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1.  Age-Dependent Prevalence of Nasopharyngeal Carriage of Streptococcus pneumoniae before Conjugate Vaccine Introduction: A Prediction Model Based on a Meta-Analysis 
PLoS ONE  2014;9(1):e86136.
Introduction
Data on the prevalence of nasopharyngeal carriage of S.pneumoniae in all age groups are important to help predict the impact of introducing pneumococcal conjugate vaccines (PCV) into routine infant immunization, given the important indirect effect of the vaccine. Yet most carriage studies are limited to children under five years of age. We here explore the association between carriage prevalence and serotype distribution in children aged ≥5 years and in adults compared to children.
Methods
We conducted a systematic review of studies providing carriage estimates across age groups in healthy populations not previously exposed to PCV, using MEDLINE and Embase. We used Bayesian linear meta-regression models to predict the overall carriage prevalence as well as the prevalence and distribution of vaccine and nonvaccine type (VT and NVT) serotypes in older age groups as a function of that in <5 y olds.
Results
Twenty-nine studies compromising of 20,391 individuals were included in the analysis. In all studies nasopharyngeal carriage decreased with increasing age. We found a strong positive linear association between the carriage prevalence in pre-school childen (<5 y) and both that in school aged children (5–17 y olds) and in adults. The proportion of VT serotypes isolated from carriers was consistently lower in older age groups and on average about 73% that of children <5 y among 5–17 y olds and adults respectively. We provide a prediction model to infer the carriage prevalence and serotype distribution in 5–17 y olds and adults as a function of that in children <5 years of age.
Conclusion
Such predictions are helpful for assessing the potential population-wide effects of vaccination programmes, e.g. via transmission models, and thus assist in the design of future pneumococcal conjugate vaccination strategies.
doi:10.1371/journal.pone.0086136
PMCID: PMC3900487  PMID: 24465920
2.  The impact of specific and non-specific immunity on the ecology of Streptococcus pneumoniae and the implications for vaccination 
More than 90 capsular serotypes of Streptococcus pneumoniae coexist despite competing for nasopharyngeal carriage and a gradient in fitness. The underlying mechanisms for this are poorly understood and make assessment of the likely population impact of vaccination challenging. We use an individual-based simulation model to generalize widely used deterministic models for pneumococcal competition and show that in these models short-term serotype-specific and serotype non-specific immunity could constitute the mechanism governing between-host competition and coexistence. We find that non-specific immunity induces between-host competition and that serotype-specific immunity limits a type's competitive advantage and allows stable coexistence of multiple serotypes. Serotypes carried at low prevalence show high variance in carriage levels, which would result in apparent outbreaks if they were highly pathogenic. Vaccination against few serotypes can lead to elimination of the vaccine types and induces replacement by others. However, in simulations where the elimination of the targeted types is achieved only by a combination of vaccine effects and the competitive pressure of the non-vaccine types, a universal vaccine with similar-type-specific effectiveness can fail to eliminate pneumococcal carriage and offers limited herd immunity. Hence, if vaccine effects are insufficient to control the majority of serotypes at the same time, then exploiting the competitive pressure by selective vaccination can help control the most pathogenic serotypes.
doi:10.1098/rspb.2013.1939
PMCID: PMC3790488  PMID: 24089337
Streptococcus pneumoniae; carriage; competition; coexistence; immunity; vaccination
3.  Assessing Optimal Target Populations for Influenza Vaccination Programmes: An Evidence Synthesis and Modelling Study 
PLoS Medicine  2013;10(10):e1001527.
Marc Baguelin and colleagues use virological, clinical, epidemiological, and behavioral data to estimate how policies for influenza vaccination programs may be optimized in England and Wales.
Please see later in the article for the Editors' Summary
Background
Influenza vaccine policies that maximise health benefit through efficient use of limited resources are needed. Generally, influenza vaccination programmes have targeted individuals 65 y and over and those at risk, according to World Health Organization recommendations. We developed methods to synthesise the multiplicity of surveillance datasets in order to evaluate how changing target populations in the seasonal vaccination programme would affect infection rate and mortality.
Methods and Findings
Using a contemporary evidence-synthesis approach, we use virological, clinical, epidemiological, and behavioural data to develop an age- and risk-stratified transmission model that reproduces the strain-specific behaviour of influenza over 14 seasons in England and Wales, having accounted for the vaccination uptake over this period. We estimate the reduction in infections and deaths achieved by the historical programme compared with no vaccination, and the reduction had different policies been in place over the period. We find that the current programme has averted 0.39 (95% credible interval 0.34–0.45) infections per dose of vaccine and 1.74 (1.16–3.02) deaths per 1,000 doses. Targeting transmitters by extending the current programme to 5–16-y-old children would increase the efficiency of the total programme, resulting in an overall reduction of 0.70 (0.52–0.81) infections per dose and 1.95 (1.28–3.39) deaths per 1,000 doses. In comparison, choosing the next group most at risk (50–64-y-olds) would prevent only 0.43 (0.35–0.52) infections per dose and 1.77 (1.15–3.14) deaths per 1,000 doses.
Conclusions
This study proposes a framework to integrate influenza surveillance data into transmission models. Application to data from England and Wales confirms the role of children as key infection spreaders. The most efficient use of vaccine to reduce overall influenza morbidity and mortality is thus to target children in addition to older adults.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every winter, millions of people catch influenza, a viral infection of the airways. Most infected individuals recover quickly, but seasonal influenza outbreaks (epidemics) kill about half a million people annually. In countries with advanced health systems, these deaths occur mainly among elderly people and among individuals with long-term illnesses such as asthma and heart disease that increase the risk of complications occurring after influenza virus infection. Epidemics of influenza occur because small but frequent changes in the influenza virus mean that an immune response produced one year through infection provides only partial protection against influenza the following year. Annual immunization with a vaccine that contains killed influenza viruses of the major circulating strains can greatly reduce a person's risk of catching influenza by preparing the immune system to respond quickly when challenged by a live influenza virus. Consequently, many countries run seasonal influenza vaccination programs that, in line with World Health Organization recommendations, target individuals 65 years old and older and people in high-risk groups.
Why Was This Study Done?
Is this approach the best use of available resources? Might, for example, vaccination of children—the main transmitters of influenza—provide more benefit to the whole population than vaccination of elderly people? Vaccination of children would not directly prevent as many influenza-related deaths as vaccination of elderly people, but it might indirectly prevent deaths in elderly adults by inducing herd immunity—vaccination of a large part of a population can protect unvaccinated members of the population by reducing the chances of an infection spreading. Policy makers need to know whether a change to an influenza vaccination program is likely to provide additional population benefits before altering the program. In this evidence synthesis and modeling study, the researchers combine (synthesize) longitudinal influenza surveillance datasets (data collected over time) from England and Wales, develop a mathematical model for influenza transmission based on these data using a Bayesian statistical approach, and use the model to evaluate the impact on influenza infections and deaths of changes to the seasonal influenza vaccination program in England and Wales.
What Did the Researchers Do and Find?
The researchers developed an influenza transmission model using clinical data on influenza-like illness consultations collected in a primary care surveillance scheme for each week of 14 influenza seasons in England and Wales, virological information on respiratory viruses detected in a subset of patients presenting with clinically suspected influenza, and data on vaccination coverage in the whole population (epidemiological data). They also incorporated data on social contacts (behavioral data) and on immunity to influenza viruses in the population (seroepidemiological data) into their model. To estimate the impact of potential changes to the current vaccination strategy in England and Wales, the researchers used their model, which replicated the patterns of disease observed in the surveillance data, to run simulated epidemics for each influenza season and for three strains of influenza virus under various vaccination scenarios. Compared to no vaccination, the current program (vaccination of people 65 years old and older and people in high-risk groups) averted 0.39 infections per dose of vaccine and 1.74 deaths per 1,000 doses. Notably, the model predicted that extension of the program to target 5–16-year-old children would increase the efficiency of the program and would avert 0.70 infections per dose and 1.95 deaths per 1,000 doses.
What Do These Findings Mean?
The finding that the transmission model developed by the researchers closely fit the available surveillance data suggests that the model should be able to predict what would have happened in England and Wales over the study period if an alternative vaccination regimen had been in place. The accuracy of such predictions may be limited, however, because the vaccination model is based on a series of simplifying assumptions. Importantly, given that influenza vaccination for children is being rolled out in England and Wales from September 2013, the model confirms that children are key spreaders of influenza and suggests that a vaccination program targeting children will reduce influenza infections and potentially influenza deaths in the whole population. More generally, the findings of this study support wider adoption of national vaccination strategies designed to block influenza transmission and to target those individuals most at risk from the complications of influenza infection.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371.journal.pmed.1001527.
The UK National Health Service Choices website provides information for patients about seasonal influenza and about vaccination; Public Health England (formerly the Health Protection Agency) provides information on influenza surveillance in the UK, including information about the primary care surveillance database used in this study
The World Health Organization provides information on seasonal influenza (in several languages)
The European Influenzanet is a system to monitor the activity of influenza-like illness with the aid of volunteers via the Internet
The US Centers for Disease Control and Prevention also provides information for patients and health professionals on all aspects of seasonal influenza, including information about vaccination and about the US influenza surveillance system; its website contains a short video about personal experiences of influenza
Flu.gov, a US government website, provides access to information on seasonal influenza and vaccination
MedlinePlus has links to further information about influenza and about immunization (in English and Spanish)
doi:10.1371/journal.pmed.1001527
PMCID: PMC3793005  PMID: 24115913
4.  Mathematical Modelling Long-Term Effects of Replacing Prevnar7 with Prevnar13 on Invasive Pneumococcal Diseases in England and Wales 
PLoS ONE  2012;7(7):e39927.
Introduction
England and Wales recently replaced the 7-valent pneumococcal conjugate vaccine (PCV7) with its 13-valent equivalent (PCV13), partly based on projections from mathematical models of the long-term impact of such a switch compared to ceasing pneumococcal conjugate vaccination altogether.
Methods
A compartmental deterministic model was used to estimate parameters governing transmission of infection and competition between different groups of pneumococcal serotypes prior to the introduction of PCV13. The best-fitting parameters were used in an individual based model to describe pneumococcal transmission dynamics and effects of various options for the vaccination programme change in England and Wales. A number of scenarios were conducted using (i) different assumptions about the number of invasive pneumococcal disease cases adjusted for the increasing trend in disease incidence prior to PCV7 introduction in England and Wales, and (ii) a range of values representing serotype replacement induced by vaccination of the additional six serotypes in PCV13.
Results
Most of the scenarios considered suggest that ceasing pneumococcal conjugate vaccine use would cause an increase in invasive pneumococcal disease incidence, while replacing PCV7 with PCV13 would cause an overall decrease. However, the size of this reduction largely depends on the level of competition induced by the additional serotypes in PCV13. The model estimates that over 20 years of PCV13 vaccination, around 5000–62000 IPD cases could be prevented compared to stopping pneumococcal conjugate vaccination altogether.
Conclusion
Despite inevitable uncertainty around serotype replacement effects following introduction of PCV13, the model suggests a reduction in overall invasive pneumococcal disease incidence in all cases. Our results provide useful evidence on the benefits of PCV13 to countries replacing or considering replacing PCV7 with PCV13, as well as data that can be used to evaluate the cost-effectiveness of such a switch.
doi:10.1371/journal.pone.0039927
PMCID: PMC3396640  PMID: 22808073
5.  Prediction of serotypes causing invasive pneumococcal disease in unvaccinated and vaccinated populations 
Epidemiology (Cambridge, Mass.)  2011;22(2):199-207.
Introduction
Before the introduction of the heptavalent pneumococcal conjugate vaccine (Prevnar-7), the relative prevalence of serotypes of Streptococcus pneumoniae was fairly stable worldwide. We sought to develop a statistical tool to predict the relative frequency of different serotypes among disease isolates in the pre- and post-Prevnar-7 eras using the limited amount of data that is widely available.
Methods
We initially used pre-Prevnar-7 carriage prevalence and estimates of invasiveness derived from case-fatality data as predictors for the relative abundance of serotypes causing invasive pneumococcal disease during the pre- and post-Prevnar-7 eras, using negative binomial regression. We fit the model to pre-Prevnar-7 invasive pneumococcal disease data from England and Wales and used these data to (1) evaluate the performance of the model using several datasets and (2) evaluate the utility of the country-specific carriage data. We then fit an alternative model that used polysaccharide structure, a correlate of prevalence that does not require country-specific information and could be useful in determining the post-vaccine population structure, as a predictor.
Results
Predictions from the initial model fit data from several pediatric populations in the pre-Prevnar-7 era. Following the introduction of Prevnar-7, the model still had a good negative predictive value, though substantial unexplained variation remained. The alternative model had a good negative predictive value but poor positive predictive value. Both models demonstrate that the pneumococcal population follows a somewhat predictable pattern even after vaccination.
Conclusions
This approach provides a preliminary framework to evaluate the potential patterns and impact of serotypes causing invasive pneumococcal disease.
doi:10.1097/EDE.0b013e3182087634
PMCID: PMC3142570  PMID: 21646962
7.  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
9.  Can Reactive School Closures help critical care provision during the current influenza pandemic? 
PLoS Currents  2009;1:RRN1119.
Although the current H1N1 influenza strain is now considered to be relatively mild, it still has the potential to place a serious burden on health services. The closure of schools has been postulated as a means of reducing transmission between children and hence reducing the number of cases at the peak of an epidemic; however if instigated nationally such a policy has severe economic costs. Reactive short-duration closure of schools in regions where health services are close to capacity offers a potential compromise, but it is unclear over what spatial scale and timeframe closures would need to be made to have a substantial impact. Here, using detailed geographic information for England, we assess how localized school closures could alleviate the burden on hospital intensive care units (ICUs) that are reaching capacity. We show that, for a range of epidemiologically plausible assumptions, considerable local coordination of school closures is needed to achieve a substantial reduction in the number of hospitals that are over capacity at the epidemic peak. The heterogeneity in demand per hospital means that even widespread school closures are unlikely to impact on whether demand will exceed capacity for many hospital ICUs. These results re-enforce the UK policy of not utilising school closures as a control mechanism, but have far wider international public-health implications. The spatial heterogeneities in both population density and hospital capacity that give rise to our results are present in many Northern Hemisphere countries where a second wave of influenza is predicted this autumn and winter. This leads us to believe that even widespread reactive school closures are unlikely to eliminate problems of demand exceeding local capacity in many regions.
doi:10.1371/currents.RRN1119
PMCID: PMC2766491  PMID: 20029657

Results 1-9 (9)