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1.  Impact of routine PCV7 (Prevenar) vaccination of infants on the clinical and economic burden of pneumococcal disease in Malaysia 
BMC Infectious Diseases  2011;11:248.
Background
Pneumococcal disease is the leading cause of vaccine-preventable death in children younger than 5 years of age worldwide. The World Health Organization recommends pneumococcal conjugate vaccine as a priority for inclusion into national childhood immunization programmes. Pneumococcal vaccine has yet to be included as part of the national vaccination programme in Malaysia although it has been available in the country since 2005. This study sought to estimate the disease burden of pneumococcal disease in Malaysia and to assess the cost effectiveness of routine infant vaccination with PCV7.
Methods
A decision model was adapted taking into consideration prevalence, disease burden, treatment costs and outcomes for pneumococcal disease severe enough to result in a hospital admission. Disease burden were estimated from the medical records of 6 hospitals. Where local data was unavailable, model inputs were obtained from international and regional studies and from focus group discussions. The model incorporated the effects of herd protection on the unvaccinated adult population.
Results
At current vaccine prices, PCV7 vaccination of 90% of a hypothetical 550,000 birth cohort would incur costs of RM 439.6 million (US$128 million). Over a 10 year time horizon, vaccination would reduce episodes of pneumococcal hospitalisation by 9,585 cases to 73,845 hospitalisations with cost savings of RM 37.5 million (US$10.9 million) to the health system with 11,422.5 life years saved at a cost effectiveness ratio of RM 35,196 (US$10,261) per life year gained.
Conclusions
PCV7 vaccination of infants is expected to be cost-effective for Malaysia with an incremental cost per life year gained of RM 35,196 (US$10,261). This is well below the WHO's threshold for cost effectiveness of public health interventions in Malaysia of RM 71,761 (US$20,922).
doi:10.1186/1471-2334-11-248
PMCID: PMC3189895  PMID: 21936928
2.  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
3.  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
4.  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
5.  Type-Specific Antibodies to Pneumococcal Capsular Polysaccharide Acquired either Naturally or after Vaccination with Prevenar in Children with Underlying Chronic or Recurrent Lung Diseases 
Clinical and Vaccine Immunology  2006;13(6):665-670.
The antibody response to capsular polysaccharides of pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F elicited either naturally or after vaccination with Prevenar was investigated in a cohort of children (n = 163) with underlying chronic or recurrent lung diseases at risk of developing pneumococcal pneumonia and ultimately invasive disease. Serum concentrations of serotype-specific antibodies, as measured by enzyme-linked immunosorbent assay, in unvaccinated children (n = 88) were higher in nasopharyngeal carriers (n = 10) than in noncarriers (n = 78) both at baseline and during follow-up. However, the antibody levels depended on the serotype and age of the children. During the study period, 35% of unvaccinated noncarriers and 60% of unvaccinated carriers displayed serum antibodies to all serotypes above the reported WHO working group putative protective serum concentration against invasive disease (0.2 μg/ml). Overall, children vaccinated with Prevenar before enrollment (n = 61), irrespective of their carrier status, displayed significantly higher serum levels of antibodies to all serotypes than unvaccinated children. More than 85% of the vaccinated children had protective serum antibody concentrations at baseline; although antibody titers tended to decrease over time, the above-mentioned figure remained without change at the end of follow-up. The vaccine Prevenar elicited a significant rise in serum antibody concentrations against all serotypes in 14 children vaccinated at entry. All of these children acquired and maintained serum antibody levels of >0.2 μg/ml throughout the study (a mean of 13 months of follow-up). These data support the systematic use of the vaccine Prevenar in children with underlying chronic or recurrent lung diseases and stress the fact that a percentage of vaccinated children may need to be revaccinated in order to achieve protection against pneumococcal disease.
doi:10.1128/CVI.00079-06
PMCID: PMC1489555  PMID: 16760325
6.  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
7.  Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this analysis was to determine the effectiveness of the influenza vaccination and the pneumococcal vaccination in patients with chronic obstructive pulmonary disease (COPD) in reducing the incidence of influenza-related illness or pneumococcal pneumonia.
Clinical Need: Condition and Target Population
Influenza Disease
Influenza is a global threat. It is believed that the risk of a pandemic of influenza still exists. Three pandemics occurred in the 20th century which resulted in millions of deaths worldwide. The fourth pandemic of H1N1 influenza occurred in 2009 and affected countries in all continents.
Rates of serious illness due to influenza viruses are high among older people and patients with chronic conditions such as COPD. The influenza viruses spread from person to person through sneezing and coughing. Infected persons can transfer the virus even a day before their symptoms start. The incubation period is 1 to 4 days with a mean of 2 days. Symptoms of influenza infection include fever, shivering, dry cough, headache, runny or stuffy nose, muscle ache, and sore throat. Other symptoms such as nausea, vomiting, and diarrhea can occur.
Complications of influenza infection include viral pneumonia, secondary bacterial pneumonia, and other secondary bacterial infections such as bronchitis, sinusitis, and otitis media. In viral pneumonia, patients develop acute fever and dyspnea, and may further show signs and symptoms of hypoxia. The organisms involved in bacterial pneumonia are commonly identified as Staphylococcus aureus and Hemophilus influenza. The incidence of secondary bacterial pneumonia is most common in the elderly and those with underlying conditions such as congestive heart disease and chronic bronchitis.
Healthy people usually recover within one week but in very young or very old people and those with underlying medical conditions such as COPD, heart disease, diabetes, and cancer, influenza is associated with higher risks and may lead to hospitalization and in some cases death. The cause of hospitalization or death in many cases is viral pneumonia or secondary bacterial pneumonia. Influenza infection can lead to the exacerbation of COPD or an underlying heart disease.
Streptococcal Pneumonia
Streptococcus pneumoniae, also known as pneumococcus, is an encapsulated Gram-positive bacterium that often colonizes in the nasopharynx of healthy children and adults. Pneumococcus can be transmitted from person to person during close contact. The bacteria can cause illnesses such as otitis media and sinusitis, and may become more aggressive and affect other areas of the body such as the lungs, brain, joints, and blood stream. More severe infections caused by pneumococcus are pneumonia, bacterial sepsis, meningitis, peritonitis, arthritis, osteomyelitis, and in rare cases, endocarditis and pericarditis.
People with impaired immune systems are susceptible to pneumococcal infection. Young children, elderly people, patients with underlying medical conditions including chronic lung or heart disease, human immunodeficiency virus (HIV) infection, sickle cell disease, and people who have undergone a splenectomy are at a higher risk for acquiring pneumococcal pneumonia.
Technology
Influenza and Pneumococcal Vaccines
Trivalent Influenza Vaccines in Canada
In Canada, 5 trivalent influenza vaccines are currently authorized for use by injection. Four of these are formulated for intramuscular use and the fifth product (Intanza®) is formulated for intradermal use.
The 4 vaccines for intramuscular use are:
Fluviral (GlaxoSmithKline), split virus, inactivated vaccine, for use in adults and children ≥ 6 months;
Vaxigrip (Sanofi Pasteur), split virus inactivated vaccine, for use in adults and children ≥ 6 months;
Agriflu (Novartis), surface antigen inactivated vaccine, for use in adults and children ≥ 6 months; and
Influvac (Abbott), surface antigen inactivated vaccine, for use in persons ≥ 18 years of age.
FluMist is a live attenuated virus in the form of an intranasal spray for persons aged 2 to 59 years. Immunization with current available influenza vaccines is not recommended for infants less than 6 months of age.
Pneumococcal Vaccine
Pneumococcal polysaccharide vaccines were developed more than 50 years ago and have progressed from 2-valent vaccines to the current 23-valent vaccines to prevent diseases caused by 23 of the most common serotypes of S pneumoniae. Canada-wide estimates suggest that approximately 90% of cases of pneumococcal bacteremia and meningitis are caused by these 23 serotypes. Health Canada has issued licenses for 2 types of 23-valent vaccines to be injected intramuscularly or subcutaneously:
Pneumovax 23® (Merck & Co Inc. Whitehouse Station, NJ, USA), and
Pneumo 23® (Sanofi Pasteur SA, Lion, France) for persons 2 years of age and older.
Other types of pneumococcal vaccines licensed in Canada are for pediatric use. Pneumococcal polysaccharide vaccine is injected only once. A second dose is applied only in some conditions.
Research Questions
What is the effectiveness of the influenza vaccination and the pneumococcal vaccination compared with no vaccination in COPD patients?
What is the safety of these 2 vaccines in COPD patients?
What is the budget impact and cost-effectiveness of these 2 vaccines in COPD patients?
Research Methods
Literature search
Search Strategy
A literature search was performed on July 5, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2000 to July 5, 2010. The search was updated monthly through the AutoAlert function of the search up to January 31, 2011. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Data extraction was carried out by the author.
Inclusion Criteria
studies comparing clinical efficacy of the influenza vaccine or the pneumococcal vaccine with no vaccine or placebo;
randomized controlled trials published between January 1, 2000 and January 31, 2011;
studies including patients with COPD only;
studies investigating the efficacy of types of vaccines approved by Health Canada;
English language studies.
Exclusion Criteria
non-randomized controlled trials;
studies investigating vaccines for other diseases;
studies comparing different variations of vaccines;
studies in which patients received 2 or more types of vaccines;
studies comparing different routes of administering vaccines;
studies not reporting clinical efficacy of the vaccine or reporting immune response only;
studies investigating the efficacy of vaccines not approved by Health Canada.
Outcomes of Interest
Primary Outcomes
Influenza vaccination: Episodes of acute respiratory illness due to the influenza virus.
Pneumococcal vaccination: Time to the first episode of community-acquired pneumonia either due to pneumococcus or of unknown etiology.
Secondary Outcomes
rate of hospitalization and mechanical ventilation
mortality rate
adverse events
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses. The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Efficacy of the Influenza Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The influenza vaccination was associated with significantly fewer episodes of influenza-related acute respiratory illness (ARI). The incidence density of influenza-related ARI was:
All patients: vaccine group: (total of 4 cases) = 6.8 episodes per 100 person-years; placebo group: (total of 17 cases) = 28.1 episodes per 100 person-years, (relative risk [RR], 0.2; 95% confidence interval [CI], 0.06−0.70; P = 0.005).
Patients with severe airflow obstruction (forced expiratory volume in 1 second [FEV1] < 50% predicted): vaccine group: (total of 1 case) = 4.6 episodes per 100 person-years; placebo group: (total of 7 cases) = 31.2 episodes per 100 person-years, (RR, 0.1; 95% CI, 0.003−1.1; P = 0.04).
Patients with moderate airflow obstruction (FEV1 50%−69% predicted): vaccine group: (total of 2 cases) = 13.2 episodes per 100 person-years; placebo group: (total of 4 cases) = 23.8 episodes per 100 person-years, (RR, 0.5; 95% CI, 0.05−3.8; P = 0.5).
Patients with mild airflow obstruction (FEV1 ≥ 70% predicted): vaccine group: (total of 1 case) = 4.5 episodes per 100 person-years; placebo group: (total of 6 cases) = 28.2 episodes per 100 person-years, (RR, 0.2; 95% CI, 0.003−1.3; P = 0.06).
The Kaplan-Meier survival analysis showed a significant difference between the vaccinated group and the placebo group regarding the probability of not acquiring influenza-related ARI (log-rank test P value = 0.003). Overall, the vaccine effectiveness was 76%. For categories of mild, moderate, or severe COPD the vaccine effectiveness was 84%, 45%, and 85% respectively.
With respect to hospitalization, fewer patients in the vaccine group compared with the placebo group were hospitalized due to influenza-related ARIs, although these differences were not statistically significant. The incidence density of influenza-related ARIs that required hospitalization was 3.4 episodes per 100 person-years in the vaccine group and 8.3 episodes per 100 person-years in the placebo group (RR, 0.4; 95% CI, 0.04−2.5; P = 0.3; log-rank test P value = 0.2). Also, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD.
Fewer patients in the vaccine group compared with the placebo group required mechanical ventilation due to influenza-related ARIs. However, these differences were not statistically significant. The incidence density of influenza-related ARIs that required mechanical ventilation was 0 episodes per 100 person-years in the vaccine group and 5 episodes per 100 person-years in the placebo group (RR, 0.0; 95% CI, 0−2.5; P = 0.1; log-rank test P value = 0.4). In addition, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD. The effectiveness of the influenza vaccine in preventing influenza-related ARIs and influenza-related hospitalization was not related to age, sex, severity of COPD, smoking status, or comorbid diseases.
safety
Overall, significantly more patients in the vaccine group than the placebo group experienced local adverse reactions (vaccine: 17 [27%], placebo: 4 [6%]; P = 0.002). Significantly more patients in the vaccine group than the placebo group experienced swelling (vaccine 4, placebo 0; P = 0.04) and itching (vaccine 4, placebo 0; P = 0.04). Systemic reactions included headache, myalgia, fever, and skin rash and there were no significant differences between the 2 groups for these reactions (vaccine: 47 [76%], placebo: 51 [81%], P = 0.5).
With respect to lung function, dyspneic symptoms, and exercise capacity, there were no significant differences between the 2 groups at 1 week and at 4 weeks in: FEV1, maximum inspiratory pressure at residual volume, oxygen saturation level of arterial blood, visual analogue scale for dyspneic symptoms, and the 6 Minute Walking Test for exercise capacity.
There was no significant difference between the 2 groups with regard to the probability of not acquiring total ARIs (influenza-related and/or non-influenza-related); (log-rank test P value = 0.6).
Summary of Efficacy of the Pneumococcal Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The Kaplan-Meier survival analysis showed no significant differences between the group receiving the penumoccocal vaccination and the control group for time to the first episode of community-acquired pneumonia due to pneumococcus or of unknown etiology (log-rank test 1.15; P = 0.28). Overall, vaccine efficacy was 24% (95% CI, −24 to 54; P = 0.33).
With respect to the incidence of pneumococcal pneumonia, the Kaplan-Meier survival analysis showed a significant difference between the 2 groups (vaccine: 0/298; control: 5/298; log-rank test 5.03; P = 0.03).
Hospital admission rates and median length of hospital stays were lower in the vaccine group, but the difference was not statistically significant. The mortality rate was not different between the 2 groups.
Subgroup Analysis
The Kaplan-Meier survival analysis showed significant differences between the vaccine and control groups for pneumonia due to pneumococcus and pneumonia of unknown etiology, and when data were analyzed according to subgroups of patients (age < 65 years, and severe airflow obstruction FEV1 < 40% predicted). The accumulated percentage of patients without pneumonia (due to pneumococcus and of unknown etiology) across time was significantly lower in the vaccine group than in the control group in patients younger than 65 years of age (log-rank test 6.68; P = 0.0097) and patients with a FEV1 less than 40% predicted (log-rank test 3.85; P = 0.0498).
Vaccine effectiveness was 76% (95% CI, 20−93; P = 0.01) for patients who were less than 65 years of age and −14% (95% CI, −107 to 38; P = 0.8) for those who were 65 years of age or older. Vaccine effectiveness for patients with a FEV1 less than 40% predicted and FEV1 greater than or equal to 40% predicted was 48% (95% CI, −7 to 80; P = 0.08) and −11% (95% CI, −132 to 47; P = 0.95), respectively. For patients who were less than 65 years of age (FEV1 < 40% predicted), vaccine effectiveness was 91% (95% CI, 35−99; P = 0.002).
Cox modelling showed that the effectiveness of the vaccine was dependent on the age of the patient. The vaccine was not effective in patients 65 years of age or older (hazard ratio, 1.53; 95% CI, 0.61−a2.17; P = 0.66) but it reduced the risk of acquiring pneumonia by 80% in patients less than 65 years of age (hazard ratio, 0.19; 95% CI, 0.06−0.66; P = 0.01).
safety
No patients reported any local or systemic adverse reactions to the vaccine.
PMCID: PMC3384373  PMID: 23074431
8.  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
9.  Pneumococcal conjugate vaccines PREVenar13 and SynflorIX in sequence or alone in high-risk Indigenous infants (PREV-IX_COMBO): protocol of a randomised controlled trial 
BMJ Open  2015;5(1):e007247.
Introduction
Otitis media (OM) starts within weeks of birth in almost all Indigenous infants living in remote areas of the Northern Territory (NT). OM and associated hearing loss persist from infancy throughout childhood and often into adulthood. Educational and social opportunities are greatly compromised. Pneumococcus and non-typeable Haemophilus influenzae (NTHi) are major OM pathogens that densely colonise the nasopharynx and infect the middle ear from very early in life. Our hypothesis is that compared to current single vaccine schedules, a combination of vaccines starting at 1 month of age, may provide earlier, broadened protection.
Methods and analyses
This randomised outcome assessor, blinded controlled trial will recruit 425 infants between 28 and 38 days of age and randomly allocate them (1:1:1) to one of three pneumococcal conjugate vaccine (PCV) schedules: Synflorix at 2, 4, 6 months of age, Prevenar13 at 2, 4 and 6 months of age, or an investigational schedule of Synflorix at 1, 2 and 4 months plus Prevenar13 at 6 months of age. The blinded primary outcomes at 7 months of age are immunogenicity of specific vaccine antigens (geometric mean concentration (GMC) and proportion of participants with above threshold GMC of 0.35 µg/L). Secondary outcomes at all timepoints are additional immunogenicity measures and proportion of participants with nasopharyngeal carriage of vaccine-type pneumococci and NTHi, and any OM, including any tympanic membrane perforation. Parental interviews will provide data on common risk factors for OM.
Ethics and dissemination
Ethical approval has been obtained from NT Department of Health and Menzies HREC (EC00153), Central Australian HREC (EC00155) and West Australian Aboriginal Health Ethics Committee (WAAHEC- 377-12/2011). Final trial results, data analyses, interpretation and conclusions will be presented in appropriate written and oral formats to parents and guardians, participating communities, local, national and international conferences, and published in peer-reviewed open access journals.
Trial registration numbers
ACTRN12610000544077 and NCT01174849.
doi:10.1136/bmjopen-2014-007247
PMCID: PMC4298104  PMID: 25596202
IMMUNOLOGY; MICROBIOLOGY; PUBLIC HEALTH
10.  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
11.  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
12.  Prevention of pneumococcal diseases in the post-seven valent vaccine era: A European perspective 
BMC Infectious Diseases  2012;12:207.
Background
The burden of invasive pneumococcal disease in young children decreased dramatically following introduction of the 7-valent pneumococcal conjugate vaccine (PCV7). The epidemiology of S. pneumoniae now reflects infections caused by serotypes not included in PCV7. Recently introduced higher valency pneumococcal vaccines target the residual burden of invasive and non-invasive infections, including those caused by serotypes not included in PCV7. This review is based on presentations made at the European Society of Pediatric Infectious Diseases in June 2011.
Discussion
Surveillance data show increased circulation of the non-PCV7 vaccine serotypes 1, 3, 6A, 6C, 7 F and 19A in countries with routine vaccination. Preliminary evidence suggests that broadened serotype coverage offered by higher valency vaccines may be having an effect on invasive disease caused by some of those serotypes, including 19A, 7 F and 6C. Aetiology of community acquired pneumonia remains a difficult clinical diagnosis. However, recent reports indicate that pneumococcal vaccination has reduced hospitalisations of children for vaccine serotype pneumonia. Variations in serotype circulation and occurrence of complicated and non-complicated pneumonia caused by non-PCV7 serotypes highlight the potential of higher valency vaccines to decrease the remaining burden. PCVs reduce nasopharyngeal carriage and acute otitis media (AOM) caused by vaccine serotypes. Recent investigations of the interaction between S. pneumoniae and non-typeable H. influenzae suggest that considerable reduction in severe, complicated AOM infections may be achieved by prevention of early pneumococcal carriage and AOM infections. Extension of the vaccine serotype spectrum beyond PCV7 may provide additional benefit in preventing the evolution of AOM. The direct and indirect costs associated with pneumococcal disease are high, thus herd protection and infections caused by non-vaccine serotypes both have strong effects on the cost effectiveness of pneumococcal vaccination. Recent evaluations highlight the public health significance of indirect benefits, prevention of pneumonia and AOM and coverage of non-PCV7 serotypes by higher valency vaccines.
Summary
Routine vaccination has greatly reduced the burden of pneumococcal diseases in children. The pneumococcal serotypes present in the 7-valent vaccine have greatly diminished among disease isolates. The prevalence of some non-vaccine serotypes (e.g. 1, 7 F and 19A) has increased. Pneumococcal vaccines with broadened serotype coverage are likely to continue decreasing the burden of invasive disease, and community acquired pneumonia in children. Further reductions in pneumococcal carriage and increased prevention of early AOM infections may prevent the evolution of severe, complicated AOM. Evaluation of the public health benefits of pneumococcal conjugate vaccines should include consideration of non-invasive pneumococcal infections, indirect effects of vaccination and broadened serotype coverage.
doi:10.1186/1471-2334-12-207
PMCID: PMC3462147  PMID: 22954038
Pneumococcal conjugate vaccine; Invasive pneumococcal disease; Community-acquired pneumonia; Acute otitis media; Vaccine serotype coverage; Epidemiology-incidence
13.  Immunogenicity of a Reduced Schedule of Meningococcal Group C Conjugate Vaccine Given Concomitantly with the Prevenar and Pediacel Vaccines in Healthy Infants in the United Kingdom▿  
This study investigated the use of two doses of three different meningococcal group C conjugate (MCC) vaccines when given for primary immunization with a seven-valent pneumococcal conjugate vaccine (PCV7) and Pediacel, a combination product containing five acellular pertussis components, diphtheria and tetanus toxoids, Haemophilus influenzae type b (Hib) conjugate, and inactivated-poliovirus vaccine. The immune response after a single dose of MCC is also presented. Infants were randomized to receive two doses of one of the MCC vaccines and PCV7 at 2 and 3 months or at 2 and 4 months of age. Meningococcal group C serum bactericidal antibody (SBA) geometric mean titers, Hib-polyribosylribitol phosphate (PRP) immunoglobulin G (IgG) geometric mean concentrations (GMCs), and diphtheria and tetanus antitoxin GMCs, together with the proportions of infants achieving putative protective levels, were determined. A total of 393 infants were recruited. Following the first dose of NeisVac-C (MCC conjugated to tetanus toxoid), 97% of infants achieved protective levels (SBA titer of ≥8), compared with 80% and 53%, respectively, for Menjugate and Meningitec (both of which are conjugated to CRM197). SBA responses to MCC vaccines were not significantly different when administered at 2 and 3 or 2 and 4 months of age. Following two doses of each MCC, 98 to 100% of infants achieved protective levels. Both PRP IgG and tetanus responses were significantly enhanced when Pediacel was coadministered with NeisVac-C. This study demonstrates that NeisVac-C and Menjugate generate good immunogenicity after the first dose at 2 months of age when coadministered with PCV7 and Pediacel and merit further investigation in single-dose priming strategies.
doi:10.1128/CVI.00420-08
PMCID: PMC2643544  PMID: 19091990
14.  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
15.  Vaccine Escape Recombinants Emerge after Pneumococcal Vaccination in the United States 
PLoS Pathogens  2007;3(11):e168.
The heptavalent pneumococcal conjugate vaccine (PCV7) was introduced in the United States (US) in 2000 and has significantly reduced invasive pneumococcal disease; however, the incidence of nonvaccine serotype invasive disease, particularly due to serotype 19A, has increased. The serotype 19A increase can be explained in part by expansion of a genotype that has been circulating in the US prior to vaccine implementation (and other countries since at least 1990), but also by the emergence of a novel “vaccine escape recombinant” pneumococcal strain. This strain has a genotype that previously was only associated with vaccine serotype 4, but now expresses a nonvaccine serotype 19A capsule. Based on prior evidence for capsular switching by recombination at the capsular locus, the genetic event that resulted in this novel serotype/genotype combination might be identifiable from the DNA sequence of individual pneumococcal strains. Therefore, the aim of this study was to characterise the putative recombinational event(s) at the capsular locus that resulted in the change from a vaccine to a nonvaccine capsular type. Sequencing the capsular locus flanking regions of 51 vaccine escape (progeny), recipient, and putative donor pneumococci revealed a 39 kb recombinational fragment, which included the capsular locus, flanking regions, and two adjacent penicillin-binding proteins, and thus resulted in a capsular switch and penicillin nonsusceptibility in a single genetic event. Since 2003, 37 such vaccine escape strains have been detected, some of which had evolved further. Furthermore, two new types of serotype 19A vaccine escape strains emerged in 2005. To our knowledge, this is the first time a single recombinational event has been documented in vivo that resulted in both a change of serotype and penicillin nonsusceptibility. Vaccine escape by genetic recombination at the capsular locus has the potential to reduce PCV7 effectiveness in the longer term.
Author Summary
The 7-valent pneumococcal conjugate vaccine is a remarkable public health success story. It has significantly reduced invasive pneumococcal disease in the United States not only by protecting vaccinated children, but also by protecting unvaccinated older children and adults by herd immunity. However, there was always a concern that use of a limited-valency vaccine would result in an increase in disease due to nonvaccine serotypes, and this has now occurred in the US. The predominant nonvaccine serotype causing invasive disease is 19A, and this increase is partially explained by “vaccine escape” pneumococci, strains that have exchanged the genes that encode a vaccine serotype 4 capsule for genes that encode a nonvaccine serotype 19A capsule. These strains are then able to escape vaccine-induced immunity. Characterisation of the genetic event that resulted in these vaccine escape strains was the focus of our study and the results were surprising. The results of this study have important relevance to the long-term effectiveness of the current vaccine and to the development of future pneumococcal vaccines.
doi:10.1371/journal.ppat.0030168
PMCID: PMC2077903  PMID: 18020702
16.  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
17.  Cost-effectiveness of new adult pneumococcal vaccination strategies in Italy 
Community-acquired pneumonia (CAP) and invasive pneumococcal disease (IPD) are very relevant pathologies among elderly people (≥ 65 y old), with a consequent high disease burden. Immunization with the 23-valent pneumococcal polysaccharide vaccine (PPV23) has been differently implemented in the Italian regions in the past years, reaching overall low coverage rates even in those with medical indications. In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) became available and recommended in the universal Italian infant immunization program. Since October 2012, indications for use of PCV13 were extended to subjects ≥ 50 y to prevent invasive pneumococcal diseases. The Italian decision makers should now revise regional indications for the prevention of pneumococcal diseases in the elderly. Pharmaco-economic analyses represent a useful tool to value the feasibility of new immunization programs and their sustainability. Therefore, an ad hoc population model was developed in order to value the clinical and economic impact of an adult pneumococcal vaccination program in Italy.
Particularly, different immunization scenarios were modeled: vaccination of 65 y-olds (1 cohort strategy), simultaneous vaccination of people aged 65 and 70 y (double cohort strategy) and, lastly, immunization of people aged 65, 70 and 75 y (triple cohort strategy), thus leading to the vaccination of 5, 10 and 15 cohorts during the 5 y of the program. In addition, the administration of a PPV23 dose one year after PCV13 was evaluated, in order to verify the economic impact of the supplemental serotype coverage in elderly people. The mathematical model valued the clinical impact of PCV13 vaccination on the number of bacteraemic pneumococcal pneumonia (BPP) and pneumococcal meningitis (PM) cases, and related hospitalizations and deaths. Although PCV13 is not yet formally indicated for the prevention of pneumococcal CAP by the European Medicine Agency (differently from FDA, whose indications include all pneumococcal diseases in subjects ≥ 50 y), the model calculated also the possible impact of vaccination on CAP cases (non-bacteraemic), considering the rate of this disease due to S. pneumoniae. The results of the analysis show that, in Italy, an age-based PCV13 vaccination program in elderly people is cost-effective from the payer perspective, with costs per QALY ranging from 17,000 to 22,000 Euro, according to the adopted vaccination strategy. The subsequent PPV23 offer results in an increment of costs per QALY (from 21,000 to 28,000 Euro, according to the vaccination strategy adopted). Pneumococcal vaccination using the conjugate vaccine turned out to be already favorable in the second year of implementation, with incremental costs per QALY comparable to those of other already adopted prevention activities in Italy (for instance, universal HPV vaccination of 12 y-old girls), with further benefits obtained when extending the study period beyond the 5-y horizon of our analysis.
doi:10.4161/hv.23268
PMCID: PMC3891731  PMID: 23295824
pneumococcal conjugate vaccine; elderly; economic evaluation; cost-effectiveness; pneumococcal disease
18.  Modeling the impact of the 7-valent pneumococcal conjugate vaccine in Chinese infants: an economic analysis of a compulsory vaccination 
Background
The purpose of this study was to compare, from a Chinese societal perspective, the projected health benefits, costs, and cost-effectiveness of adding pneumococcal conjugate heptavalent vaccine (PCV-7) to the routine compulsory child immunization schedule.
Methods
A decision-tree model, with data and assumptions adapted for relevance to China, was developed to project the health outcomes of PCV-7 vaccination (compared with no vaccination) over a 5-year period as well as a lifetime. The vaccinated birth cohort included 16,000,000 children in China. A 2 + 1 dose schedule at US$136.51 per vaccine dose was used in the base-case analysis. One-way sensitivity analysis was used to test the robustness of the model. The impact of a net indirect effect (herd immunity) was evaluated. Outcomes are presented in terms of the saved disease burden, costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio.
Results
In a Chinese birth cohort, a PCV-7 vaccination program would reduce the number of pneumococcus-related infections by at least 32% and would prevent 2,682 deaths in the first 5 years of life, saving $1,190 million in total costs and gaining an additional 9,895 QALYs (discounted by 3%). The incremental cost per QALY was estimated to be $530,354. When herd immunity was taken into account, the cost per QALY was estimated to be $95,319. The robustness of the model was influenced mainly by the PCV-7 cost per dose, effectiveness herd immunity and incidence of pneumococcal diseases. With and without herd immunity, the break-even costs in China were $29.05 and $25.87, respectively.
Conclusions
Compulsory routine infant vaccination with PCV-7 is projected to substantially reduce pneumococcal disease morbidity, mortality, and related costs in China. However, a universal vaccination program with PCV-7 is not cost-effective at the willingness-to-pay threshold that is currently recommended for China by the World Health Organization.
doi:10.1186/1472-6963-14-56
PMCID: PMC3918139  PMID: 24507480
Cost-effectiveness analysis; PCV-7; Pneumococcal disease; Vaccine
19.  Vaccination of children with a live-attenuated, intranasal influenza vaccine – analysis and evaluation through a Health Technology Assessment 
Background: Influenza is a worldwide prevalent infectious disease of the respiratory tract annually causing high morbidity and mortality in Germany. Influenza is preventable by vaccination and this vaccination is so far recommended by the The German Standing Committee on Vaccination (STIKO) as a standard vaccination for people from the age of 60 onwards. Up to date a parenterally administered trivalent inactivated vaccine (TIV) has been in use almost exclusively. Since 2011 however a live-attenuated vaccine (LAIV) has been approved additionally. Consecutively, since 2013 the STIKO recommends LAIV (besides TIV) for children from 2 to 17 years of age, within the scope of vaccination by specified indications. LAIV should be preferred administered in children from 2 to 6 of age. The objective of this Health Technology Assessment (HTA) is to address various research issues regarding the vaccination of children with LAIV. The analysis was performed from a medical, epidemiological and health economic perspective, as well as from an ethical, social and legal point of view.
Method: An extensive systematic database research was performed to obtain relevant information. In addition a supplementary research by hand was done. Identified literature was screened in two passes by two independent reviewers using predefined inclusion and exclusion criteria. Included literature was evaluated in full-text using acknowledged standards. Studies were graded with the highest level of evidence (1++), if they met the criteria of European Medicines Agency (EMA)-Guidance: Points to consider on applications with 1. meta-analyses; 2. one pivotal study.
Results: For the medical section, the age of the study participants ranges from 6 months to 17 years. Regarding study efficacy, in children aged 6 months to ≤7 years, LAIV is superior to placebo as well as to a vac-cination with TIV (Relative Risk Reduction – RRR – of laboratory confirmed influenza infection approx. 80% and 50%, respectively). In children aged >7 to 17 years (= 18th year of their lives), LAIV is superior to a vaccination with TIV (RRR 32%). For this age group, no studies that compared LAIV with placebo were identified. It can be concluded that there is high evidence for superior efficacy of LAIV (compared to placebo or TIV) among children aged 6 months to ≤7 years. For children from >7 to 17 years, there is moderate evidence for superiority of LAIV for children with asthma, while direct evidence for children from the general population is lacking for this age group. Due to the efficacy of LAIV in children aged 6 months to ≤7 years (high evidence) and the efficacy of LAIV in children with asthma aged >7 to 17 years (moderate evidence), LAIV is also very likely to be efficacious among children in the general population aged >7 to 17 years (indirect evidence). In the included studies with children aged 2 to 17 years, LAIV was safe and well-tolerated; while in younger children LAIV may increase the risk of obstruction of the airways (e.g. wheezing).
In the majority of the evaluated epidemiological studies, LAIV proved to be effective in the prevention of influenza among children aged 2–17 years under everyday conditions (effectiveness). The trend appears to indicate that LAIV is more effective than TIV, although this can only be based on limited evidence for methodological reasons (observational studies). In addition to a direct protective effect for vaccinated children themselves, indirect protective ("herd protection") effects were reported among non-vaccinated elderly population groups, even at relatively low vaccination coverage of children. With regard to safety, LAIV generally can be considered equivalent to TIV. This also applies to the use among children with mild chronically obstructive conditions, from whom LAIV therefore does not have to be withheld. In all included epidemiological studies, there was some risk of bias identified, e.g. due to residual confounding or other methodology-related sources of error.
In the evaluated studies, both the vaccination of children with previous illnesses and the routine vaccination of (healthy) children frequently involve cost savings. This is especially the case if one includes indirect costs from a societal perspective. From a payer perspective, a routine vaccination of children is often regarded as a highly cost-effective intervention. However, not all of the studies arrive at consistent results. In isolated cases, relatively high levels of cost-effectiveness are reported that make it difficult to perform a conclusive assessment from an economic perspective. Based on the included studies, it is not possible to make a clear statement about the budget impact of using LAIV. None of the evaluated studies provides results for the context of the German healthcare setting.
The efficacy of the vaccine, physicians' recommendations, and a potential reduction in influenza symptoms appear to play a role in the vaccination decision taken by parents/custodians on behalf of their children. Major barriers to the utilization of influenza vaccination services are a low level of perception and an underestimation of the disease risk, reservations concerning the safety and efficacy of the vaccine, and potential side effects of the vaccine. For some of the parents surveyed, the question as to whether the vaccine is administered as an injection or nasal spray might also be important.
Conclusion: In children aged 2 to 17 years, the use of LAIV can lead to a reduction of the number of influenza cases and the associated burden of disease. In addition, indirect preventive effects may be expected, especially among elderly age groups. Currently there are no data available for the German healthcare setting. Long-term direct and indirect effectiveness and safety should be supported by surveillance programs with a broader use of LAIV.
Since there is no general model available for the German healthcare setting, statements concerning the cost-effectiveness can be made only with precaution. Beside this there is a need to conduct health eco-nomic studies to show the impact of influenza vaccination for children in Germany. Such studies should be based on a dynamic transmission model. Only these models are able to include the indirect protective effects of vaccination correctly.
With regard to ethical, social and legal aspects, physicians should discuss with parents the motivations for vaccinating their children and upcoming barriers in order to achieve broader vaccination coverage.
The present HTA provides an extensive basis for further scientific approaches and pending decisions relating to health policy.
doi:10.3205/hta000119
PMCID: PMC4219018  PMID: 25371764
Health Technology Assessment; HTA; LAIV; live attenuated vaccine; TIV; trivalent inactivated vaccine
20.  Economic evaluation of pneumococcal conjugate vaccination in The Gambia 
BMC Infectious Diseases  2010;10:260.
Background
Gambia is the second GAVI support-eligible country to introduce the 7-valent pneumococcal conjugate vaccine (PCV7), but a country-specific cost-effectiveness analysis of the vaccine is not available. Our objective was to assess the potential impact of PCVs of different valences in The Gambia.
Methods
We synthesized the best available epidemiological and cost data using a state-transition model to simulate the natural histories of various pneumococcal diseases. For the base-case, we estimated incremental cost (in 2005 US dollars) per disability-adjusted life year (DALY) averted under routine vaccination using PCV9 compared to no vaccination. We extended the base-case results for PCV9 to estimate the cost-effectiveness of PCV7, PCV10, and PCV13, each compared to no vaccination. To explore parameter uncertainty, we performed both deterministic and probabilistic sensitivity analyses. We also explored the impact of vaccine efficacy waning, herd immunity, and serotype replacement, as a part of the uncertainty analyses, by assuming alternative scenarios and extrapolating empirical results from different settings.
Results
Assuming 90% coverage, a program using a 9-valent PCV (PCV9) would prevent approximately 630 hospitalizations, 40 deaths, and 1000 DALYs, over the first 5 years of life of a birth cohort. Under base-case assumptions ($3.5 per vaccine), compared to no intervention, a PCV9 vaccination program would cost $670 per DALY averted in The Gambia. The corresponding values for PCV7, PCV10, and PCV13 were $910, $670, and $570 per DALY averted, respectively. Sensitivity analyses that explored the implications of the uncertain key parameters showed that model outcomes were most sensitive to vaccine price per dose, discount rate, case-fatality rate of primary endpoint pneumonia, and vaccine efficacy against primary endpoint pneumonia.
Conclusions
Based on the information available now, infant PCV vaccination would be expected to reduce pneumococcal diseases caused by S. pneumoniae in The Gambia. Assuming a cost-effectiveness threshold of three times GDP per capita, all PCVs examined would be cost-effective at the tentative Advance Market Commitment (AMC) price of $3.5 per dose. Because the cost-effectiveness of a PCV program could be affected by potential serotype replacement or herd immunity effects that may not be known until after a large scale introduction, type-specific surveillance and iterative evaluation will be critical.
doi:10.1186/1471-2334-10-260
PMCID: PMC2944347  PMID: 20815900
21.  Modelling cost effectiveness of meningococcal serogroup C conjugate vaccination campaign in England and Wales 
BMJ : British Medical Journal  2002;324(7341):809.
Objectives
To assess the cost effectiveness of a meningococcal serogroup C conjugate vaccination campaign in 0-17 year olds.
Design
Cost effectiveness analysis from the perspective of the healthcare provider.
Setting
England and Wales.
Main outcome measure
Cost per life year saved.
Results
In 1998-9, immediately before the introduction of meningococcal C vaccination, the burden of serogroup C disease was considerable, with an estimated 1137 cases in people aged 0-17 years and at least 72 deaths. The vaccination campaign is estimated to have cost between £126m ($180m, €207m) and £241m ($343m, €395m), depending on the price of the vaccine. Under base case assumptions the cost per life year saved from the vaccination campaign is estimated to be £6259. School based vaccination was more cost effective than general practice based vaccination because of lower delivery costs. Immunisation of infants aged under 1 year was the least cost effective component of the campaign because, although this maximises the life years gained, the three dose schedule required is more expensive than other methods of delivery. Estimates of the cost per life year saved were sensitive to assumptions on the future incidence of disease and the case fatality ratio.
Conclusions
Meningococcal C vaccination is likely to be more cost effective in all age groups when the incidence of disease is high. It is also more cost effective when given to children aged 1-4 (by general practitioners) and to children and young people aged 5-17 years at school than when administered to infants under 12 months of age or young people aged 16-17 years who are not at school.
What is already known on this topicThe burden of group C meningococcal disease in England and Wales in the late 1990s was considerableIn November 1999 the United Kingdom was the first country to introduce mass vaccination against group C meningococcal diseaseThere are no published economic evaluations of the vaccination campaignWhat this study addsThis economic evaluation supports the introduction of the meningococcal C vaccineSchool based vaccination is more cost effective than routine vaccination of infants because delivery costs are lower and fewer doses are required
PMCID: PMC100788  PMID: 11934772
22.  Assessment of Health Benefits and Cost-Effectiveness of 10-Valent and 13-Valent Pneumococcal Conjugate Vaccination in Kenyan Children 
PLoS ONE  2013;8(6):e67324.
Background
The GAVI Alliance supported10-valent pneumococcal conjugate vaccine (PCV10) introduction in Kenya. We estimated the cost-effectiveness of introducing either PCV10 or the13-valent vaccine (PCV13) from a societal perspective and explored the incremental impact of including indirect vaccine effects.
Methods
The costs and effects of pneumococcal vaccination among infants born in Kenya in 2010 were assessed using a decision analytic model comparing PCV10 or PCV13, in turn, with no vaccination. Direct vaccine effects were estimated as a reduction in the incidence of pneumococcal meningitis, sepsis, bacteraemic pneumonia and non-bacteraemic pneumonia. Pneumococcal disease incidence was extrapolated from a population-based hospital surveillance system in Kilifi and adjustments were made for variable access to care across Kenya. We used vaccine efficacy estimates from a trial in The Gambia and accounted for serotype distribution in Kilifi. We estimated indirect vaccine protection and serotype replacement by extrapolating from the USA. Multivariable sensitivity analysis was conducted using Monte Carlo simulation. We assumed a vaccine price of US$ 3.50 per dose.
Findings
The annual cost of delivering PCV10 was approximately US$14 million. We projected a 42.7% reduction in pneumococcal disease episodes leading to a US$1.97 million reduction in treatment costs and a 6.1% reduction in childhood mortality annually. In the base case analysis, costs per discounted DALY and per death averted by PCV10, amounted to US$ 59 (95% CI 26–103) and US$ 1,958 (95% CI 866–3,425), respectively. PCV13 introduction improved the cost-effectiveness ratios by approximately 20% and inclusion of indirect effects improved cost-effectiveness ratios by 43–56%. The break-even prices for introduction of PCV10 and PCV13 are US$ 0.41 and 0.51, respectively.
Conclusions
Introducing either PCV10 or PCV13 in Kenya is highly cost-effective from a societal perspective. Indirect effects, if they occur, would significantly improve the cost-effectiveness.
doi:10.1371/journal.pone.0067324
PMCID: PMC3691111  PMID: 23826268
23.  Cost-Effectiveness of Pneumococcal Vaccines for Adults in the United States 
Advances in Therapy  2014;31(4):392-409.
Introduction
In 2012, the Advisory Committee on Immunization Practices (ACIP) revised recommendations for adult pneumococcal vaccination to include a sequential regimen of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) for certain high-risk adults with immunocompromising conditions. This study, from a payer perspective, examined: (1) the cost-effectiveness of the new 2012 ACIP vaccine policy recommendation relative to the 1997 ACIP recommendation; (2) the cost-effectiveness of potential future pneumococcal vaccination policies; and (3) key assumptions that influence study results.
Methods
A static cohort model that incorporated costs, health outcomes, and quality-adjusted life-year (QALY) losses associated with invasive pneumococcal disease and non-bacteremic pneumococcal pneumonia (NBPP) was developed to evaluate seven pneumococcal vaccination strategies for a 50-year-old adult cohort over a 50-year period using incremental cost-effectiveness ratios (ICERs).
Results
For objective 1, the 2012 ACIP recommendation is the more economically efficient strategy (ICER was $25,841 per QALY gained vs. no vaccination). For objective 2, the most efficient vaccination policy would be to maintain the 2012 recommendation for PPSV23 for healthy and immunocompetent adults with comorbidities, and to modify the recommendation for adults with immunocompromising conditions by replacing PPSV23 with a sequential regimen of PCV13 and PPSV23 at age 65 (ICER was $23,416 per QALY gained vs. no vaccination). For objective 3, cost-effectiveness ratios for alternative pneumococcal vaccine policies were highly influenced by assumptions used for vaccine effectiveness against NBPP and accounting for the herd protection effects of pediatric PCV13 vaccination on adult pneumococcal disease.
Conclusion
Modifying the 2012 recommendation to include an additional dose of PCV13 at age 65, followed by PPSV23, for adults with immunocompromising conditions appears to be a cost-effective vaccine policy. Given the uncertainty in the available data and the absence of key influential data, comprehensive sensitivity analyses should be conducted by policy-makers when evaluating new adult pneumococcal vaccine strategies.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-014-0115-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s12325-014-0115-y
PMCID: PMC4003344  PMID: 24718851
Cost-effectiveness; Health outcomes; Pneumococcal vaccination; Quality-adjusted life-year; Vaccine effectiveness
24.  Accelerating Policy Decisions to Adopt Haemophilus influenzae Type b Vaccine: A Global, Multivariable Analysis 
PLoS Medicine  2010;7(3):e1000249.
Jessica Shearer and colleagues analyze data from 147 countries to identify factors that influence the time taken to introduce routine vaccination against Haemophilus influenzae type b (Hib).
Background
Adoption of new and underutilized vaccines by national immunization programs is an essential step towards reducing child mortality. Policy decisions to adopt new vaccines in high mortality countries often lag behind decisions in high-income countries. Using the case of Haemophilus influenzae type b (Hib) vaccine, this paper endeavors to explain these delays through the analysis of country-level economic, epidemiological, programmatic and policy-related factors, as well as the role of the Global Alliance for Vaccines and Immunisation (GAVI Alliance).
Methods and Findings
Data for 147 countries from 1990 to 2007 were analyzed in accelerated failure time models to identify factors that are associated with the time to decision to adopt Hib vaccine. In multivariable models that control for Gross National Income, region, and burden of Hib disease, the receipt of GAVI support speeded the time to decision by a factor of 0.37 (95% CI 0.18–0.76), or 63%. The presence of two or more neighboring country adopters accelerated decisions to adopt by a factor of 0.50 (95% CI 0.33–0.75). For each 1% increase in vaccine price, decisions to adopt are delayed by a factor of 1.02 (95% CI 1.00–1.04). Global recommendations and local studies were not associated with time to decision.
Conclusions
This study substantiates previous findings related to vaccine price and presents new evidence to suggest that GAVI eligibility is associated with accelerated decisions to adopt Hib vaccine. The influence of neighboring country decisions was also highly significant, suggesting that approaches to support the adoption of new vaccines should consider supply- and demand-side factors.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, immunization averts more than 2 million deaths by preparing people's immune systems to recognize and attack disease-causing organisms (pathogens) rapidly and effectively. Although the immune system is designed to protect the human body against infections, the first time a person is exposed to a pathogen (usually during early childhood) their immune system can take some time to respond. As a result, they can become seriously ill or even die. However, the immune system “learns” from the experience and when the pathogen is encountered again, the immune system swings into action much more quickly. Immunization or vaccination is a safe way to make individuals resistant to infectious diseases. It works by exposing them to weakened or dead pathogens or to pathogen molecules (antigens) that the immune system recognizes as foreign. Widespread, routine immunization of children is, therefore, an essential component of national and global strategies to reduce childhood illnesses and deaths.
Why Was This Study Done?
Although many factors affect the uptake of immunization (in particular, vaccine prices), national policy decisions to adopt new vaccines are an essential step toward improving coverage. Unfortunately, these decisions are often delayed in developing countries. Thus, although many industrialized countries have routinely immunized their children with the highly effective Haemophilus influenza type b (Hib) conjugate vaccine since it became available in the early 1990s, only 13 low-income countries were using the vaccine in 2004. Hib bacteria, which cause pneumonia (lung infection) and meningitis (brain inflammation), kill about 370,000 unvaccinated young children every year. In this study, the researchers try to explain delays in the adoption of routine Hib vaccination in developing countries by analyzing the associations between Hib vaccination and factors such as national economic status, local Hib burden, and eligibility for support from the Global Alliance for Vaccines and Immunisation (GAVI Alliance; a public–private partnership that offers financial, technical, and health systems support for the introduction of national immunization programs to developing countries that meet certain eligibility criteria).
What Did the Researchers Do and Find?
The researchers used a statistical approach called accelerated failure time analysis to analyze data collected in 147 countries between 1990 and 2007 on vaccine costs, Hib disease incidence, GAVI eligibility, and other factors that could influence decision-makers' perceptions of the costs and benefits of Hib vaccination. After allowing for gross national income, region, and burden of Hib disease, the researchers identified several factors that influenced the time between the availability of a Hib conjugate vaccine in a country and a decision being made to introduce routine Hib vaccination. The receipt of GAVI support speeded the decision to adopt vaccination by 63%, for example, and sharing borders with two or more countries that had adopted the vaccine speeded the decision by 50%. By contrast, for each 1% increase in vaccine costs, the time to decision to adopt vaccination was delayed by 2%. The 1998 and 2006 World Health Organization recommendations on routine Hib vaccination and the existence of local studies on Hib disease had no influence on the time to decision.
What Do These Findings Mean?
These findings confirm previous studies that showed that increases in the price of Hib vaccine increase the time to adoption. In addition, they suggest that GAVI eligibility accelerates decisions to adopt this vaccine and show that the decisions made by neighboring countries are important, which suggests that policy diffusion may occur. Thus, in the case of adoption of the Hib vaccine, both supply-side and demand-side factors seem to be important. Its is relevant to note that during writing of the article, JCS, MLS, MRR, APB, and RAH were employed by the Hib Initiative, which was funded by the GAVI Alliance. The findings do not necessarily represent the views, policies or decisions of the Hib Initiative or the GAVI Alliance. Importantly, these findings are explanatory, not predictive, so they cannot be applied directly to new vaccines to improve their rate of adoption. Nevertheless, these findings highlight the potential importance of setting up formal and informal networks to facilitate policy diffusion and suggest that long-term price and supply certainty might be factors that could help to accelerate national decisions to adopt new and/or underutilized vaccines and other public-health technologies.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000249.
The World Health Organization provides information on immunization and on Haemophilus influenza type b (in several languages)
The GAVI Alliance Web site describes the work of this public–private partnership and provides details of developing countries eligible for Hib vaccination support
The Hib Initiative aims to reduce the risk of childhood death and disability through sustained use of Hib vaccine
MedlinePlus provides links to further resources on immunization and information on the Haemophilus influenzae type b vaccine (in English and Spanish)
doi:10.1371/journal.pmed.1000249
PMCID: PMC2838745  PMID: 20305714
25.  Dynamic models of pneumococcal carriage and the impact of the Heptavalent Pneumococcal Conjugate Vaccine on invasive pneumococcal disease 
Background
The 7-valent pneumococcal conjugate vaccine has been introduced in national immunisation programmes of most industrialised countries and recently in two African GAVI eligible countries (Rwanda and The Gambia). However the long term effects of PCV are still unclear, as beneficial direct and herd immunity effects might be countered by serotype replacement.
Method
A dynamic, age-structured, compartmental model of Streptococcus pneumoniae transmission was developed to predict the potential impact of PCV7 on the incidence of invasive disease accounting for both herd immunity and serotype replacement effects. The model was parameterised using epidemiological data from England and Wales and pre and post-vaccination surveillance data from the US.
Results
Model projections showed that serotype replacement plays a crucial role in determining the overall effect of a PCV7 vaccination programme and could reduce, negate or outweigh its beneficial impact. However, using the estimate of the competition parameter derived from the US post-vaccination experience, an infant vaccination programme would prevent 39,000 IPD cases in the 20 years after PCV7 introduction in the UK. Adding a catch-up campaign for under 2 or under 5 year olds would provide a further reduction of 1,200 or 3,300 IPD cases respectively, mostly in the first few years of the programme.
Conclusions
This analysis suggests that a PCV vaccination programme would eradicate vaccine serotypes from circulation. However, the increase in carriage of non-vaccine serotypes, and the consequent increase in invasive disease, could reduce, negate or outweigh the benefit. These results are sensitive to changes in the protective effect of the vaccine, and, most importantly, to the level of competition between vaccine and non-vaccine types. The techniques developed here can be used to assess the introduction of vaccination programmes in developing countries and provide the basis for cost-effectiveness analyses.
doi:10.1186/1471-2334-10-90
PMCID: PMC2867993  PMID: 20377886

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