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1.  Effects of Community-Wide Vaccination with PCV-7 on Pneumococcal Nasopharyngeal Carriage in The Gambia: A Cluster-Randomized Trial 
PLoS Medicine  2011;8(10):e1001107.
In a cluster-randomized trial conducted in Gambian villages, Anna Roca and colleagues find that vaccination of children with pneumococcal conjugate vaccines reduced vaccine-type pneumococcal carriage even among nonvaccinated older children and adults.
Background
Introduction of pneumococcal conjugate vaccines (PCVs) of limited valency is justified in Africa by the high burden of pneumococcal disease. Long-term beneficial effects of PCVs may be countered by serotype replacement. We aimed to determine the impact of PCV-7 vaccination on pneumococcal carriage in rural Gambia.
Methods and Findings
A cluster-randomized (by village) trial of the impact of PCV-7 on pneumococcal nasopharyngeal carriage was conducted in 21 Gambian villages between December 2003 to June 2008 (5,441 inhabitants in 2006). Analysis was complemented with data obtained before vaccination. Because efficacy of PCV-9 in young Gambian children had been shown, it was considered unethical not to give PCV-7 to young children in all of the study villages. PCV-7 was given to children below 30 mo of age and to those born during the trial in all study villages. Villages were randomized (older children and adults) to receive one dose of PCV-7 (11 vaccinated villages) or meningococcal serogroup C conjugate vaccine (10 control villages). Cross-sectional surveys (CSSs) to collect nasopharyngeal swabs were conducted before vaccination (2,094 samples in the baseline CSS), and 4–6, 12, and 22 mo after vaccination (1,168, 1,210, and 446 samples in CSS-1, -2, and -3, respectively).
A time trend analysis showed a marked fall in the prevalence of vaccine-type pneumococcal carriage in all age groups following vaccination (from 23.7% and 26.8% in the baseline CSS to 7.1% and 8.5% in CSS-1, in vaccinated and control villages, respectively). The prevalence of vaccine-type pneumococcal carriage was lower in vaccinated than in control villages among older children (5 y to <15 y of age) and adults (≥15 y of age) at CSS-2 (odds ratio [OR] = 0.15 [95% CI 0.04–0.57] and OR = 0.32 [95% CI 0.10–0.98], respectively) and at CSS-3 (OR = 0.37 [95% CI 0.15–0.90] for older children, and 0% versus 7.6% for adults in vaccinated and control villages, respectively). Differences in the prevalence of non-vaccine-type pneumococcal carriage between vaccinated and control villages were small.
Conclusions
Vaccination of Gambian children reduced vaccine-type pneumococcal carriage across all age groups, indicating a “herd effect” in non-vaccinated older children and adults. No significant serotype replacement was detected.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The prevention of pneumococcal disease, especially in children in developing countries, is a major international public health priority. Despite all the international attention on the UN's Millennium Development Goal 4—to reduce deaths in children under five years by two-thirds between 1990 and 2015—pneumonia, sepsis, and meningitis together compose more than 25% of the 10 million deaths occurring in children less than five years of age. Streptococcus pneumoniae is a leading bacterial cause of these diseases, and the World Health Organization estimates that approximately 800,000 children die each year of invasive pneumococcal disease.
Pneumococcal conjugate vaccines are currently available and protect against the serotypes that most commonly cause invasive pneumococcal disease in young children in North America and Europe. Such vaccines have been highly successful in reducing the incidence of invasive pneumococcal disease in both vaccinated children and in the non-vaccinated older population by reducing nasopharyngeal carriage (presence of pneumococcal bacteria in the back of the nose) in vaccinated infants, resulting in decreased transmission to contacts—the so-called herd effect. However, few countries with the highest burden of invasive pneumococcal disease, especially those in sub-Saharan Africa, have introduced the vaccine into their national immunization programs.
Why Was This Study Done?
The features of pneumococcal nasopharyngeal carriage and invasive pneumococcal disease in sub-Saharan Africa are different than in other regions. Therefore, careful evaluation of the immune effects of vaccination requires long-term, longitudinal studies. As an alternative to such long-term observational studies, and to anticipate the potential long-term effects of the introduction of pneumococcal conjugate vaccination in sub-Saharan Africa, the researchers conducted a cluster-randomized (by village) trial in The Gambia in which the whole populations of some villages were immunized with the vaccine PCV-7, and other villages received a control.
What Did the Researchers Do and Find?
With full consent from communities, the researchers randomized 21 similar villages in a rural region of western Gambia to receive pneumococcal conjugate vaccine or a control—meningococcal serogroup C conjugated vaccine, which is unlikely to affect pneumococcal carriage rates. For ethical reasons, the researchers only randomized residents aged over 30 months—all young infants received PCV-7, as a similar vaccine had already been shown to be effective in young infants. Before immunization began, the researchers took nasopharyngeal swabs from a random selection of village residents to determine the baseline pneumococcal carriage rates of both the serotypes of pneumococci covered by the vaccine (vaccine types, VTs) and the serotypes of pneumococci not covered in the vaccine (non-vaccine types, NVTs). The researchers then took nasopharyngeal swabs from a random sample of 1,200 of village residents in both groups of villages in cross-sectional surveys at 4–6, 12, and 22 months after vaccination. Villagers and laboratory staff were unaware of which vaccine was which (that is, they were blinded).
Before immunization, the overall prevalence of pneumococcal carriage in both groups was high, at 71.1%, and decreased with age. After vaccination, the overall prevalence of pneumococcal carriage in all three surveys was similar between vaccinated and control villages, showing a marked fall. However, the prevalence of carriage of VT pneumococci was significantly lower in vaccinated than in control villages in all surveys for all age groups. The prevalence of carriage of NVT pneumococci was similar in vaccinated and in control villages, except for a slightly higher prevalence of NVT pneumococci among vaccinated communities in adults at 4–6 months after vaccination. The researchers also found that the overall prevalence of pneumococcal carriage fell markedly after vaccination and reached minimum levels at 12 months in both study arms and in all age groups.
What Do These Findings Mean?
These findings show that vaccination of young Gambian children reduced carriage of VT pneumococci in vaccinated children but also in vaccinated and non-vaccinated older children and adults, revealing a potential herd effect from vaccination of young children. Furthermore, the immunological pressure induced by vaccinating whole communities did not lead to a community-wide increase in carriage of NVT pneumococci during a two-year period after vaccination. The researchers plan to conduct more long-term follow-up studies to determine nasopharyngeal carriage in these communities.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001107.
The World Health Organization has information about pneumococcus
The US Centers for Disease Control and Prevention provides information about pneumococcal conjugate vaccination
doi:10.1371/journal.pmed.1001107
PMCID: PMC3196470  PMID: 22028630
2.  Effect of Pneumococcal Conjugate Vaccination on Serotype-Specific Carriage and Invasive Disease in England: A Cross-Sectional Study 
PLoS Medicine  2011;8(4):e1001017.
A cross sectional study by Stefan Flasche and coworkers document the serotype replacement of Streptococcus pneumoniae that has occurred in England since the introduction of PCV7 vaccination.
Background
We investigated the effect of the 7-valent pneumococcal conjugate vaccine (PCV7) programme in England on serotype-specific carriage and invasive disease to help understand its role in serotype replacement and predict the impact of higher valency vaccines.
Methods and Findings
Nasopharyngeal swabs were taken from children <5 y old and family members (n = 400) 2 y after introduction of PCV7 into routine immunization programs. Proportions carrying Streptococcus pneumoniae and serotype distribution among carried isolates were compared with a similar population prior to PCV7 introduction. Serotype-specific case∶carrier ratios (CCRs) were estimated using national data on invasive disease. In vaccinated children and their contacts vaccine-type (VT) carriage decreased, but was offset by an increase in non-VT carriage, with no significant overall change in carriage prevalence, odds ratio 1.06 (95% confidence interval 0.76–1.49). The lower CCRs of the replacing serotypes resulted in a net reduction in invasive disease in children. The additional serotypes covered by higher valency vaccines had low carriage but high disease prevalence. Serotype 11C emerged as predominant in carriage but caused no invasive disease whereas 8, 12F, and 22F emerged in disease but had very low carriage prevalence.
Conclusion
Because the additional serotypes included in PCV10/13 have high CCRs but low carriage prevalence, vaccinating against them is likely to significantly reduce invasive disease with less risk of serotype replacement. However, a few serotypes with high CCRs could mitigate the benefits of higher valency vaccines. Assessment of the effect of PCV on carriage as well as invasive disease should be part of enhanced surveillance activities for PCVs.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pneumococcal diseases—major causes of illness and death in children and adults worldwide—are caused by Streptococcus pneumoniae, a bacterium that often colonizes the nasopharynx (the area of the throat behind the nose). Carriage of S. pneumoniae bacteria does not necessarily cause disease. However, these bacteria can cause local, noninvasive diseases such as ear infections and sinusitis and, more rarely, they can spread into the lungs, the bloodstream, or the covering of the brain, where they cause pneumonia, septicemia, and meningitis, respectively. Although these invasive pneumococcal diseases (IPDs) can be successfully treated if administered early, they can be fatal. Consequently, it is better to protect people against IPDs through vaccination than risk infection. Vaccination primes the immune system to recognize and attack disease-causing organisms (pathogens) rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules (antigens) that it recognizes as foreign.
Why Was This Study Done?
There are more than 90 S. pneumoniae variants or “serotypes” characterized by different polysaccharide (complex sugar) coats, which trigger the immune response against S. pneumoniae and determine each serotype's propensity to cause IPD. The pneumococcal conjugate vaccine PCV7 contains polysaccharides (linked to a protein carrier) from the seven serotypes mainly responsible for IPD in the US in 2000 when routine childhood PCV7 vaccination was introduced in that country. PCV7 prevents both IPD caused by the serotypes it contains and carriage of these serotypes, which means that, after vaccination, previously uncommon, nonvaccine serotypes can colonize the nasopharynx. If these serotypes have a high invasiveness potential, then “serotype replacement” could reduce the benefits of vaccination. In this cross-sectional study (a study that investigates the relationship between a disease and an intervention in a population at one time point), the researchers investigate the effect of the UK PCV7 vaccination program (which began in 2006) on serotype-specific carriage and IPD in England to understand the role of PCV7 in serotype replacement and to predict the likely impact of vaccines containing additional serotypes (higher valency vaccines).
What Did the Researchers Do and Find?
The researchers examined nasopharyngeal swabs taken from PCV7-vaccinated children and their families for S. pneumoniae, determined the serotype of any bacteria they found, and compared the proportion of people carrying S. pneumoniae (carrier prevalence) and the distribution of serotypes in this study population and in a similar population that was studied in 2000/2001, before the PCV vaccination program began. Overall, there was no statistically significant change in carrier prevalence, but carriage of vaccine serotypes decreased in vaccinated children and their contacts whereas carriage of nonvaccine serotypes increased. The serotype-specific case-to-carrier ratios (CCRs; a measure of serotype invasiveness that was estimated using national IPD data) of the replacing serotypes were generally lower than those of the original serotypes, which resulted in a net reduction in IPD in children. Moreover, before PCV7 vaccination began, PCV7-included serotypes were responsible for similar proportions of pneumococcal carriage and disease; afterwards, the additional serotypes present in the higher valency vaccines PVC10 and PVC13 were responsible for a higher proportion of disease than carriage. Finally, three serotypes not present in the higher valency vaccines with outstandingly high CCRs (high invasiveness potential) are identified.
What Do These Findings Mean?
These findings document the serotype replacement of S. pneumoniae that has occurred in England since the introduction of PCV7 vaccination and highlight the importance of assessing the effects of pneumococcal vaccines on carriage as well as on IPDs. Because the additional serotypes included in PCV10 and PCV13 have high CCRs but low carriage prevalence and because most of the potential replacement serotypes have low CCRs, these findings suggest that the introduction of higher valency vaccines should further reduce the occurrence of invasive disease with limited risk of additional serotype replacement. However, the emergence of a few serotypes that have high CCRs but are not included in PCV10 and PCV13 might mitigate the benefits of higher valency vaccines. In other words, although the recent introduction of PCV13 into UK vaccination schedules is likely to have an incremental benefit on the reduction of IPD compared to PCV7, this benefit might be offset by increases in the carriage of some high CCR serotypes. These serotypes should be considered for inclusion in future vaccines.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001017.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination
The US National Foundation for Infectious Diseases has a fact sheet on pneumococcal diseases
The UK Health Protection Agency provides information on pneumococcal disease and on pneumococcal vaccines
The World Health Organization also provides information on pneumococcal vaccines
MedlinePlus has links to further information about pneumococcal infections (in English and Spanish)
doi:10.1371/journal.pmed.1001017
PMCID: PMC3071372  PMID: 21483718
3.  The dynamics of nasopharyngeal streptococcus pneumoniae carriage among rural Gambian mother-infant pairs 
BMC Infectious Diseases  2010;10:195.
Background
Streptococcus pneumoniae is an important cause of community acquired pneumonia, sepsis, meningitis and otitis media globally and has been incriminated as a major cause of serious childhood bacterial infections in The Gambia. Better understanding of the dynamics of transmission and carriage will inform control strategies.
Methods
This study was conducted among 196 mother-infant pairs recruited at birth from six villages in the West Kiang region of The Gambia. Nasopharyngeal swabs were collected from mother-infant pairs at birth (within 12 hours of delivery), 2, 5 and 12 months. Standard techniques of culture were used to identify carriage and serotype S. pneumoniae.
Results
Of 46 serotypes identified, the 6 most common, 6A, 6B, 14, 15, 19F and 23F, accounted for 67.3% of the isolates from infants. Carriage of any serotype among infants rose from 1.5% at birth to plateau at approximately 80% by 2 m (prevalence at 2 m = 77%; 5 m = 86%; 12 m = 78%). Likewise, maternal carriage almost doubled in the first 2 months post-partum and remained elevated for the next 10 m (prevalence at birth = 13%; 2 m = 24%; 5 m = 22%; 12 m = 21%). Carriage was significantly seasonal in both infants and mothers with a peak in December and lowest transmission in August. The total number of different serotypes we isolated from each infant varied and less than would be expected had the serotypes assorted independently. In contrast, this variability was much as expected among mothers. The half-life of a serotype colony was estimated to be 1.90 m (CI95%: 1.66-2.21) in infants and 0.75 m (CI95%: 0.55-1.19) in mothers. While the odds for a serotype to be isolated from an infant increased by 9-fold if it had also been isolated from the mother, the population attributable fraction (PAF) of pneumococcal carriage in infants due to maternal carriage was only 9.5%. Some marked differences in dynamics were observed between vaccine and non-vaccine serotypes.
Conclusions
Colonisation of the nasopharynx in Gambian infants by S. pneumoniae is rapid and highly dynamic. Immunity or inter-serotype competition may play a role in the dynamics. Reducing mother-infant transmission would have a minimal effect on infant carriage.
doi:10.1186/1471-2334-10-195
PMCID: PMC2910019  PMID: 20602782
4.  Age-Specific Cluster of Cases of Serotype 1 Streptococcus pneumoniae Carriage in Remote Indigenous Communities in Australia ▿  
Seven-valent pneumococcal conjugate vaccination commenced in 2001 for Australian indigenous infants. Pneumococcal carriage surveillance detected substantial replacement with nonvaccine serotypes and a cluster of serotype 1 carriage. Our aim was to review Streptococcus pneumoniae serotype 1 carriage and invasive pneumococcal disease (IPD) data for this population and to analyze serotype 1 isolates. Carriage data were collected between 1992 and 2004 in the Darwin region, one of the five regions in the Northern Territory. Carriage data were also collected in 2003 and 2005 from four regions in the Northern Territory. Twenty-six cases of serotype 1 IPD were reported from 1994 to 2007 in the Northern Territory. Forty-four isolates were analyzed by BOX typing and 11 by multilocus sequence typing. In the Darwin region, 26 children were reported carrying serotype 1 (ST227) in 2002 but not during later surveillance. Scattered cases of serotype 1 carriage were noted in two other regions. Cocolonization of serotype 1 with other pneumococcal serotypes was common (34% serotype 1-positive swabs). In conclusion, pneumococcal carriage studies detected intermittent serotype 1 carriage and an ST227 cluster in children in indigenous communities in the Northern Territory of Australia. There was no apparent increase in serotype 1 IPD during this time. The rate of serotype 1 cocolonization with other pneumococcal serotypes suggests that carriage of this serotype may be underestimated.
doi:10.1128/CVI.00283-08
PMCID: PMC2643542  PMID: 19091995
5.  The descriptive epidemiology of Streptococcus pneumoniae and Haemophilus influenzae nasopharyngeal carriage in children and adults in Kilifi District, Kenya 
Background
Transmission and nasopharyngeal colonization are necessary steps en route to invasive pneumococcal or Haemophilus influenzae disease but their patterns vary geographically. In East Africa we do not know how these pathogens are transmitted between population sub-groups nor which serotypes circulate commonly.
Methods
We did two cross-sectional nasopharyngeal swab surveys selecting subjects randomly from a population register to estimate prevalence and risk-factors for carriage in 2004. H. influenzae type b vaccine was introduced in 2001.
Results
Of 450 individuals sampled in the dry season, 414 were resampled during the rainy season. Among subjects 0-4, 5-9 and 10-85 years old pneumococcal carriage prevalence was 57%, 41% and 6.4%, respectively. H. influenzae prevalence was 26%, 24% and 3.0%, respectively. Prevalence of H. influenzae type b in children <5 years was 1.7%. Significant risk factors for pneumococcal carriage were rainy season (OR 1.65), coryza (OR 2.29) and co-culture of non-capsulate H. influenzae (OR 7.46). Coryza was also a risk factor for H. influenzae carriage (OR 1.90). Of 128 H. influenzae isolates 113 were non-capsulate. Among 279 isolates of Streptococcus pneumoniae 40 serotypes were represented and the distribution of serotypes varied significantly with age; 7-valent vaccine-types, vaccine-related types and non-vaccine types comprised 47%, 19% and 34% of strains from children aged <5 years. Among older persons they comprised 25%, 28% and 47%, respectively (p=0.005).
Conclusions
The study shows that pneumococcal carriage is common up to 9 years of age and that the majority of serotypes carried at all ages, are not covered specifically by the 7-valent pneumococcal conjugate vaccine.
doi:10.1097/INF.0b013e31814da70c
PMCID: PMC2382474  PMID: 18162940
Nasopharyngeal carriage; Streptococcus pneumoniae; Haemophilus influenzae; developing country; children; adults; serotypes
6.  Dynamics of pneumococcal nasopharyngeal carriage in healthy children attending a day care center in northern Spain. influence of detection techniques on the results 
Background
Pneumococcal nasopharyngeal carriage precedes invasive infection and is the source for dissemination of the disease. Differences in sampling methodology, isolation or identification techniques, as well as the period (pre -or post-vaccination) when the study was performed, can influence the reported rates of colonization and the distribution of serotypes carried.
Objectives
To evaluate the prevalence and dynamics of pneumococcal nasopharyngeal colonization in healthy children aged 6-34 months attending a day care center with a high level of hygiene and no overcrowding. The study was performed 3-4 years after the 7-valent pneumococcal vaccine was introduced, using multiple methodologies to detect and characterize the isolates.
Methods
Over 12 months, 25 children were sampled three times, 53 children twice and 27 children once. Three Streptococcus pneumoniae typing techniques were used: Quellung, Pneumotest-Latex-kit and multiplex-polymerase chain reaction (PCR). The similarity of isolates of the same serotype was established by pulsed field gel electrophoresis (PFGE) and occasionally the multilocus sequence type (ST) was also determined.
Results
Overall pneumococcal carriage and multiple colonization rates were 89.5% (94/105) and 39%, respectively. Among 218 pneumococci detected, 21 different serotypes and 13 non-typeable isolates were found. The most prevalent serotypes were 19A, 16F and 15B. Serotypes 15B, 19A and 21 were mainly found as single carriage; in contrast serotypes 6B, 11A and 20, as well as infrequent serotypes, were isolated mainly as part of multiple carriage. Most 19A isolates were ST193 but most serotypes showed high genetic heterogeneity. Changes in the pneumococci colonizing each child were frequent and the same serotype detected on two occasions frequently showed a different genotype. By multiplex-PCR, 100% of pneumococci could be detected and 94% could be serotyped versus 80.3% by the Quellung reaction and Pneumotest-Latex in combination (p < 0.001).
Conclusions
Rates of S. pneumoniae carriage and multiple colonization were very high. Prevalent serotypes differed from those found in similar studies in the pre-vaccination period. In the same child, clearance of a pneumococcal strain and acquisition of a new one was frequent in a short period of time. The most effective technique for detecting pneumococcal nasopharyngeal carriers was multiplex-PCR.
doi:10.1186/1471-2334-12-69
PMCID: PMC3383471  PMID: 22440017
Streptococcus pneumoniae; Cocolonization; Multiple colonization; Multiplex-PCR; Quellung reaction; Pneumotest-Latex kit
7.  A prospective study of urinary pneumococcal antigen detection in healthy Karen mothers with high rates of pneumococcal nasopharyngeal carriage 
BMC Infectious Diseases  2011;11:108.
Background
Detection of Streptococcus pneumoniae C-polysaccharide in urine is a useful rapid diagnostic test for pneumococcal infections in adults. In young children, high rates of false positive results have been documented due to detection of concurrent nasopharyngeal pneumococcal carriage. The relationship between pneumococcal carriage and urinary antigen detection in adults from developing countries with high pneumococcal carriage prevalence has not been well established.
Methods
We nested an evaluation of the BinaxNOW S. pneumoniae test within a longitudinal mother-infant pneumococcal carriage study in Karen refugees on the Thailand-Myanmar border. Paired urine and nasopharyngeal swab specimens were collected from 98 asymptomatic women at a routine study follow-up visit. The urine specimens were analyzed with the BinaxNOW test and the nasopharyngeal swabs were semi-quantitatively cultured to identify pneumococcal colonization.
Results
24/98 (25%) women were colonized by S. pneumoniae but only three (3%) had a positive BinaxNOW urine test. The sensitivity of the BinaxNOW test for detection of pneumococcal colonization was 4.2% (95% CI: 0.1 - 21.1%) with a specificity of 97.3% (95% CI: 90.6 - 99.7%). Pneumococcal colonization was not associated with having a positive BinaxNOW test (odds ratio 1.6; 95% CI: 0.0 - 12.7; p = 0.7).
Conclusions
Significant numbers of false positive results are unlikely to be encountered when using the BinaxNOW test to diagnose pneumococcal infection in adults from countries with moderate to high rates of pneumococcal colonization.
doi:10.1186/1471-2334-11-108
PMCID: PMC3114734  PMID: 21521533
8.  The presence of the pilus locus is a clonal property among pneumococcal invasive isolates 
BMC Microbiology  2008;8:41.
Background
Pili were recently recognized in Streptococcus pneumoniae and implicated in the virulence of this bacterium, which led to the proposal of using these antigens in a future pneumococcal vaccine. However, pili were found to be encoded by the rlrA islet that was not universally distributed in the species. We examined the distribution of the pilus islet, using the presence of the rlrA gene as a marker for the locus, among a collection of invasive isolates recovered in Portugal and analyzed its association with capsular serotypes, clusters defined by the pulsed-field gel electrophoretic profiles (PFGE) and multilocus sequence types.
Results
Only a minority of the isolates were positive for the presence of the rlrA gene (27%). There was a high correspondence between the serotype and the presence or absence of rlrA (Wallace coefficient, W = 0.778). In particular, there was an association between the presence of rlrA and the vaccine serotypes 4, 6B, 9V and 14 whereas the gene was significantly absent from other serotypes, namely 1, 7F, 8, 12B and 23F, a group that included a vaccine serotype (23F) and serotype 1 associated with enhanced invasiveness. Even within serotypes, there was variation in the presence of the pilus islet between PFGE clones and a higher Wallace coefficient (W = 0.939) indicates that carriage of the islet is a clonal property of pneumococci. Analysis of rlrA negative isolates revealed heterogeneity in the genomic region downstream of the rfl gene, the region where the islet is found in other isolates, compatible with recent loss of the islet in some lineages.
Conclusion
The pilus islet is present in a minority of pneumococcal isolates recovered from human invasive infections and is therefore not an essential virulence factor in these infections. Carriage of the pilus islet is a clonal property of pneumococci that may vary between isolates expressing the same serotype and loss and acquisition of the islet may be ongoing.
doi:10.1186/1471-2180-8-41
PMCID: PMC2270847  PMID: 18307767
9.  Comparison of the Prevalence of Common Bacterial Pathogens in the Oropharynx and Nasopharynx of Gambian Infants 
PLoS ONE  2013;8(9):e75558.
Background
CRM- based pneumococcal conjugate vaccines generally have little impact on the overall prevalence of pneumococcal carriage because of serotype replacement. In contrast, protein vaccines could substantially reduce the overall prevalence of pneumococcal carriage with potential microbiological and clinical consequences. Therefore, trials of pneumococcal protein vaccines need to evaluate their impact on carriage of other potentially pathogenic bacteria in addition to the pneumococcus.
Methods
As a prelude to a trial of an investigational pneumococcal vaccine containing pneumococcal polysaccharide conjugates and pneumococcal proteins, the prevalence of carriage of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella species and Staphylococcus aureus in the nasopharynx of 1030 Gambian infants (median age 35 weeks) was determined. An oropharyngeal swab was obtained at the same time from the first 371 infants enrolled. Standard microbiological techniques were used to evaluate the bacterial flora of the pharynx and to compare that found in the oropharynx and in the nasopharynx.
Results
The overall pneumococcal carriage rate was high. Isolation rates of S. pneumoniae and Moraxella species were significantly higher using nasopharyngeal rather than oropharyngeal swabs (76.1% [95% CI 73.4%,78.7%] vs. 21.3% [95% CI 17.2%,25.8%] and 48.9% [95% CI 45.8%, 52.0%] vs. 20.5% % [95% CI 16.5%,25.0%] respectively). In contrast, S. aureus and H. influenzae were isolated more frequently from oropharyngeal than from nasopharyngeal swabs (65.0% [95% CI 59.9%, 69.8%] vs. 33.6% [95% CI 30.7%, 36.5%] and 31.8% [95% CI 16.5%, 25.0%] vs. 22.4% [95% CI 19.9%, 25.1%] respectively). No group A β haemolytic streptococci were isolated.
Conclusion
Collection of an oropharyngeal swab in addition to a nasopharyngeal swab will provide little additional information on the impact of a novel pneumococcal vaccine on pneumococcal carriage but it might provide additional, valuable information on the impact of the vaccine on the overall microbiota of the pharynx.
doi:10.1371/journal.pone.0075558
PMCID: PMC3781055  PMID: 24086570
10.  Nasopharyngeal carriage, serotype distribution and antimicrobial resistance of Streptococcus pneumoniae among children from Brazil before the introduction of the 10-valent conjugate vaccine 
BMC Infectious Diseases  2013;13:318.
Background
Streptococcus pneumoniae remains a major cause of childhood morbidity and mortality worldwide. Nasopharyngeal colonization plays an important role in the development and transmission of pneumococcal diseases, and infants and young children are considered to be the main reservoir of this pathogen. The aim of this study was to evaluate the rates and characteristics associated with nasopharyngeal carriage, the distribution of serotypes and the antimicrobial resistance profiles of Streptococcus pneumoniae among children in a large metropolitan area in Brazil before the introduction of the 10-valent pneumococcal conjugate vaccine.
Methods
Between March and June 2010, nasopharyngeal swabs were collected from 242 children aged <6 years attending one day care center and the emergency room of a pediatric hospital. Pneumococcal isolates were identified by conventional methods and serotypes were determined by a sequential multiplex PCR assay and/or the Quellung reaction. The antimicrobial susceptibilities of the pneumococci were assessed by the disk diffusion method. MICs for erythromycin and penicillin were also performed. Erythromycin resistance genes were investigated by PCR.
Results
The overall colonization rate was 49.2% and it was considerably higher among children in the day care center. Pneumococcal carriage was more common among day care attenders and cohabitants with young siblings. The most prevalent serotypes were 6B, 19F, 6A, 14, 15C and 23F, which accounted for 61.2% of the isolates. All isolates were susceptible to clindamycin, levofloxacin, rifampicin and vancomycin. The highest rate of non-susceptibility was observed for sulphamethoxazole-trimethoprim (51.2%). Penicillin non-susceptible pneumococci (PNSP) accounted for 27.3% of the isolates (MICs of 0.12-4 μg/ml). Penicillin non-susceptibility was strongly associated with serotypes 14 and 23F. Hospital attendance and the presence of respiratory or general symptoms were frequently associated with PNSP carriage. The two erythromycin-resistant isolates (MICs of 2 and 4 μg/ml) belonged to serotype 6A, presented the M phenotype and harbored the mef(A/E) gene.
Conclusions
Correlations between serotypes, settings and penicillin non-susceptibility were observed. Serotypes coverage projected for the 10-valent pneumococcal conjugate vaccine was low (45.5%), but pointed out the potential reduction of PNSP nasopharyngeal colonization by nearly 20%.
doi:10.1186/1471-2334-13-318
PMCID: PMC3718621  PMID: 23849314
Streptococcus pneumoniae; Nasopharyngeal carriage; Serotypes; Antimicrobial resistance; Pneumococcal conjugate vaccines
11.  Epidemiology of nasopharyngeal carriage of respiratory bacterial pathogens in children and adults: cross-sectional surveys in a population with high rates of pneumococcal disease 
BMC Infectious Diseases  2010;10:304.
Background
To determine the prevalence of carriage of respiratory bacterial pathogens, and the risk factors for and serotype distribution of pneumococcal carriage in an Australian Aboriginal population.
Methods
Surveys of nasopharyngeal carriage of Streptococcus pneumoniae, non-typeable Haemophilus influenzae, and Moraxella catarrhalis were conducted among adults (≥16 years) and children (2 to 15 years) in four rural communities in 2002 and 2004. Infant seven-valent pneumococcal conjugate vaccine (7PCV) with booster 23-valent pneumococcal polysaccharide vaccine was introduced in 2001. Standard microbiological methods were used.
Results
At the time of the 2002 survey, 94% of eligible children had received catch-up pneumococcal vaccination. 324 adults (538 examinations) and 218 children (350 examinations) were enrolled. Pneumococcal carriage prevalence was 26% (95% CI, 22-30) among adults and 67% (95% CI, 62-72) among children. Carriage of non-typeable H. influenzae among adults and children was 23% (95% CI, 19-27) and 57% (95% CI, 52-63) respectively and for M. catarrhalis, 17% (95% CI, 14-21) and 74% (95% CI, 69-78) respectively. Adult pneumococcal carriage was associated with increasing age (p = 0.0005 test of trend), concurrent carriage of non-typeable H. influenzae (Odds ratio [OR] 6.74; 95% CI, 4.06-11.2) or M. catarrhalis (OR 3.27; 95% CI, 1.97-5.45), male sex (OR 2.21; 95% CI, 1.31-3.73), rhinorrhoea (OR 1.66; 95% CI, 1.05-2.64), and frequent exposure to outside fires (OR 6.89; 95% CI, 1.87-25.4). Among children, pneumococcal carriage was associated with decreasing age (p < 0.0001 test of trend), and carriage of non-typeable H. influenzae (OR 9.34; 95% CI, 4.71-18.5) or M. catarrhalis (OR 2.67; 95% CI, 1.34-5.33). Excluding an outbreak of serotype 1 in children, the percentages of serotypes included in 7, 10, and 13PCV were 23%, 23%, and 29% (adults) and 22%, 24%, and 40% (2-15 years). Dominance of serotype 16F, and persistent 19F and 6B carriage three years after initiation of 7PCV is noteworthy.
Conclusions
Population-based carriage of S. pneumoniae, non-typeable H. influenzae, and M. catarrhalis was high in this Australian Aboriginal population. Reducing smoke exposure may reduce pneumococcal carriage. The indirect effects of 10 or 13PCV, above those of 7PCV, among adults in this population may be limited.
doi:10.1186/1471-2334-10-304
PMCID: PMC2974682  PMID: 20969800
12.  Prevalence and Clonal Distribution of pcpA, psrP and Pilus-1 among Pediatric Isolates of Streptococcus pneumoniae 
PLoS ONE  2012;7(7):e41587.
Streptococcus pneumoniae is the leading cause of vaccine-preventable deaths globally. The objective of this study was to determine the distribution and clonal type variability of three potential vaccine antigens: Pneumococcal serine-rich repeat protein (PsrP), Pilus-1, and Pneumococcal choline binding protein A (PcpA) among pneumococcal isolates from children with invasive pneumococcal disease and healthy nasopharyngeal carriers. We studied by Real-Time PCR a total of 458 invasive pneumococcal isolates and 89 nasopharyngeal pneumococcal isolates among children (total = 547 strains) collected in Barcelona, Spain, from January 2004 to July 2010. pcpA, psrP and pilus-1 were detected in 92.8%, 51.7% and 14.4% of invasive isolates and in 92.1%, 48.3% and 18% of carrier isolates, respectively. Within individual serotypes the prevalence of psrP and pilus-1 was highly dependent on the clonal type. pcpA was highly prevalent in all strains with the exception of those belonging to serotype 3 (33.3% in serotype 3 isolates vs. 95.1% in other serotypes; P<.001). psrP was significantly more frequent in those serotypes that are less apt to be detected in carriage than in disease; 58.7% vs. 39.1% P<.001. Antibiotic resistance was associated with the presence of pilus-1 and showed a negative correlation with psrP. These results indicate that PcpA, and subsequently Psrp and Pilus-1 together might be good candidates to be used in a next-generation of multivalent pneumococcal protein vaccine.
doi:10.1371/journal.pone.0041587
PMCID: PMC3404996  PMID: 22848535
13.  Comparison of Antibiotic Resistance and Serotype Composition of Carriage and Invasive Pneumococci among Bangladeshi Children: Implications for Treatment Policy and Vaccine Formulation 
Journal of Clinical Microbiology  2003;41(12):5582-5587.
The nasopharyngeal carriage of Streptococcus pneumoniae is thought to pose a risk for invasive pneumococcal diseases, and the evaluation of carriage strains is thus often used to inform antibiotic treatment and vaccination strategies for these diseases. In this study, the age-specific prevalences, resistance to antibiotics, and serotype distributions of 1,340 carriage strains were analyzed and compared to 71 pneumococcal strains isolated from the cerebrospinal fluid of children under 5 years old with meningitis. Overall, the nasal carriage rate was 47%. One-fourth (26%) of the infants under 1 month of age and one-half (48%) of the infants under 12 months of age were colonized with S. pneumoniae. Rural children were colonized earlier than those from urban areas. Approximately one-fourth and one-half of the cases of pneumococcal meningitis occurred in the first 3 and 6 months of life, respectively. The respective rates of resistance for carriage and meningitis strains to penicillin (7 and 3%), cotrimoxazole (77 and 69%), and erythromycin (2 and 1%) were similar, whereas chloramphenicol resistance was lower among carriage strains (3%) than among meningitis strains (15.5%). The predominant serogroups of carriage and invasive isolates were variable and widely divergent. Thus, hypothetical 7-, 9-, and 11-valent vaccines, based on the predominant carriage strains of the present study, would cover only 23, 26, and 30%, respectively, of the serotypes causing meningitis. Further, currently available 7-, 9-, and 11-valent vaccines would protect against only 26, 43, and 48%, respectively, of these meningitis cases. In conclusion, while the surveillance of carriage strains for resistance to antibiotics appears useful in the design of empirical treatment guidelines for invasive pneumococcal disease, data on the serotypes of carriage strains have limited value in vaccine formulation strategies, particularly for meningitis cases.
doi:10.1128/JCM.41.12.5582-5587.2003
PMCID: PMC308982  PMID: 14662944
14.  A Longitudinal Study of Streptococcus pneumoniae Carriage in a Cohort of Infants and Their Mothers on the Thailand-Myanmar Border 
PLoS ONE  2012;7(5):e38271.
Background
Pneumococcal disease is a major cause of childhood death. Almost a third of the world's children live in Southeast Asia, but there are few data from the region on pneumococcal colonization or disease. Our aim was to document the dynamics of pneumococcal carriage in a rural SE Asian birth cohort.
Methods
We studied 234 Karen mother-infant pairs in Northwestern Thailand. Infants were followed from birth and nasopharyngeal swabs were taken from mother and infant at monthly intervals until 24 months old.
Results
8,386 swabs were cultured and 4,396 pneumococci characterized. Infants became colonized early (median 45.5 days; 95% confidence interval [CI] 44.5-46.0) and by 24 months had a median of seven (range 0–15) carriage episodes. Maternal smoking and young children in the house were associated with earlier colonization (hazard ratio [HR] 1.5 (95% CI 1.1–2.1) and 1.4 (95% CI 1.0–1.9)). For the four commonest serotypes and non-typeable pneumococci, previous exposure to homologous or heterologous serotypes resulted in an extended interval to reacquisition of the same serotype. Previous colonization by serotypes 14 and 19F was also associated with reduced carriage duration if subsequently reacquired (HR [first reacquisition] 4.1 (95% CI 1.4–12.6) and 2.6 (1.5–4.7)). Mothers acquired pneumococci less frequently, and carried them for shorter periods, than infants (acquisition rate 0.5 vs. 1.1 /100 person-days, p<0.001; median duration 31.0 vs. 60.5 days, p = 0.001). 55.8% of pneumococci from infants were vaccine serotypes (13-valent pneumococcal conjugate vaccine, PCV13), compared with 27.5% from mothers (p<0.001). Non-typeable pneumococcal carriage was common, being carried at least once by 55.1% of infants and 32.0% of mothers.
Conclusions
Pneumococcal carriage frequency and duration are influenced by previous exposure to both homologous and heterologous serotypes. These data will inform vaccination strategies in this population.
doi:10.1371/journal.pone.0038271
PMCID: PMC3365031  PMID: 22693610
15.  Age-Dependent Prevalence of Nasopharyngeal Carriage of Streptococcus pneumoniae before Conjugate Vaccine Introduction: A Prediction Model Based on a Meta-Analysis 
PLoS ONE  2014;9(1):e86136.
Introduction
Data on the prevalence of nasopharyngeal carriage of S.pneumoniae in all age groups are important to help predict the impact of introducing pneumococcal conjugate vaccines (PCV) into routine infant immunization, given the important indirect effect of the vaccine. Yet most carriage studies are limited to children under five years of age. We here explore the association between carriage prevalence and serotype distribution in children aged ≥5 years and in adults compared to children.
Methods
We conducted a systematic review of studies providing carriage estimates across age groups in healthy populations not previously exposed to PCV, using MEDLINE and Embase. We used Bayesian linear meta-regression models to predict the overall carriage prevalence as well as the prevalence and distribution of vaccine and nonvaccine type (VT and NVT) serotypes in older age groups as a function of that in <5 y olds.
Results
Twenty-nine studies compromising of 20,391 individuals were included in the analysis. In all studies nasopharyngeal carriage decreased with increasing age. We found a strong positive linear association between the carriage prevalence in pre-school childen (<5 y) and both that in school aged children (5–17 y olds) and in adults. The proportion of VT serotypes isolated from carriers was consistently lower in older age groups and on average about 73% that of children <5 y among 5–17 y olds and adults respectively. We provide a prediction model to infer the carriage prevalence and serotype distribution in 5–17 y olds and adults as a function of that in children <5 years of age.
Conclusion
Such predictions are helpful for assessing the potential population-wide effects of vaccination programmes, e.g. via transmission models, and thus assist in the design of future pneumococcal conjugate vaccination strategies.
doi:10.1371/journal.pone.0086136
PMCID: PMC3900487  PMID: 24465920
16.  Pneumococcal Nasopharyngeal Carriage following Reduced Doses of a 7-Valent Pneumococcal Conjugate Vaccine and a 23-Valent Pneumococcal Polysaccharide Vaccine Booster▿ †  
Clinical and Vaccine Immunology : CVI  2010;17(12):1970-1976.
This study was conducted to evaluate the effect of a reduced-dose 7-valent pneumococcal conjugate vaccine (PCV) primary series followed by a 23-valent pneumococcal polysaccharide vaccine (23vPPS) booster on nasopharyngeal (NP) pneumococcal carriage. For this purpose, Fijian infants aged 6 weeks were randomized to receive 0, 1, 2, or 3 PCV doses. Within each group, half received 23vPPS at 12 months. NP swabs were taken at 6, 9, 12, and 17 months and were cultured for Streptococcus pneumoniae. Isolates were serotyped by multiplex PCR and a reverse line blot assay. There were no significant differences in PCV vaccine type (VT) carriage between the 3- and 2-dose groups at 12 months. NP VT carriage was significantly higher (P, <0.01) in the unvaccinated group than in the 3-dose group at the age of 9 months. There appeared to be a PCV dose effect in the cumulative proportion of infants carrying the VT, with less VT carriage occurring with more doses of PCV. Non-PCV serotype (NVT) carriage rates were similar for all PCV groups. When groups were pooled by receipt or nonreceipt of 23vPPS at 12 months, there were no differences in pneumococcal, VT, or NVT carriage rates between the 2 groups at the age of 17 months. In conclusion, there appeared to be a PCV dose effect on VT carriage, with less VT carriage occurring with more doses of PCV. By the age of 17 months, NVT carriage rates were similar for all groups. 23vPPS had no impact on carriage, despite the substantial boosts in antibody levels.
doi:10.1128/CVI.00117-10
PMCID: PMC3008188  PMID: 20943882
17.  Identifying an appropriate PCV for use in Senegal, recent insights concerning Streptococcus pneumoniae NP carriage and IPD in Dakar 
BMC Infectious Diseases  2014;14(1):627.
Background
Since 2000, the Global Alliance for Vaccines and Immunization (GAVI) and WHO have supported the introduction of the Pneumococcal Conjugate Vaccine (PCV) in the immunization programs of developing countries. The highest pneumococcal nasopharyngeal carriage rates have been reported (40-60%) in these countries, and the highest incidence and case fatality rates of pneumococcal infections have been demonstrated in Africa.
Methods
Studies concerning nasopharyngeal pneumococcal carriage and pneumococcal infection in children less than 5 years old were conducted in Dakar from 2007 to 2008. Serotype, antibiotic susceptibility and minimum inhibitory concentrations were determined. In addition, among 17 overall publications, 6 manuscripts of the Senegalese literature published from 1972 to 2013 were selected for data comparisons.
Results
Among the 264 children observed, 132 (50%) children generated a nasopharyngeal (NP) positive culture with Streptococcus pneumoniae. The five most prevalent serotypes, were 6B (9%), 19 F (9%), 23 F (7.6%), 14 (7.6%) and 6A (6.8%). Fifteen percent of the strains (20/132) showed reduced susceptibility to penicillin and 3% (4/132) showed reduced susceptibility to anti-pneumococcal fluoroquinolones. Among the 196 suspected pneumococcal infections, 62 (31.6%) Streptococcus pneumoniae were isolated. Serogroup 1 was the most prevalent serotype (21.3%), followed by 6B (14.9%), 23 F (14.9%) and 5 (8.5%). Vaccine coverage for PCV-7, PCV-10 and PCV-13, were 36.2% (17/47), 66% (31/47) and 70.2% (33/47) respectively. Reduced susceptibility to penicillin and anti-pneumococcal fluoroquinolones was 6.4% and 4.3%, respectively, and the overall lethality was 42.4% (14/33).
Conclusions
This study confirms a high rate of carriage and disease caused by Streptococcus pneumoniae serotypes contained within the current generation of pneumococcal conjugate vaccines and consistent with reports from other countries in sub-Saharan Africa prior to PCV introduction. Antimicrobial resistance in this small unselected sample confirms a low rate of antibiotic resistance. Case-fatality is high. Introduction of a high valency pneumococcal vaccine should be a priority for health planners with the establishment of an effective surveillance system to monitor post vaccine changes.
doi:10.1186/s12879-014-0627-8
PMCID: PMC4258793  PMID: 25471219
Streptococcus pneumoniae; Nasopharyngeal carriage; Invasive pneumococcal disease; Serotypes; Antibiotic resistance; Children; Sub-Saharan Africa; Senegal
18.  Maternal Antibodies to Pneumolysin but Not to Pneumococcal Surface Protein A Delay Early Pneumococcal Carriage in High-Risk Papua New Guinean Infants▿  
Clinical and Vaccine Immunology : CVI  2009;16(11):1633-1638.
Immunization of pregnant women can be an efficient strategy to induce early protection in infants in developing countries. Pneumococcal protein-based vaccines may have the capacity to induce pneumococcal serotype-independent protection. To understand the potential of maternal pneumococcal protein-specific antibodies in infants in high-risk areas, we studied the placental transfer of naturally acquired antibodies to pneumolysin (Ply) and pneumococcal surface protein A family 1 and 2 (PspA1 and PspA2) in relation to onset of pneumococcal nasopharyngeal carriage in infants in Papua New Guinea (PNG). In this study, 76% of the infants carried Streptococcus pneumoniae in the upper respiratory tract within the first month of life, at a median age of 19 days. Maternal and cord blood antibody titers to Ply (ρ = 0.824, P < 0.001), PspA1 (ρ = 0.746, P < 0.001), and PspA2 (ρ = 0.631, P < 0.001) were strongly correlated. Maternal pneumococcal carriage (hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.25 to 5.39) and younger maternal age (HR, 0.74; 95% CI, 0.54 to 1.00) were independent risk factors for early carriage, while higher cord Ply-specific antibody titers predicted a significantly delayed onset (HR, 0.71; 95% CI, 0.52 to 1.00) and cord PspA1-specific antibodies a significantly younger onset of carriage in PNG infants (HR, 1.57; 95% CI, 1.03 to 2.40). Maternal vaccination with a pneumococcal protein-based vaccine should be considered as a strategy to protect high-risk infants against pneumococcal disease by reducing carriage risks in both mothers and infants.
doi:10.1128/CVI.00247-09
PMCID: PMC2772384  PMID: 19776196
19.  Genetic Diversity of PspA Types among Nasopharyngeal Isolates Collected during an Ongoing Surveillance Study of Children in Brazil 
Journal of Clinical Microbiology  2006;44(8):2838-2843.
Pneumococcal surface protein A (PspA) has been considered a potential candidate for human vaccines because of its serotype-independent protective immunity. Nasopharyngeal (NP) pneumococcal colonization is highly prevalent in infants and precedes the invasive disease. Thus, prevention of NP colonization may reduce the burden of pneumococcal disease in children. Scarce information focusing on PspA from pneumococcal carriage in humans is available. We examined the genetic diversity of PspA from NP isolates obtained during an ongoing pneumococcal surveillance study with children. PspA families and clades of 183 community-acquired Streptococcus pneumoniae NP isolates from healthy children (n = 97) and children with respiratory tract infections (n = 48), pneumonia (n = 33), or meningitis (n = 5) were investigated. Overall, 79.8% (n = 146) of the pneumococcal isolates were classified as PspA family 1 (35.5%) and family 2 (44.3%), whereas 20.2% of the isolates could not be typed. The distribution of PspA families and clades did not differ significantly according to the clinical status of the children. A dendrogram comparing the genetic relationship between the amino acid sequences of the clade-defining region of PspA from NP strains together with 24 invasive reference strains (GenBank) closely reproduced the profile of the families and clades previously reported for pneumococcal invasive strains. These findings strengthen the idea that the use of PspA as a vaccine antigen may protect children against carriage as well as invasive pneumococcal disease.
doi:10.1128/JCM.00156-06
PMCID: PMC1594641  PMID: 16891500
20.  Direct Effect of 10-Valent Conjugate Pneumococcal Vaccination on Pneumococcal Carriage in Children Brazil 
PLoS ONE  2014;9(6):e98128.
Background
10-valent conjugate pneumococcal vaccine/PCV10 was introduced in the Brazilian National Immunization Program along the year of 2010. We assessed the direct effectiveness of PCV10 vaccination in preventing nasopharyngeal/NP pneumococcal carriage in infants.
Methods
A cross-sectional population-based household survey was conducted in Goiania Brazil, from December/2010-February/2011 targeting children aged 7–11 m and 15–18 m. Participants were selected using a systematic sampling. NP swabs, demographic data, and vaccination status were collected from 1,287 children during home visits. Main outcome and exposure of interest were PCV10 vaccine-type carriage and dosing schedules (3p+0, 2p+0, and one catch-up dose), respectively. Pneumococcal carriage was defined by a positive culture and serotyping was performed by Quellung reaction. Rate ratio/RR was calculated as the ratio between the prevalence of vaccine-types carriage in children exposed to different schedules and unvaccinated for PCV10. Adjusted RR was estimated using Poisson regression. PCV10 effectiveness/VE on vaccine-type carriage was calculated as 1-RR*100.
Results
The prevalence of pneumococcal carriage was 41.0% (95%CI: 38.4–43.7). Serotypes covered by PCV10 and PCV13 were 35.2% and 53.0%, respectively. Vaccine serotypes 6B (11.6%), 23F (7.8%), 14 (6.8%), and 19F (6.6%) were the most frequently observed. After adjusted for confounders, children who had received 2p+0 or 3p+0 dosing schedule presented a significant reduction in pneumococcal vaccine-type carriage, with PCV10 VE equal to 35.9% (95%CI: 4.2–57.1; p = 0.030) and 44.0% (95%CI: 14.–63.5; p = 0.008), respectively, when compared with unvaccinated children. For children who received one catch-up dose, no significant VE was detected (p = 0.905).
Conclusion
PCV10 was associated with high protection against vaccine-type carriage with 2p+0 and 3p+0 doses for children vaccinated before the second semester of life. The continuous evaluation of carriage serotypes distribution is likely to be useful for evaluating the long-term effectiveness and impact of pneumococcal vaccination on serotypes reduction.
doi:10.1371/journal.pone.0098128
PMCID: PMC4043727  PMID: 24892409
21.  Clustering of serotypes in a longitudinal study of Streptococcus pneumoniae carriage in three day care centres 
Background
Streptococcus pneumoniae (pneumococcus) causes a wide range of clinical manifestations that together constitute a major burden of disease worldwide. The main route of pneumococcal transmission is through asymptomatic colonisation of the nasopharynx. Studies of transmission are currently of general interest because of the impact of the new conjugate-polysaccharide vaccines on nasopharyngeal colonisation (carriage). Here we report the first longitudinal study of pneumococcal carriage that records serotype specific exposure to pneumococci simultaneously within the two most important mixing groups, families and day care facilities.
Methods
We followed attendees (N = 59) with their family members (N = 117) and the employees (N = 37) in three Finnish day care centres for 9 months with monthly sampling of nasopharyngeal carriage. Pneumococci were cultured, identified and serotyped by standard methods.
Results
Children in day care constitute a core group of pneumococcal carriage: of the 36 acquisitions of carriage with documented exposure to homologous pneumococci, the attendee had been exposed in her/his day care centre in 35 cases and in the family in 9 cases. Day care children introduce pneumococci to the family: 66% of acquisitions of a new serotype in a family were associated with simultaneous or previous carriage of the same type in the child attending day care. Consequently, pneumococcal transmission was found to take place as micro-epidemics driven by the day care centres. Each of the three day care centres was dominated by a serotype of its own, accounting for 100% of the isolates of that serotype among all samples from the day care attendees.
Conclusion
The transmission of pneumococci is more intense within than across clusters defined by day care facilities. The ensuing micro-epidemic behaviour enhances pneumococcal transmission.
doi:10.1186/1471-2334-8-173
PMCID: PMC2639357  PMID: 19116005
22.  Indirect Effect of 7-Valent Pneumococcal Conjugate Vaccine on Pneumococcal Carriage in Newborns in Rural Gambia: A Randomised Controlled Trial 
PLoS ONE  2012;7(11):e49143.
Background
Gambian infants frequently acquire Streptococcus pneumoniae soon after birth. We investigated the indirect effect of 7-valent pneumococcal conjugate vaccine (PCV-7) on pneumococcal acquisition in newborn Gambian babies.
Methods
Twenty-one villages were randomised to receive PCV-7 to all subjects (11 vaccinated villages) or to infants aged 2–30 months (10 control villages). Other control villagers received Meningococcal C conjugate vaccine. From 328 babies born during the trial, nasopharyngeal swabs were collected after birth, then weekly until 8 weeks of age when they received their first dose of PCV-7. Pneumococcal carriage and acquisition rates were compared between the study arms and with a baseline study.
Results
57.4% of 2245 swabs were positive for S. pneumoniae. Overall carriage was similar in both arms. In vaccinated villages fewer infants carried pneumococci of vaccine serotypes (VT) (16.9% [31/184] vs. 37.5% [54/144], p<0.001) and more carried pneumococci of non-vaccine serotypes (NVT) (80.9% [149/184] vs. 75.7% [109/144], p = 0.246). Infants from vaccinated villages had a significantly lower acquisition rate of VT (HR 0.39 [0.26–0.58], p<0.001) and increased acquisition of NVT (HR 1.16 [0.87–1.56], p = 0.312). VT carriage (51.6% vs. 37.5%, p = 031 in control and 46.1% vs. 16.8%, p<0.001 in vaccinated villages) and acquisition rates (HR 0.68 [0.50–0.92], p = 0.013 in control villages and HR 0.31 [0.19–0.50], p<.001 in vaccinated villages) were significantly lower in both study arms than in the baseline study. NVT carriage (63.2% vs. 75.7%, p = 0.037 in control and 67.2% vs. 75.3%, p = 0.005 in vaccinated villages) and acquisition rates (HR 1.48 [1.06–2.06], p = 0.022) and (HR 1.52 [1.11–2.10], p = 0.010 respectively) were significantly higher.
Conclusion
PCV-7 significantly reduced carriage of VT pneumococci in unvaccinated infants. This indirect effect likely originated from both the child and adult vaccinated populations. Increased carriage of NVT pneumococci needs ongoing monitoring.
Trial Registration
ISRCTN Register 51695599
doi:10.1371/journal.pone.0049143
PMCID: PMC3504064  PMID: 23185303
23.  Comparative analysis of Streptococcus pneumoniae transmission in Portuguese and Finnish day-care centres 
BMC Infectious Diseases  2013;13:180.
Background
Day-care centre (DCC) attendees play a central role in maintaining the circulation of Streptococcus pneumoniae (pneumococcus) in the population. The prevalence of pneumococcal carriage is highest in DCC attendees but varies across countries and is found to be consistently lower in Finland than in Portugal. We compared key parameters underlying pneumococcal transmission in DCCs to understand which of these contributed to the observed differences in carriage prevalence.
Methods
Longitudinal data about serotype-specific carriage in DCC attendees in Portugal (47 children in three rooms; mean age 2 years; range 1–3 years) and Finland (91 children in seven rooms; mean age 4 years; range 1–7 years) were analysed with a continuous-time event history model in a Bayesian framework. The monthly rates of within-room transmission, community acquisition and clearing carriage were estimated.
Results
The posterior mean of within-room transmission rate was 1.05 per month (Portugal) vs. 0.63 per month (Finland). The smaller rate of clearance in Portugal (0.57 vs. 0.73 per month) is in accordance with the children being younger. The overall community rate of acquisition was larger in the Portuguese setting (0.25 vs. 0.11 per month), in agreement with that the groups belonged to a larger DCC. The model adequately predicted the observed levels of carriage prevalence and longitudinal patterns in carriage acquisition and clearance.
Conclusions
The difference in prevalence of carriage (61% in Portuguese vs. 26% among Finnish DCC attendees) was assigned to the longer duration of carriage in younger attendees and a significantly higher rate of within-room transmission and community acquisition in the Portuguese setting.
doi:10.1186/1471-2334-13-180
PMCID: PMC3652738  PMID: 23597389
Streptococcus pneumoniae; Pneumococcus; Day care; Child; Transmission; Carriage; Prevalence; Longitudinal studies; Portugal; Finland; Statistical models; Bayesian inference; Data augmentation
24.  Pre-Vaccination Nasopharyngeal Pneumococcal Carriage in a Nigerian Population: Epidemiology and Population Biology 
PLoS ONE  2012;7(1):e30548.
Background
Introduction of pneumococcal vaccines in Nigeria is a priority as part of the Accelerated Vaccine Introduction Initiative (AVI) of the Global Alliance for Vaccines and Immunisation (GAVI). However, country data on the burden of pneumococcal disease (IPD) is limited and coverage by available conjugate vaccines is unknown. This study was carried out to describe the pre vaccination epidemiology and population biology of pneumococcal carriage in Nigeria.
Methods
This was a cross sectional survey. Nasopharyngeal swabs (NPS) were obtained from a population sample in 14 contiguous peri-urban Nigerian communities. Data on demographic characteristics and risk factor for carriage were obtained from all study participants. Pneumococci isolated from NPS were characterised by serotyping, antimicrobial susceptibility and Multi Locus Sequencing Typing (MLST).
Results
The prevalence of pneumococcal carriage was 52.5%. Carriage was higher in children compared to adults (67.4% vs. 26%), highest (≈90%) in infants aged <9 months and reduced significantly with increasing age (P<0.001). Serotypes 19F (18.6%) and 6A (14.4%) were most predominant. Potential vaccine coverage was 43.8%, 45.0% and 62% for PCV-7, PCV-10 and PCV-13 respectively. There were 16 novel alleles, 72 different sequence types (STs) from the isolates and 3 Sequence Types (280, 310 and 5543) were associated with isolates of more than one serotype indicative of serotype switching. Antimicrobial resistance was high for cotrimoxazole (93%) and tetracycline (84%), a third of isolates had intermediate resistance to penicillin. Young age was the only risk factor significantly associated with carriage.
Conclusions
Pneumococcal carriage and serotype diversity is highly prevalent in Nigeria especially in infants. Based on the coverage of serotypes in this study, PCV-13 is the obvious choice to reduce disease burden and prevalence of drug resistant pneumococci. However, its use will require careful monitoring. Our findings provide sound baseline data for impact assessment following vaccine introduction in Nigeria.
doi:10.1371/journal.pone.0030548
PMCID: PMC3265474  PMID: 22291984
25.  Prevention of pneumococcal diseases in the post-seven valent vaccine era: A European perspective 
BMC Infectious Diseases  2012;12:207.
Background
The burden of invasive pneumococcal disease in young children decreased dramatically following introduction of the 7-valent pneumococcal conjugate vaccine (PCV7). The epidemiology of S. pneumoniae now reflects infections caused by serotypes not included in PCV7. Recently introduced higher valency pneumococcal vaccines target the residual burden of invasive and non-invasive infections, including those caused by serotypes not included in PCV7. This review is based on presentations made at the European Society of Pediatric Infectious Diseases in June 2011.
Discussion
Surveillance data show increased circulation of the non-PCV7 vaccine serotypes 1, 3, 6A, 6C, 7 F and 19A in countries with routine vaccination. Preliminary evidence suggests that broadened serotype coverage offered by higher valency vaccines may be having an effect on invasive disease caused by some of those serotypes, including 19A, 7 F and 6C. Aetiology of community acquired pneumonia remains a difficult clinical diagnosis. However, recent reports indicate that pneumococcal vaccination has reduced hospitalisations of children for vaccine serotype pneumonia. Variations in serotype circulation and occurrence of complicated and non-complicated pneumonia caused by non-PCV7 serotypes highlight the potential of higher valency vaccines to decrease the remaining burden. PCVs reduce nasopharyngeal carriage and acute otitis media (AOM) caused by vaccine serotypes. Recent investigations of the interaction between S. pneumoniae and non-typeable H. influenzae suggest that considerable reduction in severe, complicated AOM infections may be achieved by prevention of early pneumococcal carriage and AOM infections. Extension of the vaccine serotype spectrum beyond PCV7 may provide additional benefit in preventing the evolution of AOM. The direct and indirect costs associated with pneumococcal disease are high, thus herd protection and infections caused by non-vaccine serotypes both have strong effects on the cost effectiveness of pneumococcal vaccination. Recent evaluations highlight the public health significance of indirect benefits, prevention of pneumonia and AOM and coverage of non-PCV7 serotypes by higher valency vaccines.
Summary
Routine vaccination has greatly reduced the burden of pneumococcal diseases in children. The pneumococcal serotypes present in the 7-valent vaccine have greatly diminished among disease isolates. The prevalence of some non-vaccine serotypes (e.g. 1, 7 F and 19A) has increased. Pneumococcal vaccines with broadened serotype coverage are likely to continue decreasing the burden of invasive disease, and community acquired pneumonia in children. Further reductions in pneumococcal carriage and increased prevention of early AOM infections may prevent the evolution of severe, complicated AOM. Evaluation of the public health benefits of pneumococcal conjugate vaccines should include consideration of non-invasive pneumococcal infections, indirect effects of vaccination and broadened serotype coverage.
doi:10.1186/1471-2334-12-207
PMCID: PMC3462147  PMID: 22954038
Pneumococcal conjugate vaccine; Invasive pneumococcal disease; Community-acquired pneumonia; Acute otitis media; Vaccine serotype coverage; Epidemiology-incidence

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