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1.  Validity of a reported history of chickenpox in targeting varicella vaccination at susceptible adolescents in England☆ 
Vaccine  2014;32(10):1213-1217.
Highlights
•Chickenpox history may enable cost-effective vaccination of susceptible individuals.•We tested the validity of reported chickenpox history in adolescents.•Vaccine would be wasted in most adolescents with a negative or uncertain history.•6–9% of those with a positive chickenpox history would remain susceptible.•These data are needed to inform cost-effectiveness of proposed vaccine programmes.
Introduction
In the UK, primary varicella is usually a mild infection in children, but can cause serious illness in susceptible pregnant women and adults. The UK Joint Committee on Vaccination and Immunisation is considering an adolescent varicella vaccination programme. Cost-effectiveness depends upon identifying susceptibles and minimising vaccine wastage, and chickenpox history is one method to screen for eligibility. To inform this approach, we estimated the proportion of adolescents with varicella antibodies by reported chickenpox history.
Methods
Recruitment occurred through secondary schools in England from February to September 2012. Parents were asked about their child's history of chickenpox, explicitly setting the context in terms of the implications for vaccination. 247 adolescents, whose parents reported positive (120), negative (77) or uncertain (50) chickenpox history provided oral fluid for varicella zoster virus-specific immunoglobulin-G (VZV-IgG) testing.
Results
109 (90.8% [85.6–96.0%]) adolescents with a positive chickenpox history, 52 (67.5% [57.0–78.1%]) with a negative history and 42 (84.0% [73.7–94.3%]) with an uncertain history had VZV-IgG suggesting prior infection. Combining negative and uncertain histories, 74% had VZV-IgG (best-case). When discounting low total-IgG samples and counting equivocals as positive (worst-case), 84% had VZV-IgG. We also modelled outcomes by varying the negative predictive value (NPV) for the antibody assay, and found 74–87% under the best-case and 84–92% under the worst-case scenario would receive vaccine unnecessarily as NPV falls to 50%.
Conclusion
Reported chickenpox history discriminates between varicella immunity and susceptibility in adolescents, but significant vaccine wastage would occur if this approach alone were used to determine vaccine eligibility. A small but important proportion of those with positive chickenpox history would remain susceptible. These data are needed to determine whether reported history, with or without oral fluid testing in those with negative and uncertain history, is sufficiently discriminatory to underpin a cost-effective adolescent varicella vaccination programme.
doi:10.1016/j.vaccine.2013.06.098
PMCID: PMC3969712  PMID: 23871823
Varicella; Chickenpox; Reported history; Validity; Adolescent; Vaccination programme
2.  The Social Life of Infants in the Context of Infectious Disease Transmission; Social Contacts and Mixing Patterns of the Very Young 
PLoS ONE  2013;8(10):e76180.
Insight into how humans interact helps further understanding of the transmission of infectious diseases. For diseases such as pertussis, infants are at particular risk for severe outcomes. To understand the contact pattern of infants, especially those too young to be vaccinated, we sent contact diaries to a representative sample of 1000 mothers in the United Kingdom. We received 115 responses with a total of 758 recorded contacts. The average number of daily contacts for an infant was 6.68 overall and 5.7 for those aged ≤10 weeks. Of the latter, 2.1 (37%) contacts were with non-household members and were >15 minutes duration, suggesting that a cocooning programme may miss a substantial proportion of exposures leading to disease transmission. The least contact was between adolescents and infants. Thus the impact of adolescent (pertussis) vaccination on infants would likely be limited, unless it reduces transmission to other age groups whose contact with infants is greater.
doi:10.1371/journal.pone.0076180
PMCID: PMC3797797  PMID: 24146835
4.  A Cost Effectiveness and Capacity Analysis for the Introduction of Universal Rotavirus Vaccination in Kenya: Comparison between Rotarix and RotaTeq Vaccines 
PLoS ONE  2012;7(10):e47511.
Background
Diarrhoea is an important cause of death in the developing world, and rotavirus is the single most important cause of diarrhoea associated mortality. Two vaccines (Rotarix and RotaTeq) are available to prevent rotavirus disease. This analysis was undertaken to aid the decision in Kenya as to which vaccine to choose when introducing rotavirus vaccination.
Methods
Cost-effectiveness modelling, using national and sentinel surveillance data, and an impact assessment on the cold chain.
Results
The median estimated incidence of rotavirus disease in Kenya was 3015 outpatient visits, 279 hospitalisations and 65 deaths per 100,000 children under five years of age per year. Cumulated over the first five years of life vaccination was predicted to prevent 34% of the outpatient visits, 31% of the hospitalizations and 42% of the deaths. The estimated prevented costs accumulated over five years totalled US$1,782,761 (direct and indirect costs) with an associated 48,585 DALYs. From a societal perspective Rotarix had a cost-effectiveness ratio of US$142 per DALY (US$5 for the full course of two doses) and RotaTeq US$288 per DALY ($10.5 for the full course of three doses). RotaTeq will have a bigger impact on the cold chain compared to Rotarix.
Conclusion
Vaccination against rotavirus disease is cost-effective for Kenya irrespective of the vaccine. Of the two vaccines Rotarix was the preferred choice due to a better cost-effectiveness ratio, the presence of a vaccine vial monitor, the requirement of fewer doses and less storage space, and proven thermo-stability.
doi:10.1371/journal.pone.0047511
PMCID: PMC3480384  PMID: 23115650
5.  Effect of Serotype on Focus and Mortality of Invasive Pneumococcal Disease: Coverage of Different Vaccines and Insight into Non-Vaccine Serotypes 
PLoS ONE  2012;7(7):e39150.
Background
Differences in pathogenicity between pneumococcal serotypes are important when assessing the potential benefit of different valency vaccines. We investigated the effect of serotype on clinical presentation, outcome, and quality of life lost from invasive pneumococcal disease (IPD) in the context of the 7, 10, and 13 valent pneumococcal conjugate vaccines (PCV7, PCV10, PCV13).
Method
Serotyped IPD cases in England were linked to the national dataset of hospital admissions for April 2002 to March 2011. Based on patients’ diagnostic codes and vital status at the end of the admission, disease focus (meningitis, empyema, sepsis, or respiratory disease) and case fatality rates by serotype and age group (5, 5–64, and 65 years and over) were obtained. Using these data the quality adjusted life years (QALY) lost from the IPD remaining when use of PCV7 stopped in 2010 was estimated for the serotypes covered by higher valency vaccines.
Results
The linked dataset contained 23,688 cases with information on diagnosis, mortality, and serotype. There were significant differences between serotypes in the propensity to cause meningitis, death, and QALY loss in each of the investigated age groups. As a result, vaccines’ coverage of disease burden differed by endpoint. For example, in children under 5 years in 2009/10, PCV10 covered 39% of meningitis, 19% of deaths and 28% of the QALY loss of attributable to IPD, whereas the respective percentages for PCV13 were 65%, 67%, and 66%. The highest QALY loss per serotype in this age group was for 6A. Non-PCV serotypes causing the highest QALY loss were 22F and 33F in <5 year olds and 31 in older individuals.
Conclusion
Marked differences exist between serotypes in clinical presentation and outcome, and these should be considered when evaluating the potential impact of higher valency vaccines on overall disease burden and associated QALY loss.
doi:10.1371/journal.pone.0039150
PMCID: PMC3398022  PMID: 22815698
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
8.  The Impact of Pandemic Influenza H1N1 on Health-Related Quality of Life: A Prospective Population-Based Study 
PLoS ONE  2011;6(3):e17030.
Background
While the H1N1v influenza pandemic in 2009 was clinically mild, with a low case-fatality rate, the overall disease burden measured in quality-adjusted life years (QALY) lost has not been estimated. Such a measure would allow comparison with other diseases and assessment of the cost-effectiveness of pandemic control measures.
Methods and Findings
Cases of H1N1v confirmed by polymerase chain reaction (PCR) and PCR negative cases with similar influenza-like illness (ILI controls) in 7 regions of England were sent two questionnaires, one within a week of symptom onset and one two weeks later, requesting information on duration of illness, work loss and antiviral use together with EQ-5D questionnaires. Results were compared with those for seasonal influenza from a systematic literature review. A total QALY loss for the 2009 pandemic in England was calculated based on the estimated total clinical cases and reported deaths. A total of 655 questionnaires were sent and 296 (45%) returned. Symptoms and average illness duration were similar between confirmed cases and ILI controls (8.8 days and 8.7 days respectively). Days off work were greater for cases than ILI controls (7.3 and 4.9 days respectively, p = 0.003). The quality-adjusted life days lost was 2.92 for confirmed cases and 2.74 for ILI controls, with a reduction in QALY loss after prompt use of antivirals in confirmed cases. The overall QALY loss in the pandemic was estimated at 28,126 QALYs (22,267 discounted) of which 40% was due to deaths (24% with discounting).
Conclusion
Given the global public health significance of influenza, it is remarkable that no previous prospective study of the QALY loss of influenza using standardised and well validated methods has been performed. Although the QALY loss was minor for individual patients, the estimated total burden of influenza over the pandemic was substantial when compared to other infectious diseases.
doi:10.1371/journal.pone.0017030
PMCID: PMC3047534  PMID: 21399678
9.  Modelling the impact of local reactive school closures on critical care provision during an influenza pandemic 
Despite the fact that the 2009 H1N1 pandemic influenza strain was less severe than had been feared, both seasonal epidemics of influenza-like-illness and future influenza pandemics have 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; this is supported by the marked reduction in cases during school holidays observed across the world during the 2009 pandemic. However, a national policy of long-duration school closures could have 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 time frame closures would need to be made to be effective. Here, using detailed geographical 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 where capacity is exceeded at the peak of the epidemic. The heterogeneity in demand per hospital ICU bed means that even widespread school closures are unlikely to have an impact on whether demand will exceed capacity for many hospitals. These results support the UK decision not to use localized 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 exist in many developed countries, while our model assumptions are sufficiently general to cover a wide range of pathogens. This leads us to believe that when a pandemic has severe implications for ICU capacity, only widespread school closures (with their associated costs and organizational challenges) are sufficient to mitigate the burden on the worst-affected hospitals.
doi:10.1098/rspb.2010.2688
PMCID: PMC3145187  PMID: 21288945
influenza; pandemic; schools; modelling; intensive care unit; hospitals
10.  Assessing the potential effects and cost-effectiveness of programmatic herpes zoster vaccination of elderly in the Netherlands 
Background
Herpes zoster (HZ) is a painful disease affecting a considerable part of the elderly. Programmatic HZ vaccination of elderly people may considerably reduce HZ morbidity and its related costs, but the extent of these effects is unknown. In this article, the potential effects and cost-effectiveness of programmatic HZ vaccination of elderly in the Netherlands have been assessed according to a framework that was developed to support evidence-based decision making regarding inclusion of new vaccines in the Dutch National Immunization Program.
Methods
An analytical framework was used combining a checklist, which structured relevant data on the vaccine, pathogen and disease, and a cost-effectiveness analysis. The cost-effectiveness analysis was performed from a societal perspective, using a Markov-cohort-model. Simultaneous vaccination with influenza was assumed.
Results
Due to the combination of waning immunity after vaccination and a reduced efficacy of vaccination at high ages, the most optimal cost-effectiveness ratio (€21716 per QALY) for HZ vaccination in the Netherlands was found for 70-year olds. This estimated ratio is just above the socially accepted threshold in the Netherlands of €20000 per QALY. If additional reduction of postherpetic neuralgia was included, the cost-effectiveness ratio improved (~€10000 per QALY) but uncertainty for this scenario is high.
Conclusions
Vaccination against HZ at the age of 70 years seems marginally cost-effective in the Netherlands. Due to limited vaccine efficacy a considerable part of the disease burden caused by HZ will remain, even with optimal acceptance of programmatic vaccination.
doi:10.1186/1472-6963-10-237
PMCID: PMC2928772  PMID: 20707884
12.  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
13.  Vaccination of risk groups in England using the 13 valent pneumococcal conjugate vaccine: economic analysis 
Objective To estimate the cost effectiveness of vaccinating people with high risk conditions against invasive pneumococcal disease using the 13 valent pneumococcal conjugate vaccine.
Design Economic evaluation using a cohort model from the perspective of healthcare providers.
Setting England.
Participants People aged 2 years and older at increased risk of invasive pneumococcal disease due to chronic kidney disease; splenic dysfunction; HIV infection; a compromised immune system; chronic heart, liver, or respiratory disease; or diabetes.
Main outcome measures Costs, gains in life years and quality adjusted life years (QALYs), and incremental cost effectiveness ratios.
Results Increasing indirect protection resulting from the vaccination programme of infants using the 13 valent pneumococcal conjugate vaccine means that the burden of disease preventable by targeting high risk groups will diminish in time. Under base case assumptions—that is, no overall impact on non bacteraemic pneumonia in high risk groups and assuming the high risk vaccination programme would be launched two to three years after the infant programme—the incremental cost effectiveness ratio was estimated to be more than £30 000 (€37 216; $48 210) per QALY gained for most risk groups. If, however, the vaccine does not offer protection against non-bacteraemic pneumococcal pneumonia or the vaccine was introduced concomitantly with the infant 13 valent pneumococcal conjugate vaccination programme then vaccinating high risk people would (more) likely be cost effective. Sensitivity analyses showed that the cost effectiveness was particularly sensitive to assumed herd benefits and vaccine efficacy estimates.
Conclusion Under base case assumptions it is unlikely that a pneumococcal vaccination programme aimed at risk groups could be considered cost effective. Uncertainty could be substantially reduced by establishing the effectiveness of the 13 valent pneumococcal conjugate vaccine against non-bacteraemic pneumococcal pneumonia, particularly in at risk groups.
doi:10.1136/bmj.e6879
PMCID: PMC3482156  PMID: 23103369

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