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1.  Pneumococcal conjugate vaccination in Canadian infants and children younger than five years of age: Recommendations and expected benefits 
Introduction
Streptococcus pneumoniae infection may result in invasive pneumococcal disease (IPD), such as bacteremia, meningitis and bacteremic pneumonia, or in non-IPD, such as pneumonia, sinusitis and otitis media. In June 2001, a heptavalent pneumococcal conjugate vaccine (PCV7) (Prevnar, Wyeth Pharmaceuticals, Canada) was approved for use in children in Canada. The objective of the present paper is to review S pneumoniae-induced disease incidence and vaccine recommendations in Canadian infants and children younger than five years of age. Particular attention is given to the expected benefits of vaccination in Canada based on postmarketing data and economic modelling.
Methods
Searches were performed on PubMed and Web of Science databases and specific Canadian journals using the key words 'pneumococc*', 'vaccine', 'conjugate', 'infant' and 'Canadian'.
Results and Discussion
PCV7 appears to be safe and effective against IPD and non-IPD in children younger than five years of age and, more importantly, in children younger than two years of age (who are at highest risk for IPD). An examination of postmarketing data showed a reduction in incidence of pneumococcal disease in age groups that were vaccinated and in older age groups, indicating the likelihood of herd protection. Concurrently, there was a reduction in the occurrence of antimicrobial-resistant isolates.
Conclusions
The results from the present review suggest that PCV7 is currently benefiting Canadian children and society by lowering S pneumoniae-associated disease. Additional gains from herd protection and further reductions in antimicrobial resistance will be achieved as more Canadian children younger than five years of age are routinely vaccinated with PCV7.
PMCID: PMC2095050  PMID: 18418479
Conjugate; Economic; Infant; Pneumococcus; Post-marketing; Prevnar; Streptococcus pneumoniae
2.  New adhesin functions of surface-exposed pneumococcal proteins 
BMC Microbiology  2010;10:190.
Background
Streptococcus pneumoniae is a widely distributed commensal Gram-positive bacteria of the upper respiratory tract. Pneumococcal colonization can progress to invasive disease, and thus become lethal, reason why antibiotics and vaccines are designed to limit the dramatic effects of the bacteria in such cases. As a consequence, pneumococcus has developed efficient antibiotic resistance, and the use of vaccines covering a limited number of serotypes such as Pneumovax® and Prevnar® results in the expansion of non-covered serotypes. Pneumococcal surface proteins represent challenging candidates for the development of new therapeutic targets against the bacteria. Despite the number of described virulence factors, we believe that the majority of them remain to be characterized. This is the reason why pneumococcus invasion processes are still largely unknown.
Results
Availability of genome sequences facilitated the identification of pneumococcal surface proteins bearing characteristic motifs such as choline-binding proteins (Cbp) and peptidoglycan binding (LPXTG) proteins. We designed a medium throughput approach to systematically test for interactions between these pneumococcal surface proteins and host proteins (extracellular matrix proteins, circulating proteins or immunity related proteins). We cloned, expressed and purified 28 pneumococcal surface proteins. Interactions were tested in a solid phase assay, which led to the identification of 23 protein-protein interactions among which 20 are new.
Conclusions
We conclude that whether peptidoglycan binding proteins do not appear to be major adhesins, most of the choline-binding proteins interact with host proteins (elastin and C reactive proteins are the major Cbp partners). These newly identified interactions open the way to a better understanding of host-pneumococcal interactions.
doi:10.1186/1471-2180-10-190
PMCID: PMC2911433  PMID: 20624274
3.  Optimal Serotype Compositions for Pneumococcal Conjugate Vaccination under Serotype Replacement 
PLoS Computational Biology  2014;10(2):e1003477.
Pneumococcal conjugate vaccination has proved highly effective in eliminating vaccine-type pneumococcal carriage and disease. However, the potential adverse effects of serotype replacement remain a major concern when implementing routine childhood pneumococcal conjugate vaccination programmes. Applying a concise predictive model, we present a ready-to-use quantitative tool to investigate the implications of serotype replacement on the net effectiveness of vaccination against invasive pneumococcal disease (IPD) and to guide in the selection of optimal vaccine serotype compositions. We utilise pre-vaccination data on pneumococcal carriage and IPD and assume partial or complete elimination of vaccine-type carriage, its replacement by non-vaccine-type carriage, and stable case-to-carrier ratios (probability of IPD per carriage episode). The model predicts that the post-vaccination IPD incidences in Finland for currently available vaccine serotype compositions can eventually decrease among the target age group of children <5 years of age by 75%. However, due to replacement through herd effects, the decrease among the older population is predicted to be much less (20–40%). We introduce a sequential algorithm for the search of optimal serotype compositions and assess the robustness of inferences to uncertainties in data and assumptions about carriage and IPD. The optimal serotype composition depends on the age group of interest and some serotypes may be highly beneficial vaccine types in one age category (e.g. 6B in children), while being disadvantageous in another. The net effectiveness will be improved only if the added serotype has a higher case-to-carrier ratio than the average case-to-carrier ratio of the current non-vaccine types and the degree of improvement in effectiveness depends on the carriage incidence of the serotype. The serotype compositions of currently available pneumococcal vaccines are not optimal and the effectiveness of vaccination in the population at large could be improved by including new serotypes in the vaccine (e.g. 22 and 9N).
Author Summary
The bacterial pathogen Streptococcus pneumoniae (pneumococcus) is a major contributor to child mortality worldwide. Hence, effective pneumococcal vaccination programmes are globally among the most cost-effective public health interventions. Three different conjugate vaccine compositions, targeting 7, 10 or 13 pneumococcal serotypes, have been used in infant vaccination programmes. The use of these vaccines has both decreased the disease burden and changed the patterns of pneumococcal carriage in locations where they have been in use. However, due to serotype replacement, where the lost vaccine serotype carriage is replaced by carriage of the non-vaccine serotypes, the net effect of vaccination on the disease burden has generally been milder than expected. Here, we apply a concise model for serotype replacement and present a ready-to-use tool for the prediction of patterns in post-vaccination pneumococcal incidence of carriage and invasive disease. We introduce a sequential algorithm for the identification of the most optimal additional serotypes to current vaccine formulations and demonstrate how differences in the invasiveness across serotypes imply that the disease incidence may either decrease or increase after vaccination. The methods we outline have direct relevance in decision making while reviewing the performance of the current pneumococcal vaccination programmes.
doi:10.1371/journal.pcbi.1003477
PMCID: PMC3923658  PMID: 24550722
4.  Development of a Fourfold Multiplexed Opsonophagocytosis Assay for Pneumococcal Antibodies against Additional Serotypes and Discovery of Serological Subtypes in Streptococcus pneumoniae Serotype 20 
Opsonophagocytic killing assays (OPAs) are important in vitro surrogate markers of protection in vaccine studies of Streptococcus pneumoniae. We have previously reported the development of a 4-fold multiplexed OPA (MOPA) for the 13 serotypes in Prevnar 13. Because new conjugate vaccines with increased valence are being developed, we developed 4-fold MOPAs for an additional 13 serotypes: serotypes 6C and 6D, plus the 11 serotypes contained in Pneumovax but not in Prevnar 13. A high level of nonspecific killing (NSK) was observed for three serotypes (10A, 15B, and 33F) in multiple batches of baby rabbit complement. The NSK could be reduced by preadsorbing the complement with encapsulated, as well as unencapsulated, pneumococcal strains. The MOPA results compared well with the results of single-serotype OPA for all serotypes except for serotype 3. For serotype 3, the results obtained from the MOPA format were ∼40% higher than those of the single-serotype format. Interassay precision of MOPA was determined with 5 serum samples, and the coefficient of variation was generally <30% for all serotypes. MOPA was also specific for all serotypes except for serotype 20; i.e., free homologous polysaccharide (PS), but not unrelated PS, could completely and efficiently inhibit opsonization. However, serotype 20 PS from ATCC could efficiently inhibit opsonization of one serotype 20 target strain but not three other type 20 target strains even at a high (>80 mg/liter) PS concentration. This suggests the presence of serologic heterogeneity among serotype 20 strains.
doi:10.1128/CVI.00086-12
PMCID: PMC3370448  PMID: 22518015
5.  A Pneumococcal Carriage Study in Danish Pre-school Children before the Introduction of Pneumococcal Conjugate Vaccination 
We present data on pneumococcal carriage before the introduction of the heptavalent-pneumococcal conjugated vaccine (PCV7) in Denmark. In the pre-PCV7 period, the incidence of invasive pneumococcal disease (IPD) among children younger than 5 years was approximately 25 per 100.000 population, with the highest incidence rates observed in children younger than 2 years of age. The study included 437 children aged 12-72 months attending day care centres (DCC) and was conducted during 48 months. In total, 56% (n=247) of children were pneumococcal carriers with the highest prevalence in children aged 12–23 months (69%), the proportion significantly declining with increasing age. PCV7 serotypes accounted for 33%, PCV10 for 34%, and PCV13 for 57% of all carried isolates. The proportion of serotypes included in the three conjugate vaccines was higher among IPD isolates compared to carrier isolates (range 35– 90%). We found that the frequency of carriage was high among Danish pre-school children attending DCC and serotypes were not frequently covered by PCV7 in the pre-PCV7 period.
doi:10.2174/1874285801206010040
PMCID: PMC3355352  PMID: 22611459
Children; nasopharyngeal carriage; Streptococcus pneumoniae; serotypes; vaccine.
6.  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
7.  A mathematical model of serotype replacement in pneumococcal carriage following vaccination 
A number of childhood vaccination programmes have recently introduced vaccination against Streptococcus pneumoniae, the pneumococcus, a major cause of pneumonia and meningitis. The pneumococcal conjugate vaccines (PCVs) that are currently in use only protect against some serotypes of the bacterium, and there is now strong evidence that those serotypes not included in the vaccine increase in prevalence among most vaccinated populations. We present a mathematical model for the dynamics of nasopharyngeal carriage of S. pneumoniae that allows for carriage with multiple serotypes. The model is used to predict the prevalence of vaccine type (VT) and non-VT (NVT) serotypes following the introduction of PCV. Parameter estimates for the model are obtained by maximum likelihood using pre-vaccination data from The Gambia. The model predicts that low (1, 6A and 9V) and medium (4, 5, 7F, 14, 18C, 19A and 19F) prevalence serotypes can be eliminated through vaccination, but that the overall prevalence of carriage will be reduced only slightly because of an increase in the prevalence of NVT serotypes. Serotype replacement will be sequential, with high and medium prevalence NVT serotypes dominating initially, followed by an increase of serotypes of low prevalence. We examine the impact of a hypothetical vaccine that provides partial protection against all serotypes, and find that this reduces overall carriage, but is unable to eliminate low or medium prevalence serotypes.
doi:10.1098/rsif.2013.0786
PMCID: PMC3808555  PMID: 24132203
serotype replacement; bacterial carriage; mathematical model; pneumococcal vaccine
8.  Changes in Molecular Epidemiology of Streptococcus pneumoniae Causing Meningitis following Introduction of Pneumococcal Conjugate Vaccination in England and Wales 
Journal of Clinical Microbiology  2013;51(3):820-827.
The introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in September 2006 has markedly reduced the burden of invasive pneumococcal disease (IPD) including meningitis in England and Wales. This study examined changes in the molecular epidemiology of pneumococcal isolates causing meningitis from July 2004 to June 2009. The Health Protection Agency conducts enhanced pneumococcal surveillance in England and Wales. In addition to serotyping, pneumococcal isolates causing meningitis were genotyped by multilocus sequence typing (MLST). A total of 1,030 isolates were both serotyped and genotyped over the 5-year period. Fifty-two serotypes, 238 sequence types (STs), and 87 clonal complexes were identified, with no significant difference in the yearly Simpson's diversity index values (range, 0.974 to 0.984). STs commonly associated with PCV7 serotypes declined following PCV implementation, with a proportionally greater decline in ST124 (commonly associated with serotype 14). No other ST showed significant changes in distribution, even within individual serotypes. Replacement disease following PCV7 introduction was mainly due to serotypes 1, 3, 7F, 19A, 22F, and 33F through clonal expansion. A single instance of possible capsule switching was identified where one ST4327 clone expressed a serotype 14 capsule in 2005 and a serotype 28A capsule in 2009. In 2008 to 2009, ST191 (7F) became the most prevalent clone causing meningitis (10.3%). Case fatality (145 fatalities/1,030 cases; 14.1%) was high across all age groups and serotype groups. Thus, the introduction of PCV7 resulted in an increase in non-PCV7 serotypes, including some not covered by the 13-valent vaccine, such as serotypes 22F and 33F, emphasizing the importance of long-term epidemiological and molecular surveillance.
doi:10.1128/JCM.01917-12
PMCID: PMC3592052  PMID: 23269742
9.  Virulence of Streptococcus pneumoniae serotype 6C in experimental otitis media 
Increases in colonization with serotypes of Streptococcus pneumoniae not contained within the 7-valent pneumococcal conjugate vaccine (PCV) have been reported among children following introduction. Serotype 6C has emerged as prevalent in nasopharyngeal colonization and acute otitis media (AOM), though it is uncommonly recovered from children with invasive pneumococcal disease. Vaccine serotypes within PCV7 have been replaced by nonvaccine serotypes without significant changes in the overall carriage rate. We hypothesize 1) that serotypes vary in their ability to evade host defenses and establish AOM following colonization and 2) the observed reduction in pneumococcal otitis results from a reduced disease potential by some ‘replacement serotypes’. We compared the capacity of S. pneumoniae serotypes 6C and 19A to produce experimental otitis media (EOM) in a chinchilla model. The proportion of chinchillas that developed culture positive EOM and density of middle ear infection was evaluated. EOM was found in 28/82 (34%) ears challenged with 6C compared to 13/18(72.2%) with 19A [p=0.0003]. When disease due to 6C did occur, it was characterized by lowdensity infection. Our findings demonstrate that challenge with serotype 6C results in EOM less frequently than 19A. These data support the need for greater knowledge regarding differences among serotypes to produce AOM.
doi:10.1016/j.micinf.2012.02.008
PMCID: PMC3382049  PMID: 22414497
Streptococcus pneumoniae; complement; virulence
10.  Mathematical Modelling Long-Term Effects of Replacing Prevnar7 with Prevnar13 on Invasive Pneumococcal Diseases in England and Wales 
PLoS ONE  2012;7(7):e39927.
Introduction
England and Wales recently replaced the 7-valent pneumococcal conjugate vaccine (PCV7) with its 13-valent equivalent (PCV13), partly based on projections from mathematical models of the long-term impact of such a switch compared to ceasing pneumococcal conjugate vaccination altogether.
Methods
A compartmental deterministic model was used to estimate parameters governing transmission of infection and competition between different groups of pneumococcal serotypes prior to the introduction of PCV13. The best-fitting parameters were used in an individual based model to describe pneumococcal transmission dynamics and effects of various options for the vaccination programme change in England and Wales. A number of scenarios were conducted using (i) different assumptions about the number of invasive pneumococcal disease cases adjusted for the increasing trend in disease incidence prior to PCV7 introduction in England and Wales, and (ii) a range of values representing serotype replacement induced by vaccination of the additional six serotypes in PCV13.
Results
Most of the scenarios considered suggest that ceasing pneumococcal conjugate vaccine use would cause an increase in invasive pneumococcal disease incidence, while replacing PCV7 with PCV13 would cause an overall decrease. However, the size of this reduction largely depends on the level of competition induced by the additional serotypes in PCV13. The model estimates that over 20 years of PCV13 vaccination, around 5000–62000 IPD cases could be prevented compared to stopping pneumococcal conjugate vaccination altogether.
Conclusion
Despite inevitable uncertainty around serotype replacement effects following introduction of PCV13, the model suggests a reduction in overall invasive pneumococcal disease incidence in all cases. Our results provide useful evidence on the benefits of PCV13 to countries replacing or considering replacing PCV7 with PCV13, as well as data that can be used to evaluate the cost-effectiveness of such a switch.
doi:10.1371/journal.pone.0039927
PMCID: PMC3396640  PMID: 22808073
11.  Using the Indirect Cohort Design to Estimate the Effectiveness of the Seven Valent Pneumococcal Conjugate Vaccine in England and Wales 
PLoS ONE  2011;6(12):e28435.
Background
The 7-valent pneumococcal conjugate vaccine (PCV-7) was introduced in the United Kingdom in 2006 with a 2,3 and 13month schedule, and has led to large decreases in invasive pneumococcal disease (IPD) caused by the vaccine serotypes in both vaccinated and unvaccinated cohorts. We estimated the effectiveness of PCV-7 against IPD.
Methods and Findings
We used enhanced surveillance data, collated at the Health Protection Agency, on vaccine type (n = 153) and non vaccine type (n = 919) IPD cases eligible for PCV-7. The indirect cohort method, a case-control type design which uses non vaccine type cases as controls, was used to estimate effectiveness of various numbers of doses as well as for each vaccine serotype. Possible bias with this design, caused by differential serotype replacement in vaccinated and unvaccinated individuals, was estimated after deriving formulae to quantify the bias. The results showed good effectiveness, increasing from 56% (95% confidence interval (CI): -7-82) for a single dose given under one year of age to 93% (95% CI: 70-98) for two doses under one year of age plus a booster dose in the second year of life. Serotype specific estimates indicated higher effectiveness against serotypes 4, 14 and 18C and lower effectiveness against 6B. Under the assumption of complete serotype replacement by non vaccine serotypes in carriage, we estimated that effectiveness estimates may be overestimated by about 2 to 5%.
Conclusions
This study shows high effectiveness of PCV-7 under the reduced schedule used in the UK. This finding agrees with the large reductions seen in vaccine type IPD in recent years in England and Wales. The formulae derived to assess the bias of the indirect cohort method for PCV-7 can also be used when using the design for other vaccines that affect carriage such as the recently introduced 13 valent pneumococcal conjugate vaccine.
doi:10.1371/journal.pone.0028435
PMCID: PMC3229580  PMID: 22164292
12.  Streptococcus pneumoniae Clonal Complex 199: Genetic Diversity and Tissue-Specific Virulence 
PLoS ONE  2011;6(4):e18649.
Streptococcus pneumoniae is an important cause of otitis media and invasive disease. Since introduction of the heptavalent pneumococcal conjugate vaccine, there has been an increase in replacement disease due to serotype 19A clonal complex (CC)199 isolates. The goals of this study were to 1) describe genetic diversity among nineteen CC199 isolates from carriage, middle ear, blood, and cerebrospinal fluid, 2) compare CC199 19A (n = 3) and 15B/C (n = 2) isolates in the chinchilla model for pneumococcal disease, and 3) identify accessory genes associated with tissue-specific disease among a larger collection of S. pneumoniae isolates. CC199 isolates were analyzed by comparative genome hybridization. One hundred and twenty-seven genes were variably present. The CC199 phylogeny split into two main clades, one comprised predominantly of carriage isolates and another of disease isolates. Ability to colonize and cause disease did not differ by serotype in the chinchilla model. However, isolates from the disease clade were associated with faster time to bacteremia compared to carriage clade isolates. One 19A isolate exhibited hypervirulence. Twelve tissue-specific genes/regions were identified by correspondence analysis. After screening a diverse collection of 326 isolates, spr0282 was associated with carriage. Four genes/regions, SP0163, SP0463, SPN05002 and RD8a were associated with middle ear isolates. SPN05002 also associated with blood and CSF, while RD8a associated with blood isolates. The hypervirulent isolate's genome was sequenced using the Solexa paired-end sequencing platform and compared to that of a reference serotype 19A isolate, revealing the presence of a novel 20 kb region with sequence similarity to bacteriophage genes. Genetic factors other than serotype may modulate virulence potential in CC199. These studies have implications for the long-term effectiveness of conjugate vaccines. Ideally, future vaccines would target common proteins to effectively reduce carriage and disease in the vaccinated population.
doi:10.1371/journal.pone.0018649
PMCID: PMC3077395  PMID: 21533186
13.  Evidence that pneumococcal serotype replacement in Massachusetts following conjugate vaccination is now complete 
Epidemics  2010;2(2):80-84.
Invasive pneumococcal disease (IPD) has been reduced in the US following conjugate vaccination (PCV7) targeting seven pneumococcal serotypes in 2000. However, increases in IPD due to other serotypes have been observed, in particular 19A. How much this “serotype replacement” will erode the benefits of vaccination and over what timescale is unknown. We used a population genetic approach to test first whether the selective impact of vaccination could be detected in a longitudinal carriage sample, and secondly how long it persisted for following introduction of vaccine in 2000. To detect the selective impact of the vaccine we compared the serotype diversity of samples from pneumococcal carriage in Massachusetts children collected in 2001, 2004 and 2007 with others collected in the pre-vaccine era in Massachusetts, the UK and Finland. The 2004 sample was significantly (p >0.0001) more diverse than pre-vaccine samples, indicating the selective pressure of vaccination. The 2007 sample showed no significant difference in diversity from the pre-vaccine period, and exhibited similar population structure, but with different serotypes. In 2007 the carriage frequency of 19A was similar to that of the most common serotype in pre-vaccine samples. We suggest that serotype replacement involving 19A may be complete in Massachusetts due to similarities in population structure to pre-vaccine samples. These results suggest that the replacement phenomenon occurs rapidly with high vaccine coverage, and may allay concerns about future increases in disease due to 19A. For other serotypes, the future course of replacement disease remains to be determined.
doi:10.1016/j.epidem.2010.03.005
PMCID: PMC2963072  PMID: 21031138
Streptococcus pneumoniae; Infectious disease epidemiology; Nasopharyngeal carriage; Population genetics
14.  Dynamic models of pneumococcal carriage and the impact of the Heptavalent Pneumococcal Conjugate Vaccine on invasive pneumococcal disease 
Background
The 7-valent pneumococcal conjugate vaccine has been introduced in national immunisation programmes of most industrialised countries and recently in two African GAVI eligible countries (Rwanda and The Gambia). However the long term effects of PCV are still unclear, as beneficial direct and herd immunity effects might be countered by serotype replacement.
Method
A dynamic, age-structured, compartmental model of Streptococcus pneumoniae transmission was developed to predict the potential impact of PCV7 on the incidence of invasive disease accounting for both herd immunity and serotype replacement effects. The model was parameterised using epidemiological data from England and Wales and pre and post-vaccination surveillance data from the US.
Results
Model projections showed that serotype replacement plays a crucial role in determining the overall effect of a PCV7 vaccination programme and could reduce, negate or outweigh its beneficial impact. However, using the estimate of the competition parameter derived from the US post-vaccination experience, an infant vaccination programme would prevent 39,000 IPD cases in the 20 years after PCV7 introduction in the UK. Adding a catch-up campaign for under 2 or under 5 year olds would provide a further reduction of 1,200 or 3,300 IPD cases respectively, mostly in the first few years of the programme.
Conclusions
This analysis suggests that a PCV vaccination programme would eradicate vaccine serotypes from circulation. However, the increase in carriage of non-vaccine serotypes, and the consequent increase in invasive disease, could reduce, negate or outweigh the benefit. These results are sensitive to changes in the protective effect of the vaccine, and, most importantly, to the level of competition between vaccine and non-vaccine types. The techniques developed here can be used to assess the introduction of vaccination programmes in developing countries and provide the basis for cost-effectiveness analyses.
doi:10.1186/1471-2334-10-90
PMCID: PMC2867993  PMID: 20377886
15.  Clinical Implications of Pneumococcal Serotypes: Invasive Disease Potential, Clinical Presentations, and Antibiotic Resistance 
Streptococcus pneumoniae can asymptomatically colonize the nasopharynx and cause a diverse range of illnesses. This clinical spectrum from colonization to invasive pneumococcal disease (IPD) appears to depend on the pneumococcal capsular serotype rather than the genetic background. According to a literature review, serotypes 1, 4, 5, 7F, 8, 12F, 14, 18C, and 19A are more likely to cause IPD. Although serotypes 1 and 19A are the predominant causes of invasive pneumococcal pneumonia, serotype 14 remains one of the most common etiologic agents of non-bacteremic pneumonia in adults, even after 7-valent pneumococcal conjugate vaccine (PCV7) introduction. Serotypes 1, 3, and 19A pneumococci are likely to cause empyema and hemolytic uremic syndrome. Serotype 1 pneumococcal meningitis is prevalent in the African meningitis belt, with a high fatality rate. In contrast to the capsule type, genotype is more closely associated with antibiotic resistance. CC320/271 strains expressing serotype 19A are multidrug-resistant (MDR) and prevalent worldwide in the era of PCV7. Several clones of MDR serotype 6C pneumococci emerged, and a MDR 6D clone (ST282) has been identified in Korea. Since the pneumococcal epidemiology of capsule types varies geographically and temporally, a nationwide serosurveillance system is vital to establishing appropriate vaccination strategies for each country.
doi:10.3346/jkms.2013.28.1.4
PMCID: PMC3546102  PMID: 23341706
Streptococcus pneumoniae; Polysaccharides, Bacterial; Bacterial Capsules; Serotyping; Pneumococcal Infections
16.  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
17.  Vaccination against pneumococcus in West Africa: perspectives and prospects 
Background
Pneumococcal vaccination has become obligatory due to the enormous burden of pneumococcal diseases. Quite recently, pneumococcal conjugate vaccines have been developed, and have been shown to be superior to the previous polyvalent polysaccharide vaccine of the organism. Pneumococcal conjugate vaccines (PCVs) are being introduced in many West African countries and it is important to understand the expected performance, relevance, and limitations of these vaccines in the subregion.
Aim
The objective of the study presented here was to provide epidemiological insights into PCVs in West Africa based on the prevailing pneumococcal serotypes in the subregion.
Methods
A systematic review was carried out on pneumococcal serotypes causing invasive and noninvasive diseases in West Africa. Studies included in the review were those that reported at least 20 serotyped pneumococcal isolates and which were conducted prior to the introduction of PCVs in the region in 2009. The proportion of pneumococcal disease associated with each serotype as well as the serotype coverage of various PCVs (PCV7, PCV10, and PCV13) were calculated.
Results
The data covered 718 serotyped pneumococcal isolates from six West African countries: Burkina Faso, Ghana, Nigeria, Mali, Senegal, and The Gambia. The 718 isolates covered more than 20 serotypes. Serotype 1 was the most prevalent serotype (32%), followed by serotype 5 (15%), serotype 6 (7%), serotype 2 (6%), serotype 3 (6%), and serotype 12 (5%). The estimated serotype coverage of PCVs among the West African countries was 2%–36% for PCV7, 39%–80% for PCV10, and 65%–87% for PCV13.
Conclusion
A pneumococcal capsular vaccine for use in West Africa must contain serotypes 1 and 5, the most important serotypes responsible for pneumococcal disease in the region. Consequently, while PCV10 and PCV13 are generally suitable for use in West Africa, PCV7 is unsuitable.
doi:10.2147/IJGM.S45842
PMCID: PMC3775674  PMID: 24049454
pneumococcus; conjugate vaccines; serotype; PVC10; PVC13; pneumococcal disease; Streptococcus pneumoniae
18.  Decrease in Pneumococcal Co-Colonization following Vaccination with the Seven-Valent Pneumococcal Conjugate Vaccine 
PLoS ONE  2012;7(1):e30235.
Understanding the epidemiology of pneumococcal co-colonization is important for monitoring vaccine effectiveness and the occurrence of horizontal gene transfer between pneumococcal strains. In this study we aimed to evaluate the impact of the seven-valent pneumococcal conjugate vaccine (PCV7) on pneumococcal co-colonization among Portuguese children. Nasopharyngeal samples from children up to 6 years old yielding a pneumococcal culture were clustered into three groups: pre-vaccine era (n = 173), unvaccinated children of the vaccine era (n = 169), and fully vaccinated children (4 doses; n = 150). Co-colonization, serotype identification, and relative serotype abundance were detected by analysis of DNA of the total bacterial growth of the primary culture plate using the plyNCR-RFLP method and a molecular serotyping microarray-based strategy. The plyNCR-RFLP method detected an overall co-colonization rate of 20.1%. Microarray analysis confirmed the plyNCR-RFLP results. Vaccination status was the only factor found to be significantly associated with co-colonization: co-colonization rates were significantly lower (p = 0.004; Fisher's exact test) among fully vaccinated children (8.0%) than among children from the pre-PCV7 era (17.3%) or unvaccinated children of the PCV7 era (18.3%). In the PCV7 era there were significantly less non-vaccine type (NVT) co-colonization events than would be expected based on the NVT distribution observed in the pre-PCV7 era (p = 0.024). In conclusion, vaccination with PCV7 resulted in a lower co-colonization rate due to an asymmetric distribution between NVTs found in single and co-colonized samples. We propose that some NVTs prevalent in the PCV7 era are more competitive than others, hampering their co-existence in the same niche. This result may have important implications since a decrease in co-colonization events is expected to translate in decreased opportunities for horizontal gene transfer, hindering pneumococcal evolution events such as acquisition of antibiotic resistance determinants or capsular switch. This might represent a novel potential benefit of conjugate vaccines.
doi:10.1371/journal.pone.0030235
PMCID: PMC3257259  PMID: 22253924
19.  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
20.  Contribution of vaccines to our understanding of pneumococcal disease 
Pneumonia is the leading cause of mortality in children in developing countries and is also the leading infectious cause of death in adults. The most important cause of pneumonia is the Gram-positive bacterial pathogen, Streptococcus pneumoniae, also known as the pneumococcus. It has thus become the leading vaccine-preventable cause of death and is a successful and diverse human pathogen. The development of conjugate pneumococcal vaccines has made possible the prevention of pneumococcal disease in infants, but has also elucidated aspects of pneumococcal biology in a number of ways. Use of the vaccine as a probe has increased our understanding of the burden of pneumococcal disease in children globally. Vaccination has also elucidated the clinical spectrum of vaccine-preventable pneumococcal infections; the identification of a biological niche for multiple pneumococcal serotypes in carriage and the differential invasiveness of pneumococcal serotypes; the impact of pneumococcal transmission among children on disease burden in adults; the role of carriage as a precursor to pneumonia; the plasticity of a naturally transformable pathogen to respond to selective pressure through capsular switching and the accumulation of antibiotic-resistance determinants; and the role of pneumococcal infections in hospitalization and mortality associated with respiratory viral infections, including both seasonal and pandemic influenza. Finally, there has been a recent demonstration that pneumococcal pneumonia in children may be an important cause of hospitalization for those with underlying tuberculosis.
doi:10.1098/rstb.2011.0032
PMCID: PMC3146770  PMID: 21893542
vaccine; pneumonia; pneumococcus
21.  Invasive Pneumococcal Disease after Routine Pneumococcal Conjugate Vaccination in Children, England and Wales 
Emerging Infectious Diseases  2013;19(1):61-68.
Nonvaccine serotypes occur more often among children with comorbid conditions.
We assessed known risk factors, clinical presentation, and outcome of invasive pneumococcal disease (IPD) in children 3–59 months of age after introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in England and Wales. During September 2006–March 2010, a total of 1,342 IPD episodes occurred in 1,332 children; 14.9% (198/1,332) had comorbidities. Compared with IPD caused by PCV7 serotypes (44/248; 17.7%), comorbidities were less common for the extra 3 serotypes in the 10-valent vaccine (15/299; 5.0%) but similar to the 3 additional PCV13 serotypes (45/336; 13.4%) and increased for the 11 extra serotypes in 23-valent polysaccharide vaccine (PPV23) (39/186; 21.0%) and non-PPV23 serotypes (38/138; 27.5%). Fifty-two (3.9%) cases resulted from PCV7 failure; 9 (0.7%) case-patients had recurrent IPD. Case-fatality rate was 4.4% (58/1,332) but higher for meningitis (11.0%) and children with comorbidities (9.1%). Thus, comorbidities were more prevalent in children with IPD caused by non-PCV13 serotypes and were associated with increased case fatality.
doi:10.3201/eid1901.120741
PMCID: PMC3557991  PMID: 23259937
Invasive pneumococcal disease; risk factors; serotypes; meningitis; outcome; vaccination; bacteria; England; Wales; children
22.  Pediatric Invasive Pneumococcal Disease in the United States in the Era of Pneumococcal Conjugate Vaccines 
Clinical Microbiology Reviews  2012;25(3):409-419.
Summary: Invasive infections caused by Streptococcus pneumoniae continue to be a major cause of morbidity and mortality worldwide, especially in children under 5 years of age. In the United States, 90% of invasive pneumococcal infections in children are caused by 13 serotypes of S. pneumoniae. The licensure (in 2000) and subsequent widespread use of a heptavalent pneumococcal conjugate vaccine (PCV7) have had a significant impact on decreasing the incidence of serious invasive pneumococcal disease (IPD) in all age groups, especially in children under 2 years of age. However, the emergence of replacement non-PCV7 serotypes, especially serotype 19A, has resulted in an increase in the incidence of serious and invasive infections. In 2010, a 13-valent PCV was licensed in the United States. However, the impact that this vaccine will have on IPD remains to be seen. The objectives of this review are to discuss the epidemiology of serious and invasive pneumococcal infections in the United States in the PCV era and to review some of the pneumococcal vaccines that are in development.
doi:10.1128/CMR.00018-12
PMCID: PMC3416489  PMID: 22763632
23.  Fatal meningitis in a previously healthy young adult caused by Streptococcus pneumoniae serotype 38: an emerging serotype? 
Background
In December 2001, a fatal case of pneumococcal meningitis in a Marine Corps recruit was identified. As pneumococcal vaccine usage in recruit populations is being considered, an investigation was initiated into the causative serotype.
Case presentation
Traditional and molecular methods were utilized to determine the serotype of the infecting pneumococcus. The pneumococcal isolate was identified as serotype 38 (PS38), a serotype not covered by current vaccine formulations. The global significance of this serotype was explored in the medical literature, and found to be a rare but recognized cause of carriage and invasive disease.
Conclusion
The potential of PS38 to cause severe disease is documented in this report. Current literature does not support the hypothesis that this serotype is increasing in incidence. However, as we monitor the changing epidemiology of pneumococcal illness in the US in this conjugate era, PS38 might find a more prominent and concerning niche as a replacement serotype.
doi:10.1186/1471-2334-5-38
PMCID: PMC1156897  PMID: 15943886
24.  The Changing Epidemiology of Invasive Pneumococcal Disease at a Tertiary Children’s Hospital through the PCV7 Era 
The Pediatric infectious disease journal  2012;31(3):10.1097/INF.0b013e31823dcc72.
Background
In 2000, a 7-valent pneumococcal conjugate vaccine (PCV7) was licensed for use among U.S. children. Many sites have since reported changes in invasive pneumococcal disease (IPD). We recognized an opportunity to describe the changes in epidemiology, clinical syndromes and serotype distribution over a 14 year period including 4 years before vaccine introduction and spanning the entire PCV7 era.
Methods
Cases were defined as children <18 years of age who were cared for at Primary Children’s Medical Center for culture-confirmed IPD. We defined the pre-vaccine period as the timeframe spanning 1997–2000 and the post-vaccine period from 2001–2010. Demographics, clinical data, and outcomes were collected through electronic query and chart review. S. pneumoniae serotyping was performed using the capsular swelling method.
Results
The median age of children with IPD increased from 19 months during the pre-vaccine period to 27 months during post-vaccine period (P = 0.02) with a larger proportion of IPD among children older than 5 years. The proportion of IPD associated with pneumonia increased substantially from 29% to 50% (P < 0.001). This increase was primarily attributable to an increase in complicated pneumonia (17% to 33%; P < 0.001). Non-vaccine serotypes 7F, 19A, 22F and 3 emerged as the dominant serotypes in the post-vaccine period. Of S. pneumoniae isolates collected from children <5 years of age, for which vaccine is recommended, 67% of IPD was due to serotypes in PCV13 during 2005–2010.
Conclusions
After PCV7 was introduced, significant changes in IPD were noted. One third of IPD occurred in children older than 5 years, who were outside the age group for which PCV is recommended. Continued surveillance is warranted to identify further evolution of the epidemiology, clinical syndromes, and serotype distribution of S. pneumoniae following PCV13 licensure.
doi:10.1097/INF.0b013e31823dcc72
PMCID: PMC3299810  PMID: 22330164
Streptococcus pneumoniae; Invasive pneumococcal disease; Serotype; PCV7; PCV13
25.  7-Valent Pneumococcal Conjugate Vaccination in England and Wales: Is It Still Beneficial Despite High Levels of Serotype Replacement? 
PLoS ONE  2011;6(10):e26190.
Background
The UK introduced the 7-valent pneumococcal conjugate vaccine (PCV7) into the national vaccination program in September 2006. Previous modelling assumed that the likely impact of PCV7 on invasive pneumococcal disease (IPD) would be similar to the US experience with PCV7. However, recent surveillance data show a more rapid replacement of PCV7 IPD cases by non-PCV7 IPD cases than was seen in the US.
Methods and Findings
A previous model of pneumococcal vaccination was re-parameterised using data on vaccine coverage and IPD from England and Wales between 2006 and 2009. Disease incidence was adjusted for the increasing trend in reported IPD cases prior to vaccination. Using this data we estimated that individuals carrying PCV7 serotypes have much higher protection (96%;95% CI 72%-100%) against acquisition of NVT carriage than the 15% previously estimated from US data, which leads to greater replacement. However, even with this level of replacement, the annual number of IPD cases may be 560 (95% CI, -100 to 1230) lower ten years after vaccine introduction compared to what it may have been without vaccination. A particularly marked fall of 39% in children under 15 years by 2015/6 is predicted.
Conclusion
Our model suggests that PCV7 vaccination could result in a decrease in overall invasive pneumococcal disease, particularly in children, even in an environment of rapid replacement with non-PCV7 serotypes within 5 years of vaccine introduction at high coverage.
doi:10.1371/journal.pone.0026190
PMCID: PMC3193519  PMID: 22022559

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