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1.  Serotype-Specific Changes in Invasive Pneumococcal Disease after Pneumococcal Conjugate Vaccine Introduction: A Pooled Analysis of Multiple Surveillance Sites 
PLoS Medicine  2013;10(9):e1001517.
In a pooled analysis of data collected from invasive pneumococcal disease surveillance databases, Daniel Feikin and colleagues examine serotype replacement after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs.
Please see later in the article for the Editors' Summary
Background
Vaccine-serotype (VT) invasive pneumococcal disease (IPD) rates declined substantially following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs. Increases in non-vaccine-serotype (NVT) IPD rates occurred in some sites, presumably representing serotype replacement. We used a standardized approach to describe serotype-specific IPD changes among multiple sites after PCV7 introduction.
Methods and Findings
Of 32 IPD surveillance datasets received, we identified 21 eligible databases with rate data ≥2 years before and ≥1 year after PCV7 introduction. Expected annual rates of IPD absent PCV7 introduction were estimated by extrapolation using either Poisson regression modeling of pre-PCV7 rates or averaging pre-PCV7 rates. To estimate whether changes in rates had occurred following PCV7 introduction, we calculated site specific rate ratios by dividing observed by expected IPD rates for each post-PCV7 year. We calculated summary rate ratios (RRs) using random effects meta-analysis. For children <5 years old, overall IPD decreased by year 1 post-PCV7 (RR 0·55, 95% CI 0·46–0·65) and remained relatively stable through year 7 (RR 0·49, 95% CI 0·35–0·68). Point estimates for VT IPD decreased annually through year 7 (RR 0·03, 95% CI 0·01–0·10), while NVT IPD increased (year 7 RR 2·81, 95% CI 2·12–3·71). Among adults, decreases in overall IPD also occurred but were smaller and more variable by site than among children. At year 7 after introduction, significant reductions were observed (18–49 year-olds [RR 0·52, 95% CI 0·29–0·91], 50–64 year-olds [RR 0·84, 95% CI 0·77–0·93], and ≥65 year-olds [RR 0·74, 95% CI 0·58–0·95]).
Conclusions
Consistent and significant decreases in both overall and VT IPD in children occurred quickly and were sustained for 7 years after PCV7 introduction, supporting use of PCVs. Increases in NVT IPD occurred in most sites, with variable magnitude. These findings may not represent the experience in low-income countries or the effects after introduction of higher valency PCVs. High-quality, population-based surveillance of serotype-specific IPD rates is needed to monitor vaccine impact as more countries, including low-income countries, introduce PCVs and as higher valency PCVs are used.
Please see later in the article for the Editors' Summary
Editors’ Summary
Background
Pneumococcal disease–a major cause of illness and death in children and adults worldwide–is caused by Streptococcus pneumoniae, a bacterium that often colonizes the nose and throat harmlessly. Unfortunately, S. pneumoniae occasionally spreads into the lungs, bloodstream, or covering of the brain, where it causes pneumonia, septicemia, and meningitis, respectively. These invasive pneumococcal diseases (IPDs) can usually be successfully treated with antibiotics but can be fatal. Consequently, it is better to avoid infection through vaccination. 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 that it recognizes as foreign (antigens). Because there are more than 90 S. pneumoniae variants or “serotypes,” each characterized by a different antigenic polysaccharide (complex sugar) coat, vaccines that protect against S. pneumoniae have to include multiple serotypes. Thus, the pneumococcal conjugate vaccine PCV7, which was introduced into the US infant immunization regimen in 2000, contains polysaccharides from the seven S. pneumoniae serotypes mainly responsible for IPD in the US at that time.
Why Was This Study Done?
Vaccination with PCV7 was subsequently introduced in several other high- and middle-income countries, and IPD caused by the serotypes included in the vaccine declined substantially in children and in adults (because of reduced bacterial transmission and herd protection) in the US and virtually all these countries. However, increases in IPD caused by non-vaccine serotypes occurred in some settings, presumably because of “serotype replacement.” PCV7 prevents both IPD caused by the serotypes it contains and carriage of these serotypes. Consequently, after vaccination, previously less common, non-vaccine serotypes can colonize the nose and throat, some of which can cause IPD. In July 2010, a World Health Organization expert consultation on serotype replacement called for a comprehensive analysis of the magnitude and variability of pneumococcal serotype replacement following PCV7 use to help guide the introduction of PCVs in low-income countries, where most pneumococcal deaths occur. In this pooled analysis of data from multiple surveillance sites, the researchers investigate serotype-specific changes in IPD after PCV7 introduction using a standardized approach.
What Did the Researchers Do and Find?
The researchers identified 21 databases that had data about the rate of IPD for at least 2 years before and 1 year after PCV7 introduction. They estimated whether changes in IPD rates had occurred after PCV7 introduction by calculating site-specific rate ratios–the observed IPD rate for each post-PCV7 year divided by the expected IPD rate in the absence of PCV7 extrapolated from the pre-PCV7 rate. Finally, they used a statistical approach (random effects meta-analysis) to estimate summary (pooled) rate ratios. For children under 5 years old, the overall number of observed cases of IPD in the first year after the introduction of PCV7 was about half the expected number; this reduction in IPD continued through year 7 after PCV7 introduction. Notably, the rate of IPD caused by the S. pneumonia serotypes in PCV7 decreased every year, but the rate of IPD caused by non-vaccine serotypes increased annually. By year 7, the number of cases of IPD caused by non-vaccine serotypes was 3-fold higher than expected, but was still smaller than the decrease in vaccine serotypes, thereby leading to the decrease in overall IPD. Finally, smaller decreases in overall IPD also occurred among adults but occurred later than in children 2 years or more after PCV7 introduction.
What Do These Findings Mean?
These findings show that consistent, rapid, and sustained decreases in overall IPD and in IPD caused by serotypes included in PCV7 occurred in children and thus support the use of PCVs. The small increases in IPD caused by non-vaccine serotypes that these findings reveal are likely to be the result of serotype replacement, but changes in antibiotic use and other factors may also be involved. These findings have several important limitations, however. For example, PCV7 is no longer made and extrapolation of these results to newer PCV10 and PCV13 formulations should be done cautiously. On the other hand, many of the serotypes causing serotype replacement after PCV7 are included in these higher valency vaccines. Moreover, because the data analyzed in this study mainly came from high-income countries, these findings may not be generalizable to low-income countries. Nevertheless, based on their analysis, the researchers make recommendations for the collection and analysis of IPD surveillance data that should allow valid interpretations of the effect of PCVs on IPD to be made, an important requisite for making sound policy decisions about vaccination against pneumococcal disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001517.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination, including personal stories
Public Health England provides information on pneumococcal disease and on pneumococcal vaccines
The World Health Organization also provides information on pneumococcal vaccines
The not-for-profit Immunization Action Coalition has information on pneumococcal disease, including personal stories
MedlinePlus has links to further information about pneumococcal infections (in English and Spanish)
The International Vaccine Access Center at Johns Hopkins Bloomberg School of Public Health has more information on introduction of pneumococcal conjugate vaccines in low-income countries
doi:10.1371/journal.pmed.1001517
PMCID: PMC3782411  PMID: 24086113
2.  Impact of Pneumococcal Conjugate Vaccination of Infants on Pneumonia and Influenza Hospitalization and Mortality in All Age Groups in the United States 
mBio  2011;2(1):e00309-10.
A seven-valent pneumococcal conjugate vaccine (PCV7) introduced in the United States in 2000 has been shown to reduce invasive pneumococcal disease (IPD) in both vaccinated children and adults through induction of herd immunity. We assessed the impact of infant immunization on pneumococcal pneumonia hospitalizations and mortality in all age groups using Health Care Utilization Project State Inpatient Databases (SID) for 1996 to 2006 from 10 states; SID contain 100% samples of ICD9-coded hospitalization data for the selected states. Compared to a 1996–1997 through 1998–1999 baseline, by the 2005–2006 season, both IPD and pneumococcal pneumonia hospitalizations and deaths had decreased substantially in all age groups, including a 47% (95% confidence interval [CI], 38 to 54%) reduction in nonbacteremic pneumococcal pneumonia (ICD9 code 481 with no codes indicating IPD) in infants <2 years old and a 54% reduction (CI, 53 to 56%) in adults ≥65 years of age. A model developed to calculate the total burden of pneumococcal pneumonia prevented by infant PCV7 vaccination in the United States from 2000 to 2006 estimated a reduction of 788,838 (CI, 695,406 to 875,476) hospitalizations for pneumococcal pneumonia. Ninety percent of the reduction in model-attributed pneumococcal pneumonia hospitalizations occurred through herd immunity among adults 18 years old and older; similar proportions were found in pneumococcal disease mortality prevented by the vaccine. In the first seasons after PCV introduction, when there were substantial state differences in coverage among <5-year-olds, states with greater coverage had significantly fewer influenza-associated pneumonia hospitalizations among children, suggesting that PCV7 use also reduces influenza-attributable pneumonia hospitalizations.
IMPORTANCE
Pneumonia is the world’s leading cause of death in children and the leading infectious cause of death among U.S. adults 65 years old and older. Pneumococcal conjugate vaccination of infants has previously been shown to reduce invasive pneumococcal disease (IPD) among seniors through prevention of pneumococcal transmission from infants to adults (herd immunity). Our analysis documents a significant vaccine-associated reduction not only in IPD but also in pneumococcal pneumonia hospitalizations and inpatient mortality rates among both vaccinated children and unvaccinated adults. We estimate that fully 90% of the reduction in the pneumonia hospitalization burden occurred among adults. Moreover, states that more rapidly introduced their infant pneumococcal immunization programs had greater reductions in influenza-associated pneumonia hospitalization of children, presumably because the vaccine acts to prevent the pneumococcal pneumonia that frequently follows influenza virus infection. Our results indicate that seven-valent pneumococcal conjugate vaccine use has yielded far greater benefits through herd immunity than have previously been recognized.
doi:10.1128/mBio.00309-10
PMCID: PMC3025524  PMID: 21264063
3.  Pneumococcal Serotypes and Mortality following Invasive Pneumococcal Disease: A Population-Based Cohort Study 
PLoS Medicine  2009;6(5):e1000081.
Analyzing population-based data collected over 30 years in more than 18,000 patients with invasive pneumococcal infection, Zitta Harboe and colleagues find specific pneumococcal serotypes to be associated with increased mortality.
Background
Pneumococcal disease is a leading cause of morbidity and mortality worldwide. The aim of this study was to investigate the association between specific pneumococcal serotypes and mortality from invasive pneumococcal disease (IPD).
Methods and Findings
In a nationwide population-based cohort study of IPD in Denmark during 1977–2007, 30-d mortality associated with pneumococcal serotypes was examined by multivariate logistic regression analysis after controlling for potential confounders. A total of 18,858 IPD patients were included. Overall 30-d mortality was 18%, and 3% in children younger than age 5 y. Age, male sex, meningitis, high comorbidity level, alcoholism, and early decade of diagnosis were significantly associated with mortality. Among individuals aged 5 y and older, serotypes 31, 11A, 35F, 17F, 3, 16F, 19F, 15B, and 10A were associated with highly increased mortality as compared with serotype 1 (all: adjusted odds ratio ≥3, p<0.001). In children younger than 5 y, associations between serotypes and mortality were different than in adults but statistical precision was limited because of low overall childhood-related mortality.
Conclusions
Specific pneumococcal serotypes strongly and independently affect IPD associated mortality.
Editors' Summary
Background
Pneumococcal diseases—illnesses caused by Streptococcus pneumoniae bacteria—are leading causes of illness and death around the world. S. pneumoniae is transmitted through contact with infected respiratory secretions and usually causes noninvasive diseases such as ear infections and bronchitis. Sometimes, however, the bacteria invade the lungs (where they cause pneumonia), the bloodstream (where they cause bacteremia), or the covering of the brain (where they cause meningitis). These invasive pneumococcal diseases (IPDs) are often fatal. One million children die annually from pneumococcal disease, many of them in developing countries. In the developed world, however, IPDs mainly affect elderly people and patients with chronic conditions such as diabetes and alcoholism. Although pneumococcal diseases can sometimes be treated successfully with antibiotics, many patients die or develop long-term complications. Consequently, vaccination with “pneumococcal polysaccharide vaccine” (PPV) is recommended for everyone over 65 years old and for people between 2 and 65 years old who are at high risk of developing IPD; vaccination with “pneumococcal conjugate vaccine” (PCV) is recommended for children younger than 2 years old who are at high risk of IPDs.
Why Was This Study Done?
S. pneumoniae is not a single organism. There are actually more than 90 S. pneumoniae variants or “serotypes.” These variants are coated with different polysaccharides (complex sugar molecules) that are, in part, responsible for the deleterious effects of S. pneumonia infections. The same molecules also trigger the human immune response that kills the bacteria. Consequently, pneumococcal vaccines contain polysaccharide mixtures isolated from the S. pneumoniae serotypes responsible for most pneumococcal disease. But are these serotypes also responsible for most of the deaths caused by IPD? Until now, the few studies that have investigated the association between S. pneumoniae serotypes and death from IPD have yielded conflicting results. Here, therefore, the researchers undertook a large population-based study to discover whether there is an association between specific pneumococcal serotypes and death following IPD.
What Did the Researchers Do and Find?
The researchers linked data on the serotype of S. pneumoniae isolates sent to the Danish National Neisseria and Streptococcus Reference Center between 1977 and 2007 with clinical data from national medical databases. After allowing for other factors that might affect a person's likelihood of dying from IPD (for example, age and other illnesses), the researchers used multivariate logistic regression analysis (a statistical approach) to look for associations between S. pneumoniae serotypes and death within 30 days of admission to hospital for pneumococcal bacteremia or meningitis. Overall, 18% of the nearly 19,000 people included in this analysis died within 30 days of hospital admission; among the children younger than 5 years included in the study, the death rate was 3%. Among patients 5 years old or older, nine S. pneumoniae serotypes were associated with a more than 3-fold higher death rate (mostly from bacteremia) than serotype 1, the most common serotype isolated during the study. Interestingly, in young children, a different set of serotypes seemed to be associated with death. However, because so few children died from IPD, this result is statistically uncertain. The researchers' results also show that age, gender, having meningitis, having other illnesses, and alcoholism all affected a patient's chances of dying from IPD.
What Do These Findings Mean?
These findings show that specific pneumococcal serotypes strongly affect the likelihood that a person aged 5 years or over will die within 30 days of admission to hospital with IPD. Importantly, unlike previous studies, this study was large and comprehensive—the Danish surveillance center covers more than 90% of the Danish population—and the researchers carefully took other factors into account that might have affected a patient's chances of dying from IPD. Thus, these new insights into which pneumococcal serotypes are most deadly could help in the design of new pneumococcal vaccines, at least for people aged 5 years or older. For younger children, however, the results are not as informative and a similar study now needs to be done in developing countries, where more young people die from IPD.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000081.
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 disease
The UK Health Protection Agency also provides background information on pneumococcal disease
The GAVI's Pneumococcal Vaccines Accelerated Development and Introduction Plan focuses on pneumococcal vaccines for children
doi:10.1371/journal.pmed.1000081
PMCID: PMC2680036  PMID: 19468297
4.  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
5.  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
6.  Expansion of Serotype Coverage in the Universal Pediatric Vaccination Calendar: Short-Term Effects on Age- and Serotype-Dependent Incidence of Invasive Pneumococcal Clinical Presentations in Madrid, Spain 
Clinical and Vaccine Immunology : CVI  2013;20(10):1524-1530.
In Madrid, Spain, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7 in the pediatric universal vaccination calendar in June 2010. A prospective clinical surveillance that included all children hospitalized with culture- and/or PCR-confirmed invasive pneumococcal disease (IPD) was performed in all Madrid hospitals. The incidence rates (IRs) (defined as the number of cases/100,000 inhabitants aged <15 years) in the PCV7 (May 2007 to April 2010) versus PCV13 (May 2011 to April 2012) periods were compared. There were 499 cases in the PCV7 period and 79 cases in the PCV13 period. Globally, the IR significantly decreased from 17.09 (PCV7 period) to 7.70 (PCV13 period), with significant decreases (PCV7 versus PCV13 periods) in all age groups for bacteremic pneumonia (5.51 versus 1.56), parapneumonic pneumococcal empyema (PPE) (5.72 versus 3.12), and meningitis (2.16 versus 0.97). In the PCV13 period, significant reductions (the IR in the PCV7 period versus the IR in the PCV13 period) were found in IPDs caused by PCV13 serotypes (13.49 versus 4.38), and specifically by serotypes 1 (globally [4.79 versus 2.53], for bacteremic pneumonia [2.23 versus 0.97], and for PPE [2.26 versus 1.17]), serotype 5 (globally [1.88 versus 0.00], for bacteremic pneumonia [0.89 versus 0.00], and for PPE [0.55 versus 0.00]), and serotype 19A (globally [3.77 versus 0.49], for bacteremic pneumonia [0.72 versus 0.00], for PPE [0.89 versus 0.00], and for meningitis [0.62 versus 0.00]). IPDs caused by non-PCV13 serotypes did not increase (IR, 3.60 in the PCV7 period versus 3.31 in the PCV13 period), regardless of age or presentation. No IPDs caused by the PCV13 serotypes were found in children who received 3 doses of PCV13. The number of hospitalization days and sanitary costs were significantly lower in the PCV13 period. The switch from PCV7 to PCV13 in the universal pediatric vaccination calendar provided sanitary and economical benefits without a replacement by non-PCV13 serotypes.
doi:10.1128/CVI.00239-13
PMCID: PMC3807202  PMID: 23925887
7.  Systematic Evaluation of Serotypes Causing Invasive Pneumococcal Disease among Children Under Five: The Pneumococcal Global Serotype Project 
PLoS Medicine  2010;7(10):e1000348.
Hope Johnson and colleagues calculate the global and regional burden of serotype-specific pneumococcal disease in children under the age of five.
Background
Approximately 800,000 children die each year due to pneumococcal disease and >90% of these deaths occur in developing countries where few children have access to life-saving serotype-based vaccines. Understanding the serotype epidemiology of invasive pneumococcal disease (IPD) among children is necessary for vaccine development and introduction policies. The aim of this study was to systematically estimate the global and regional distributions of serotypes causing IPD in children <5 years of age.
Methods and Findings
We systematically reviewed studies with IPD serotype data among children <5 years of age from the published literature and unpublished data provided by researchers. Studies conducted prior to pneumococcal conjugate vaccine (PCV) introduction, from 1980 to 2007, with ≥12 months of surveillance, and reporting ≥20 serotyped isolates were included. Serotype-specific proportions were pooled in a random effects meta-analysis and combined with PD incidence and mortality estimates to infer global and regional serotype-specific PD burden. Of 1,292, studies reviewed, 169 were included comprising 60,090 isolates from 70 countries. Globally and regionally, six to 11 serotypes accounted for ≥70% of IPD. Seven serotypes (1, 5, 6A, 6B, 14, 19F, 23F) were the most common globally; and based on year 2000 incidence and mortality estimates these seven serotypes accounted for >300,000 deaths in Africa and 200,000 deaths in Asia. Serotypes included in both the 10- and 13-valent PCVs accounted for 10 million cases and 600,000 deaths worldwide.
Conclusions
A limited number of serotypes cause most IPD worldwide. The serotypes included in existing PCV formulations account for 49%–88% of deaths in Africa and Asia where PD morbidity and mortality are the highest, but few children have access to these life-saving vaccines.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Despite all the international attention on Millennium Development Goal (MDG) 4—to reduce deaths in children under 5 years by two thirds by 2015—pneumonia, sepsis, and meningitis together comprise >25% of the 10 million deaths occurring annually in children <5 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. Three pneumococcal conjugate vaccines are currently available and protect against the serotypes most commonly causing invasive pneumococcal disease in young children in North America. However, few countries with the highest burden of invasive pneumococcal disease have introduced the vaccines into their national immunization programs. Not only is it important to introduce a vaccine, but also to use a vaccine covering the appropriate serotypes prevalent in a susceptible region.
Why Was This Study Done?
Over the past few years, data on serotyping in many high burden countries has become available. The authors conducted this study (a systematic review and meta-analysis) to quantify the serotypes causing invasive pneumococcal disease in children <5 years of age in order to estimate the global and regional serotype distribution and serotype-specific disease burden. This information can then be used to estimate the potential public health impact of pneumococcal conjugate vaccine formulations and help to inform decision making for both pneumococcal vaccine development and the introduction of a vaccine into a specific region.
What Did the Researchers Do and Find?
Using published studies and unpublished data provided by researchers, the researchers systematically reviewed studies that included data on invasive pneumococcal disease serotype among children <5 years of age. The researchers then used statistical tools to pool the serotype-specific proportions and combined this information with pneumococcal disease incidence and mortality estimates to calculate the global and regional burden of serotype-specific pneumococcal disease.
The researchers reviewed 1,292 studies and included 169 suitable studies in their analysis, which included information on 60,090 isolates from 70 countries. The researchers produced regional estimates of the serotypes that caused invasive pneumococcal disease among under five-year-olds in different regions: six serotypes were identified as causing most invasive pneumococcal disease in North America; nine serotypes were identified in Africa; and 11 serotypes were identified in Asia. The researchers also found that seven serotypes (1, 5, 6A, 6B, 14, 19F, and 23F) were the most common globally and that these seven serotypes accounted for 58%–66% of invasive pneumococcal disease in every region. On the basis of incidence and mortality estimates of invasive pneumococcal disease for the year 2000 (before pneumococcal conjugate vaccines were introduced), the researchers found that these serotypes represented >300,000 deaths in Africa and 200,000 deaths in Asia.
What Do These Findings Mean?
This study shows that a limited number of serotypes cause most invasive pneumococcal disease worldwide. This finding contradicts the conventional supposition that the most common serotypes causing invasive pneumococcal disease vary greatly across geographic regions. Crucially, the findings of this study also show that the serotypes currently included in existing pneumococcal conjugate formulations account for 49%–74% of deaths in Africa and Asia where the morbidity and mortality of pneumococcal disease are the highest and where most children do not have access to current pneumococcal conjugate vaccines. Although the authors do not provide country-level estimates of serotype distribution, country-specific vaccine impact estimates can be made using country-level pneumococcal disease burden numbers combined with the regional serotype estimates provided in this study. This means that national policy makers can assess the potential impact of serotypes included in different conjugate vaccines, which should contribute to their decision-making process. In addition, manufacturers can now work from a consensus set of serotype coverage estimates to plan and design future serotype-based vaccine formulations to target the pneumococcal disease burden.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000348
The World Health Organization provides information about pneumococcus
The PneumoACTION provides information about pneumonia and pneumococcal disease
The Global Alliance for Vaccination and Immunisation has information on all aspects of vaccination and immunization
The US Centers for Disease Control provides information about pneumococcal conjugate vaccination
The Word Pneumonia Day coalition provides information about pneumonia
doi:10.1371/journal.pmed.1000348
PMCID: PMC2950132  PMID: 20957191
8.  How many individuals with asthma need to be vaccinated to prevent one case of invasive pneumococcal disease? 
Several conditions have been recognized to predispose individuals to invasive pneumococcal disease (IPD) (ie, the isolation of Streptococcus pneumoniae from a normally sterile site). Currently, individuals belonging to the groups known to be at high risk for IPD are vaccinated with the pneumococcal conjugate vaccine or the pneumococcal polysaccharide vaccine. Advisory committees in other countries have recommended adding asthma to the list of conditions that should require immunization for IPD; however, Canada has not. Accordingly, the authors of this article performed an analysis of the number of asthmatic individuals needed to vaccinate against IPD to prevent a single case, and compared the results with those for a condition already classified as high risk.
BACKGROUND:
The American Advisory Committee on Immunization Practices recommended the inclusion of adults with asthma in the high-risk category for pneumococcal vaccination based on a twofold increase in risk of invasive pneumococcal disease (IPD).
OBJECTIVE:
To determine whether, among individuals with asthma, the number needed to vaccinate (NNV) using pneumococcal conjugate vaccine (PCV)-13 or 23-valent pneumococcal polysaccharide vaccine (PPV-23) warrants its addition to the high-risk category for pneumococcal vaccination in Canada.
METHODS:
Using IPD incidence (per 10,000 individuals) figures from published articles (4.2 in high-risk asthmatics, 2.3 in low-risk asthmatics and 1.2 in healthy individuals), the NNV to prevent one case of IPD in asthmatics five to 17 years of age and 18 to 50 years of age was calculated, factoring in the proportion of pneumococcal serotypes included in vaccines (based on data from Quebec) and accounting for the possibility of waning vaccine efficacy (VE) using four scenarios.
RESULTS:
Assuming a VE of 65% for PCV-13 in asthmatics, the NNV would be 704 to 820 in low-risk and 386 to 449 in high-risk children; and 355 to 1532 in low-risk and 195 to 839 in high-risk adults (range depends on waning scenario). Assuming a VE of 65% for PPV-23 in asthmatics, the NNV would be 581 to 677 in low-risk and 318 to 371 in high-risk children; and 246 to 1059 in low-risk and 135 to 580 in high-risk adults.
CONCLUSION:
The NNV with both PCV-13 and PPV-23 in asthmatic children and adults is comparable with that of other high-risk conditions such as age ≥65 years. Therefore, the addition of asthma to the list of high-risk conditions for pneumococcal vaccination is warranted.
PMCID: PMC4173976  PMID: 25285110
Asthma; Pneumococcal; Vaccine
9.  Epidemiology, antibiotic susceptibility, and serotype distribution of Streptococcus pneumoniae associated with invasive pneumococcal disease in British Columbia - A call to strengthen public health pneumococcal immunization programs 
BACKGROUND:
This study examined the epidemiology, antibiotic susceptibility and serotype distribution of Streptococcus pneumoniae associated with invasive pneumococcal disease (IPD) in British Columbia.
METHODS:
Six hospitals and one private laboratory network participated in a prospective, sentinel laboratory based surveillance study of IPD, between October 1999 and October 2000. At each site, S pneumoniae isolates were collected and epidemiological data were gathered using a structured questionnaire, for all cases of IPD meeting the study case definition. Isolates were serotyped and tested for antimicrobial susceptibility. Bivariate associations were analyzed and multivariate logistic regression was used to identify independent risk factors associated with hospitalization or death.
RESULTS:
One hundred three reports and isolates were collected. Seventy-nine per cent of cases were community-acquired, 64% required hospitalization and 5% died. Cases with one or more assessed risk factor for IPD and of female sex were independent variables associated with hospitalization or death. One-third of isolates had reduced penicillin susceptibility and 96% of these represented serotypes contained in the 23-valent pneumococcal polysaccharide vaccine (PPV-23). Overall, 89% of serotypes identified are included in the PPV-23 vaccine and 88% of isolates from children under five years of age are found in the 7-valent pneumococcal conjugate vaccine (PCV-7). Forty-one per cent of cases qualified for publicly funded pneumococcal vaccine and 34% of eligible persons were vaccinated.
CONCLUSIONS:
Overall, pneumococcal serotypes associated with IPD in this study closely matched serotypes included in PPV-23 products currently licensed in Canada. Most serotypes associated with IPD in children under five years of age are included in a recently licenced PCV-7. One third of isolates demonstrated reduced penicillin susceptibility, most involving serotypes included in PPV-23. Effective delivery of current public health immunization programs using PPV-23 and extending protection to infants and young children using the PCV-7 will prevent many cases of IPD.
PMCID: PMC2094947  PMID: 18159467
Antibiotic susceptibility; Immunization; Serotype; Streptococcus pneumoniae
10.  Cost-effectiveness of 2 + 1 dosing of 13-valent and 10-valent pneumococcal conjugate vaccines in Canada 
BMC Infectious Diseases  2012;12:101.
Background
Thirteen-valent pneumococcal conjugate vaccine (PCV13) and 10-valent pneumococcal conjugate vaccine (PCV10) are two recently approved vaccines for the active immunization against Streptococcus pneumoniae causing invasive pneumococcal disease in infants and children. PCV13 offers broader protection against Streptococcus pneumoniae; however, PCV10 offers potential protection against non-typeable Haemophilus influenza (NTHi). We examined public health and economic impacts of a PCV10 and PCV13 pediatric national immunization programs (NIPs) in Canada.
Methods
A decision-analytic model was developed to examine the costs and outcomes associated with PCV10 and PCV13 pediatric NIPs. The model followed individuals over the remainder of their lifetime. Recent disease incidence, serotype coverage, population data, percent vaccinated, costs, and utilities were obtained from the published literature. Direct and indirect effects were derived from 7-valent pneumococcal vaccine. Additional direct effect of 4% was attributed to PCV10 for moderate to severe acute otitis media to account for potential NTHi benefit. Annual number of disease cases and costs (2010 Canadian dollars) were presented.
Results
In Canada, PCV13 was estimated to prevent more cases of disease (49,340 when considering both direct and indirect effects and 7,466 when considering direct effects only) than PCV10. This translated to population gains of 258 to 13,828 more quality-adjusted life-years when vaccinating with PCV13 versus PCV10. Annual direct medical costs (including the cost of vaccination) were estimated to be reduced by $5.7 million to $132.8 million when vaccinating with PCV13. Thus, PCV13 dominated PCV10, and sensitivity analyses showed PCV13 to always be dominant or cost-effective versus PCV10.
Conclusions
Considering the epidemiology of pneumococcal disease in Canada, PCV13 is shown to be a cost-saving immunization program because it provides substantial public health and economic benefits relative to PCV10.
doi:10.1186/1471-2334-12-101
PMCID: PMC3532329  PMID: 22530841
Vaccine; Cost-effectiveness; Pneumococcal conjugate vaccine; Pneumococcal disease
11.  Systematic Review of the Indirect Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Pneumococcal Disease and Colonization 
The Pediatric Infectious Disease Journal  2013;33(Suppl 2 Optimum Dosing of Pneumococcal Conjugate Vaccine For Infants 0 A Landscape Analysis of Evidence Supportin g Different Schedules):S161-S171.
Background:
To aid decision making for pneumococcal conjugate vaccine (PCV) use in infant national immunization programs, we summarized the indirect effects of PCV on clinical outcomes among nontargeted age groups.
Methods:
We systematically reviewed the English literature on infant PCV dosing schedules published from 1994 to 2010 (with ad hoc addition of 2011 articles) for outcomes on children >5 years of age and adults including vaccine-type nasopharyngeal carriage (VT-NP), vaccine-type invasive pneumococcal disease (VT-IPD) and syndromic pneumonia.
Results:
Of 12,980 citations reviewed, we identified 21 VT-IPD, 6 VT-NP and 9 pneumonia studies. Of these 36, 21 (58%) included 3 primary doses plus PCV or pneumococcal polysaccharide vaccine (PPV23) booster schedule (3+1 or 3+PPV23), 5 (14%) 3+0, 9 (25%) 2+1 and 1 (3%) 2+0. Most (95%) were PCV7 studies. Among observational VT-IPD studies, all schedules (2+1, 3+0 and 3+1) demonstrated reductions in incidence among young adult groups. Among syndromic pneumonia observational studies (2+1, 3+0 and 3+1), only 3+1 schedules showed significant indirect impact. Of 2 VT-NP controlled trials (3+0 and 3+1) and 3 VT-NP observational studies (2+1, 3+1 and 3+PPV23), 3+1 and 3+PPV23 schedules showed significant indirect effect. The 1 study to directly compare between schedules was a VT-NP study (2+0 vs. 2+1), which found no indirect effect on older siblings and parents of vaccinated children with either schedule.
Conclusions:
Indirect benefit of a 3+1 infant PCV dosing schedule has been demonstrated for VT-IPD, VT-NP and syndromic pneumonia; 2+1 and 3+0 schedules have demonstrated indirect effect only for VT-IPD. The choice of optimal infant PCV schedule is limited by data paucity on indirect effects, especially a lack of head-to-head studies and studies of PCV10 and PCV13.
doi:10.1097/INF.0000000000000084
PMCID: PMC3940524  PMID: 24336058
pneumococcal conjugate vaccine; nasopharyngeal carriage; pneumonia; pneumococcal disease; indirect effects
12.  Evaluation of Coseasonality of Influenza and Invasive Pneumococcal Disease: Results from Prospective Surveillance 
PLoS Medicine  2011;8(6):e1001042.
Using a combination of modeling and statistical analyses, David Fisman and colleagues show that influenza likely influences the incidence of invasive pneumococcal disease by enhancing risk of invasion in colonized individuals.
Background
The wintertime co-occurrence of peaks in influenza and invasive pneumococcal disease (IPD) is well documented, but how and whether wintertime peaks caused by these two pathogens are causally related is still uncertain. We aimed to investigate the relationship between influenza infection and IPD in Ontario, Canada, using several complementary methodological tools.
Methods and Findings
We evaluated a total number of 38,501 positive influenza tests in Central Ontario and 6,191 episodes of IPD in the Toronto/Peel area, Ontario, Canada, between 1 January 1995 and 3 October 2009, reported through population-based surveillance. We assessed the relationship between the seasonal wave forms for influenza and IPD using fast Fourier transforms in order to examine the relationship between these two pathogens over yearly timescales. We also used three complementary statistical methods (time-series methods, negative binomial regression, and case-crossover methods) to evaluate the short-term effect of influenza dynamics on pneumococcal risk. Annual periodicity with wintertime peaks could be demonstrated for IPD, whereas periodicity for influenza was less regular. As for long-term effects, phase and amplitude terms of pneumococcal and influenza seasonal sine waves were not correlated and meta-analysis confirmed significant heterogeneity of influenza, but not pneumococcal phase terms. In contrast, influenza was shown to Granger-cause pneumococcal disease. A short-term association between IPD and influenza could be demonstrated for 1-week lags in both case-crossover (odds ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.10 [1.02–1.18]) and negative binomial regression analysis (incidence rate ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.09 [1.05–1.14]).
Conclusions
Our data support the hypothesis that influenza influences bacterial disease incidence by enhancing short-term risk of invasion in colonized individuals. The absence of correlation between seasonal waveforms, on the other hand, suggests that bacterial disease transmission is affected to a lesser extent.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Although some pathogens (disease-causing organisms) cause illness all year round, others are responsible for seasonal peaks of illness. These peaks occur because of a complex interplay of factors such as the loss of immunity to the pathogen over time and seasonal changes in the pathogen's ability to infect new individuals. Thus, in temperate countries in the northern hemisphere, illness caused by influenza viruses (pathogens that infect the nose, throat, and airways) usually peaks between December and March, perhaps because weather conditions during these months favor the survival of influenza virus in the environment and thus increase its chances of being transferred among people. Another illness that peaks during the winter months in temperate regions is pneumonia, a severe lung infection that is often caused by Streptococcus pneumoniae. These bacteria can colonize the back of the throat without causing disease but occasionally spread into the lungs and other organs where they cause potentially fatal invasive pneumococcal disease (IPD).
Why Was This Study Done?
Although the co-occurrence of seasonal peaks of influenza and IPD is well documented, it is unclear whether (or how) these peaks are causally related. For example, do the peaks of influenza and IPD both occur in the winter because influenza enhances person-to-person transmission of S. pneumoniae (hypothesis 1)? Alternatively, do the diseases co-occur because influenza infection increases the risk of IPD in individuals who are already colonized with S. pneumoniae (hypothesis 2)? Healthcare professionals need to know whether there is a causal relationship between influenza and IPD so that they can target vaccination for both diseases to those individuals most at risk of developing the potentially serious complications of these diseases. In this study, the researchers use several mathematical and statistical methods and data on influenza and IPD collected in Ontario, Canada to investigate the relationship between these seasonal illnesses.
What Did the Researchers Do and Find?
Between January 1995 and October 2009, 38,501 positive influenza tests were recorded in Ontario by the Canadian national influenza surveillance network. Over the same time period, the Toronto Invasive Bacterial Diseases Network (a group of hospitals, laboratories, and doctors that undertakes population-based surveillance for serious bacterial infections in the Toronto and Peel Regions of Ontario) recorded 6,191 IPD episodes. The researchers used a mathematical method called fast Fourier transforms that compares the shape of wave forms to look for any relationship between infections with the two pathogens over yearly timescales (a test of hypothesis 1) and three statistical methods to evaluate the short-term effect of influenza dynamics on IPD risk (tests of hypothesis 2). Although they found wintertime peaks for infections with both pathogens, there was no correlation between the seasonal wave forms for influenza and IPD. That is, there was no relationship between the seasonal patterns of the two infections. By contrast, two of the statistical methods used to test hypothesis 2 revealed a short-term association between infections with influenza and with IPD. Moreover, the third statistical method (the Granger causality Wald test, a type of time-series analysis) provided evidence that data collected at intervals on influenza can be used to predict peaks in IPD infections.
What Do These Findings Mean?
These findings support (but do not prove) the hypothesis that influenza influences IPD incidence by enhancing the short-term risk of bacterial invasion in individuals already colonized with S. pneumoniae, possibly by increasing the permeability of the lining of the airways to bacteria. By contrast, the lack of correlation between the seasonal wave forms for the two diseases suggests that person-to-person transfer of S. pneumoniae is affected by influenza infections to a lesser extent. These findings have important implications for disease control policy. First, they suggest that the increased number of influenza infections in pandemic years may not necessarily be accompanied by a marked surge in IPD. Second, because the findings suggest that some cases of IPD may be influenza-attributable, the extension of influenza vaccination to school-age children and young adults (a group of people at particular risk of IPD who are not normally vaccinated against influenza) could reduce the incidence of IPD as well as the incidence of influenza.
Additional Information
Please access these Web sites via the online version of this summary at http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015493
A related research article by the same authors evaluating links between respiratory viruses and invasive meningococcal disease can be found in PLoS One (e0015493)
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of seasonal influenza and pneumococcal disease and pneumococcal vaccination
The UK National Health Service Choices website also provides information for patients about seasonal influenza and pneumococcal infection
MedlinePlus has links to further information about influenza and pneumococcal infections (in English and Spanish)
FluWatch is the Canadian national surveillance system for influenza
More information about the Toronto Invasive Bacterial Network is available
The International Association for Ecology and Health provides information on the physical environment and its influence on health
doi:10.1371/journal.pmed.1001042
PMCID: PMC3110256  PMID: 21687693
13.  Potential cost-effectiveness and benefit-cost ratios of adult pneumococcal vaccination in Germany 
Background
Invasive (IPD, defined as detection of pneumococci in sterile body fluids like meningitis or bacteremic pneumonia) and non-invasive Streptococcus pneumoniae infections (i.e. non-bacteremic pneumonia, otitis media) in adults are associated with substantial morbidity, mortality and costs. In Germany, Pneumococcal polysaccharide vaccination (PPV23) is recommended for all persons >60 years and for defined risk groups (age 5–59). The aim of this model was to estimate the potential cost-effectiveness and benefit-cost ratios of the adult vaccination program (18 years and older), considering the launch of the pneumococcal conjugate vaccine for adults (PCV13).
Methods
A cross-sectional steady state Markov model was developed to estimate the outcomes of PCV13, PPV23 vaccination schemes and ‘no vaccination’. Conservative assumptions were made if no data were available for PCV13 and PPV23 respectively. The effectiveness of individual pneumococcal vaccination in adults was adjusted for expected indirect effects due to the vaccination in infants. Data on incidences, effectiveness and costs were derived from scientific literature and publicly available databases. All resources used are indicated. Benefit-cost ratios and cost-effectiveness were evaluated from the perspective of the German Statutory Health Insurance as well as from social perspective.
Results
Under the assumption that PCV13 has a comparable effectiveness to PCV7, a vaccination program with PCV13 revealed the potential to avoid a greater number of yearly cases and deaths in IPD and pneumonia in Germany compared to PPV23. For PCV13, the costs were shown to be overcompensated by monetary savings resulting from reduction in the use of health care services. These results would render the switch from PPV23 to PCV13 as a dominant strategy compared to PPV23 and ‘no vaccination’. Given the correctness of the underlying assumptions every Euro spent on the PCV13 vaccination scheme yields savings of 2.09 € (social perspective: 2.16 €) compared to PPV23 and 1.27 € (social perspective: 1.32 €) compared to ‘no vaccination’, respectively.
Conclusions
Results of the model indicate that the health economic benefit of immunizing adults with PCV13 can be expected to outperform the sole use of PPV23, if the effectiveness of PCV13 is comparable to the effectiveness of PCV7.
doi:10.1186/2191-1991-2-4
PMCID: PMC3463422  PMID: 22828176
Cost; Effectiveness; Pneumococcal polysaccharide vaccine; Pneumococcal conjugate vaccine; Adult; Benefit-cost
14.  Incidence of pediatric invasive pneumococcal disease in the Island of Majorca (2008-2010), an area with non-universal vaccination, and estimations of serotype & children population coverage by available conjugate vaccines 
BMC Infectious Diseases  2013;13:503.
Background
The World Health Organization reported in 2007 that inclusion of PCV7 in national immunization programs should be seen as a priority, also encouraging countries to conduct appropriate surveillances for monitoring the impact of vaccination. These analyses should be conducted in specific geographical areas and should be aimed to evolution of invasive pneumococcal disease (IPD), by age groups, clinical presentation, and vaccine serotypes (and non-vaccine serotypes to detect possible replacement). This study aimed to monitor the evolution of IPD incidence in children <15 years requiring hospitalization in the Island of Majorca.
Methods
A prospective clinical surveillance of all culture and/or PCR-confirmed IPD in children <15 years was performed in all hospitals in the Island of Majorca (approximately 900,000 inhabitants) from January 2008 to December 2010. Incidence rate (IR) was calculated as cases/100000 inhabitants using children population data.
Results
66 IPDs were identified: 39 (59.1%) parapneumonic pneumococcal empyema (PPE), 16 (24.2%) bacteremic pneumonia (BP), 7 (10.6%) primary bacteremia, 3 (4.5%) meningitis, and 1 (1.5%) osteomyelitis. IRs in the three-year study period were: 64.22 for children 12- < 24 months, 37.21 for those 24-59 months, 22.62 for those <12 months, and 3.98 for children >59 months. By study year, IRs were 21.25 in 2008, 19.89 in 2009 and 9.80 in 2010. The reduction found in 2010 was significant and due to significant reductions in IRs of IPDs caused by serotypes included in PCV10 and PCV13. Overall, estimated serotype coverage by conjugate vaccines was 12.1% for PCV7, 37.9% for PCV10 and 65.2% for PCV13. Of the 66 hospitalized children with IPD, 20 had received at least one dose of PCV7 (13 cases with identified serotype). None of these 13 cases was caused by PCV7 serotypes, all were caused by PCV13 serotypes and only 53.8% by PCV10 serotypes.
Conclusions
The results of the present study evidence the importance of expanding the number of serotypes covered by PCV, and the added value of PCV13 with respect to PCV10 and PCV7, even in an area of low prevalence of 19A as the Island of Majorca.
doi:10.1186/1471-2334-13-503
PMCID: PMC3826596  PMID: 24498901
Majorca; PCV7; PCV10; PCV13; Invasive pneumococcal disease; Incidence rate
15.  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
16.  Impact of pneumococcal vaccines use on invasive pneumococcal disease in Nunavik (Quebec) from 1997 to 2010 
International Journal of Circumpolar Health  2014;73:10.3402/ijch.v73.22691.
Background
In 2000, an outbreak of severe pneumonia caused by a virulent clone of serotype 1 Streptococcus pneumoniae was detected in the Nunavik region of Quebec. A mass immunization campaign was implemented in the spring of 2002, targeting persons ≥5 years of age and using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). At the same time, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the routine immunization programme of infants, with catch-up for children up to 4 years of age.
Objectives
To describe the epidemiology of invasive pneumococcal disease (IPD) in relation to PPSV23 and PCV7 use.
Study design and methods
Retrospective analysis of IPD cases identified by the Quebec public health laboratory during the period 1997–2010.
Results
A total of 82 IPD cases were identified during the study period. In adults, serotype 1 incidence decreased following the 2002 PPSV23 mass campaign but breakthrough cases continued to occur. Following PCV7 use in children, there was a decrease in the incidence of vaccine-type IPD and replacement by other serotypes in adults. In children, a marked decrease in the annual incidence of serotypes included in PCV7 was observed following PCV7 introduction: 162/100,000 in 1997–2001 vs. 10/100,000 in 2004–2010 (p<0.01). Concomitantly, the incidence of IPD caused by serotypes not included in PCV7 increased from 29/100,000 to 109/100,000 (p=0.11).
Conclusion
The mass immunization campaign using the PPSV23 in 2002 and the introduction of PCV7 for the routine immunization of infants induced important modifications in the epidemiology of IPD. IPD rates in Nunavik remain much higher than in the southern part of the province both in children and adults. More effective pneumococcal vaccines are needed to eliminate geographic disparities in IPD risk.
doi:10.3402/ijch.v73.22691
PMCID: PMC3896896  PMID: 24455492
immunization; epidemiology; Streptococcus pneumonia; paediatric vaccine; Inuit
17.  Association between Respiratory Syncytial Virus Activity and Pneumococcal Disease in Infants: A Time Series Analysis of US Hospitalization Data 
PLoS Medicine  2015;12(1):e1001776.
Daniel Weinberger and colleagues examine a possible interaction between two serious respiratory infections in children under 2 years of age.
Please see later in the article for the Editors' Summary
Background
The importance of bacterial infections following respiratory syncytial virus (RSV) remains unclear. We evaluated whether variations in RSV epidemic timing and magnitude are associated with variations in pneumococcal disease epidemics and whether changes in pneumococcal disease following the introduction of seven-valent pneumococcal conjugate vaccine (PCV7) were associated with changes in the rate of hospitalizations coded as RSV.
Methods and Findings
We used data from the State Inpatient Databases (Agency for Healthcare Research and Quality), including >700,000 RSV hospitalizations and >16,000 pneumococcal pneumonia hospitalizations in 36 states (1992/1993–2008/2009). Harmonic regression was used to estimate the timing of the average seasonal peak of RSV, pneumococcal pneumonia, and pneumococcal septicemia. We then estimated the association between the incidence of pneumococcal disease in children and the activity of RSV and influenza (where there is a well-established association) using Poisson regression models that controlled for shared seasonal variations. Finally, we estimated changes in the rate of hospitalizations coded as RSV following the introduction of PCV7. RSV and pneumococcal pneumonia shared a distinctive spatiotemporal pattern (correlation of peak timing: ρ = 0.70, 95% CI: 0.45, 0.84). RSV was associated with a significant increase in the incidence of pneumococcal pneumonia in children aged <1 y (attributable percent [AP]: 20.3%, 95% CI: 17.4%, 25.1%) and among children aged 1–2 y (AP: 10.1%, 95% CI: 7.6%, 13.9%). Influenza was also associated with an increase in pneumococcal pneumonia among children aged 1–2 y (AP: 3.2%, 95% CI: 1.7%, 4.7%). Finally, we observed a significant decline in RSV-coded hospitalizations in children aged <1 y following PCV7 introduction (−18.0%, 95% CI: −22.6%, −13.1%, for 2004/2005–2008/2009 versus 1997/1998–1999/2000). This study used aggregated hospitalization data, and studies with individual-level, laboratory-confirmed data could help to confirm these findings.
Conclusions
These analyses provide evidence for an interaction between RSV and pneumococcal pneumonia. Future work should evaluate whether treatment for secondary bacterial infections could be considered for pneumonia cases even if a child tests positive for RSV.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Respiratory infections—bacterial and viral infections of the lungs and the airways (the tubes that take oxygen-rich air to the lungs)—are major causes of illness and death in children worldwide. Pneumonia (infection of the lungs) alone is responsible for about 15% of all child deaths. The leading cause of bacterial pneumonia in children is Streptococcus pneumoniae, which is transmitted through contact with infected respiratory secretions. S. pneumoniae usually causes noninvasive diseases such as bronchitis, but sometimes the bacteria invade the lungs, the bloodstream, or the covering of the brain, where they cause pneumonia, septicemia, or meningitis, respectively. These potentially fatal invasive pneumococcal diseases can be treated with antibiotics but can also be prevented by vaccination with pneumococcal conjugate vaccines such as PCV7. The leading cause of viral pneumonia is respiratory syncytial virus (RSV), which is also readily transmitted through contact with infected respiratory secretions. Almost all children have an RSV infection before their second birthday—RSV usually causes a mild cold-like illness. However, some children infected with RSV develop pneumonia and have to be admitted to hospital for supportive care such as the provision of supplemental oxygen; there is no specific treatment for RSV infection.
Why Was This Study Done?
Co-infections with bacteria and viruses can sometimes have a synergistic effect and lead to more severe disease than an infection with either type of pathogen (disease-causing organism) alone. For example, influenza infections increase the risk of invasive pneumococcal disease. But does pneumococcal disease also interact with RSV infection? It is important to understand the interaction between pneumococcal disease and RSV to improve the treatment of respiratory infections in young children, but the importance of bacterial infections following RSV infection is currently unclear. Here, the researchers undertake a time series analysis of US hospitalization data to investigate the association between RSV activity and pneumococcal disease in infants. Time series analysis uses statistical methods to analyze data collected at successive, evenly spaced time points.
What Did the Researchers Do and Find?
For their analysis, the researchers used data collected between 1992/1993 and 2008/2009 by the State Inpatient Databases on more than 700,000 hospitalizations for RSV and more than 16,000 hospitalizations for pneumococcal pneumonia or septicemia among children under two years old in 36 US states. Using a statistical technique called harmonic regression to measure seasonal variations in disease incidence (the rate of occurrence of new cases of a disease), the researchers show that RSV and pneumococcal pneumonia shared a distinctive spatiotemporal pattern over the study period. Next, using Poisson regression models (another type of statistical analysis), they show that RSV was associated with significant increases (increases unlikely to have happened by chance) in the incidence of pneumococcal disease. Among children under one year old, 20.3% of pneumococcal pneumonia cases were associated with RSV activity; among children 1–2 years old, 10.1% of pneumococcal pneumonia cases were associated with RSV activity. Finally, the researchers report that following the introduction of routine vaccination in the US against S. pneumoniae with PCV7 in 2000, there was a significant decline in hospitalizations for RSV among children under one year old.
What Do These Findings Mean?
These findings provide evidence for an interaction between RSV and pneumococcal pneumonia and indicate that RSV is associated with increases in the incidence of pneumococcal pneumonia, particularly in young infants. Notably, the finding that RSV hospitalizations declined after the introduction of routine pneumococcal vaccination suggests that some RSV hospitalizations may have a joint viral–bacterial etiology (cause), although it is possible that PCV7 vaccination reduced the diagnosis of RSV because fewer children were hospitalized with pneumococcal disease and subsequently tested for RSV. Because this is an ecological study (an observational investigation that looks at risk factors and outcomes in temporally and geographically defined populations), these findings do not provide evidence for a causal link between hospitalizations for RSV and pneumococcal pneumonia. The similar spatiotemporal patterns for the two infections might reflect another unknown factor shared by the children who were hospitalized for RSV or pneumococcal pneumonia. Moreover, because pooled hospitalization discharge data were used in this study, these results need to be confirmed through analysis of individual-level, laboratory-confirmed data. Importantly, however, these findings support the initiation of studies to determine whether treatment for bacterial infections should be considered for children with pneumonia even if they have tested positive for RSV.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001776.
The US National Heart, Lung, and Blood Institute provides information about the respiratory system and about pneumonia
The US Centers for Disease Control and Prevention provides information on all aspects of pneumococcal disease and pneumococcal vaccination, including personal stories and information about RSV infection
The UK National Health Service Choices website provides information about pneumonia (including a personal story) and about pneumococcal diseases
KidsHealth, a website provided by the US-based non-profit Nemours Foundation, includes information on pneumonia and on RSV (in English and Spanish)
MedlinePlus provides links to other resources about pneumonia, RSV infections, and pneumococcal infections (in English and Spanish)
HCUPnet provides aggregated hospitalization data from the State Inpatient Databases used in this study
doi:10.1371/journal.pmed.1001776
PMCID: PMC4285401  PMID: 25562317
18.  The epidemiology of invasive pneumococcal disease in the Canadian North from 1999 to 2010 
International Journal of Circumpolar Health  2013;72:10.3402/ijch.v72i0.21606.
Introduction
The International Circumpolar Surveillance network is a population-based surveillance system that collects data on invasive pneumococcal disease (IPD) in Northern Canada. A 7-valent pneumococcal conjugate vaccine was first introduced in some regions of Northern Canada in 2002, followed by 10-valent (2009) and 13-valent (PCV-13) vaccines (2010). A 23-valent polysaccharide (PPV-23) vaccine was first introduced in 1988 for special populations and adults aged 65 years and older. To describe the epidemiology in the context of pneumococcal vaccination programs, we analysed surveillance data from Northern Canada from 1999 to 2010.
Methods
A standardized case report form capturing demographic and clinical information was completed for all IPD cases in Northern Canada meeting the national case definition. Isolates were sent to a reference laboratory for confirmation, serotyping and antimicrobial resistance testing. Both laboratory and epidemiological data were sent to the Public Health Agency of Canada for analysis. Population denominators were obtained from Statistics Canada.
Results
From 1999 to 2010, 433 IPD cases were reported (average 36 cases per year). Incidence was greatest among infants aged <2 years and among those aged 65 years and older, with an average annual incidence of 133 and 67 cases per 100,000 population, respectively. After a peak in incidence in 2008, rates among infants have declined. Incidence rates varied from 2 to 16 times greater, depending on the year, among Aboriginals compared to non-Aboriginals. Hospitalization was reported in 89% of all cases and the case fatality ratio was 6.0%. Clinical manifestations varied, with some patients reporting >1 manifestation. Pneumonia was the most common (70%), followed by bacteremia/septicaemia (30%) and meningitis (8%). Approximately, 42% of cases aged <2 years in 2009 and 2010 had serotypes covered by the PCV-13. In addition, the majority (89%) of serotypes isolated in cases aged 65 years and older were included in the PPV-23 vaccine.
Conclusion
IPD continues to be a major cause of disease in Northern Canadian populations, with particularly high rates among infants and Aboriginals. Continued surveillance is needed to determine the impact of conjugate pneumococcal vaccine programs. Additional studies investigating factors that predispose infants and Aboriginal peoples would also be beneficial.
doi:10.3402/ijch.v72i0.21606
PMCID: PMC3749849  PMID: 23971011
Streptococcus pneumoniae; Canadian circumpolar region; surveillance; epidemiology; vaccine preventable disease
19.  Efficacy of Pneumococcal Nontypable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) in Young Latin American Children: A Double-Blind Randomized Controlled Trial 
PLoS Medicine  2014;11(6):e1001657.
In a double-blind randomized controlled trial, Xavier Saez-Llorens and colleagues examine the vaccine efficacy of PHiD-CV against community-acquired pneumonia in young children in Panama, Argentina, and Columbia.
Please see later in the article for the Editors' Summary
Background
The relationship between pneumococcal conjugate vaccine–induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study assessed the impact of the ten-valent pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP (B-CAP: radiologically confirmed CAP with alveolar consolidation/pleural effusion on chest X-ray, or non-alveolar infiltrates and C-reactive protein ≥ 40 µg/ml); other protocol-specified outcomes were also assessed.
Methods and Findings
This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine (hepatitis B for primary vaccination, hepatitis A at booster) at 2, 4, 6, and 15–18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo (PHiD-CV, n = 10,295; control, n = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided p = 0.002) against B-CAP (conclusive for primary objective) and 25.7% (95% CI: 8.4%, 39.6%) against World Health Organization–defined consolidated CAP. Intent-to-treat VE was 18.2% (95% CI: 5.5%, 29.1%) against B-CAP and 23.4% (95% CI: 8.8%, 35.7%) against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28–30 mo for CAP and invasive pneumococcal disease (IPD) (PHiD-CV, n = 10,211; control, n = 10,140) and AOM (n = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: −1.1%, 30.4%; one-sided p = 0.032) against clinically confirmed AOM, 67.1% (95% CI: 17.0%, 86.9%) against vaccine serotype clinically confirmed AOM, 100% (95% CI: 74.3%, 100%) against vaccine serotype IPD, and 65.0% (95% CI: 11.1%, 86.2%) against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5% (95% CI: 20.7%, 22.2%) and 22.6% (95% CI: 21.9%, 23.4%) of PHiD-CV and control recipients, respectively. There were 19 deaths (n = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (n = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases.
Conclusions
Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice.
Trial registration
www.ClinicalTrials.gov NCT00466947
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pneumococcal diseases are illnesses caused by Streptococcus pneumoniae bacteria, pathogens (disease-causing organisms) that are transmitted through contact with infected respiratory secretions. S. pneumoniae causes mucosal diseases–infections of the lining of the body cavities that are connected to the outside world–such as community-acquired pneumonia (CAP; lung infection) and acute otitis media (AOM; middle-ear infection). It also causes invasive pneumococcal diseases (IPDs) such as septicemia and meningitis (infections of the bloodstream and the covering of the brain, respectively). Although pneumococcal diseases can sometimes be treated with antibiotics, CAP and IPDs are leading global causes of childhood deaths, particularly in developing countries. It is best therefore to avoid S. pneumoniae infections through vaccination. Vaccination primes the immune system to recognize and attack pathogens rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules that it recognizes as foreign (antigens). Because there are more than 90 S. pneumoniae variants (“serotypes”), each characterized by a different antigenic polysaccharide (complex sugar) coat, S. pneumoniae vaccines have to include antigens from multiple serotypes. For example, the PHiD-CV vaccine contains polysaccharides from ten S. pneumoniae serotypes.
Why Was This Study Done?
Although in most countries PHiD-CV has been licensed for protection against IPD and pneumococcal AOM, at the time of study, it was not known how well it protected against CAP and overall AOM, which are important public health problems. In this double-blind randomized controlled trial (the Clinical Otitis Media and Pneumonia Study; COMPAS), the researchers investigate the efficacy of PHiD-CV against CAP and AOM and assess other clinical end points, such as IPD, in Latin American infants. Double-blind randomized controlled trials compare the effects of interventions by assigning study participants to different interventions randomly and measuring predefined outcomes without the study participants or researchers knowing who has received which intervention until the trial is completed. Vaccine efficacy is the reduction in the incidence of a disease (the number of new cases that occur in a population in a given time) among trial participants who receive the vaccine compared to the incidence among participants who do not receive the vaccine.
What Did the Researchers Do and Find?
The researchers enrolled around 24,000 infants living in urban areas of Argentina, Panama, and Colombia. Half the infants were given PHiD-CV at 2, 4, and 6 months of age and a booster dose at age 15–18 months. The remaining infants were given a hepatitis control vaccine at the same intervals. The trial's primary end point was likely bacterial CAP (B-CAP) –radiologically confirmed CAP, with the airspaces (alveoli) in the lungs filled with liquid instead of gas (alveolar consolidation) or with non-alveolar infiltrates and raised blood levels of C-reactive protein (a marker of inflammation). In a planned interim analysis, which was undertaken after an average follow-up of 23 months, the vaccine efficacy in the per-protocol cohort (the group of participants who actually received their assigned intervention) was 22% against B-CAP. Intent-to-treat vaccine efficacy in the interim analysis (which considered all the trial participants regardless of whether they received their assigned intervention) was 18.2%. At the end of the study (average follow up 30 months), the vaccine efficacy against B-CAP was 18.2% and 16.7% in the per-protocol and intent-to-treat cohorts, respectively. Per-protocol vaccine efficacies against clinically confirmed AOM and vaccine serotype AOM were 16.1% and 67.1%, respectively. Against any IPD and against vaccine serotype IPD, the respective vaccine efficacies were 65% and 100%. Finally, about one-fifth of children who received PHiD-CV and a similar proportion who received the control vaccine experienced a serious adverse event (for example, gastroenteritis); 19 children who received PHiD-CV died compared to 26 children who received the control vaccine.
What Do These Findings Mean?
These findings indicate that in Latin America, a region with an intermediate burden of pneumococcal disease, PHiD-CV is efficacious against a broad range of pneumococcal diseases that often affect young children. The accuracy of these findings may be limited by the withdrawal of 14% of participants from the trial because of adverse media coverage and by the low number of reported cases of AOM. Moreover, because most study participants lived in urban areas, these findings may not be generalizable to rural settings. Despite these and other study limitations, these findings provide new information about the magnitude of the effect of PHiD-CV vaccination against CAP and AOM, two mucosal pneumococcal diseases of global public health importance.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001657.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination, including personal stories
Public Health England provides information on pneumococcal disease and on pneumococcal vaccines
The not-for-profit Immunization Action Coalition has information on pneumococcal disease, including personal stories
The GAVI Alliance provides information about pneumococcal disease and the importance of vaccination
MedlinePlus has links to further information about pneumococcal infections, including pneumonia and otitis media (in English and Spanish)
More information about COMPAS is available
The European Medicines Agency provides information about PHiD-CV (Synflorix)
doi:10.1371/journal.pmed.1001657
PMCID: PMC4043495  PMID: 24892763
20.  International Circumpolar Surveillance System for Invasive Pneumococcal Disease, 1999–2005 
Emerging Infectious Diseases  2008;14(1):25-33.
Disease rates are high among indigenous persons in Arctic countries, and PCV7 has resulted in decreased rates in North American children.
The International Circumpolar Surveillance System is a population-based surveillance network for invasive bacterial disease in the Arctic. The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced for routine infant vaccination in Alaska (2001), northern Canada (2002–2006), and Norway (2006). Data for invasive pneumococcal disease (IPD) were analyzed to identify clinical findings, disease rates, serotype distribution, and antimicrobial drug susceptibility; 11,244 IPD cases were reported. Pneumonia and bacteremia were common clinical findings. Rates of IPD among indigenous persons in Alaska and northern Canada were 43 and 38 cases per 100,000 population, respectively. Rates in children <2 years of age ranged from 21 to 153 cases per 100,000 population. In Alaska and northern Canada, IPD rates in children <2 years of age caused by PCV7 serotypes decreased by >80% after routine vaccination. IPD rates are high among indigenous persons and children in Arctic countries. After vaccine introduction, IPD caused by non-PCV7 serotypes increased in Alaska.
doi:10.3201/eid1401.071315
PMCID: PMC2600171  PMID: 18258073
Streptococcus pneumoniae; invasive pneumococcal disease; IPD; surveillance; PCV7; serotype replacement; indigenous; Alaska Native; circumpolar; arctic; research
21.  Pediatric Invasive Pneumococcal Disease Caused by Vaccine Serotypes following the Introduction of Conjugate Vaccination in Denmark 
PLoS ONE  2013;8(1):e51460.
A seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the Danish childhood immunization program (2+1 schedule) in October 2007, followed by PCV13 starting from April 2010. The nationwide incidence of IPD among children younger than 5 years nearly halved after the introduction of PCV7 in the program, mainly due to a decline in IPD caused by PCV7-serotypes. We report the results from a nationwide population-based cohort study of laboratory confirmed IPD cases in children younger than 5 years during October 1, 2007 to December 31, 2010 and describe the characteristics of children suspected to present with a vaccine failure. The period between April 19 and December 31, 2010 was considered a PCV7/PCV13 transitional period, where both vaccines were offered. We identified 45 episodes of IPD caused by a PCV7 serotype (23% of the total number) and 105 (55%) caused by one of the 6 additional serotypes in PCV13. Ten children had received at least one PCV7 dose before the onset of IPD caused by a PCV7 serotype. Seven children were considered to be incompletely vaccinated before IPD, but only three cases fulfilled the criteria of vaccine failure (caused by serotypes 14, 19F and 23F). One case of vaccine failure was observed in a severely immunosuppressed child following three PCV7 doses, and two cases were observed in immunocompetent children following two infant doses before they were eligible for their booster. None of the IPD cases caused by the additional PCV13 serotypes had been vaccinated by PCV13 and there were therefore no PCV13-vaccine failures in the first 8-months after PCV13 introduction in Denmark.
doi:10.1371/journal.pone.0051460
PMCID: PMC3554759  PMID: 23365635
22.  Effectiveness and cost-effectiveness of general immunisation of infants and young children with the heptavalent conjugated pneumococcal vaccine 
Background
The European Agency for the Evaluation of Medicinal Products (EMEA) granted market authorisation to the heptavalent pneumococcal vaccine Prevenar (Wyeth) in the year 2001. The indication of Prevenar is the active immunisation of infants and young children under the age of two against invasive disease caused by Streptococcus pneumonia serotypes 4, 6B, 9V, 14, 18C, 19F and 23F. At the time of this study the German vaccination scheme advises the immunisation with Prevenar only for children at high risk.
Objectives
The objective of the study is first to determine the efficacy and effectiveness of the immunisation of all children with the heptavalent conjugated pneumococcal vaccine in Germany and second, whether a general recommendation for vaccination of all children would be cost-effective.
Methods
A systematic literature search was performed in 29 relevant databases for the period of January 1999 to June 2004. Thus 1,884 articles were identified which were then assessed according to predefined selection criteria.
Results
There is evidence for the medical effectiveness of Prevenar against invasive pneumococcal disease caused by the covered serotypes from a major double-blinded RCT undertaken in California. The vaccine shows lower values of effectiveness against otitis media and pneumonia. The values for effectiveness of the vaccine in Germany are below the data for California because of the different incidence of Serotypes. The cost-effectiveness rates for an immunisation of all children with Prevenar vary across different countries. One reason - besides different Health Systems - can be seen in the uncertainty about the duration of protection, another in the assumption on regional serotype coverage of the vaccine. From the healthcare payers' perspective a general vaccination of all children in Germany is not cost-effective, from a societal perspective the benefits from vaccination could prevail the cost. The actual price of the vaccine (if financed by the Healthcare Payer, 2004) has dropped and is lower than the assumed price in the German cost-effectiveness study. This fact could raise the cost-effectiveness-ratio of a general immunisation.
Discussion
The low evidence of information on the herd immunity effect of pneumococcal immunisation, the occurrence on serotype-replacement phenomenon and the effects on the prevalence of antibiotic-resistant strains shall be considered when deciding whether the pneumococcal vaccination for all infants and young children should be added to the German vaccination scheme. There is also little information on the duration of vaccine effectiveness and regional effectiveness because of different serotype incidence. The economic models thus incorporate some uncertainties.
Conclusion
At present, relatively few pneumococcal strains in Germany show antibiotic resistance. This situation shall further be observed while improving the data evidence for future decisions (epidemiologic data of incidence of pneumococcal diseases and serotyping of pneumococcal bacteria). From the economic perspective no distinct recommendation to add the conjugated vaccination for all children to the German vaccination scheme can be given. This situation may change if the price for the vaccine further decreases. Furthermore a future cost-effectiveness analysis for Germany should incorporate the effects of the replacement phenomenon, the herd immunisation effects and the effects of the vaccination on the antibiotic-resistant pneumococcal strains.
PMCID: PMC3011321  PMID: 21289926
23.  Recommendation for use of the newly introduced pneumococcal protein conjugate vaccines in Korea 
Korean Journal of Pediatrics  2011;54(4):146-151.
Streptococcus pneumoniae remains a leading cause of invasive infections including bacteremia and meningitis, as well as mucosal infections such as otitis media and pneumonia among children and adults. The 7-valent pneumococcal conjugate vaccine (PCV7) was licensed for use among infants and young children in many countries including Korea. The routine use of PCV7 has resulted in a decreased incidence of invasive pneumococcal disease (IPD) by the vaccine serotypes among the vaccinees and substantial declines in IPD among unvaccinated populations such as older children and adults as well. In addition, there are increasing evidences to suggest that routine immunization with PCV7 is changing the epidemiology of pneumococcal diseases such as serotype distribution of IPD, nasopharyngeal colonization, and antibiotic resistance patterns. In contrast, there is an increase in the number of IPDs caused by nonvaccine serotypes, though it is much smaller than overall declines of vaccine serotype diseases. Several vaccines containing additional serotypes have been developed and tested clinically in order to expand the range of serotypes of Streptococcus pneumoniae. Recently two new pneumococcal protein conjugate vaccines, 10-valent pneumococcal conjugate vaccine (PCV10) and 13-valent pneumococcal conjugate vaccine (PCV13), have been approved for use in several countries including Korea. This report summarizes the recommendations approved by the Committee on Infectious Diseases, the Korean Pediatric Society.
doi:10.3345/kjp.2011.54.4.146
PMCID: PMC3127147  PMID: 21738547
Streptococcus pneumoniae; Pneumococcal conjugate vaccine; Serotype
24.  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
25.  Invasive Pneumococcal Isolates from Danish Infants (0 - 90 Days) during the Years 1943 to 2013 
PLoS ONE  2014;9(8):e106180.
Background
The seven-valent pneumococcal conjugate vaccine (PCV-7) was introduced in the Danish childhood immunization program (at 3, 5 and 12 months of age) in 2007 and was replaced with PCV-13 in 2010 without changes to the schedule. After the introduction of these vaccines the incidence of invasive pneumococcal disease (IPD) due to vaccine types (VTs) declined markedly in children aged 0–2 years; however, cases among infants too young to be protected by vaccination have not been studied in detail. We present data on IPD in infants less than 90 days from 1943 until 2013.
Study design
The study included all infants younger than 90 days born from 1943 through 2013, who had not been PCV vaccinated and from whom a pneumococcus isolate from blood or cerebrospinal fluid had been submitted to the Danish national reference laboratory. All isolates were serotyped using Pneumotest Latex and Quellung reaction.
Results
A total of 216 IPD cases were identified. The age group specific incidence (total number of IPD cases per 100,000 live births) varied from 0 to 16 in the period 1943 to 2007 and from 1.7 to 9.2 in the period 2008 to 2013. IPD cases due to PCV-7 serotypes were not observed later than 2009.
Conclusion
In Danish infants younger than 90 days, IPD due to PCV-7 serotypes has decreased and has not been observed since 2009, but the total incidence of IPD has not changed.
doi:10.1371/journal.pone.0106180
PMCID: PMC4144964  PMID: 25157997

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