Assessment of Health Benefits and Cost-Effectiveness of 10-Valent and 13-Valent Pneumococcal Conjugate Vaccination in Kenyan Children

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.     

Understanding COVID-19 vaccine demand and hesitancy: A nationwide online survey in China

BackgroundThis study attempts to understand coronavirus disease 2019 (COVID-19) vaccine demand and hesitancy by assessing the public’s vaccination intention and willingness-to-pay (WTP). Confidence in COVID-19 vaccines produced in China and preference for domestically-made or foreign-made vaccines was also investigated.MethodsA nationwide cross-sectional, self-administered online survey was conducted on 1–19 May 2020. The health belief model (HBM) was used as a theoretical framework for understanding COVID-19 vaccination intent and WTP.ResultsA total of 3,541 complete responses were received. The majority reported a probably yes intent (54.6%), followed by a definite yes intent (28.7%). The perception that vaccination decreases the chances of getting COVID-19 under the perceived benefit construct (OR = 3.14, 95% CI 2.05–4.83) and not being concerned about the efficacy of new COVID-19 vaccines under the perceived barriers construct (OR = 1.65, 95% CI 1.31–2.09) were found to have the highest significant odds of a definite intention to take the COVID-19 vaccine. The median (interquartile range [IQR]) of WTP for COVID-19 vaccine was CNY¥200/US$28 (IQR CNY¥100–500/USD$14–72). The highest marginal WTP for the vaccine was influenced by socio-economic factors. The majority were confident (48.7%) and completely confident (46.1%) in domestically-made COVID-19 vaccine. 64.2% reported a preference for a domestically-made over foreign-made COVID-19 vaccine.ConclusionsThe findings demonstrate the utility of HBM constructs in understanding COVID-19 vaccination intent and WTP. It is important to improve health promotion and reduce the barriers to COVID-19 vaccination.     

Comparative Analysis of the Immunogenicity and Protective Effects of Inactivated EV71 Vaccines in Mice

Background

Enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease (HFMD). Three inactivated EV71 whole-virus vaccines of different strains developed by different manufacturers in mainland China have recently entered clinical trials. Although several studies on these vaccines have been published, a study directly comparing the immunogenicity and protective effects among them has not been carried out, which makes evaluating their relative effectiveness difficult. Thus, properly comparing newly developed vaccines has become a priority, especially in China.

Methods and Findings

This comparative immunogenicity study was carried out on vaccine strains (both live and inactivated), final container products (FCPs) without adjuvant, and corresponding FCPs containing adjuvant (FCP-As) produced by three manufacturers. These vaccines were evaluated by neutralizing antibody (NAb) responses induced by the same or different dosages at one or multiple time points post-immunization. The protective efficacy of the three vaccines was also determined in one-day-old ICR mice born to immunized female mice. Survival rates were observed in these suckling mice after challenge with 20 LD₅₀ of EV71/048M3C2. Three FCP-As, in a dose of 200 U, generated nearly 100% NAb positivity rates and similar geometric mean titers (GMTs), especially at 14–21 days post-inoculation. However, the dynamic NAb responses were different among three vaccine strains or three FCPs. The FCP-As at the lowest dose used in clinical trials (162 U) showed good protective effects in suckling mice against lethal challenge (90–100% survival), while the ED₅₀ of NAb responses and protective effects varied among three FCP-As.

Conclusions

These studies establish a standard method for measuring the immunogenicity of EV71 vaccines in mice. The data generated from our mouse model study indicated a clear dose-response relationship, which is important for vaccine quality control and assessment, especially for predicting protective efficacy in humans when combined with future clinical trial results.     

The Monetary Burden of Cystic Echinococcosis in Iran

Cystic echinococcosis (CE) is a globally distributed parasitic infection of humans and livestock. The disease is of significant medical and economic importance in many developing countries, including Iran. However, the socioeconomic impact of the disease, in most endemic countries, is not fully understood. The purpose of the present study was to determine the monetary burden of CE in Iran. Epidemiological data, including prevalence and incidence of CE in humans and animals, were obtained from regional hospitals, the scientific literature, and official government reports. Economic data relating to human and animal disease, including cost of treatment, productivity losses, and livestock production losses were obtained from official national and international datasets. Monte Carlo simulation methods were used to represent uncertainty in input parameters. Mean number of surgical CE cases per year for 2000–2009 was estimated at 1,295. The number of asymptomatic individuals living in the country was estimated at 635,232 (95% Credible Interval, CI 149,466–1,120,998). The overall annual cost of CE in Iran was estimated at US$232.3 million (95% CI US$103.1–397.8 million), including both direct and indirect costs. The cost associated with human CE was estimated at US$93.39 million (95% CI US$6.1–222.7 million) and the annual cost associated with CE in livestock was estimated at US$132 million (95% CI US$61.8–246.5 million). The cost per surgical human case was estimated at US$1,539. CE has a considerable economic impact on Iran, with the cost of the disease approximated at 0.03% of the country''s gross domestic product. Establishment of a CE surveillance system and implementation of a control program are necessary to reduce the economic burden of CE on the country. Cost-benefit analysis of different control programs is recommended, incorporating present knowledge of the economic losses due to CE in Iran.     

Potential Cost-Effectiveness of a New Infant Tuberculosis Vaccine in South Africa - Implications for Clinical Trials: A Decision Analysis

Novel tuberculosis vaccines are in varying stages of pre-clinical and clinical development. This study seeks to estimate the potential cost-effectiveness of a BCG booster vaccine, while accounting for costs of large-scale clinical trials, using the MVA85A vaccine as a case study for estimating potential costs. We conducted a decision analysis from the societal perspective, using a 10-year time frame and a 3% discount rate. We predicted active tuberculosis cases and tuberculosis-related costs for a hypothetical cohort of 960,763 South African newborns (total born in 2009). We compared neonatal vaccination with bacille Calmette-Guérin alone to vaccination with bacille Calmette-Guérin plus a booster vaccine at 4 months. We considered booster efficacy estimates ranging from 40% to 70%, relative to bacille Calmette-Guérin alone. We accounted for the costs of Phase III clinical trials. The booster vaccine was assumed to prevent progression to active tuberculosis after childhood infection, with protection decreasing linearly over 10 years. Trial costs were prorated to South Africa''s global share of bacille Calmette-Guérin vaccination. Vaccination with bacille Calmette-Guérin alone resulted in estimated tuberculosis-related costs of $89.91 million 2012 USD, and 13,610 tuberculosis cases in the birth cohort, over the 10 years. Addition of the booster resulted in estimated cost savings of $7.69–$16.68 million USD, and 2,800–4,160 cases averted, for assumed efficacy values ranging from 40%–70%. A booster tuberculosis vaccine in infancy may result in net societal cost savings as well as fewer active tuberculosis cases, even if efficacy is relatively modest and large scale Phase III studies are required.     

Epidemiological Characteristics and Spatial-Temporal Clusters of Hand,Foot, and Mouth Disease in Zhejiang Province,China, 2008-2012

Hand, foot and mouth disease (HFMD) is one of the major public health concerns in China. Being the province with high incidence rates of HFMD, the epidemiological features and the spatial-temporal patterns of Zhejiang Province were still unknown. The objective of this study was to investigate the epidemiological characteristics and the high-incidence clusters, as well as explore some potential risk factors. The surveillance data of HFMD during 2008–2012 were collected from the communicable disease surveillance network system of Zhejiang Provincial Center for Disease Control and Prevention. The distributions of age, gender, occupation, season, region, pathogen’s serotype and disease severity were analyzed to describe the epidemiological features of HFMD in Zhejiang Province. Seroprevalence survey for human enterovirus 71 (EV71) in 549 healthy children of Zhejiang Province was also performed, as well as 27 seroprevalence publications between 1997 and 2015 were summarized. The spatial-temporal methods were performed to explore the clusters at county level. Furthermore, pathogens’ serotypes such as EV71 and coxsackievirus A16 (Cox A16) and meteorological factors were analyzed to explore the potential factors associated with the clusters. A total of 454,339 HFMD cases were reported in Zhejiang Province during 2008–2012, including 1688 (0.37%) severe cases. The annual average incidence rate was 172.98 per 100,000 (ranged from 72.61 to 270.04). The male-to-female ratio for mild cases was around 1.64:1, and up to 1.87:1 for severe cases. Of the total cases, children aged under three years old and under five years old accounted for almost 60% and 90%, respectively. Among all enteroviruses, the predominant serotype was EV71 (49.70%), followed by Cox A16 (26.05%) and other enteroviruses (24.24%) for mild cases. In severe cases, EV71 (82.85%) was the major causative agent. EV71 seroprevalence survey in healthy children confirmed that occult infection was common in children. Furthermore, literature summary for 26 seroprevalence studies during 1997–2015 confirmed that 0–5 years group showed lowest level of EV71 seroprevalence (29.1% on average) compared to the elder children (6–10 years group: 54.6%; 11–20 years group: 61.8%). Global positive spatial autocorrelation patterns (Moran’s Is>0.25, P<0.05) were discovered not only for mild cases but also for severe cases, and local positive spatial autocorrelation patterns were revealed for counties from the eastern coastal and southern regions. The retrospective space-time cluster analysis also confirmed these patterns. Risk factors analyses implied that more EV71 and less sunshine were associated with the clusters of HFMD in Zhejiang Province. Our study confirmed that Zhejiang Province was one of the highly epidemic provinces in China and that the epidemiological characteristics of HFMD were similar to other provinces. Occult infection in elder children and adults was one of the important reasons why most HFMD cases were children aged under-five. Combining the results of spatial autocorrelation analysis and the space-time cluster analysis, the major spatial-temporal clusters were from the eastern coastal and southern regions. The distribution of pathogens’ serotypes and the level of sunshine could be risk factors for, and serve as an early warning of, the outbreak of HFMD in Zhejiang Province.     

Challenges to licensure of enterovirus 71 vaccines

Human enteroviruses usually cause self-limited infections except polioviruses and enterovirus 71 (EV71), which frequently involve neurological complications. EV71 vaccines are being evaluated in humans. However, several challenges to licensure of EV71 vaccines need to be addressed. Firstly, EV71 and coxsackievirus A (CA) are frequently found to co-circulate and cause hand-foot-mouth disease (HFMD). A polyvalent vaccine that can provide protection against EV71 and prevalent CA are desirable. Secondly, infants are the target population of HFMD vaccines and it would need multi-national efficacy trials to prove clinical protection and speed up the licensure and usage of HFMD vaccines in children. An international network for enterovirus surveillance and clinical trials is urgently needed. Thirdly, EV71 is found to evolve quickly in the past 15 years. Prospective cohort studies are warranted to clarify clinical and epidemiological significances of the antigenic and genetic variations between different EV71 genogroups, which is critical for vaccine design.     

Comparative Study of the Cytokine/Chemokine Response in Children with Differing Disease Severity in Enterovirus 71-Induced Hand,Foot, and Mouth Disease

Background

Enterovirus 71 (EV71) infection can lead to a rapidly progressing, life-threatening, and severe neurological disease in young children, including the development of human hand, foot, and mouth disease (HFMD). This study aims to further characterize the specific immunological features in EV71–mediated HFMD patients presenting with differing degrees of disease severity.

Methodology

Comprehensive cytokine and chemokine expression were broadly evaluated by cytokine antibody array in EV71–infected patients hospitalized for HFMD compared to Coxsackievirus A16-infected patients and age-matched healthy controls. More detailed analysis using Luminex-based cytokine bead array was performed in EV71–infected patients stratified into diverse clinic outcomes. Additionally, immune cell frequencies in peripheral blood and EV71–specific antibodies in plasma were also examined.

Principal Findings

Expression of several cytokines and chemokines were significantly increased in plasma from EV71–infected patients compared to healthy controls, which further indicated that: (1) GM-CSF, MIP-1β, IL-2, IL-33, and IL-23 secretion was elevated in patients who rapidly developed disease and presented with uncomplicated neurological damage; (2) G-CSF and MCP-1 were distinguishably secreted in EV71 infected very severe patients presenting with acute respiratory failure; (3) IP-10, MCP-1, IL-6, IL-8, and G-CSF levels were much higher in cerebrospinal fluid than in plasma from patients with neurological damage; (4) FACS analysis revealed that the frequency of CD19⁺HLADR⁺ mature B cells dynamically changed over time during the course of hospitalization and was accompanied by dramatically increased EV71–specific antibodies. Our data provide a panoramic view of specific immune mediator and cellular immune responses of HFMD and may provide useful immunological profiles for monitoring the progress of EV71–induced fatal neurological symptoms with acute respiratory failure.     

Co-Circulation and Genomic Recombination of Coxsackievirus A16 and Enterovirus 71 during a Large Outbreak of Hand,Foot, and Mouth Disease in Central China

A total of 1844 patients with hand, foot, and mouth disease (HFMD), most of them were children of age 1–3-year-old, in Central China were hospitalized from 2011 to 2012. Among them, 422 were infected with coxsackievirus A16 (CVA16), 334 were infected with enterovirus 71 (EV71), 38 were co-infected with EV71 and CVA16, and 35 were infected with other enteroviruses. Molecular epidemiology analysis revealed that EV71 and CVA16 were detected year-round, but EV71 circulated mainly in July and CVA16 circulated predominantly in November, and incidence of HFMD was reduced in January and February and increased in March. Clinical data showed that hyperglycemia and neurologic complications were significantly higher in EV71-infected patients, while upper respiratory tract infection and C-reactive protein were significantly higher in CVA16-associated patients. 124 EV71 and 80 CVA16 strains were isolated, among them 56 and 68 EV71 strains were C4a and C4b, while 25 and 55 CVA16 strains were B1a and B1b, respectively. Similarity plots and bootscan analyses based on entire genomic sequences revealed that the three C4a sub-genotype EV71 strains were recombinant with C4b sub-genotype EV71 in 2B–2C region, and the three CVA16 strains were recombinant with EV71 in 2A–2B region. Thus, CVA16 and EV71 were the major causative agents in a large HFMD outbreak in Central China. HFMD incidence was high for children among household contact and was detected year-round, but outbreak was seasonal dependent. CVA16 B1b and EV71 C4b reemerged and caused a large epidemic in China after a quiet period of many years. Moreover, EV71 and CVA16 were co-circulated during the outbreak, which may have contributed to the genomic recombination between the pathogens. It should gain more attention as there may be an upward trend in co-circulation of the two pathogens globally and the new role recombination plays in the emergence of new enterovirus variants.     

Preclinical Evaluation of the Immunogenicity and Safety of an Inactivated Enterovirus 71 Candidate Vaccine

Human enterovirus 71 (EV71) is a significant cause of morbidity and mortality from Hand, Foot and Mouth Disease (HFMD) and neurological complications, particularly in young children in the Asia-Pacific region. There are no vaccines or antiviral therapies currently available for prevention or treatment of HFMD caused by EV71. Therefore, the development of therapeutic and preventive strategies against HFMD is of growing importance. We report the immunogenic and safety profile of inactivated, purified EV71 preparations formulated with aluminum hydroxide adjuvant in preclinical studies in mice and rabbits. In mice, the candidate vaccine formulations elicited high neutralizing antibody responses. A toxicology study of the vaccine formulations planned for human use performed in rabbits showed no vaccine-related pathological changes and all animals remained healthy. Based on these preclinical studies, Phase 1 clinical testing of the EV71 inactivated vaccine was initiated.     

Hand,Foot, and Mouth Disease in China: Modeling Epidemic Dynamics of Enterovirus Serotypes and Implications for Vaccination

Background

Hand, foot, and mouth disease (HFMD) is a common childhood illness caused by serotypes of the Enterovirus A species in the genus Enterovirus of the Picornaviridae family. The disease has had a substantial burden throughout East and Southeast Asia over the past 15 y. China reported 9 million cases of HFMD between 2008 and 2013, with the two serotypes Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16) being responsible for the majority of these cases. Three recent phase 3 clinical trials showed that inactivated monovalent EV-A71 vaccines manufactured in China were highly efficacious against HFMD associated with EV-A71, but offered no protection against HFMD caused by CV-A16. To better inform vaccination policy, we used mathematical models to evaluate the effect of prospective vaccination against EV-A71-associated HFMD and the potential risk of serotype replacement by CV-A16. We also extended the model to address the co-circulation, and implications for vaccination, of additional non-EV-A71, non-CV-A16 serotypes of enterovirus.

Methods and Findings

Weekly reports of HFMD incidence from 31 provinces in Mainland China from 1 January 2009 to 31 December 2013 were used to fit multi-serotype time series susceptible–infected–recovered (TSIR) epidemic models. We obtained good model fit for the two-serotype TSIR with cross-protection, capturing the seasonality and geographic heterogeneity of province-level transmission, with strong correlation between the observed and simulated epidemic series. The national estimate of the basic reproduction number, R ₀, weighted by provincial population size, was 26.63 for EV-A71 (interquartile range [IQR]: 23.14, 30.40) and 27.13 for CV-A16 (IQR: 23.15, 31.34), with considerable variation between provinces (however, predictions about the overall impact of vaccination were robust to this variation). EV-A71 incidence was projected to decrease monotonically with higher coverage rates of EV-A71 vaccination. Across provinces, CV-A16 incidence in the post-EV-A71-vaccination period remained either comparable to or only slightly increased from levels prior to vaccination. The duration and strength of cross-protection following infection with EV-A71 or CV-A16 was estimated to be 9.95 wk (95% confidence interval [CI]: 3.31, 23.40) in 68% of the population (95% CI: 37%, 96%). Our predictions are limited by the necessarily short and under-sampled time series and the possible circulation of unidentified serotypes, but, nonetheless, sensitivity analyses indicate that our results are robust in predicting that the vaccine should drastically reduce incidence of EV-A71 without a substantial competitive release of CV-A16.

Conclusions

The ability of our models to capture the observed epidemic cycles suggests that herd immunity is driving the epidemic dynamics caused by the multiple serotypes of enterovirus. Our results predict that the EV-A71 and CV-A16 serotypes provide a temporary immunizing effect against each other. Achieving high coverage rates of EV-A71 vaccination would be necessary to eliminate the ongoing transmission of EV-A71, but serotype replacement by CV-A16 following EV-A71 vaccination is likely to be transient and minor compared to the corresponding reduction in the burden of EV-A71-associated HFMD. Therefore, a mass EV-A71 vaccination program of infants and young children should provide significant benefits in terms of a reduction in overall HFMD burden.     

Economic Analysis of Pandemic Influenza Vaccination Strategies in Singapore

Background

All influenza pandemic plans advocate pandemic vaccination. However, few studies have evaluated the cost-effectiveness of different vaccination strategies. This paper compares the economic outcomes of vaccination compared with treatment with antiviral agents alone, in Singapore.

Methodology

We analyzed the economic outcomes of pandemic vaccination (immediate vaccination and vaccine stockpiling) compared with treatment-only in Singapore using a decision-based model to perform cost-benefit and cost-effectiveness analyses. We also explored the annual insurance premium (willingness to pay) depending on the perceived risk of the next pandemic occurring.

Principal Findings

The treatment-only strategy resulted in 690 deaths, 13,950 hospitalization days, and economic cost of USD$497 million. For immediate vaccination, at vaccine effectiveness of >55%, vaccination was cost-beneficial over treatment-only. Vaccine stockpiling is not cost-effective in most scenarios even with 100% vaccine effectiveness. The annual insurance premium was highest with immediate vaccination, and was lower with increased duration to the next pandemic. The premium was also higher with higher vaccine effectiveness, attack rates, and case-fatality rates. Stockpiling with case-fatality rates of 0.4–0.6% would be cost-beneficial if vaccine effectiveness was >80%; while at case-fatality of >5% stockpiling would be cost-beneficial even if vaccine effectiveness was 20%. High-risk sub-groups warrant higher premiums than low-risk sub-groups.

Conclusions

The actual pandemic vaccine effectiveness and lead time is unknown. Vaccine strategy should be based on perception of severity. Immediate vaccination is most cost-effective, but requires vaccines to be available when required. Vaccine stockpiling as insurance against worst-case scenarios is also cost-effective. Research and development is therefore critical to develop and stockpile cheap, readily available effective vaccines.     

Clinical Efficacy of Therapy with Recombinant Human Interferon α1b in Hand,Foot, and Mouth Disease with Enterovirus 71 Infection

A rapid expansion of HFMD with enterovirus 71 infection outbreaks has occurred and caused deaths in recent years in China, but no vaccine or antiviral drug is currently available for EV71 infection. This study aims to provide treatment programs for HFMD patients. We conducted a randomized, double-blind, controlled trial and evaluated clinical efficacy of therapy with rHuIFN-α1b in HFMD patients with EV71 infection. There were statistical differences in outcomes including the fever clearance time, healing time of typical skin or oral mucosa lesions, and EV71 viral load of the HFMD patients among ultrasonic aerosol inhalation group, intramuscular injection group and control group. rHuIFN-α1b therapy reduced the fever clearance time, healing time of typical skin or oral mucosa lesions, and EV71 viral load in children with HFMD.Trial Registration: Chinese Clinical Trial Registry ChiCTR-TRC-14005153     

Mutations in the non-structural protein region contribute to intra-genotypic evolution of enterovirus 71

Background

Clinical manifestations of enterovirus 71 (EV71) range from herpangina, hand-foot-and-mouth disease (HFMD), to severe neurological complications. Unlike the situation of switching genotypes seen in EV71 outbreaks during 1998–2008 in Taiwan, genotype B5 was responsible for two large outbreaks in 2008 and 2012, respectively. In China, by contrast, EV71 often persists as a single genotype in the population and causes frequent outbreaks. To investigate genetic changes in viral evolution, complete EV71 genome sequences were used to analyze the intra-genotypic evolution pattern in Taiwan, China, and the Netherlands.

Results

Genotype B5 was predominant in Taiwan’s 2008 outbreak and was re-emergent in 2012. EV71 strains from both outbreaks were phylogenetically segregated into two lineages containing fourteen non-synonymous substitutions predominantly in the non-structural protein coding region. In China, genotype C4 was first seen in 1998 and caused the latest large outbreak in 2008. Unlike shifting genotypes in Taiwan, genotype C4 persisted with progressive drift through time. A majority of non-synonymous mutations occurred in residues located in the non-structural coding region, showing annual increases. Interestingly, genotype B1/B2 in the Netherlands showed another stepwise evolution with dramatic EV71 activity increase in 1986. Phylogeny of the VP1 coding region in 1971–1986 exhibited similar lineage turnover with genotype C4 in China; however, phylogeny of the 3D-encoding region indicated separate lineage appearing after 1983, suggesting that the 3D-encoding region of genotype B2 was derived from an unidentified ancestor that contributed to intra-genotypic evolution in the Netherlands.

Conclusions

Unlike VP1 coding sequences long used for phylogenetic study of enteroviruses due to expected host immune escape, our study emphasizes a dominant role of non-synonymous mutations in non-structural protein regions that contribute to (re-)emergent genotypes in continuous stepwise evolution. Dozens of amino acid substitutions, especially in non-structural proteins, were identified via genetic changes driven through intra-genotypic evolution worldwide. These identified substitutions appeared to increase viral fitness in the population, affording valuable insights not only for viral evolution but also for prevention, control, and vaccine against EV71 infection.     

Economic and Disease Burden of Dengue in Southeast Asia

Background

Dengue poses a substantial economic and disease burden in Southeast Asia (SEA). Quantifying this burden is critical to set policy priorities and disease-control strategies.

Methods and Findings

We estimated the economic and disease burden of dengue in 12 countries in SEA: Bhutan, Brunei, Cambodia, East-Timor, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Viet Nam. We obtained reported cases from multiple sources—surveillance data, World Health Organization (WHO), and published studies—and adjusted for underreporting using expansion factors from previous literature. We obtained unit costs per episode through a systematic literature review, and completed missing data using linear regressions. We excluded costs such as prevention and vector control, and long-term sequelae of dengue. Over the decade of 2001–2010, we obtained an annual average of 2.9 million (m) dengue episodes and 5,906 deaths. The annual economic burden (with 95% certainty levels) was US$950m (US$610m–US$1,384m) or about US$1.65 (US$1.06–US$2.41) per capita. The annual number of disability-adjusted life years (DALYs), based on the original 1994 definition, was 214,000 (120,000–299,000), which is equivalent to 372 (210–520) DALYs per million inhabitants.

Conclusion

Dengue poses a substantial economic and disease burden in SEA with a DALY burden per million inhabitants in the region. This burden is higher than that of 17 other conditions, including Japanese encephalitis, upper respiratory infections, and hepatitis B.     

Economic Evaluation of Immunisation Programme of 23-Valent Pneumococcal Polysaccharide Vaccine and the Inclusion of 13-Valent Pneumococcal Conjugate Vaccine in the List for Single-Dose Subsidy to the Elderly in Japan

BackgroundCurrently in Japan, both 23-valent pneumococcal polysaccharide vaccine (PPSV–23) and 13-valent pneumococcal conjugate vaccine (PCV–13) are available for the elderly for the prevention of S. pneumoniae-related diseases. PPSV–23 was approved in 1988, while the extended use of PCV–13 was approved for adults aged 65 and older in June 2014. Despite these two vaccines being available, the recently launched national immunisation programme for the elderly only subsidised PPSV–23. The framework of the current immunisation programme lasts for five years. The elderly population eligible for the subsidised PPSV–23 shot for the 1st year are those aged 65, 70, 75, 80, 85, 90, 95 and ≥100. While from the 2nd year to the 5th year, those who will age 65, 70, 75, 80, 85, 90, 95 and 100 will receive the same subsidised shot.MethodsWe performed economic evaluations to (1) evaluate the efficiency of alternative strategies of PPSV–23 single-dose immunisation programme, and (2) investigate the efficiency of PCV–13 inclusion in the list for single-dose pneumococcal vaccine immunisation programme. Three alternative strategies were created in this study, namely: (1) current PPSV–23 strategy, (2) 65 to 80 (as “65–80 PPSV–23 strategy”), and (3) 65 and older (as “≥65 PPSV–23 strategy”). We constructed a Markov model depicting the S. pneumoniae-related disease course pathways. The transition probabilities, utility weights to estimate quality adjusted life year (QALY) and disease treatment costs were either calculated or cited from literature. Cost of per shot of vaccine was ¥8,116 (US$74; US$1 = ¥110) for PPSV–23 and ¥10,776 (US$98) for PCV–13. The model runs for 15 years with one year cycle after immunisation. Discounting was at 3%.ResultsCompared to current PPSV–23 strategy, 65–80 PPSV–23 strategy cost less but gained less, while the incremental cost-effectiveness ratios (ICERs) of ≥65 PPSV–23 strategy was ¥5,025,000 (US$45,682) per QALY gained. PCV–13 inclusion into the list for single-dose subsidy has an ICER of ¥377,000 (US$3,427) per QALY gained regardless of the PCV–13 diffusion level. These ICERs were found to be cost-effective since they are lower than the suggested criterion by WHO of three times GDP (¥11,000,000 or US$113,636 per QALY gained), which is the benchmark used in judging the cost-effectiveness of an immunisation programmne.ConclusionsThe results suggest that switching current PPSV–23 strategy to ≥65 PPSV–23 strategy or including PCV–13 into the list for single-dose subsidy to the elderly in Japan has value for money.     

Oral Ondansetron Administration in Emergency Departments to Children with Gastroenteritis: An Economic Analysis

Background

The use of antiemetics for children with vomiting is one of the most controversial decisions in the treatment of gastroenteritis in developed countries. Ondansetron, a selective serotonin receptor antagonist, has been found to be effective in improving the success of oral rehydration therapy. However, North American and European clinical practice guidelines continue to recommend against its use, stating that evidence of cost savings would be required to support ondansetron administration. Thus, an economic analysis of the emergency department administration of ondansetron was conducted. The primary objective was to conduct a cost analysis of the routine administration of ondansetron in both the United States and Canada.

Methods and Findings

A cost analysis evaluated oral ondansetron administration to children presenting to emergency departments with vomiting and dehydration secondary to gastroenteritis from a societal and health care payer''s perspective in both the US and Canada. A decision tree was developed that incorporated the frequency of vomiting, intravenous insertion, hospitalization, and emergency department revisits. Estimates of the monetary costs associated with ondansetron use, intravenous rehydration, and hospitalization were derived from administrative databases or emergency department use. The economic burden in children administered ondansetron plus oral rehydration therapy was compared to those not administered ondansetron employing deterministic and probabilistic simulations. We estimated the costs or savings to society and health care payers associated with the routine administration of ondansetron. Sensitivity analyses considered variations in costs, treatment effects, and exchange rates. In the US the administration of ondansetron to eligible children would prevent approximately 29,246 intravenous insertions and 7,220 hospitalizations annually. At the current average wholesale price, its routine administration to eligible children would annually save society US$65.6 million (US$49.1–US$81.1) and health care payers US$61.1 million (US$46.2–US$76.3). In Canada the administration of ondansetron to eligible children would prevent 4,065 intravenous insertions and 1,003 hospitalizations annually. Its routine administration would annually save society CDN$1.72 million (CDN$1.15–CDN$1.89) and the health care system CDN$1.18 million (CDN$0.88–CDN$1.41).

Conclusions

In countries where intravenous rehydration is often employed, the emergency department administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis results in significant monetary savings compared to a no-ondansetron policy. Please see later in the article for the Editors'' Summary     

Monoclonal neutralizing antibodies against EV71 screened from mice immunized with yeast-produced virus-like particles

Periodic outbreaks of hand, foot and mouth disease(HFMD) occur in children under 5 years old, and can cause death in some cases. The C4 strain of enterovirus 71(EV71) is the main pathogen that causes HFMD in China. Although no drugs against EV71 are available, some studies have shown that candidate vaccines or viral capsid proteins can produce anti-EV71 immunity. In this study, female BABL/c mice(6–8 weeks old) were immunized with virus-like particles(VLPs) of EV71 produced in yeast to screen for anti-EV71 antibodies. Two hybridomas that could produce neutralizing antibodies against EV71 were obtained. Both neutralizing m Abs(D4 and G12) were confirmed to bind the VP1 capsid protein of EV71, and could protect 95% cells from 100 TCID50 EV71 infection at 25 μg/m L solution(lowest concentration). Those two neutralizing m Abs identified in the study may be promising candidates in development for m Abs to treat EV71 infection, and utilized as suitable reagents for use in diagnostic tests and biological studies.     

The Cross-Neutralizing Activity of Enterovirus 71 Subgenotype C4 Vaccines in Healthy Chinese Infants and Children

Background

EV71 is one of major etiologic causes of hand-foot-mouth disease (HFMD) and leads to severe neurological complications in young children and infants. Recently inactivated EV71 vaccines have been developed by five manufactures and clinically show good safety and immunogenicity. However, the cross-neutralizing activity of these vaccines remains unclear, and is of particular interest because RNA recombination is seen more frequently in EV71 epidemics.

Methodology/Principal Findings

In this post-hoc study, sera from a subset of 119 infants and children in two clinical trials of EV71 subgenotype C4 vaccines (ClinicalTrials.gov Identifier: NCT01313715 and NCT01273246), were detected for neutralizing antibody (NTAb) titres with sera from infected patients as controls. Cytopathogenic effect method was employed to test NTAb against EV71 subgenotype B4, B5, C2, C4 and C5, which were prominent epidemic strains worldwide over the past decade. To validate the accuracy of the results, ELISpot assay was employed in parallel to detect NTAb in all the post-vaccine sera. After two-dose vaccination, 49 out of 53 participants in initially seronegative group and 52 out of 53 participants in initially seropositive group showed less than 4-fold differences in NTAb titers against five EV71 strains, whereas corresponding values among sera from pediatric patients recovering from EV71-induced HFMD and subclinically infected participants were 8/8 and 41/43, respectively. The geometric mean titers of participants against five subgenotypes EV71 all grew significantly after vaccinations, irrespective of the baseline NTAb titer. The relative fold increase in antibody titers (NTAb-FI) against B4, B5, C2, and C5 displayed a positive correlation to the NTAb-FI against C4.

Conclusions/Significance

The results demonstrated broad cross-neutralizing activity induced by two C4 EV71 vaccines in healthy Chinese infants and children. However, the degree of induced cross-protective immunity, and the potential escape evolution for EV71 still need to be monitored and researched in future for these new vaccines.