 000 population-year (p 0.003). In the post-vaccine period IPP caused by vaccine serotypes decreased (–36%; 95% CI, –52 to –15) while IPP caused by non-vaccine serotypes increased (71%; 95% CI, 41–106). IPP in the post-vaccine period was associated with higher rates of septic shock (19.1% vs. 31.1%, p <0.001). Among patients aged 50–65 years there was a trend towards a greater proportion of case-fatalities (11.6–23.5%, p 0.087). Independent risk factors for septic shock were IPP caused by serotype 3 (OR 2.38; 95% CI, 1.16–4.87) and serotype 19A (OR 6.47, 95% CI, 1.55–27). Serotype 1 was associated with a lower risk of death (OR 0.1; 95% CI, 0.01–0.78). In conclusion, the incidence of IPP in the post-vaccine period has increased in our setting, it is caused mainly by non-vaccine serotypes and it is associated with higher rates of septic shock.     

Experience with pneumococcal polysaccharide conjugate vaccine (conjugated to CRM197 carrier protein) in children and adults

Streptococcus pneumoniae-related infections are a major cause of morbidity and mortality in people of all ages worldwide. Pneumococcal vaccine development started in 1911 with a whole cell vaccine and more recently multivalent plain polysaccharide and polysaccharide conjugate vaccines have been developed. The recent vaccines rely on capsular polysaccharide antigens to induce serotype-specific immune responses. We summarize here the presentations on pneumococcal polysaccharide conjugate vaccine (conjugated to CRM197 carrier protein) given during the integrated symposium organized and funded by Pfizer International Operations during the 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 31 March to 3 April 2012, London, UK. A dramatic reduction in the incidence of invasive pneumococcal diseases (IPD) due to vaccine serotypes (VST-IPD) has been reported since the introduction of a hepta-valent pneumococcal conjugate vaccine (PCV7). An indirect (herd) effect has been demonstrated to be associated with PCV7 infant vaccination programmes, with many studies reporting reductions in VST-IPD in populations that are not eligible for PCV7 vaccination. Since 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) has been introduced into national immunization programmes and results from early surveillance suggest that this vaccine also has an impact on the serotypes unique to PCV13, as well as continuing to protect against the PCV7 serotypes. Data from a passive surveillance system in Europe in 2009, for instance, showed that the highest incidence of IPD remains in those aged >65 years and in children <5 years. PCV13 has now been licensed for vaccination of adults >50 years based on safety and immunogenicity data; an efficacy trial is being conducted. Regardless of previous pneumococcal vaccination status, if the use of 23-valent polysaccharide is considered appropriate, it is recommended to give PCV13 first. Novel immunization strategies remain the only practical means to reduce significantly the remaining global mortality and morbidity due to S. pneumoniae in adults.     

Invasive pneumococcal disease among children in a health district of Barcelona: early impact of pneumococcal conjugate vaccine

This study evaluated the impact of heptavalent pneumococcal conjugate vaccine (HPCV) on invasive pneumococcal disease (IPD) in children aged < or = 5 years in Barcelona, Spain. The incidence of IPD, vaccine uptake and prevalence of nasopharyngeal colonisation were analysed in two different periods: 1999-2001 (pre-licence period), and 2002-2004 (post-licence period). In total, 121 cases of IPD were identified. The overall incidence of IPD decreased from 96.9 cases/100,000 to 90.6 cases/100,000 (OR 0.93, 95% CI 0.69-1.26, p 0.71) between the two periods. The proportion of cases caused by non-vaccine-related serotypes (NVS) increased from 21% to 43.7% (OR 2.9, 95% CI 1.2-7, p 0.01). IPD was diagnosed in seven vaccinated children, six of whom were infected by NVS. There was a trend of diminishing prevalence of resistance to penicillin and macrolides in 2002-2004. The incidence of empyema increased from 1.7 to 8.5/100,000 (OR 4.5, 95% CI 0.91-18, p 0.06). The rate of vaccination ranged from 4.8% to 34%. It was concluded that the rates of IPD in this area did not decrease following the introduction of HPCV. The low uptake of vaccine and the greater proportion of colonisation/infection by NVS probably explain these findings. A trend of increasing empyema was also apparent. A decrease in the prevalence of penicillin and macrolide resistance paralleled the progressive uptake of vaccine.     

Development of 5-valent conjugate pneumococcal protein A – Capsular polysaccharide pneumococcal vaccine against invasive pneumococcal disease

In this study, we synthesized a 5-valent pneumococcal conjugate vaccine, which was prepared with the pneumococcal capsular polysaccharides (PCPs) (from Streptococcus pneumoniae 1, 5, 6B, 19F, 23F) and pneumococcal surface protein A (PspA) mediated by 1,4-butanediol diglycidyl ether. The PspA cloned from serotype 19 strain showed good cross-immune response to 1, 5, 6B, and 23F serotypes of Streptococcus pneumonia (S. pneumoniae). Analysis of the maturation process of conjugate polyclonal antibody showed that conjugation with the protein carrier converted the polysaccharide from a weak T cell-independent (TI) antigen to a T cell-dependent (TD) antigen, although antibodies affinity to polysaccharide was not as strong as it to PspA in conjugate. We used an invasive disease mouse model to evaluate the protective efficacy of this conjugate vaccine. Active and passive protection against intraperitoneal challenge with virulent type 6B strain showed that the median survival times for mice immunized with conjugate were significantly longer than that of mice treated with capsular polysaccharides or PspA alone. Our study's results showed that immunization of the 5-valent PspA-capsular polysaccharides conjugate vaccine could afford strong protection to mice against the invasion of 1, 5, 6B, 19F, 23F serotypes S. pneumoniae.     

Changes in Streptococcus pneumoniae serotypes causing invasive disease with non-universal vaccination coverage of the seven-valent conjugate vaccine

The pneumococcal seven-valent conjugate vaccine (PCV7) has been administered in Portugal since late 2001 through the private sector. To evaluate the impact of PCV7 use, the serotypes and antimicrobial susceptibility of pneumococci causing invasive disease in Portugal during 2003–2005 were determined and compared with available data for the period 1999–2002. Changes in serotype distribution compatible with the introduction of PCV7 were shown for children ≤5 years of age from 2003 onwards and for adults from 2004 onwards. PCV7 use with coverage of 43% of children with four doses in the 2004 birth cohort, although substantially below universal coverage, seems to have contributed to greatly reducing the proportion of invasive infections due to vaccine serotypes  4, 6B, 14 and 23F. Similarly, significant indirect effects on the serotype distribution of pneumococci causing infections in adults were noted, with reductions in the proportion of invasive infections caused by serotypes  4, 5 and 14. These changes were accompanied by an increase in the proportion of two non-vaccine serotypes: 19A isolates in all age groups and 7F isolates in adults. Whereas serotypes  6B, 14 and 19A were associated with multidrug resistance, isolates expressing serotypes  4 and 7F were fully susceptible for the most part. There were no changes in the proportion of resistant isolates within each serotype and, in spite of the changes in serotype prevalence, there was not an overall reduction in the proportion of infections caused by resistant pneumococci.     

Post-marketing effectiveness of Prevnar [pneumococcal 7-valent conjugate vaccine (diphtheria CRM197 protein)] and implications for adult immunization

Pneumococcal pneumonia is a significant health concern for pediatric, healthy adult, and elderly populations. The newly licensed pneumococcal 7-valent conjugate (diphtheria CRM197 protein) vaccine, Prevnar, and a second generation experimental 9-valent product have demonstrated, for the first time, a clear and significant impact on pneumococcal pneumonia in children. The potential for saccharide-conjugate vaccines to help prevent pneumococcal pneumonia in adult and elderly populations and potential barriers to the introduction of a conjugate vaccine in adults are discussed.     

Invasive pneumococcal disease caused by ceftriaxone-resistant Streptococcus pneumoniae in Taiwan

Background

Invasive pneumococcal disease (IPD) was associated with mortality, but the risk factors associated with mortality remains controversial.

High invasiveness of pneumococcal serotypes included in the new generation of conjugate vaccines

The implementation of the seven-valent pneumococcal conjugate vaccine, PCV7, has resulted in significant changes in the pneumococcal population being carried and causing disease. We aimed to determine the invasive disease potential of serotypes causing invasive paediatric disease in the era of conjugate vaccines in Catalonia, Spain, and their potential coverage by the 13-valent pneumococcal conjugate vaccine, PCV13. As a secondary objective, we evaluated whether implementation of PCV7 had resulted in significant changes in the invasive disease potential of the most frequent serotypes circulating in the area. Two pneumococcal collections obtained from children admitted to the University Hospital Sant Joan de Déu (Barcelona, Spain) between 2007 and 2011 were compared: a first set of 159 invasive disease isolates, and a second set of 209 nasopharyngeal isolates recovered from healthy children admitted for minor surgery. The most common invasive serotypes were 1 (24.5%, n = 39), 19A (21.2%, n = 34), 5 (8.8%, n = 14), 7F (8.8%, n = 14) and 3 (5%, n = 8). The most common serotypes in carriage were 19A (10%, n = 21), 6C (9%, n = 19), 23B (8.1%, n = 17), 6A (7.6%, n = 16) and 19F (6.2%, n = 13). A significantly higher propensity to cause invasive disease was observed for serotypes 1, 3, 5, 7F and 19A, all of which are included in PCV13. After false-discovery-rate correction, the results were robust for serotypes 1, 5, 7F and 19A. Non-PCV13 serotypes had a low invasive disease potential. Our data reinforce the need for continuous surveillance and should encourage efforts to introduce universal vaccination with PCV13 in children in our region.     

Comparison of secular trends in pneumococcal serotypes causing invasive disease in Denver, Colorado (1971–2004) and serotype coverage by marketed pneumococcal vaccines

Invasive pneumococcal isolates from three hospitals in Denver, CO, USA were serotyped between 1971 and 2004. Serotype 14 was most common (13.2%), and other prevalent serotypes (3, 4, 6, 9 and 19) together accounted for 44.1% of the isolates. All prevalent serotypes and 91.3% of the total isolates were covered by pneumococcal polysaccharide vaccine, while 79.1% of prevalent serotypes and 56.7% of total isolates were covered by pneumococcal conjugate vaccine. Serotypes 6, 9 and 14 were more common in the final decade than in the first decade studied (37.3% vs. 20.2%), whereas serotypes 3 and 23 were more common in the first decade (18.5% vs. 11.0%).     

Impact of pneumococcal conjugate vaccine in children on the serotypic epidemiology of adult invasive pneumococcal diseases in Taiwan

Background

Invasive pneumococcal disease (IPD) causes significant morbidity and mortality, especially in children and older adults. Pneumococcal 7-valent and 13-valent conjugate vaccines (PCV7 and PCV13) were introduced in Taiwan in 2005 and 2011, respectively, for children. This study was conducted to evaluate the impact of PCV administered in children on adult IPD.

Evaluation and Optimization of an ELISA Procedure to Quantify Antibodies Against Pneumococcal Polysaccharides Included in the 13-Valent Conjugate Vaccine

The 13-valent pneumococcal conjugate vaccine (PCV-13) is recommended for HIV-infected people, although its effectiveness in this population remains under evaluation. In this study, we describe the development, optimization, and analytical validation of an ELISA procedure to measure specific antibodies for the pneumococcal polysaccharide serotypes included in PCV13 vaccine, testing sera obtained from HIV-infected outpatients (n = 30) who received the vaccine. The protocol followed the last version of WHO guidelines, based on the new standard 007sp, with the modification of employing Statens Serum Institut (SSI) antigens.

We supplied the assay performance validation in terms of sensitivity, reproducibility, precision and accuracy. In addition we detailed optimal antigen-coating concentrations and ELISA conditions common to all 13 serotypes, suitable for laboratories performing these assays in order to standardize the method. Our procedure showed reproducibility and reliability, making it a valid alternative for evaluating the response to pneumococcal serotypes included in PCV13 vaccine.     

Dynamic transmission models and economic evaluations of pneumococcal conjugate vaccines: a quality appraisal and limitations

BackgroundOf over 90 serotypes of Streptococcus pneumoniae, only seven were included in the first pneumococcal conjugate vaccine (PCV). While PCV reduced the disease incidence, in part because of a herd immunity effect, a replacement effect was observed whereby disease was increasingly caused by serotypes not included in the vaccine. Dynamic transmission models can account for these effects to describe post-vaccination scenarios, whereas economic evaluations can enable decision-makers to compare vaccines of increasing valency for implementation.AimThe aim of this review was to examine epidemiological and economic models and their assumptions for their potential contributions to future research and immunisation policy.SourcesPubmed, Scopus, Ovid, ISI Web of Knowledge, Centre of Reviews and Dissemination (CRD) databases were searched.ContentTwenty-three dynamic transmission models and 21 economic models were retrieved and reviewed. Published models employed various templates, revealing several key uncertainties regarding the biology and epidemiology of pneumococcal infection. While models suggested that PCVs will reduce the burden of disease, the extent to which they are predicted to do so depended on various assumptions regarding features of pneumococcal infection and epidemiology that governed PCV cost-effectiveness as well. Such features include the duration of protection and competitive interactions between serotypes, which are unclear at present, but which directly relate to herd immunity and serotype replacement.ImplicationsEconomic evaluations are not typically based on transmission dynamic models and hence omit indirect herd immunity effects. The two tools could be used in conjunction to inform decision-makers on vaccine implementation, but so far there have been few attempts to build economic evaluations on transmission dynamic models, and none in this field. Future directions for research could include studies to evaluate key parameters for the models involving herd immunity, serotype competition and the natural history of infection.     

The role of ZmpC in the clinical manifestation of invasive pneumococcal disease

IntroductionThe clinical severity and course of invasive pneumococcal disease (IPD) differs substantially between patients. Streptococcus pneumoniae harbors large genetic variability. Zinc metalloproteinase C (ZmpC), a secreted pneumococcal protein involved in neutrophil extravasation, inflammation and tissue remodeling, is present in a minority of IPD isolates. We investigated whether the presence of zmpC was associated with the clinical manifestation of IPD.Material and methodsIPD patients admitted to two Dutch hospitals between 2000 and 2013 were included in the study. Detailed clinical data were collected and the serotype and presence of zmpC were determined in the corresponding blood culture isolates.ResultsZmpC was present in 21% of the 542 included IPD cases and was mainly associated with serotypes 8, 4, 33A/F and 11A/D. Infection with S. pneumoniae positive for zmpC was more frequently observed in females (p = 0.048) and patients with a history of smoking (p = 0.033). Although no relation to clinical syndrome was observed, zmpC positive cases more often presented with cough, dyspnea and sepsis (p-values 0.026, 0.001 and 0.018), and more frequently required ICU admission (p = 0.011) compared to zmpC negative cases.ConclusionThe presence of zmpC was associated with a more severe clinical manifestation of IPD. This study demonstrates that information on pneumococcal genetic background may be useful to identify vulnerable individuals, to monitor clinical presentation and to predict the course of IPD.     

Distribution of serotypes and antibiotic resistance of invasive pneumococcal disease isolates among children aged 5 years and under in Saudi Arabia (2000–2004)

To determine vaccine coverage of invasive pneumococcal disease (IPD) in Saudi Arabian children aged 5 years and under, 350 IPD isolates were tested for antibiotic susceptibility. Of these 46%, 42% and 12% were penicillin-sensitive, pencillin-intermediate, and penicillin-resistant, respectively. Rates of resistance to erythromycin and cefotaxime were 26% and 6%, respectively. The potential serotype coverage of the PCV7 vaccine in Saudi Arabia among children <5 years of age is 62%, and vaccine coverage significantly improved in children <2 years of age, to reach 83% against IPD isolates. PCV7 is expected to have a substantial impact on the burden of invasive and antibiotic-resistant pneumococcal disease in Saudi Arabia.     

Dynamic transmission models and economic evaluations of pneumococcal conjugate vaccines: a quality appraisal and limitations

BackgroundOf over 90 serotypes of Streptococcus pneumoniae, only 7 were included in the first pneumococcal conjugate vaccine (PCV). While PCV reduced the disease incidence, in part because of a herd immunity effect, a replacement effect was observed whereby disease was increasingly caused by serotypes not included in the vaccine. Dynamic transmission models can account for these effects to describe post-vaccination scenarios, whereas economic evaluations can enable decision-makers to compare vaccines of increasing valency for implementation.ObjectiveThe aim of this review was to examine epidemiological and economic models and their assumptions for their potential contributions to future research and immunisation policy.SourcesPubmed, Scopus, Ovid, ISI Web of Knowledge, Centre of Reviews and Dissemination (CRD) databases were searched.ContentTwenty-three dynamic transmission models and twenty-one economic models were retrieved and reviewed. Published models employed various templates, revealing several key uncertainties regarding the biology and epidemiology of pneumococcal infection. While models suggested that PCVs will reduce the burden of disease, the extent to which they are predicted to do so depended on various assumptions regarding features of pneumococcal infection and epidemiology that governed PCV cost-effectiveness as well. Such features include the duration of protection and competitive interactions between serotypes, which are unclear at present, but which directly relate to herd immunity and serotype replacement.ImplicationsEconomic evaluations are not typically based on transmission dynamic models and hence omit indirect herd immunity effects. The two tools could be used in conjunction to inform decision-makers on vaccine implementation, but so far there have been few attempts to build economic evaluations on transmission dynamic models, and none in this field. Future directions for research could include studies to evaluate key parameters for the models involving herd immunity, serotype competition and the natural history of infection.