Heptavalent Pneumococcal Conjugate Vaccine Research Articles

Burden of pneumococcal disease in children in Cuba before the introduction of a novel pneumococcal conjugate vaccine

# Background The Cuban heptavalent conjugate pneumococcal vaccine will be introduced for children beginning in 2020. We estimated the burden of pneumococcal cases and deaths in children 1-59 months in 2015. # Methods Mortality and morbidity attributable to pneumococcus were estimated for each of the three primary syndromes commonly associated with pneumococcus: pneumonia, meningitis, and invasive non-pneumonia, non-meningitis (NPNM). Vaccine randomized clinical trial data were used to estimate the proportion of pneumonia deaths attributable to pneumococcus. Data from Cuba were obtained from two domestic sources: National Bacterial Meningitis Surveillance System and the laboratory register from the National Reference Laboratory. Syndrome-specific pneumococcal mortality proportions were applied to all-cause pneumonia and meningitis death estimates prepared by the World Health Organization Maternal Child Epidemiology Estimation (WHO/MCEE) collaboration. The proportion of pneumonia cases attributable to pneumococcus was applied to estimates of all-cause clinical and severe pneumonia also prepared by the WHO/MCEE collaboration. Pneumococcal NPNM morbidity and mortality estimates were prepared using the ratio pneumococcal meningitis to pneumococcal invasive disease. Estimates were adjusted for HIV prevalence and access to health care. # Results In 2015, pneumococcus was estimated to cause 970 severe cases (uncertainty range, UR=692-1209) and 39 deaths (UR=23-59) among children 1-59 months. The estimated incidence rate of severe pneumonia was 149 (UR=112-170) per 100,000 children 1-59 months. The estimated case fatality ratio (CFR) was 2% (UR=1-2%). Over a period of one year, 22 deaths were attributed to pneumococcal pneumonia (UR=16-23), 9 (UR=14-19) to pneumococcal meningitis, and 8 (UR=3-17) to pneumococcal bacteremia. The CFR due pneumococcal meningitis was 18% (UR= 8-37%) in 2015. # Conclusions Reduced morbidity and mortality due to pneumococcal disease in Cuba could be achieved with the accelerated introduction of a novel PCV product in children.

Safety and immunogenicity of the Cuban heptavalent pneumococcal conjugate vaccine in healthy infants. Results from a double-blind randomized control trial Phase I

BackgroundCuba has a new pneumococcal conjugate vaccine candidate (PCV7-TT). This study evaluates the safety and immunogenicity in healthy infants using 2p+1 vaccination schedule. MethodsA phase I, controlled, randomized and double blind clinical trial was designed. 30 unvaccinated healthy infants were included. 20 subjects were assigned to study group (PCV7-TT) and 10 to control group (Synflorix®) to receive the vaccines at 7, 8 months of age (primary series) and 11 months (booster dose). Blood samples were collected 30 days after second dose and post booster for antibodies measure analysis by ELISA and OPA. The statistics analysis included the frequency of occurrence for adverse events and the immune response. Non-parametric tests were used to compare the immune response. The clinical trial was published in the Cuban Public Register of Clinical Trials with code RPCEC00000173 available at http://registroclinico.sld.cu. ResultsOverall, the safety profile of PCV7-TT was similar to Synflorix®. Local reactions were predominant and systemic events were mild in severity. Swelling and redness were frequently associated with PCV7-TT mainly after the first dose (50% and 40% respectively). 15% and 10% of subject reported severe swelling after first dose with PCV7-TT and after second dose with Synflorix®. Mild fever (≥38–≤39), vomiting and sleep disturb were the systemic events reported. 100% of infants achieved pneumococcal IgG antibody concentrations ≥0.35 µg/ml after booster dose for serotypes 1, 14, 18C and 19F in each vaccine group. For serotypes 5, 6B and 23F, more than 80% infants vaccinated with Synflorix® or PCV7-TT achieved protective IgG GMC ≥ 0.35 µg/ml after booster dose. OPA proportion’s responders to the seven common serotypes were 89.5% or more after the primary dose and 100% after booster dose in vaccinated with PCV7-TT. ConclusionsThe Cuban PCV7-TT is safe, well tolerated and immunogenic in healthy infants.

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

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

Immunogenicity Induced by the Heptavalent Pneumococcal Conjugate Vaccine among Thai Children at High Risk for Severe Pneumococcal Disease

Background: Streptococcus pneumoniae, an important pathogen worldwide, causes a wide range of diseases mostly in young children and older adults. The heptavalent pneumococcal conjugate vaccine (PCV7) that is composed of seven serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F), was most prevalent in Thailand during this vaccination study. Aim: To determine immune responses to PCV7 among Thai children with high risk for invasive pneumococcal disease and whether children had specific antibody responses to related serotype 19A. Methods: The antibody-mediated opsonophagocytic killing assay (OPKA) was employed to detect the humoral immune response. One hundred and twenty-nine children (72 males and 57 females) were enrolled and divided into three groups according to age and vaccine dosages received: >12 months and received two vaccine doses, 7-12 months and received three vaccine doses, and 2-6 months and received four vaccine doses. These groups were then categorised into five groups based on disease: congenital heart disease, prematurity, chronic lung disease, haematological disease, and HIV. Serotype-specific antibody responses from children in all disease groups were comparatively analysed. Results: Low antibody responses to serotypes 9V and 23F, moderate responsive antibody titres to serotypes 4, 18C, 19A, and 19F, and high antibody responses to serotypes 6B and 14 were observed. Conclusion: These results suggest that children at high risk of invasive pneumococcal disease could develop functional antibody responses to some vaccine serotypes after PCV7 vaccination.

Effectiveness of different vaccine schedules for heptavalent and 13-valent conjugate vaccines against pneumococcal disease in the Community of Madrid.

The heptavalent pneumococcal conjugate vaccine (PCV-7) was added to the childhood routine vaccination program in the Community of Madrid in November of 2006 with 3+1 recommended doses and a catch-up for those under 2years old. In June 2010, PCV-7 was replaced by 13-valent vaccine (PCV-13) with 2+1 recommended doses. In July of 2012, the PCV-13 was removed from the funded program and reintroduced again (2+1 recommended doses) in December 2014. In between, children were vaccinated privately with 3+1 recommended doses of PCV-13. The aim of this study was to evaluate the effectiveness of each vaccination schedule used in the Community of Madrid. We included all cases of invasive pneumococcal disease (IPD) reported between 2007 and 2015 to the Notifiable Diseases Surveillance System. Vaccination information was obtained from the Immunization Registry. Vaccine effectiveness (VE) was estimated using the indirect cohort design for cases with serotype information. A total 779 cases were included in the study. Among them 47.6% of the cases were primo-vaccinated with booster, 20% primo-vaccinated, 15.9% incompletely primo-vaccinated and 16.5% not vaccinated. The VE for ≥1 doses of any PCV was 82% (CI 95%: 67.8-89.9%): 91.9% (CI 95%: 76.5-97.2%) for PCV-7 and 77.2% (48.6-89.9%) for PCV-13. VE in those receiving the full 2+1 or 3+1 schedules was 100% for both vaccines. A high number of vaccine failures were reported in children before they had the opportunity to receive the booster dose, especially due to PCV-13-non-PCV-7 serotypes. VE was higher for PCV-7 compared to PCV-13, except for those that received the complete schedule with booster that achieved 100% of VE, which shows the relevance of the vaccines and complying with all doses scheduled.

A Population-Based Assessment of the Impact of 7- and 13-Valent Pneumococcal Conjugate Vaccines on Macrolide-Resistant Invasive Pneumococcal Disease: Emergence and Decline of Streptococcus pneumoniae Serotype 19A (CC320) With Dual Macrolide Resistance Mechanisms.

Macrolide efflux encoded by mef(E)/mel and ribosomal methylation encoded by erm(B) confer most macrolide resistance in Streptococcus pneumoniae. Introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) in 2000 reduced macrolide-resistant invasive pneumococcal disease (MR-IPD) due to PCV7 serotypes (6B, 9V, 14, 19F, and 23F). In this study, the impact of PCV7 and PCV13 on MR-IPD was prospectively assessed. A 20-year study of IPD performed in metropolitan Atlanta, Georgia, using active, population-based surveillance formed the basis for this study. Genetic determinants of macrolide resistance were evaluated using established techniques. During the decade of PCV7 use (2000-2009), MR-IPD decreased rapidly until 2002 and subsequently stabilized until the introduction of PCV13 in 2010 when MR-IPD incidence decreased further from 3.71 to 2.45/100000 population. In 2003, serotype 19A CC320 isolates containing both mef(E)/mel and erm(B) were observed and rapidly expanded in 2005-2009, peaking in 2010 (incidence 1.38/100000 population), accounting for 36.1% of MR-IPD and 11.7% of all IPD isolates. Following PCV13 introduction, dual macrolide-resistant IPD decreased 74.1% (incidence 0.32/100000 in 2013). However, other macrolide-resistant serotypes (eg, 15A and 35B) not currently represented in PCV formulations increased modestly. The selective pressures of widespread macrolide use and PCV7 and PCV13 introductions on S. pneumoniae were associated with changes in macrolide resistance and the molecular basis over time in our population. Durable surveillance and programs that emphasize the judicious use of antibiotics need to continue to be a focus of public health strategies directed at S. pneumoniae.

Pneumococcal carriage and serotype variation before and after introduction of pneumococcal conjugate vaccines in patients with acute otitis media in Switzerland

BackgroundAcute otitis media (AOM) is an important cause for antibiotic prescription within the paediatric population and Streptococcus pneumoniae is a major pathogen associated with AOM episodes. This study aimed at analysing the influence of the heptavalent and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13) on pneumococcal carriage and serotype distribution in AOM. MethodsNasopharyngeal swabs (NPS) and middle ear fluid (MEF) were collected within a Swiss surveillance study of outpatients from all ages with AOM between 2004 and 2015, covering three vaccination eras (pre-PCV7, PCV7 and PCV13). Samples were cultured for pneumococcal identification, and the association of vaccine era with pneumococcal carriage was investigated by logistic regression analysis adjusting for sociodemographic factors. FindingsIn total, 3300 NPS and 620 MEF were included in this study. The number of samples from patients with AOM dropped over vaccination eras and S. pneumoniae was less frequently isolated in the PCV13 era as compared to the other two eras. The latest (PCV13) vaccination era was independently associated with a reduced pneumococcal carriage within NPS (adjusted odds ratio 0.65, 95%-CI 0.45–0.94). Investigating serotype epidemiology, vaccine serotypes decreased significantly after the conjugate vaccine introductions with the exception of serotype 3. Within the non-PCV13 serotypes, a particular increase of serogroups 11, 15 and 23 was observed in both NPS and MEF. ConclusionA substantial change in pneumococcal carriage and serotype epidemiology suggests an impact of the conjugate vaccines on pneumococcal AOM in Switzerland.

Impact of the Pneumococcal Heptavalent Conjugated Vaccine on <i>Streptococcus pneumoniae</i> Nasopharyngeal Carriage and Antimicrobial Susceptibility in Children 2-5-Year-Old in Beijing, China

Streptococcus pneumoniae is a primary cause of illness and death among children younger than 5 years in China. The heptavalent pneumococcal conjugate vaccine (PCV7) was the only conjugated vaccine (PCV) available in China from 2008 to 2013. This randomized, controlled, open-label study conducted at 46 Beijing clinics involved 3281 healthy 2-5-year-old Chinese children, randomized 1:1 to receive one dose of the S. pneumoniae heptavalent conjugated vaccine (PCV7) (n = 1643) or Haemophilus influenzae type b conjugate vaccine (Hib) (n = 1638). The main objective of this study was to investigate the impact of PCV7 against that of Hib vaccination in the nasopharyngeal S. pneumoniae colonization in healthy Chinese children. Nasopharyngeal (NP) samples for culture, serotyping and antimicrobial susceptibility testing were collected before vaccination and at Day 60 and 180 post-vaccination. A total 3281 children were enrolled in the study. Demographic characteristics were similar among both study groups: 1641 children received PCV7. Before immunization, S. pneumoniae was isolated in 338 and 360 children in the PCV7 (144 PCV7 isolates) and Hib groups (145 PCV7 isolates), respectively. At Day 180, PCV7 vaccination was more effective than Hib vaccination in reduction NP carriage (20.2% [P = 0.052]) and new acquisition (19.0% [P = 0.066]). When reductions in NP carriage and new acquisition of PCV7 VT plus 6A was analyzed, reduction in the PCV7 vaccinated group achieved statistical significance (P = 0.034 and P = 0.042 versus Hib, respectively). NP carriage of NVT increased in both groups (P = 0.305 between study groups at Day 180). PCV7 decreased NP carriage of non-susceptible VT to amoxicillin (P = 0.000), ceftriaxone (P = 0.047) and MDR (P = 0.024) versus Hib. PCV7 vaccination in Chinese children 2 to 5 years of age was more effective than vaccination with Hib in the reduction of S. pneumoniae nasopharyngeal carriage, new acquisition and non-susceptible isolates.

Etiology of Acute Otitis Media in Children Less Than 5 Years of Age: A Pooled Analysis of 10 Similarly Designed Observational Studies.

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. 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. 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)]. 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.

Individual-level effects of antibiotics on colonizing otitis pathogens in the nasopharynx

BackgroundAlthough there is evidence of an association between antibiotic consumption and resistant bacteria on a population level, the relationship on an individual level has been less well studied, particularly in terms of nasopharyngeal colonization. We have therefore analysed this association, using data from a closely followed cohort of children taking part in a vaccination trial. Methods109 children with early onset of acute otitis media (AOM) were randomised to heptavalent pneumococcal conjugate vaccine (PCV7) or no vaccination. They were followed for three years with scheduled appointments as well as sick visits. Nasopharyngeal cultures were obtained at all visits. Antibiotic treatments were recorded, as were risk factors for AOM, including siblings, short breast-feeding and parental smoking. Data were entered into a Cox regression model, and the findings of Streptococcus pneumoniae and Haemophilus influenzae with reduced susceptibility to the penicillin group were related to the number of previous courses of antibiotics. ResultsThere was evidence of an association between the amount of previously consumed betalactams and colonization with beta-lactamasenegative ampicillin-resistant (BLNAR) H. influenzae (RR 1.21; 95% CI 1.03–1.43; p = 0.03), and also with the most commonly prescribed drug; amoxicillin (RR 1.39; 95% CI 1.09–1.76; p = 0.01). There was no evidence for an association between antibiotic consumption and betalactamase producing H. influenzae or S. pneumoniae with reduced susceptibility to penicillin. Furthermore, there was no evidence of an association between resistant bacteria and AOM risk factors or PCV7. ConclusionIn this subgroup of children, most of whom were given several courses of antibiotics in early childhood, there was evidence of an association between betalactam/amoxicillin consumption and nasopharyngeal colonization with BLNAR strains, bacteria that have increased in prevalence during the last 10–15 years, and that are notoriously difficult to treat with oral antibiotics.

Streptococcus pneumoniae as cause of infection in infants less than 60 days of age: serotypes and antimicrobial susceptibility.

The aim of this study was to determine the distribution of serotypes and the antimicrobial susceptibilities of Streptococcus pneumoniae clinical isolates causing invasive and non-invasive disease in children aged ≤60 days in hospitals in Mexico. A 15-year retrospective study was conducted for the period 2000 to 2014. Pneumococcal clinical isolates were serotyped by Quellung reaction, and antimicrobial susceptibility testing was performed with the broth microdilution method. A total of 126 pneumococcal isolates were collected. Pneumonia was the most frequent diagnosis (40.5%), followed by meningitis (29.4%), septicemia (16.7%), and other clinical entities, including otitis media and conjunctivitis (13.5%). The most frequent serotypes before the introduction of heptavalent pneumococcal conjugate vaccine (PCV7) were 19F, 23F, 7F, and 35B. Serotypes 3, 6A, 10A, 12F, and 15A/B increased after the introduction of PCV7. Serotype 19A was isolated most frequently in the pneumonia and meningitis cases only after the introduction of PCV7, and it displayed a high resistance to penicillin. Although the number of infections in infants aged ≤60 days was low, such infections were not unusual events. New vaccination strategies should be evaluated to limit the risks in this age group.

Streptococcus pneumoniae colonisation in children and adolescents with asthma: impact of the heptavalent pneumococcal conjugate vaccine and evaluation of potential effect of thirteen-valent pneumococcal conjugate vaccine

BackgroundThe main aim of this study was to evaluate Streptococcus pneumoniae carriage in a group of school-aged children and adolescents with asthma because these results might indicate the theoretical risk of invasive pneumococcal disease (IPD) of such patients and the potential protective efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13).MethodsOropharyngeal samples were obtained from 423 children with documented asthma (300 males, 70.9 %), and tested for the autolysin-A-encoding (lytA) and the wzg (cpsA) gene of S. pneumoniae by means of real-time polymerase chain reaction.Results S. pneumoniae was identified in the swabs of 192 subjects (45.4 %): 48.4 % of whom were aged <10 years, 46.9 % aged 10–14 years, and 4.7 % aged ≥15 years (p < 0.001). Carriage was significantly less frequent among the children who had received recent antibiotic therapy (odds ratio [OR 0.41]; 95 % confidence interval [95 % CI] 0.22–0.76). Multivariate analyses showed no association between carriage and vaccination status, with ORs of 1.05 (95 % CI 0.70–1.58) for carriers of any pneumococcal serotype, 1.08 (95 % CI 0.72–1.62) for carriers of any of the serotypes included in 7-valent pneumococcal conjugate vaccine (PCV7), and 0.76 (95 % CI 0.45–1.28) for carriers of any of the six additional serotypes of PCV13. Serotypes 19 F, 4 and 9 V were the most frequently identified serotypes in vaccinated subjects.ConclusionsThese results showed that carriage of S. pneumoniae is relatively common in all school-aged children and adolescents with asthma, regardless of the severity of disease and the administration of PCV7 in the first years of life. This highlights the problem of the duration of the protection against colonisation provided by pneumococcal conjugate vaccine, and the importance of re-colonization by the same pneumococcal serotypes included in the previously used vaccine.

Impact of the Pneumococcal Conjugate Vaccine and Antibiotic Use on Nasopharyngeal Colonization by Antibiotic Nonsusceptible Streptococcus pneumoniae, Alaska, 2000[FIGURE DASH]2010.

We describe the relative impact of the heptavalent pneumococcal conjugate vaccine (PCV7, introduced 2001) and antibiotic use on colonization by antibiotic-resistant pneumococci in urban Alaskan children during 2000-2010. We obtained nasopharyngeal swab specimens from a convenience sample of children aged <5 years at clinics annually during 2000-2004 and 2008-2010. PCV7 status and antibiotic use <90 days before enrollment were determined by interview/medical records review. Pneumococci were characterized by serotype and susceptibility to penicillin (PCN). Isolates with full PCN resistance (PCN-R) or intermediate PCN resistance (PCN-I) were classified as PCN-NS. We recruited 3496 children (median, 452 per year). During 2000-2010, a range of 18-29% per year of children used PCN/amoxicillin (P value for trend = 0.09); the proportion age-appropriately vaccinated with PCV7 increased (0[FIGURE DASH]90%; P < 0.01). Among pneumococcal isolates, the PCV7-serotype proportion decreased (53-<1%; P < 0.01) and non[FIGURE DASH]PCV7-serotype proportion increased (43-95%; P < 0.01). PCN-R pneumococcal colonization prevalence decreased (23-9%; P < 0.01) and PCN-I pneumococcal colonization prevalence increased (13-24%; P < 0.01); overall PCN-NS pneumococcal colonization prevalence was unchanged. PCN-NS among colonizing PCV7-type and non[FIGURE DASH]PCV7-type pneumococci remained unchanged; a mean of 31% per year of PCV7-type and 10% per year of non[FIGURE DASH]PCV7-type isolates were PCN-R, and 10% per year of PCV7 and 20% per year of non[FIGURE DASH]PCV7-type isolates were PCN-I. Overall, PCN-NS pneumococcal colonization remained unchanged during 2000-2010 because increased colonization by predominantly PCN-I non-PCV7 serotypes offset decreased colonization by predominantly PCN-R PCV7 serotypes. Proportion PCN-NS did not increase within colonizing pneumococcal serotype groups (PCV7 vs. non-PCV7) despite stable PCN use in our population.

Antibiotic susceptibility of Streptococcus pneumoniae in healthy carrier children in Murcia (Spain)

Abstract Introduction and objectives Streptococcus pneumoniae (SP) is a human pathogen that involves a high use of antibiotics. The objective of the study was to determine the susceptibility to commonly used antibiotics and their associated risk factors, in order to promote rational use of antibiotics. Patients and methods In a multicentre study was conducted in summer 2009 and winter 2010 on children attending paediatric clinics in the Region of Murcia. A nasopharyngeal sample was collected and an epidemiological questionnaire was completed. The study included 1562 children aged 1 and 4 years old. Results Almost one-third (31.3%, 489/1562) of children were nasal carriers. A sensitivity study was carried out on 376 isolates, of which 343 were serotyped. Almost two-thirds (61.7%, 964/1562) of children had received at least one dose of PCV7 (heptavalent pneumococcal conjugate vaccine), and 12.8% (44/343) of the isolates belonged to PCV7 serotypes. The prevalence rates of penicillin resistance (meningitis infections criteria CMI > 0.06 mg/L) were 28.1%; however, this percentage was 54% in PCV7 serotypes. None of the isolates had (MIC > 2 mg/L), so prevalence rates of susceptibility with non-meningitis infections criteria were 100%. There was a high percentage of erythromycin resistance (45.7%). The factors favouring resistance to penicillin and cefotaxime were the consumption of antibiotics in the previous month and the carrying of vaccine serotypes. On the other hand, the age of 4 years old was a protective factor of resistance. The 14, 35B, 19A, 15A, and 19F serotypes were less susceptible to penicillin. Conclusions Both oral amoxicillin given to outpatients and intravenous penicillin or ampicillin to hospitalized patients are excellent options for the treatment of non-meningeal infections, as seen with pneumonia in these kinds of environments, where there is low incidence of isolates highly resistant to penicillin (CMI ≥ 2 mg/L).

The impact of heptavalent pneumococcal conjugate vaccine on the incidence of childhood community-acquired pneumonia and bacteriologically confirmed pneumococcal pneumonia in Japan.

Heptavalent pneumococcal conjugate vaccine (PCV7) was introduced to Japan in 2010. We investigated the impact of PCV7 on childhood community-acquired pneumonia (CAP) and pneumococcal pneumonia (PP). Children aged <5 years living in Chiba city, Japan, who were admitted to hospitals were enrolled to estimate the incidence of CAP based on the mid-year population. PP was determined by the presence of Streptococcus pneumoniae in cultured blood and/or sputum samples of CAP patients. The incidence of CAP and S. pneumoniae isolated from PP patients was compared before (April 2008-March 2009) and after (April 2012-March 2013) the introduction of PCV7 immunization. The annual incidence of CAP was reduced [incidence rate ratio 0·81, 95% confidence interval (CI) 0·73-0·90]. When comparing post-vaccine with pre-vaccine periods, the odds ratio for PP incidence was 0·60 (95% CI 0·39-0·93, P = 0·024). PCV7-covered serotypes markedly decreased (66·6% in pre-vaccine vs. 15·6% in post-vaccine, P < 0·01), and serotypes 6C, 15A, 15C and 19A increased. Multidrug-resistant international clones in the pre-vaccine period (Spain6B-2/ST90, Taiwan19F-14/ST236) decreased, while Sweden15A-25/ST63 was the dominant clone in the post-vaccine period. A significant reduction in the incidence of both CAP hospitalizations and culture-confirmed PP of vaccine serotypes was observed at 2 years after PCV7 vaccination.

Pharyngeal colonization by Streptococcus pneumoniae in older children and adolescents in a geographical area characterized by relatively limited pneumococcal vaccination coverage.

The aim of this study was to evaluate the relation between colonization and vaccination status with pneumococcal conjugate vaccine (PCV) in older children and adolescents living in an area characterized by relatively limited vaccination coverage. Oropharyngeal swabs were obtained from 2076 randomly selected healthy school-age children and adolescents, and the extracted genomic DNA was tested for Streptococcus pneumoniae by means of real-time polymerase chain reaction. All of the positive cases were subsequently serotyped, and the association between vaccination status with the heptavalent PCV (PCV7) and pneumococcal colonization was determined. S. pneumoniae was identified in the oropharyngeal swabs of 1201 subjects (57.9%), and its prevalence declined with age (74.9% in subjects aged <10 years, 51.8% in those aged 10-14 years and 32.7% in those aged ≥15 years; P < 0.001). There were more carriers of any pneumococcal serotype, any of the serotypes in PCV7, or any of the 6 additional serotypes in 13-valent PCV (PCV13) among the vaccinated than the unvaccinated subjects, but no association emerged after adjustment for age and other selected covariates. Sub-analyses by serotype and age groups revealed significant differences in the case of serotypes 3 and 19A among children aged <10 years (odds ratios of 2.03 and 2.18, respectively). These results show the absence of any long-term effect of PCV7 on colonization, and raise doubts concerning the recent suggestion to use carriage to evaluate the efficacy of PCVs. The high prevalence of carriers in all of the age groups independent of previous pneumococcal vaccination indicates that further studies are needed to evaluate whether the extensive use of PCVs in healthy older children and adolescents might reduce pharyngeal colonization of these subjects thereby increasing herd immunity.

The risk of pneumococcal infections after immunization with pneumococcal conjugate vaccine compared to non-vaccinated inflammatory arthritis patients

Objectives: To examine the risk of putative pneumococcal infections in adult arthritis patients on different anti-rheumatic drugs immunized with heptavalent pneumococcal conjugate vaccine (Prevenar 7; PCV7) and non-vaccinated individually matched arthritis patients.Method: All individuals in a cohort of 505 patients with rheumatoid arthritis (RA) or spondylarthropathy (SpA) receiving different anti-rheumatic treatments were immunized with a single dose of PCV7 (exposed group). Of these, 497 patients (RA = 248; SpA = 249) were included. For each vaccinated patient, we identified four reference subjects (n = 1988) from the same geographic area, individually matched for age, gender, and diagnosis. These were considered unexposed to conjugated pneumococcal vaccination. The Skåne Healthcare Register (SHR) was searched for all individuals seeking health care for putative pneumococcal infections occurring 4 years before vaccination and up to 4.5 years after vaccination using ICD-10 diagnostic codes. The following infections were considered as serious cases: pneumonia, other lower respiratory infections, meningitis, sepsis, and septic arthritis. The relative risk (RR) of infection was calculated as the number of events after/number of events before vaccination. Ratios of relative risk (RRRs) were calculated between vaccinated and non-vaccinated groups of patients. A generalized estimating equation (GEE) was used to handle correlated data for several events in the same individual.Results: Although statistically non-significant, the point estimate of the RRR [0.55, 95% confidence interval (CI) 0.25–1.22] suggested a reduced risk of serious pneumococcal infections in vaccinated patients compared to the unexposed group.Conclusions: Vaccination with PCV7 tended to reduce the risk of putative serious pneumococcal infections by about 45% compared to non-vaccinated patients in this observational cohort study.

Streptococcus pneumoniae Serotypes Identified in Mexican Children with Invasive Disease Before and After the Introduction of PCV7 (1993–2012)

Streptococcus pneumoniae is the leading cause of acute otitis media, pneumonia, meningitis, and sepsis. The heptavalent pneumococcal conjugate vaccine (PCV7) was incorporated into the national immunization program in Mexico in 2008. The aim of the study was to analyze the frequency of S. pneumoniae serotypes isolated from children ≤5 years of age with invasive diseases before and after the introduction of PCV7. Isolates from sterile fluids, tissues and other body fluids were obtained from 1993 to 2012. Isolates collected in hospitals for the surveillance network were sent to the Instituto Nacional de Salud Publica. Serotyping was done using the Quellung reaction. The pre-vaccination period was considered from 1993-2007. A total of 1346 isolates were collected during 1993-2012. In the pre-vaccination era, serotypes included in PCV7 accounted for 59.7% of the strains, whereas in 2012 they represented only 21% of cases. There was a significant decrease in all PCV7-included serotypes. A gradual increase of the 19A serotype was detected during the vaccination period from 7% in 2008 to 39% of the isolates in 2012. In this year, 29% of the serotypes causing invasive disease were not included in any of the pneumococcal conjugate vaccines. The emergence of PCV7 non-included serotypes after vaccination demands increased surveillance. Currently in Mexico, the 13-valent conjugate vaccine (PCV13) offers better coverage than the 10-valent pneumococcal conjugate vaccine (PCV10).

Impact of Seven Valent Pneumococcal Conjugate Vaccine on Nasopharyngeal Carriage in Young Children in Okinawa, Japan

In Japan, the heptavalent pneumococcal conjugate vaccine (PCV7) became available in February 2010 and was subsidized by the national funding system from May 2011 in Okinawa, after which it was incorporated into the national immunization practice (NIP) in April 2013 using a 3 + 1 schedule for all infants. We conducted an annual survey in 2012 to determine the effect of PCV7 on nasopharyngeal colonization by pneumococcal serotypes and to analyze the risk factors for colonization in infants. Nasopharyngeal swabs for pneumococcal isolation and serotyping were obtained from infant 2 to 22 months of age before and after PCV7 immunization among 4 clinics in Okinawa, Japan. Between January 2012 and December 2012, nasopharyngeal swabs for bacterial cultures were obtained among 782 infants aged 2 to 22 months old and demographic data was obtained among 725 participant infants. Among the 725 evaluable infants, 193 pneumococcal strains were detected in 180 infants for an overall nasopharyngeal carriage of 24.8%. The main capsular serotypes isolated were 6C (16.1%), 19A (12.4%) and 15B (9.8%). Carriage of PCV7 serotypes accounted for 21.8% (42/193). The result of multivariate data analysis showed the pneumococcal carriage rate of non-PCV7 serotypes was significantly (P < 0.001) high in infant with siblings and daycare attendance. On the other hand, the result of multivariate data analysis showed that carriage rate of PCV7 serotype had only significantly high risk in infant with siblings and did not have a significant risk dependent on age and daycare attendance. Carriage PCV7 serotypes increased in the presence of other siblings, while PCV7 vaccination was shown to eliminate daycare attendance as a risk. The results of this study demonstrates that PCV7 vaccination decrease the overall nasopharyngeal carriage of PCV7 serotypes in vaccinated children including children at risk such as children attending day-care centers.

Impacts of the 13-Valent Pneumococcal Conjugate Vaccine in Children.

Applications of the heptavalent pneumococcal conjugate vaccine (PCV7) in the pediatric immunization schedule have dramatically reduced the incidence of pneumococcal diseases in both vaccinated children and unvaccinated individuals of all ages. However, increased infections caused by non-PCV7 serotypes have been reported by several groups. To overcome this problem, new vaccines covering more serotypes including the emerging serotypes have been developed. The 13-valent pneumococcal conjugate vaccine (PCV13) currently covers the 7 PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) and 6 additional serotypes 1, 3, 5, 6A, 7F, and 19A. After the first year of PCV13 applications in the immunization schedule in young children, global evaluation studies demonstrated that PCV13 provided a wider coverage and more effective prevention than PCV7 against invasive pneumococcal diseases (IPDs), mucosal pneumococcal diseases, and pneumococcal carriage. We reviewed the effects of PCV13 in the control of pneumococcal diseases in children based on previous studies.