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Highlights • An effective and affordable injectable rotavirus vaccine may be attractive to LMICs. • Co-administering oral and injectable vaccines is acceptable to many stakeholders. • Oral vaccine with a birth dose is favored over a higher cost, standalone injectable. • Providing rotavirus vaccine in a DTP combination is the most preferred option., Background Currently available live, oral rotavirus vaccines (LORVs) have significantly reduced severe rotavirus hospitalizations and deaths worldwide. However, LORVs are not as effective in low- and middle-income countries (LMIC) where rotavirus disease burden is highest. Next-generation rotavirus vaccine (NGRV) candidates in development may have a greater public health impact where they are needed most. The feasibility and acceptability of possible new rotavirus vaccines were explored as part of a larger public health value proposition for injectable NGRVs in LMICs. Objective To assess national stakeholder preferences for currently available LORVs and hypothetical NGRVs and understand rationales and drivers for stated preferences. Methods Interviews were conducted with 71 national stakeholders who influence vaccine policy and national programming. Stakeholders from Ghana, Kenya, Malawi, Peru, Senegal, and Sri Lanka were interviewed using a mixed-method guide. Vaccine preferences were elicited on seven vaccine comparisons involving LORVs and hypothetical NGRVs based on information presented comparing the vaccines’ attributes. Reasons for vaccine preference were elicited in open-ended questions, and the qualitative data were analyzed on key preference drivers. Results Nearly half of the national stakeholders interviewed preferred a highly effective standalone, injectable NGRV over current LORVs. When presented as having similar efficacy to the LORV, however, very few stakeholders preferred the injectable NGRV, even at substantially lower cost. Similarly, a highly effective standalone injectable NGRV was generally not favored over an equally effective oral NGRV following a neonatal-infant schedule, despite higher cost of the neonatal option. An NGRV-DTP-containing combination vaccine was strongly preferred over all other options, whether delivered alone with efficacy similar to current LORVs or co-administered alongside an LORV (LORV + NGRV-DTP) to increase efficacy. Conclusion Results from these national stakeholder interviews provide valuable insights to inform ongoing and future NGRV research and development.

Publisher's version (útgefin grein), Background: Antimicrobial resistance is a growing global health threat. To preserve the effectiveness of antimicrobials, it is important to reduce demand for antimicrobials. Objectives: The objective of the study was to screen the existing peer-reviewed literature to identify articles that addressed the potential impact of influenza or Pneumococcus vaccination on antibiotic usage. Data sources: PubMed, Embase Study eligibility criteria: Clinical studies where antimicrobial prescribing was assessed in both vaccinated and unvaccinated populations. Participants and interventions: All patient populations were included (infants, children, adults and elderly), where the effects of the intervention (vaccination) was assessed Results: We identified unique 3638 publications, of which 26 were judged to be of sufficiently high quality to allow the calculation of the potential impact of vaccination. Of these studies 23/26 found a significant reduction in antibiotic use by at least one of the parameters assessed. Limitations: Different measures used to define anti-microbial use, studies typically focus on specific risk groups and most studies are from high-income countries. Conclusions and implications of key findings: Despite the limitations of the review, the evidence indicates that improved coverage with existing vaccines may significantly reduce antimicrobial demand. This suggests it may be a valuable tool for antimicrobial stewardship.Key messages While vaccines against a number of pathogens have been studied for their ability to reduce antimicrobial use, currently only vaccination against influenza or pneumococcus has generated sufficient data for analysis Vaccination against either influenza or pneumococcus significantly reduced overall antimicrobial prescribing rates, both in vaccinated individuals and at a population level Maintaining and expanding vaccination coverage thus appears to be a key tool for antimicrobial stewardship., GlaxoSmithKline Biologicals S.A. funded the independent assessment by Pallas and all costs related to the development of this review article, but did not provide payment to the authors.

While current live, oral rotavirus vaccines (LORVs) are reducing severe diarrhea everywhere, their effectiveness is lower in high burden settings. Alternative approaches are in advanced stages of clinical development, including injectable next-generation rotavirus vaccine (iNGRV) candidates, which have the potential to better protect children, be combined with existing routine immunizations and be more affordable than current LORVs. In an effort to better understand the real public health value of iNGRVs and to help inform decisions by international agencies, funders, and vaccine manufacturers, we conducted an impact and cost-effectiveness analysis examining 20 rotavirus vaccine use cases. We evaluated several currently licensed LORVs, one neonatal oral NGRV (oNGRV), one iNGRV, and one iNGRV-DTP (iNGRV comprising part of a DTP-containing combination) over a ten-year timeframe in 137 low- and middle-income countries. The most promising use case identified was a high efficacy iNGRV-DTP, predicted to have the lowest vaccine program cost (US$1.4 billion), the highest vaccine benefit (750,000 rotavirus deaths averted, 13 million rotavirus hospital admissions averted, US$ 2.7 billion health-care cost averted), and most favorable cost-effectiveness (cost-saving). iNGRV-DTP vaccine remained the most affordable, safe, and cost-effective option even when it was assumed to have equivalent efficacy to the current LORVs. This study shows that while the development of iNGRVs with superior efficacy to currently licensed LORVs would be ideal, iNGRVs with similar efficacy to LORVs would offer substantial public health value. It also highlights the economic value of accelerating the development of DTP-based combination vaccines that include iNGRV to provide rotavirus protection.

Background Live oral rotavirus vaccines (LORVs) have significantly reduced rotavirus hospitalizations and deaths worldwide. However, LORVs are less effective in low- and middle-income countries (LMICs). Next-generation rotavirus vaccines (NGRVs) may be more effective but require administration by injection or a neonatal oral dose, adding operational complexity. Healthcare providers (HPs) were interviewed to assess rotavirus vaccine preferences and identify delivery issues as part of an NGRV value proposition. Objective Determine HP vaccine preferences about delivering LORVs compared to injectable (iNGRV) and neonatal oral (oNGRV) NGRVs. Methods 64 HPs from Ghana, Kenya, Malawi, Peru, and Senegal were interviewed following a mixed-method guide centered on three vaccine comparisons: LORV vs. iNGRV; LORV vs. oNGRV; oNGRV vs. iNGRV. HPs reviewed attributes for each vaccine in the comparisons, then indicated and explained their preference. Additional questions elicited views about co-administering iNGRV+LORV for greater public health impact, a possible iNGRV-DTP-containing combination vaccine, and delivering neonatal doses. Results Almost all HPs preferred oral vaccine options over iNGRV, with many emphasizing an aversion to additional injections. Despite this strong preference, HPs described challenges delivering oral doses. Preferences for LORV vs. oNGRV were split, marked by disparate views on rotavirus disease epidemiology and the safety, need, and feasibility of delivering neonatal vaccines. Although overwhelmingly enthusiastic about an iNGRV-DTP-containing combination option, several HPs had concerns. HP views were divided on the feasibility of co-administering iNGRV+LORV, citing challenges around logistics and caregiver sensitization. Conclusion Our findings provide valuable insights on delivering NGRVs in routine immunization. Despite opposition to injectables, openness to co-administering LORV+iNGRV to improve efficacy suggests future HP support of iNGRV if adequately informed of its advantages. Rationales for LORV vs. oNGRV underscore needs for training on rotavirus epidemiology and stronger service integration. Expressed challenges delivering existing LORVs merit further examination and indicate need for improved delivery.

Summary Background Pneumococcal diseases are a leading cause of morbidity and mortality among children globally, and the burden of these diseases might be worsened by antimicrobial resistance. To understand the effect of pneumococcal conjugate vaccine (PCV) deployment on antimicrobial resistance in pneumococci, we assessed the susceptibility of paediatric pneumococcal isolates to various antimicrobial drugs before and after PCV implementation. Methods We did a systematic review of studies reporting antimicrobial susceptibility profiles of paediatric pneumococcal isolates between 2000 and 2020 using PubMed and the Antimicrobial Testing Leadership and Surveillance database (ATLAS; Pfizer). Population-based studies of invasive pneumococcal disease or nasopharyngeal colonisation were eligible for inclusion. As primary outcome measures, we extracted the proportions of isolates that were non-susceptible or resistant to penicillin, macrolides, sulfamethoxazole–trimethoprim, third-generation cephalosporins, and tetracycline from each study. Where available, we also extracted data on pneumococcal serotypes. We estimated changes in the proportion of isolates with reduced susceptibility or resistance to each antibiotic class using random-effects meta-regression models, adjusting for study-level and region-level heterogeneity, as well as secular trends, invasive or colonising isolate source, and countries' per-capita gross domestic product. Findings From 4910 studies screened for inclusion, we extracted data from 559 studies on 312 783 paediatric isolates. Susceptibility of isolates varied substantially across regions both before and after implementation of any PCV product. On average across all regions, we estimated significant absolute reductions in the proportions of pneumococci showing non-susceptibility to penicillin (11·5%, 95% CI 8·6–14·4), sulfamethoxazole–trimethoprim (9·7%, 4·3–15·2), and third-generation cephalosporins (7·5%, 3·1–11·9), over the 10 years after implementation of any PCV product, and absolute reductions in the proportions of pneumococci resistant to penicillin (7·3%, 5·3–9·4), sulfamethoxazole–trimethoprim (16·0%, 11·0–21·2), third-generation cephalosporins (4·5%, 0·3–8·7), macrolides (3·6%, 0·7–6·6) and tetracycline (2·0%, 0·3–3·7). We did not find evidence of changes in the proportion of isolates non-susceptible to macrolides or tetracycline after PCV implementation. Observed changes in penicillin non-susceptibility were driven, in part, by replacement of vaccine-targeted serotypes with non-vaccine serotypes that were less likely to be non-susceptible. Interpretation Implementation of PCVs has reduced the proportion of circulating pneumococci resistant to first-line antibiotic treatments for pneumonia. This effect merits consideration in assessments of vaccine impact and investments in coverage improvements. Funding Bill & Melinda Gates Foundation.

SCOPUS: re.j, info:eu-repo/semantics/published

Bronchoalveolar lavage (BAL) is widely regarded as providing "gold standard" samples for infective lower respiratory tract disease. Current approaches have been adopted empirically without robust assessment and hence carry many assumptions that have not been tested. Many of these uncertainties were highlighted in the ATS pediatric bronchoscopy guidelines. This study was designed to explore some of these issues. BAL was undertaken via an endotracheal tube in 13 subjects aged less than 6 years with persistent bacterial bronchitis and five healthy controls. Aliquots of the same pooled BAL sample were sent to two accredited laboratories. one producing semiquantitative results and the other quantitative results. For five patients potentially pathogenic bacteria were grown by one laboratory but not the other, while in three more there were discrepancies in the organisms reported. Despite being symptomatic and off antibiotics, only 3 of 13 patients were reported to have a pathogen at a density of more than 1 × 104 colony forming unit. There was at best a poor correlation between semiquantitative and quantitative data. Potential pathogens were cultured in two of five control samples. The results suggest that the results from conventional microbiological assessment of BAL samples can be highly variable and that the proposal that a discrete cut-off is of value in patients with chronic endobronchial infection is probably invalid.

Background: Estimation of the magnitude of the herd effect on invasive pneumococcal disease (IPD) is important when evaluating health benefits and cost-effectiveness of paediatric pneumococcal conjugate vaccine (PCV) programmes and may influence policy makers’ decisions on PCV use. Several epidemiological, programmatic, and immunological factors can affect the magnitude of the PCV herd effect. We investigated to what extent the choice of analytical methodology may also influence herd effect estimates. Methods: To estimate the magnitude of the herd effect from paediatric PCV programmes, we examined overall IPD incidence rates in ≥65-year-olds from Finland, Australia, England/Wales, and the United States under different analytical scenarios. We used two different statistical methods: before/after comparison of average IPD incidence rates and interrupted time series (ITS) analysis accounting for underlying time trends. We also investigated how varying the length of the pre- and post-PCV analysis periods influenced the outcomes. Results: The estimated impact of paediatric PCV programmes on IPD incidence rates in adults ≥65 years varied substantially across the different scenarios within each country. The choice of statistical method and analysis periods contributed to this variation, and their influence varied by setting. For the datasets from England/Wales and the United States, the different scenarios produced relatively minor variation in estimated impact. For the Australian and Finnish datasets, differences were more prominent. In particular, for Finland, opposite conclusions could be drawn depending on the methodology: while no estimated herd effect was seen with the before/after method, a herd effect was evident with the ITS method. Conclusions: The choice of statistical method and analysis periods can substantially influence the magnitude of estimated herd effects from paediatric PCV programmes. It is important to consider the reliability and presence of pre-PCV patterns in the IPD surveillance data used for analysis, the methodology and associated assumptions used to estimate herd effects., SCOPUS: ar.j, info:eu-repo/semantics/published

We previously reported 10-valent pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) efficacy in a double-blind randomized trial (ClinicalTrials.gov: NCT00466947) against various diseases, including acute otitis media (AOM). Here, we provide further analyses. In the Panamanian subset, 7,359 children were randomized (1:1) to receive PHiD-CV or control vaccine at age 2/4/6 and 15–18 months. Of these, 2,000 had nasopharyngeal swabs collected. AOM cases were captured when parents sought medical attention for children with AOM symptoms; surveillance was enhanced approximately 2 y into the study through regular telephone calls or home visits by study personnel, who advised parents to visit the clinic if their child had AOM symptoms. Mean follow-up was 31.4 months. Clinical AOM (C-AOM) cases were assessed by physicians and confirmed by otorhinolaryngologists. Middle ear fluid samples, taken from children with C-AOM after specific informed consent, and nasopharyngeal samples were cultured for pathogen identification. For 7,359 children, 2,574 suspected AOM cases were assessed by a primary healthcare physician; 649 cases were C-AOM cases as per protocol definition. From the 503 MEF samples collected, 158 resulted in a positive culture. In the intent-to-treat cohort (7,214 children), PHiD-CV showed VE against first C-AOM (24.0% [95% CI: 8.7, 36.7]) and bacterial (B-AOM) episodes (48.0% [20.3, 66.1]) in children

Supplemental Digital Content is available in the text., Background: Acute otitis media (AOM) is an important cause of childhood morbidity and antibiotic prescriptions. However, the relative importance of the well-known otopathogens, Streptococcus pneumoniae (Spn) and Haemophilus influenzae (Hflu), remains unclear because of a limited number of tympanocentesis-based studies that vary significantly in populations sampled, case definitions and heptavalent pneumococcal conjugate vaccine use. Methods: We conducted a pooled analysis of results from 10 AOM etiology studies of similar design, the protocols of which were derived from a common protocol and conducted in children 3 months to 5 years of age in different countries. Generalized estimating equations were used to account for within-study correlations. Results: The majority, 55.5% (95% confidence interval: 47.0%–65.7%) of 1124 AOM episodes, were bacterial pathogen positive: 29.1% (24.8%–34.1%) yielded Hflu and 23.6% (19.0%–29.2%) Spn. Proportions of Hflu and Spn were higher and lower, respectively, in heptavalent pneumococcal conjugate vaccine–vaccinated children. Hflu and Spn were each isolated from 20% to 35% of children in every 1-year age range. Hflu was less likely to be isolated from first (vs. subsequent) episodes [relative risk (RR): 0.71 (0.60–0.84)]. Spn was more often isolated from sporadic (vs. recurrent) cases [RR: 0.76 (0.61–0.97)]; the opposite was true for Hflu [RR: 1.4 (1.00–1.96)]. Spn cases were more likely to present with severe (vs. mild) symptoms [RR: 1.42 (1.01–2.01)] and Hflu cases with severe tympanic membrane inflammation [RR: 1.35 (1.06–1.71)]. Conclusions: Spn and Hflu remain the leading otopathogens in all populations examined. While associated with overlapping symptoms and severity, they exhibit some differences in their likelihood to cause disease in specific subpopulations.

Brazil introduced the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, Synflorix™, GSK Vaccines) in the routine childhood immunization program in 2010 with a 3+1 schedule (with catch-up for children

Streptococcus pneumoniae has more than 95 serotypes, each of which presumably can cause sepsis, meningitis, pneumonia, and acute otitis media. Pneumococcal conjugate vaccines (PCV) targeted against a limited number of serotypes have nonetheless revealed an impressive impact on each manifestation of pneumococcal disease. At the same time, growing evidence of significant non-vaccine type (NVT) replacement disease following implementation of infant PCV programs has raised questions about the long-term viability of PCV immunization strategies and how to optimize PCV formulations. We discuss here theoretical and practical considerations regarding serotype replacement, and provide a snapshot of the most important NVT types seen to date after implementation of the 2 higher-valent PCVs.

Clinical assessments of vaccines to prevent pneumococcal community-acquired pneumonia (CAP) require sensitive and specific case definitions, but there is no gold standard diagnostic test. To develop a new case definition suitable for vaccine efficacy studies, we applied latent class analysis (LCA) to the results from 7 diagnostic tests for pneumococcal etiology on clinical specimens from 323 elderly persons with radiologically confirmed pneumonia enrolled in the Finnish Community-Acquired Pneumonia Epidemiology study during 2005–2007. Compared with the conventional use of LCA, which is mainly to determine sensitivities and specificities of different tests, we instead used LCA as an appropriate instrument to predict the probability of pneumococcal etiology for each CAP case based on individual test profiles, and we used the predictions to minimize the sample size that would be needed for a vaccine efficacy trial. When compared with the conventional laboratory criteria of encapsulated pneumococci in culture, in blood culture or high-quality sputum culture, or urine antigen positivity, our optimized case definition for pneumococcal CAP resulted in a trial sample size that was almost 20,000 subjects smaller. We believe that the novel application of LCA detailed here to determine a case definition for pneumococcal CAP could also be similarly applied to other diseases without a gold standard.

Pneumococcal conjugate vaccines have proven highly effective in decreasing invasive disease and pneumonia in young children. However, there is considerable geographic variability in the impact of these vaccines on other disease endpoints and in other age groups. Investigation of the possible causes of this variability would greatly improve our understanding of pneumococcal pathophysiology and stimulate the effort to design more broadly effective vaccines.

Background Acute otitis media (AOM) is the most common bacterial childhood infection. However, caregivers with children having mild episodes often do not seek healthcare services, which may lead to an under-appreciation of the disease experienced by the community. The objectives of this survey were to estimate the proportion of primary caregivers who went to a healthcare facility when they suspected that their child aged 6 to

Antimicrobial treatment decreases bacterial culture yields. We assessed the impact of antimicrobial treatment on pneumococcal assays in a prospective study of community-acquired pneumonia (CAP) in the elderly. We enrolled 323 cases aged ≥65 years with radiologically confirmed CAP and collected detailed data on antimicrobial exposure and pneumococcal assays on various samples. Complete antimicrobial use data were available for 303 (94%) cases; 61% had no antimicrobial exposure, 19% had received antibiotics at the acute visit only, and 20% within 2 weeks before the acute visit (15% ongoing and 5 % completed treatment). Ongoing use before the visit reduced pneumococcal detection by culture (nasopharyngeal swab 2 vs. 16% in the unexposed; high-quality sputum 0 vs. 25%) and sputum lytA polymerase chain reaction (PCR) (0 vs. 25%). Urine antigen test and serology were not affected. Among those who had received antibiotics only at the acute visit before study sampling, serology (29 vs. 15%), urine antigen (19 vs. 8%), and blood culture (9 vs. 2%) were more often positive than among the unexposed. Antimicrobial exposure before the visit reduced both culture and PCR-based detection. Patients given antibiotics at the visit had higher proportions of positive blood culture, serology, and urine antigen tests, suggesting higher pneumococcal CAP prevalence.

Streptococcus pneumoniae is a major cause of childhood morbidity and mortality worldwide. A heptavalent polysaccharide-protein conjugate vaccine (PCV) has proven highly effective in preventing pneumococcal disease in industrialized countries. Two higher-valent pneumococcal conjugate vaccines are now widely available, even in the poorest countries. These differ from each other in the number of serotypes and carrier proteins used for their conjugation. Some have assumed that the only meaningful clinical difference between PCV formulations is a function of the number of serotypes each contains. A careful review of recent clinical data with these and several unlicensed PCV formulations points to important similarities but also that some key properties of each vaccine likely differ from one another.

We conducted a prospective population-based epidemiological study to prepare a setting for documentation of the efficacy of novel vaccines against pneumococcal (Pnc) community-acquired pneumonia (CAP) in the elderly. Specific objectives were to demonstrate setting feasibility, to construct a case definition for Pnc CAP, and to estimate its incidence.We prospectively enrolled patients with clinical and radiological findings compatible with CAP at municipal on-call clinics serving an elderly population (age ≥ 65 y) of approximately 29,500. Sputum, urine, nasopharyngeal swab (NPS), and blood samples were analyzed using diverse methods for the identification of Pnc (culture, PCR, antigen tests, serology) and of other pathogens. The following case definition for Pnc CAP was derived: encapsulated Pnc in blood culture or in high-quality sputum culture or at least 2 of the following: positive urine Pnc antigen; ≥ 2-fold increase in serum anti-PsaA or anti-CbpA antibodies; encapsulated Pnc culture or LytA PCR in either sputum or NPS.We enrolled 490 clinical CAP patients during the 2-y follow-up, 53% of all clinical CAP patients in the source population; 323 were radiologically confirmed. The incidence of radiologically confirmed CAP was 5.5/1000 person-y (95% confidence interval (CI) 4.9-6.1) and 10.5/1000 person-y when adjusted for non-captured patients. The proportion of radiologically confirmed CAP caused by Pnc was estimated at 17%; i.e. 0.95/1000 person-y (95% CI 0.7-1.2) and 1.8 when adjusted for non-captured patients.We developed and documented a feasible methodology for capturing endpoints in a vaccine trial for the prevention of pneumonia. CAP incidence in the elderly population remains considerable and Streptococcus pneumoniae was one of the most commonly detected causative agents.

Reduced rates of consultations for otitis media after introduction of pneumococcal conjugate vaccines (PCVs) have been overinterpreted. This systematic review suggests that PCV is only somewhat modestly effective against all-cause otitis media., Acute otitis media (AOM) is a leading cause of visits to physicians and of antibiotic prescriptions for young children. We systematically reviewed studies on all-cause AOM episodes and physician visits in which impact was attributed to pneumococcal conjugate vaccines, either as efficacy or effectiveness. Of 18 relevant publications found, most used the 7-valent pneumococcal conjugate vaccine (7vCRM). The efficacy of 7vCRM against all-cause AOM episodes or visits was 0%–9% in randomized trials and 17%–23% in nonrandomized trials. In observational database studies, physician visits for AOM were already declining in the 3–5 years before 7vCRM introduction (mean change, −15%; range, +14% to −24%) and continued to decline afterward (mean, −19%; range, +7% to −48%). This vaccine provides some protection against OM, but other factors have also contributed to the recent decline in OM incidence. Future effectiveness studies should thus use better-controlled methods to estimate the true impact of vaccination on AOM.

Before 7-valent pneumococcal conjugate vaccine (PCV7) implementation in France, several studies had described the microbiology of acute otitis media (AOM) treatment failures. The causative pathogens were Streptococcus pneumoniae (Sp) followed by nontypable Haemophilus influenzae (NTHi). The aim of this study was to describe the epidemiology of pathogens involved in AOM treatment failures or recurrences.This French multicentric prospective study enrolled 143 children with AOM treatment failure between 2007 and 2009 observed by 8 ear, nose, and throat specialists. Failure was defined as the persistence of AOM symptoms after at least 48 hours of antibiotic therapy or their recurrence within 4 days after the end of treatment. Standardized history and physical examination findings were recorded, and culture of middle ear fluid (MEF) was obtained.Mean age was 16.9 ± 9.9 months (median, 13.7). Eighty-eight percent of children had received more than 1 dose of PCV7, and 70.6% attended day care. The most common antibiotic used at the time of treatment failure or recurrence was a combination of amoxicillin and clavulanate (51.1%). Bacteriologic sampling demonstrated that in 35% of cases (n=50), no otopathogen was cultured at the time of treatment failure or recurrence. Similar proportions of Sp and NTHi were observed in the 86 patients (60.1%) from whom only a single species was recovered from MEF (46.5% for Sp, n=40 and 45.3% for NTHi, n=39). Among Sp strains, 4.4% were penicillin susceptible, 77.8% were penicillin intermediate, and 17.8% were fully penicillin resistant, and serotype 19A represented 84.5% of all serotypes detected. Among NTHi isolates, 15.5% (n=7) were β-lactamase-producing strains (including 2 strains with only this mechanism of resistance), and strains with reduced susceptibility by changes in protein binding to penicillin (β-lactamase-negative ampicillin resistant strains) represented 35.5% of cases. Among the 50 sterile MEF samples, polymerase chain reaction was performed in 32, of which 4 were positive for HI, 3 for Sp, and 3 for both.Among children with AOM treatment failures in France, Sp and NTHi were equally distributed; 19A was the main Sp serotype, and the main resistance mechanism for NTHi was β-lactamase-negative ampicillin resistance.

Increased incidence is principally due to highly invasive nonvaccine serotypes of pneumococci, especially serotype 1., Pediatric parapneumonic empyema (PPE) has been increasing in several countries including Spain. Streptococcus pneumoniae is a major PPE pathogen; however, antimicrobial pretreatment before pleural fluid (PF) sampling frequently results in negative diagnostic cultures, thus greatly underestimating the contribution of pneumococci, especially pneumococci susceptible to antimicrobial agents, to PPE. The study aim was to identify the serotypes and genotypes that cause PPE by using molecular diagnostics and relate these data to disease incidence and severity. A total of 208 children with PPE were prospectively enrolled; blood and PF samples were collected. Pneumococci were detected in 79% of culture-positive and 84% of culture-negative samples. All pneumococci were genotyped by multilocus sequence typing. Serotypes were determined for 111 PPE cases; 48% were serotype 1, of 3 major genotypes previously circulating in Spain. Variance in patient complication rates was statistically significant by serotype. The recent PPE increase is principally due to nonvaccine serotypes, especially the highly invasive serotype 1.

Pneumococcal parapneumonic empyema is an increasingly common complication in children. Conventional microbiological cultures indicate bacterial causes in as few as 8% of cases; therefore, there is a vital need for new molecular methods of detection and diagnosis. The development and clinical evaluation of real-time PCR-based assays to detect the pneumococcal capsular wzg gene of all serotypes tested are reported here, and 24 of them have been identified in clinical specimens. Using realtime PCR assays with highly specific TaqMan MGB probes that target DNA sequences within the capsular polysaccharide gene cluster, it was possible to differentiate serotypes 1, 3, 5, 4, 6A, 6B, 7F ⁄A, 8, 9V ⁄A ⁄N ⁄L, 14, 15B ⁄C, 18C ⁄B, 19A, 19F ⁄B ⁄C, 23F and 23A. These assays showed high sensitivity (five to ten pneumococcal DNA equivalents) and they were validated with 175 clinical isolates of known serotypes. The clinical value of this approach was demonstrated by analysis of 88 culture-negative pleural fluids from children diagnosed with parapneumonic empyema in three Spanish hospitals. Pneumococcal DNA was detected in 87.5% of pleural fluids, and serotypes 1, 7F and 3 were responsible for 34.3%, 16.4% and 11.9%, respectively, of cases of parapneumonic empyema in children. Such molecular methods are critical for the diagnosis of invasive pneumococcal disease and continued epidemiological surveillance in order to monitor serotype vaccine effectiveness.

Nasopharyngeal pneumococci were collected from 635 Spanish children aged 6 months to 6 years attending four primary healthcare centres (n = 276) or two hospital emergency rooms (n = 359); 36% of the children had received ≥1 dose of pneumococcal conjugate vaccine (PCV7). Overall, the carriage rate of Streptococcus pneumoniae was 31%, with no significant differences in carriage rates according to setting. Colonization with vaccine serotypes was significantly associated with the absence of PCV7 immunization (29.4% vs. 5.9%, p

Information about the burden and epidemiological characteristics of meningitis and other invasive disease caused by Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis is of great value to healthcare decision makers to prioritize public health interventions. A group of regional experts in the Eastern Mediterranean and North African regions formed the MENA Vaccine-Preventable Diseases Regional Advisory Group to collate and discuss such information on an annual basis. This paper provides an up-to-date summary of the available epidemiological data regarding these pathogens in these regions. In doing so, it highlights the need for additional surveillance studies to better measure the burden of these diseases, as well as the potential impact of introduction of new vaccines against these pathogens.

The relationship between pneumococcal conjugate vaccine-induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study assessed the impact of the ten-valent pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP (B-CAP: radiologically confirmed CAP with alveolar consolidation/pleural effusion on chest X-ray, or non-alveolar infiltrates and C-reactive protein ≥ 40 µg/ml); other protocol-specified outcomes were also assessed.This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine (hepatitis B for primary vaccination, hepatitis A at booster) at 2, 4, 6, and 15-18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo (PHiD-CV, n = 10,295; control, n = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided p = 0.002) against B-CAP (conclusive for primary objective) and 25.7% (95% CI: 8.4%, 39.6%) against World Health Organization-defined consolidated CAP. Intent-to-treat VE was 18.2% (95% CI: 5.5%, 29.1%) against B-CAP and 23.4% (95% CI: 8.8%, 35.7%) against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28-30 mo for CAP and invasive pneumococcal disease (IPD) (PHiD-CV, n = 10,211; control, n = 10,140) and AOM (n = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: -1.1%, 30.4%; one-sided p = 0.032) against clinically confirmed AOM, 67.1% (95% CI: 17.0%, 86.9%) against vaccine serotype clinically confirmed AOM, 100% (95% CI: 74.3%, 100%) against vaccine serotype IPD, and 65.0% (95% CI: 11.1%, 86.2%) against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5% (95% CI: 20.7%, 22.2%) and 22.6% (95% CI: 21.9%, 23.4%) of PHiD-CV and control recipients, respectively. There were 19 deaths (n = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (n = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases.Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice.www.ClinicalTrials.gov NCT00466947.

Background US recommendations issued in 1999 for hepatitis A (HA) childhood immunization varied according to regional HA incidences prior to vaccination. Mathematical models of HA transmission, especially those accounting for herd protection, can be useful in formulating new, highly effective recommendations that could lead to disease elimination. Methods A mathematical model of HA transmission was designed to assess the impact of different vaccination strategies on the evolution of HA infection over time in the United States. The model represents HA transmission dynamics and is stratified by age and regions defined in the Advisory Committee for Immunization Practices 1999 recommendations. The model accounts for herd protection and HA importation, using an age-dependent "force of infection" varying over time as a function of the prevalence of subjects with infectious HA. Results The model predicts a clear benefit of vaccinating all US children at as young an age as possible. Nationwide routine immunization at 1 year of age with 70% coverage would prevent 57% of additional cases during the period 1995-2029, compared with the continuation of the regional strategy of vaccinating children at 2 years of age, as recommended by the Advisory Committee for Immunization Practices in 1999. In contrast, the model also predicts that nationwide routine immunization for children 12 years of age only would result in a 14% increase of HA cases during the period 1995-2029, compared with the number of cases predicted with the regional strategy of the immunization of 2-year-olds. Conclusions These findings highlight the importance of accounting for herd protection induced by early childhood HA vaccination. They also support the very recent Advisory Committee for Immunization Practices recommendations for universal HA immunization of 1-year-olds.

We analyzed blood and pleural fluid samples from 89 Taiwanese children with empyema thoracis and parapneumonic pleural effusion. Streptococcus pneumoniae was the major pathogen, identified in 12 children by bacterial culture and 53 children by molecular techniques, and serotype 19A was the dominant serotype. Also noteworthy was the detection of pneumococcal serotype 1, Haemophilus influenzae and Mycoplasma pneumoniae in these children.

Streptococcus pneumoniae is a major cause of acute otitis media (AOM) in young children. More than 90 immunologically distinct pneumococcal serotypes have been identified, but limited information is available regarding their relative importance in AOM.We analyzed nine existing datasets comprising pneumococcal isolates from middle ear fluid samples collected from 1994 through 2000 from 3,232 children with AOM from Finland, France, Greece, Israel, several East European countries, the US and Argentina. We examined the distribution of pneumococcal serotypes in relation to several demographic and epidemiologic variables, including gender, age, antibiotic resistance and source of culture material.The major serotypes identified included 19F and 23F, each comprising 13 to 25% of pneumococcal middle ear fluid isolates in most datasets; 14 and 6B, comprising 6 to 18%; whereas 6A, 19A and 9V each comprised 5 to 10%. Despite differences in location, study design and antibiotic susceptibility, each major serotype was prominent in most age groups of each dataset. Serotypes represented in the 7-valent pneumococcal conjugate vaccine (PCV-7, 4, 6B, 9V, 14, 18C, 19F, 23F) accounted for 60 to 70% of all pneumococcal isolates in the 6- to 59-month age range, but only 40 to 50% of isolates in children6 or/=60 months old. Serotype 3 and, in certain datasets, serotypes 1 and 5, were more important in the6- and/=60-month age groups. In each age group vaccine-related serotypes (mainly 6A and 19A) comprised an additional 10 to 15% of all pneumococcal isolates. Four serotypes (23F, 19F, 14 and 6B) accounted for 83% of all penicillin-resistant observations.This analysis of several geographically diverse datasets indicates that a limited number of serotypes, largely represented in PCV-7, accounted for the majority of episodes of pneumococcal AOM in children between 6 and 59 months of age. Certain serotypes appeared to be relatively more significant in children6 months or59 months of age.

Background Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae (H. influenzae) are considered major causes of bacterial acute otitis media (AOM) worldwide, but data from Asia on primary causes of AOM are limited. This tympanocentesis-based, multi-center, cross-sectional study assessed bacterial etiology and antimicrobial susceptibility of AOM in Thailand. Methods Children 3 to 59 months presenting with AOM (

The ability of the recently licensed 7-valent pneumococcal conjugate vaccine to cover isolates that cause otitis media, especially drug-resistant ones, was assessed using 500 recently obtained US isolates. Of these isolates, 418 (84%) belonged to vaccine-related serogroups, whereas 82 (16%) belonged to non-vaccine-related serogroups. Serotype 3 accounted for 48 (59%) of the non-vaccine-related serogroups. In addition, 93% of the isolates from patients < or =3 years of age belonged to serotypes that were included in or related to the heptavalent vaccine, compared with 49% of the isolates from older patients (P=.001). Most of the isolates (98%-100%) that were resistant to the antimicrobial agents tested were covered by the heptavalent vaccine, including 95.1% of the isolates from patients

Global immunization programs represent a great public health success story. Evidence from every region documents substantial reductions in morbidity and mortality following widespread use of vaccines developed years ago. Development and introduction of new vaccines and vaccine combinations aimed at the industrialized world market are occurring at a fast pace. A number of political and economic factors will influence the rate at which developing country immunization programs incorporate those new vaccines that could have a major public health impact. Perhaps the greatest determinant of this rate is the extent to which international and bilateral agencies and national governments appreciate the potential value of new vaccines.

To prospectively identify the bacterial aetiology and antimicrobial susceptibility of problematic (recurrent and treatment failure) acute otitis media in Spanish children several years after the introduction of 7-valent pneumococcal conjugate vaccine.Tympanocentesis or careful sampling of spontaneous otorrhoea was performed on children aged 3 to36 months with recurrent acute otitis media, acute otitis media treatment failure or unresolved acute otitis media.105 acute otitis media episodes (77 sampled by tympanocentesis, 28 otorrhoea samples) were evaluated: 46 recurrent, 35 treatment failures, 24 unresolved acute otitis media. 74 episodes (70.4%) had at least one bacterium identified on culture: Streptococcus pneumoniae was identified in 21 episodes, Haemophilus influenzae (all non-typeable) in 44, Streptococcus pyogenes in 2, Moraxella catarrhalis in 2. No statistically significant difference in bacterial aetiology by episode type was detected. Non-typeable H. influenzae was the most commonly isolated pathogen in all acute otitis media types and in all age sub-groups. Forty percent of S. pneumoniae isolates were multi-drug resistant. Pneumococcal serotype 19A was the most frequently identified serotype (7/21 episodes). Multi-drug resistance was found in 56% of 19A isolates. Of non-typeable H. influenzae isolates, 15% were ampicillin resistant and 13% were amoxicillin/clavulanate resistant. S. pneumoniae and non-typeable H. influenzae DNA were each detected in 57% of samples culture negative for these pathogens, including 12 co-infections.Combining culture and polymerase chain reaction results, H. influenzae and S. pneumoniae may be implicated in 70% and 43% of clinically problematic bacterial acute otitis media episodes, respectively. The impact of new vaccines to prevent both S. pneumoniae and non-typeable H. influenzae acute otitis media may be substantial in this population and is worth investigating.

Vaccination with the protein-polysaccharide conjugate vaccine, PCV7, has significantly reduced the burden of pneumococcal disease in populations where it is in widespread use and has had an important public health benefit. This vaccine targets only 7 of the more than 92 pneumococcal serotypes, and there have been concerns that the non-vaccine serotypes (NVTs) could increase in prevalence and reduce the benefits of vaccination. Indeed, among asymptomatic carriers, the prevalence of NVTs has increased substantially, and as a result, there has been little or no net change in the carriage prevalence of the bacteria. In many populations, there has been an increase in pneumococcal disease caused by NVT, but in most cases this increase in NVT disease has been less than the increase in NVT carriage. In this article, we review the evidence for serotype replacement in carriage and disease and address the surveillance biases that might affect these findings. We then discuss possible reasons for the discrepancy between near-complete replacement in carriage and partial replacement for disease, and address the possibility that differences in invasiveness between vaccine serotypes and those causing replacement could contribute to this difference. We contend that the magnitude of serotype replacement in disease can be attributed, in part, to a combination of lower invasiveness of the replacing serotypes, biases in the pre-vaccine carriage data (unmasking), and biases in the disease surveillance systems that could underestimate the true amount of replacement. We conclude by discussing the potential for serotype replacement in disease in the future and the need for ongoing surveillance.

Streptococcus pneumoniae and Haemophilus influenzae have been consistently reported to be the two major bacterial pathogens responsible for acute otitis media (AOM), mainly from studies in the US and Europe. However, data on bacterial pathogens causing AOM in Latin America are limited. Understanding the relative importance of these pathogens in a specific setting, the serotype distribution, and their antibiotic susceptibility levels is important to provide local vaccine and treatment recommendations. We therefore conducted a prospective, multi-center, tympanocentesis-based epidemiological study of Mexican children three months to less than five years of age. Fifty percent of episodes were in children who had received at least one dose of PCV7. Overall, 64% of samples were culture positive for bacterial pathogens. H. influenzae and S. pneumoniae were the leading causes of bacterial AOM, detected in 34% and 29% of AOM episodes, respectively. The most commonly isolated S. pneumoniae serotypes were 19A, 19F and 23F. All H. influenzae isolates were identified as non-typeable. Seventy-four percent of S. pneumoniae were susceptible to penicillin, while 97% were susceptible to amoxicillin/clavulanate. All H. influenzae samples were susceptible to amoxicillin/clavulanate and cefotaxime, 95% to cefuroxime and 75% to ampicillin. Both S. pneumoniae and non-typable H. influenzae represent important targets for vaccination strategies to reduce AOM in Mexican children.

The principal virulence factor ofStreptococcus pneumoniaeis capsular polysaccharide, and encapsulated pneumococci are more common causes of disease than unencapsulated strains. This study analysed the presence of capsular genes in 59 pneumococcal isolates using two PCR methods targeted at thecpsAandcpsBgenes of the capsular biosynthesis locus. The PCR method targeted at thecpsBgene, reported to be essential for encapsulation, was developed in this study. Of 59 pneumococcal isolates, 49 (83 %) were obtained from the sputum samples of elderly patients (≥65 years) with community-acquired pneumonia (CAP) and 10 (17 %) were from those with other acute lower respiratory tract infections (ARIs). Forty (82 %) of the CAP isolates and two (20 %) of the ARI isolates were encapsulated, as assessed by conventional immunochemical methods. Forty-one (98 %) of the 42 encapsulated strains had thecpsBgene present, and in 38 strains thecpsAgene was also detected. One of the unencapsulated isolates gave a positive result for thecpsBgene, and neither of the capsular locus genes were present in all the other unencapsulated strains. The distribution of encapsulated and unencapsulated isolates differed significantly between the two patient groups regardless of whether the presence of capsule was determined immunochemically (PcpsBPCR (P=0.002). ThecpsBPCR developed here was found to be a rapid and reliable method to detect the pneumococcal capsule locus and may have potential in sputum diagnostics when investigating the pneumococcal aetiology of CAP.

Universal infant vaccination with the 7-valent pneumococcal conjugate vaccine (PCV7) has nearly eliminated PCV7-serotype invasive pneumococcal disease (IPD) in young U.S. children, but has been accompanied by increases in the incidence of serotype 19A IPD. Because antibiotic-non-susceptible 19A has increased more than antibiotic-susceptible 19A, antibiotic selection pressure could be contributing to this trend. We developed a dynamic compartmental transmission model of pneumococcus to better understand the causes of this rise and to estimate the impact of vaccines or changes in antibiotic use on future IPD incidence in the U.S. in

Background Introduction of the 7-valent pneumococcal conjugate vaccine (7vCRM) in several countries has led to a rapid, significant drop in vaccine-type invasive pneumococcal disease (IPD) in immunized children. In the United States and some other countries with high antibiotic use, a subsequent rise in serotype 19A IPD has been taken to indicate that the 19F conjugate in the vaccine provides no cross-protection against the immunologically related 19A. Discussion We systematically assessed the clinical efficacy and effectiveness of 19F-containing vaccines against 19A disease or nasopharyngeal carriage by searching English-language articles in the electronic databases PubMed, Current contents, Scopus, and Embase from 1985 to 2008. The vaccine efficacy and effectiveness point estimates were consistently positive for modest protection against 19A IPD and acute otitis media (AOM). However, statistical significance was not reached in any individual study. No consistent impact of 7vCRM on 19A nasopharyngeal colonization could be detected. These findings are discussed in context of immunogenicity analyses indicating that 7vCRM induces functionally active anti-19A antibodies after the booster dose, and that other 19F-containing vaccine formulations may elicit higher levels of such antibodies after both primary and booster doses. Summary Taken together, these results suggest that 19F-conjugates can provide some protection against 19A disease. The magnitude of this protection in a given setting will likely depend on several factors. These include the anti-19A immunogenicity of the specific vaccine formulation, the number of doses of that formulation needed to elicit the response, and the burden of 19A disease that occurs after those doses. It is possible that a modest protective effect may be obscured by the presence of countervailing selection pressures (such as high antibiotic use) that favor an increase in colonization with antibiotic-non-susceptible strains of 19A.

New pneumococcal conjugate vaccines (PCVs) are now becoming available. These formulations differ from the heptavalent diphtheria toxin variant conjugate vaccine (7vCRM, Prevenar/Prevnar) both in the number of serotypes and in serotype-specific immunogenicity. This review proposes an algorithm that attempts to predict the overall impact of these differences in vaccine formulation and immunogenicity on invasive pneumococcal disease (IPD) effectiveness. It builds on the principles underlying WHO licensure criteria for new PCVs, that serotype-specific anti-polysaccharide immunogenicity is potentially predictive of effectiveness. The algorithm used three sources of information: serotype-specific effectiveness data for 7vCRM, serotype-specific head-to-head immunogenicity data with 7vCRM and a recently licensed 10-valent pneumococcal non-typeable H. influenzae protein D-conjugate vaccine (PHiD-CV, Synflorix), and epidemiological information regarding the serotypes causing IPD in young children. Based on this algorithm, PHiD-CV and 7vCRM are predicted to prevent approximately 60-80% and 45-80%, respectively of IPD in young children worldwide, with significant variability by country and region.

Background Parapneumonic empyema continues to be a disease of significant morbidity and mortality among children despite recent advances in medical management. To date, only a limited number of studies have assessed the burden of empyema in Asia. Methods We surveyed medical records of four representative large pediatric hospitals in China, Korea, Taiwan and Vietnam using ICD-10 diagnostic codes to identify children Results During the study period, we identified 1,379 children diagnosed with empyema or pleural effusion (China, n = 461; Korea, n = 134; Taiwan, n = 119; Vietnam, n = 665). Diagnoses of pleural effusion (n = 1,074) were 3.5 times more common than of empyema (n = 305), although the relative proportions of empyema and pleural effusion noted in hospital records varied widely between the four sites, most likely because of marked differences in coding practices. Although pleural effusions were reported more often than empyema, children with empyema were more likely to have a cultured pathogen. In addition, we found that median age and gender distribution of children with these conditions were similar across the four countries. Among 1,379 empyema and pleural effusion specimens, 401 (29%) were culture positive. Staphylococcus aureus (n = 126) was the most common organism isolated, followed by Streptococcus pneumoniae (n = 83), Pseudomonas aeruginosa (n = 37) and Klebsiella (n = 35) and Acinetobacter species (n = 34). Conclusion The age and gender distribution of empyema and pleural effusion in children in these countries are similar to the US and Western Europe. S. pneumoniae was the second leading bacterial cause of empyema and pleural effusion among Asian children. The high proportion of culture-negative specimens among patients with pleural effusion or empyema suggests that culture may not be a sufficiently sensitive diagnostic method to determine etiology in the majority of cases. Future prospective studies in different countries would benefit from standardized case definitions and coding practices for empyema. In addition, more sensitive diagnostic methods would improve detection of pathogens and could result in better prevention, treatment and outcomes of this severe disease.

A small number of serotypes are responsible for most invasive pneumococcal disease in children worldwide. Serotypes 1 and 5 were among the first pneumococcal serotypes to be identified, reflecting their great prominence as causes of disease in the early part of the 20th century. In the antibiotic era, these serotypes persist as important causes of disease in children in most countries even though they, unlike some other common serotypes, remain sensitive to antimicrobial agents. These types also exhibit a high level of virulence, cause disease clusters or outbreaks, infect all age groups, and cause severe disease. Future vaccine formulations that protect against these types are important for developed and developing countries alike.

Active surveillance of ambulatory and hospitalized children 2-23 months old in Cordoba, Argentina for invasive pneumococcal disease and radiographically confirmed "obvious" pneumonia revealed annual incidences of 206.8 and 2422 cases, respectively, per 100,000 children. The invasive pneumococcal disease incidence was substantially higher than those previously reported from Latin America and Europe.

The bacterial species Streptococcus pneumoniae consists of 90 immunologically distinct serotypes, of which some possess distinct epidemiological properties. Certain serotypes are much more likely to be associated with nasopharyngeal colonisation than to cause invasive disease. Compared with transient or infrequent colonisers, serotypes carried at high rates by young children may rapidly elicit age-associated natural immunity to invasive disease. Other serotypes seem to be of disproportionate importance as causes of disease in very young infants, in older children, in immunocompromised individuals, or in elderly people. Some serotypes seem to be associated with particular disease syndromes, such as complicated pneumonias in children, or with higher rates of hospitalisation in children or mortality in adults, or are consistently responsible for outbreaks in certain populations. Since pneumococcal conjugate vaccines are directed at specific serotypes, national immunisation advisory committees may wish to consider these serotype-specific properties when considering which vaccine formulation to introduce into a national programme.

Protection against serotype 1 could not be demonstrated in two randomized trials of 9 valent pneumococcal conjugate vaccines. An analysis of the timing of type 1 cases among vaccinees and controls shows that the vaccine failures occurred among cases occurring after the first year of life. Vaccination was given as three doses in infancy with no booster dose. These data suggest that a booster dose given at 9 months of age, or early in the second year of life, should be evaluated for protection against type 1 pneumococcal disease.

Summary The development of glycoconjugate vaccines for Streptococcus pneumoniae that are effective in very young children has renewed interest in identification of which among the more than 90 pneumococcal serotypes are most likely to cause invasive pneumococcal disease (IPD). Serotype distribution is thought to vary geographically, even between regions as socio economically similar as western Europe and North America. To explain these variations, we note the considerable variation that exists between reported rates of IPD in young children in the USA and west European countries. We postulate that this variation is attributable to different blood-culture rates and practices, and that mild IPD is probably underdiagnosed and under-reported in western Europe. On the basis of a comparison of serotype distributions between the two regions, we also postulate that those serotypes found at similar frequencies in both regions are virulent and rarely cause mild disease. As a result, reported distributions of IPD serotypes, especially when expressed as percentages, might be strongly skewed by the distribution of clinical presentations in a particular study population.

To assess whether certain serogroups of Streptococcus pneumoniae are preferentially associated with specific disease manifestations, we analyzed all recent pneumococcal disease studies and assessed the relative frequency of isolation of each serogroup by clinical site (as a proxy for different disease states). In all age groups, serogroups 1 and 14 were more often isolated from blood, and serogroups 6, 10, and 23 were more often isolated from cerebrospinal fluid (CSF); in young children, serogroups 3, 19, and 23 were more often isolated from middle ear fluid (MEF). Serogroups represented in conjugate vaccines were isolated slightly less frequently from CSF than from blood or MEF. Nonetheless, serogroups in the 9-valent conjugate vaccine formulation still comprised approximately 75% of pneumococcal isolates from the CSF of young children in Europe and in the United States and Canada. These analyses indicate that pneumococcal conjugate vaccines could potentially prevent a substantial proportion of episodes of bacteremic disease, pneumonia, meningitis, and otitis media, especially in young children.

We analyzed70 recent data sets to compare the serogroups causing invasive pneumococcal disease (IPD) with those represented in conjugate vaccine formulations. Five to 8 and 10-11 serogroups comprise at least 75% of pneumococcal isolates from young children and older children/adults, respectively, in each geographic region. Serogroups in the 7-valent formulation (4, 6, 9, 14, 18, 19, and 23) cause 70%-88% of IPD in young children in the United States and Canada, Oceania, Africa, and Europe, and65% in Latin America and Asia. Serogroups in the 9-valent formulation (7-valent+1, 5) cause 80%-90% of IPD in each region except Asia (66%). Serogroup 1 accounts for6% of IPD in each region, including Europe, except the United States and Canada and Oceania. In contrast, several serogroups not found in 7-, 9-, and 11-valent conjugate formulations are significant causes of disease in older children/adults. Nevertheless, each conjugate formulation could prevent a substantial IPD burden in each region and age group.

Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Instituto de Investigaci?n Nutricional. Lima, Peru. W. Henrietta. Wyeth-Lederle Vaccines. New York, NY, USA. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Johns Hopkins University. School of Hygiene and Public Health. Baltimore, USA. Objectives and methods. With the purpose of better understanding the efficacy of the lower titer [4 ? 104 plaque-forming units (pfu)] tetravalent rhesus-human reassortant rotavirus vaccine (RRV-TV) against diarrheal episodes of different severities, the Peruvian and Brazilian efficacy data were reanalyzed with a 20-point scoring system. Mild, moderate/severe and very severe rotavirus diarrhea were scored as 0 to 8, 9 to 14 and 14, respectively. Results. In the Peruvian study one dose of vaccine yielded 64% (P = 0.04) protection against pure cases of rotavirus disease (i.e. those in which no other enteropathogen was found) with clinical scores ranging from 9 to 14. Protective efficacy against very severe rotavirus gastroenteritis could not be assessed because of the small number of cases. In Brazil there was a trend in preventing ?all? and ?pure? cases of rotavirus diarrhea scored 9 to 14 (44%, P = 0.06, and 45%, P = 0.08, respectively) and the vaccine was 75% (P = 0.02) protective against pure rotavirus diarrhea scored 14. No protection was observed for mild rotavirus diarrhea (scores 9). These data were compared with those from trials in Venezuela (4 ? 105 pfu/dose), US (4 ? 104 pfu/dose and 4 ? 105 pfu/dose) and Finland (4 ? 105 pfu/dose). Combining the Peruvian (one dose, pure cases) and Brazilian studies together, the levels of protection against 9- to 14-scored rotavirus diarrhea are comparable with those from the Venezuelan (47%) and American (57, 57 and 65%) efficacy trials. In Brazil the level of protection (75%) against pure, 14-scored rotavirus diarrhea is similar to the efficacy rates yielded in the three US trials (82, 80 and 69%) and the Finnish trial (100%) for episodes of the same severity. Conclusions. Our reanalysis provides evidence that, at least against moderate/severe rotavirus gastroenteritis, RRV-TV, 4 ? 104 pfu/dose is potentially as efficacious as RRV-TV, 4 ? 105 pfu/ dose, even in settings with very high rotavirus disease burden. The reanalysis of the Peruvian data suggests that one and three vaccine doses may yield similar efficacy rates. It is also suggested that vaccine efficacy against most severe episodes in Peru and Brazil was not evident because of the trial design used in those studies (i.e. prospective, active home surveillance rather than a catchment trial), resulting in too few cases of severe disease even in the placebo group. To confirm these findings, future trials with this vaccine are necessary in developing countries with high diarrhea morbidity rates. These trials should use catchment designs and focus on the evaluation of the efficacy of one or three doses of RRV-TV against moderate to severe/very severe rotavirus diarrhea.