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Background: Rapid diagnostic tests (RDTs) for coronavirus disease (COVID) are used in low- and middle-income countries (LMICs) to inform treatment decisions. However, to date, it is unclear when this use is cost-effective. Existing analyses are limited to a narrow set of countries and uses. The aim of this study is to assess the cost-effectiveness of COVID RDTs to inform the treatment of patients with severe illness in LMICs, considering real world practice., Methods and Findings: We assessed the cost-effectiveness of COVID testing across LMICs using a decision tree model, differentiating results by country income level, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) prevalence, and testing scenario (none, RDTs, polymerase chain reaction tests-PCRs and combinations). LMIC experts defined realistic care pathways and treatment options. Using a healthcare provider perspective and net monetary benefit approach, we assessed both intended (COVID symptom alleviation) and unintended (treatment side effects) health and economic impacts for each testing scenario. We included the side effects of corticosteroids, which are often the only available treatment for COVID. Because side effects depend both on the treatment and the patient's underlying illness (COVID or COVID-like illnesses, such as influenza), we considered the prevalence of COVID-like illnesses in our analyses. We found that SARS-CoV-2 testing of patients with severe COVID-like illness can be cost-effective in all LMICs, though only in some circumstances. High influenza prevalence among suspected COVID cases improves cost-effectiveness, since incorrectly provided corticosteroids may worsen influenza outcomes. In low- and some lower-middle-income countries, only patients with a high index of suspicion for COVID should be tested with RDTs, while other patients should be presumed to not have COVID. In some lower-middle-income and upper-middle-income countries, suspected severe COVID cases should almost always be tested. Further, in these settings, negative test results in patients with a high initial index of suspicion should be confirmed through PCR and, during influenza outbreaks, positive results in patients with a low initial index of suspicion should also be confirmed with a PCR. The use of interleukin-6 receptor blockers, when supported by testing, may also be cost-effective in higher-income LMICs. The cost at which they would be cost-effective in low-income countries ($162 to $406 per treatment course) is below current prices. The primary limitation of our analysis is substantial uncertainty around some of the parameters in our model due to limited data, most notably on current COVID mortality with standard of care, and insufficient evidence on the impact of corticosteroids on patients with severe influenza., Conclusions: COVID testing can be cost-effective to inform treatment of LMIC patients with severe COVID-like disease. The optimal algorithm is driven by country income level and health budgets, the level of suspicion that the patient may have COVID, and influenza prevalence. Further research to better characterize the unintended effects of corticosteroids, particularly on influenza cases, could improve decision making around the treatment of those with COVID-like symptoms in LMICs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bonnet et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A quasi-experimental study was conducted to evaluate the effectiveness of a pay-it-forward strategy for increasing influenza vaccination among children and older adults compared to a self-paid vaccination strategy in China. Pay-it-forward is an innovative community-engaged intervention in which participants receive a free influenza vaccination and are then asked if they would like to donate or create a message to support subsequent vaccinations. This economic evaluation used a decision-tree model to compare pay-it-forward to a standard of care arm in which patients had to pay for their own influenza vaccine. The analysis was performed from the healthcare provider perspective and costs were calculated with 2020 United States dollars. The time horizon was one year. In the base case analysis, pay-it-forward was more effective (111 vs 55 people vaccinated) but more costly than standard-of-care ($4477 vs $2725). Pay-it-forward spurred 96.4% (107/111) of individuals to voluntarily donate to support influenza vaccination for high-risk groups in China. Further costing and implementation research is needed to inform scale up., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Tang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Respiratory syncytial virus (RSV) infections are among the primary causes of death for children under 5 years of age worldwide. A notable challenge with many of the upcoming prophylactic interventions against RSV is their short duration of protection, making the age profile of key interest to the design of prevention strategies., Methods and Findings: We leverage the RSV data collected on cases, hospitalizations, and deaths in a systematic review in combination with flexible generalized additive mixed models (GAMMs) to characterize the age burden of RSV incidence, hospitalization, and hospital-based case fatality rate (hCFR). Due to the flexible nature of GAMMs, we estimate the peak, median, and mean incidence of infection to inform discussions on the ideal "window of protection" of prophylactic interventions. In a secondary analysis, we reestimate the burden of RSV in all low- and middle-income countries. The peak age of community-based incidence is 4.8 months, and the mean and median age of infection is 18.9 and 14.7 months, respectively. Estimating the age profile using the incidence coming from hospital-based studies yields a slightly younger age profile, in which the peak age of infection is 2.6 months and the mean and median age of infection are 15.8 and 11.6 months, respectively. More severe outcomes, such as hospitalization and in-hospital death have a younger age profile. Children under 6 months of age constitute 10% of the population under 5 years of age but bear 20% to 29% of cases, 28% to 39% of hospitalizations, and 38% to 50% of deaths. On an average year, we estimate 28.23 to 31.34 million cases of RSV, between 2.95 to 3.35 million hospitalizations, and 16,835 to 19,909 in-hospital deaths in low, lower- and upper middle-income countries. In addition, we estimate 17,254 to 23,875 deaths in the community, for a total of 34,114 to 46,485 deaths. Globally, evidence shows that community-based incidence may differ by World Bank Income Group, but not hospital-based incidence, probability of hospitalization, or the probability of in-hospital death (p ≤ 0.01, p = 1, p = 0.86, 0.63, respectively). Our study is limited mainly due to the sparsity of the data, especially for low-income countries (LICs). The lack of information for some populations makes detecting heterogeneity between income groups difficult, and differences in access to care may impact the reported burden., Conclusions: We have demonstrated an approach to synthesize information on RSV outcomes in a statistically principled manner, and we estimate that the age profile of RSV burden depends on whether information on incidence is collected in hospitals or in the community. Our results suggest that the ideal prophylactic strategy may require multiple products to avert the risk among preschool children., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: LW received grants from Research Foundation Flanders (FWO) during the conduct of the study and fees from Pfizer outside the submitted work for discussions on economic evaluation, for a total of <€3000 combined, fully paid directly to the University of Antwerp. PB reports a grant from the Respiratory Syncytial Virus Consortium in Europe (RESCEU), Innovative Medicines Initiative 2 of the European Commission, Joint Undertaking under grant agreement No 116019, during the conduct of the study; and outside the submitted work he reports grants from Pfizer, GSK, Merck and the Innovative Medicines Initiative 2 of the European Commission (N° 101034339 project PROMISE: Preparing for RSV immunisation and surveillance in Europe) as well as consultancy fees., (Copyright: © 2023 Antillón et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Most individuals developing tuberculosis (TB) are working age adults living in low- and middle-income countries (LMICs). The resulting disability and death impact economic productivity and burden health systems. New TB vaccine products may reduce this burden. In this study, we estimated the impact of introducing novel TB vaccines on gross domestic product (GDP) growth in 105 LMICs., Methods and Findings: We adapted an existing macroeconomic model to simulate country-level GDP trends between 2020 and 2080, comparing scenarios for introduction of hypothetical infant and adolescent/adult vaccines to a no-new-vaccine counterfactual. We parameterized each scenario using estimates of TB-related mortality, morbidity, and healthcare spending from linked epidemiological and costing models. We assumed vaccines would be introduced between 2028 and 2047 and estimated incremental changes in GDP within each country from introduction to 2080, in 2020 US dollars. We tested the robustness of results to alternative analytic specifications. Both vaccine scenarios produced greater cumulative GDP in the modeled countries over the study period, equivalent to $1.6 (95% uncertainty interval: $0.8, 3.0) trillion for the adolescent/adult vaccine and $0.2 ($0.1, 0.4) trillion for the infant vaccine. These GDP gains were substantially lagged relative to the time of vaccine introduction, particularly for the infant vaccine. GDP gains resulting from vaccine introduction were concentrated in countries with higher current TB incidence and earlier vaccine introduction. Results were sensitive to secular trends in GDP growth but relatively robust to other analytic assumptions. Uncertain projections of GDP could alter these projections and affect the conclusions drawn by this analysis., Conclusions: Under a range of assumptions, introducing novel TB vaccines would increase economic growth in LMICs., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Members of the funder (EP, NG, MZ) participated as authors on the study and critically reviewed the analysis, reviewed and revised the manuscript, and approved the final manuscript as submitted. All other authors have declared that no competing interests exist., (Copyright: © 2023 Portnoy et al. This is an open access article distributed under the Creative Commons Attribution IGO License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/3.0/igo/. In any use of this article, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article’s original URL.)

While safe and efficacious COVID-19 vaccines have achieved high coverage in high-income settings, roll-out remains slow in sub-Saharan Africa. By April 2022, Nigeria, a country of over 200 million people, had only distributed 34 million doses. To ensure the optimal use of health resources, cost-effectiveness analyses can inform key policy questions in the health technology assessment process. We carried out several cost-effectiveness analyses exploring different COVID-19 vaccination scenarios in Nigeria. In consultation with Nigerian stakeholders, we addressed three key questions: what vaccines to buy, how to deliver them and what age groups to target. We combined an epidemiological model of virus transmission parameterised with Nigeria specific data with a costing model that incorporated local resource use assumptions and prices, both for vaccine delivery as well as costs associated with care and treatment of COVID-19. Scenarios of vaccination were compared with no vaccination. Incremental cost-effectiveness ratios were estimated in terms of costs per disability-adjusted life years averted and compared to commonly used cost-effectiveness ratios. Viral vector vaccines are cost-effective (or cost saving), particularly when targeting older adults. Despite higher efficacy, vaccines employing mRNA technologies are less cost-effective due to high current dose prices. The method of delivery of vaccines makes little difference to the cost-effectiveness of the vaccine. COVID-19 vaccines can be highly effective and cost-effective (as well as cost-saving), although an important determinant of the latter is the price per dose and the age groups prioritised for vaccination. From a health system perspective, viral vector vaccines may represent most cost-effective choices for Nigeria, although this may change with price negotiation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ruiz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Group B Streptococcus (GBS) can cause invasive disease (iGBS) in young infants, typically presenting as sepsis or meningitis, and is also associated with stillbirth and preterm birth. GBS vaccines are under development, but their potential health impact and cost-effectiveness have not been assessed globally., Methods and Findings: We assessed the health impact and value (using net monetary benefit (NMB), which measures both health and economic effects of vaccination into monetary units) of GBS maternal vaccination in an annual cohort of 140 million pregnant women across 183 countries in 2020. Our analysis uses a decision tree model, incorporating risks of GBS-related health outcomes from an existing Bayesian disease burden model. We extrapolated country-specific GBS-related healthcare costs using data from a previous systematic review and calculated quality-adjusted life years (QALYs) lost due to infant mortality and long-term disability. We assumed 80% vaccine efficacy against iGBS and stillbirth, following the WHO Preferred Product Characteristics, and coverage based on the proportion of pregnant women receiving at least 4 antenatal visits. One dose was assumed to cost $50 in high-income countries, $15 in upper-middle income countries, and $3.50 in low-/lower-middle-income countries. We estimated NMB using alternative normative assumptions that may be adopted by policymakers. Vaccinating pregnant women could avert 127,000 (95% uncertainty range 63,300 to 248,000) early-onset and 87,300 (38,100 to 209,000) late-onset infant iGBS cases, 31,100 deaths (14,400 to 66,400), 17,900 (6,380 to 49,900) cases of moderate and severe neurodevelopmental impairment, and 23,000 (10,000 to 56,400) stillbirths. A vaccine effective against GBS-associated prematurity might also avert 185,000 (13,500 to 407,000) preterm births. Globally, a 1-dose vaccine programme could cost $1.7 billion but save $385 million in healthcare costs. Estimated global NMB ranged from $1.1 billion ($-0.2 to 3.8 billion) under the least favourable normative assumptions to $17 billion ($9.1 to 31 billion) under the most favourable normative assumptions. The main limitation of our analysis was the scarcity of data to inform some of the model parameters such as those governing health-related quality of life and long-term costs from disability, and how these parameters may vary across country contexts., Conclusions: In this study, we found that maternal GBS vaccination could have a large impact on infant morbidity and mortality. Globally, a GBS maternal vaccine at reasonable prices is likely to be a cost-effective intervention., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: FS is employed by the UK NSC which developed the policy recommendation for maternal GBS screening. RH is member of the World Health Organisation., (Copyright: © 2023 Procter et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Tuberculosis (TB) is preventable and curable but eliminating it has proven challenging. Safe and effective TB vaccines that can rapidly reduce disease burden are essential for achieving TB elimination. We assessed future costs, cost-savings, and cost-effectiveness of introducing novel TB vaccines in low- and middle-income countries (LMICs) for a range of product characteristics and delivery strategies., Methods and Findings: We developed a system of epidemiological and economic models, calibrated to demographic, epidemiological, and health service data in 105 LMICs. For each country, we assessed the likely future course of TB-related outcomes under several vaccine introduction scenarios, compared to a "no-new-vaccine" counterfactual. Vaccine scenarios considered 2 vaccine product profiles (1 targeted at infants, 1 at adolescents/adults), both assumed to prevent progression to active TB. Key economic inputs were derived from the Global Health Cost Consortium, World Health Organization (WHO) patient cost surveys, and the published literature. We estimated the incremental impact of vaccine introduction for a range of health and economic outcomes. In the base-case, we assumed a vaccine price of $4.60 and used a 1× per-capita gross domestic product (GDP) cost-effectiveness threshold (both varied in sensitivity analyses). Vaccine introduction was estimated to require substantial near-term resources, offset by future cost-savings from averted TB burden. From a health system perspective, adolescent/adult vaccination was cost-effective in 64 of 105 LMICs. From a societal perspective (including productivity gains and averted patient costs), adolescent/adult vaccination was projected to be cost-effective in 73 of 105 LMICs and cost-saving in 58 of 105 LMICs, including 96% of countries with higher TB burden. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $283 to 474 billion in economic benefits by 2050. Limited data availability required assumptions and extrapolations that may omit important country-level heterogeneity in epidemiology and costs., Conclusions: TB vaccination would be highly impactful and cost-effective in most LMICs. Further efforts are needed for future development, adoption, and implementation of novel TB vaccines., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Members of the funder (NG, MZ, SYS, RH, IGB, NN) participated as authors on the study and critically reviewed the analysis, reviewed and revised the manuscript, and approved the final manuscript as submitted. All other authors have declared that no competing interests exist., (Copyright: © 2023 Portnoy et al. This is an open access article distributed under the Creative Commons Attribution IGO License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/3.0/igo/. In any use of this article, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article’s original URL.)

Forecasts based on epidemiological modelling have played an important role in shaping public policy throughout the COVID-19 pandemic. This modelling combines knowledge about infectious disease dynamics with the subjective opinion of the researcher who develops and refines the model and often also adjusts model outputs. Developing a forecast model is difficult, resource- and time-consuming. It is therefore worth asking what modelling is able to add beyond the subjective opinion of the researcher alone. To investigate this, we analysed different real-time forecasts of cases of and deaths from COVID-19 in Germany and Poland over a 1-4 week horizon submitted to the German and Polish Forecast Hub. We compared crowd forecasts elicited from researchers and volunteers, against a) forecasts from two semi-mechanistic models based on common epidemiological assumptions and b) the ensemble of all other models submitted to the Forecast Hub. We found crowd forecasts, despite being overconfident, to outperform all other methods across all forecast horizons when forecasting cases (weighted interval score relative to the Hub ensemble 2 weeks ahead: 0.89). Forecasts based on computational models performed comparably better when predicting deaths (rel. WIS 1.26), suggesting that epidemiological modelling and human judgement can complement each other in important ways., Competing Interests: The authors have declared that no competing interests exist.

Background: Multiple Coronavirus Disease 2019 (COVID-19) vaccines appear to be safe and efficacious, but only high-income countries have the resources to procure sufficient vaccine doses for most of their eligible populations. The World Health Organization has published guidelines for vaccine prioritisation, but most vaccine impact projections have focused on high-income countries, and few incorporate economic considerations. To address this evidence gap, we projected the health and economic impact of different vaccination scenarios in Sindh Province, Pakistan (population: 48 million)., Methods and Findings: We fitted a compartmental transmission model to COVID-19 cases and deaths in Sindh from 30 April to 15 September 2020. We then projected cases, deaths, and hospitalisation outcomes over 10 years under different vaccine scenarios. Finally, we combined these projections with a detailed economic model to estimate incremental costs (from healthcare and partial societal perspectives), disability-adjusted life years (DALYs), and incremental cost-effectiveness ratio (ICER) for each scenario. We project that 1 year of vaccine distribution, at delivery rates consistent with COVAX projections, using an infection-blocking vaccine at $3/dose with 70% efficacy and 2.5-year duration of protection is likely to avert around 0.9 (95% credible interval (CrI): 0.9, 1.0) million cases, 10.1 (95% CrI: 10.1, 10.3) thousand deaths, and 70.1 (95% CrI: 69.9, 70.6) thousand DALYs, with an ICER of $27.9 per DALY averted from the health system perspective. Under a broad range of alternative scenarios, we find that initially prioritising the older (65+) population generally prevents more deaths. However, unprioritised distribution has almost the same cost-effectiveness when considering all outcomes, and both prioritised and unprioritised programmes can be cost-effective for low per-dose costs. High vaccine prices ($10/dose), however, may not be cost-effective, depending on the specifics of vaccine performance, distribution programme, and future pandemic trends. The principal drivers of the health outcomes are the fitted values for the overall transmission scaling parameter and disease natural history parameters from other studies, particularly age-specific probabilities of infection and symptomatic disease, as well as social contact rates. Other parameters are investigated in sensitivity analyses. This study is limited by model approximations, available data, and future uncertainty. Because the model is a single-population compartmental model, detailed impacts of nonpharmaceutical interventions (NPIs) such as household isolation cannot be practically represented or evaluated in combination with vaccine programmes. Similarly, the model cannot consider prioritising groups like healthcare or other essential workers. The model is only fitted to the reported case and death data, which are incomplete and not disaggregated by, e.g., age. Finally, because the future impact and implementation cost of NPIs are uncertain, how these would interact with vaccination remains an open question., Conclusions: COVID-19 vaccination can have a considerable health impact and is likely to be cost-effective if more optimistic vaccine scenarios apply. Preventing severe disease is an important contributor to this impact. However, the advantage of prioritising older, high-risk populations is smaller in generally younger populations. This reduction is especially true in populations with more past transmission, and if the vaccine is likely to further impede transmission rather than just disease. Those conditions are typical of many low- and middle-income countries., Competing Interests: The authors have declared that no competing interests exist.

Mathematical models have played a key role in understanding the spread of directly-transmissible infectious diseases such as Coronavirus Disease 2019 (COVID-19), as well as the effectiveness of public health responses. As the risk of contracting directly-transmitted infections depends on who interacts with whom, mathematical models often use contact matrices to characterise the spread of infectious pathogens. These contact matrices are usually generated from diary-based contact surveys. However, the majority of places in the world do not have representative empirical contact studies, so synthetic contact matrices have been constructed using more widely available setting-specific survey data on household, school, classroom, and workplace composition combined with empirical data on contact patterns in Europe. In 2017, the largest set of synthetic contact matrices to date were published for 152 geographical locations. In this study, we update these matrices with the most recent data and extend our analysis to 177 geographical locations. Due to the observed geographic differences within countries, we also quantify contact patterns in rural and urban settings where data is available. Further, we compare both the 2017 and 2020 synthetic matrices to out-of-sample empirically-constructed contact matrices, and explore the effects of using both the empirical and synthetic contact matrices when modelling physical distancing interventions for the COVID-19 pandemic. We found that the synthetic contact matrices show qualitative similarities to the contact patterns in the empirically-constructed contact matrices. Models parameterised with the empirical and synthetic matrices generated similar findings with few differences observed in age groups where the empirical matrices have missing or aggregated age groups. This finding means that synthetic contact matrices may be used in modelling outbreaks in settings for which empirical studies have yet to be conducted., Competing Interests: The authors have declared that no competing interests exist.

Neonatal invasive disease caused by Group B Streptococcus (GBS) is responsible for much acute mortality and long-term morbidity. To guide development of better prevention strategies, including maternal vaccines that protect neonates against GBS, it is necessary to estimate the burden of this condition globally and in different regions. Here, we present a Bayesian model that estimates country-specific invasive GBS (iGBS) disease incidence in children aged 0 to 6 days. The model combines different types of epidemiological data, each of which has its own limitations: GBS colonization prevalence in pregnant women, risk of iGBS disease in children born to GBS-colonized mothers and direct estimates of iGBS disease incidence where available. In our analysis, we present country-specific maternal GBS colonization prevalence after adjustment for GBS detection assay used in epidemiological studies. We then integrate these results with other epidemiological data and estimate country-level incidence of iGBS disease including in countries with no studies that directly estimate incidence. We are able to simultaneously estimate two key epidemiological quantities: the country-specific incidence of early-onset iGBS disease, and the risk of iGBS disease in babies born to GBS-colonized women. Overall, we believe our method will contribute to a more comprehensive quantification of the global burden of this disease, inform cost-effectiveness assessments of potential maternal GBS vaccines and identify key areas where data are necessary., Competing Interests: The authors have declared that no competing interests exist.

Background: Hand, foot and mouth disease (HFMD) is a common illness in China that mainly affects infants and children. The objective of this study is to assess the economic cost and health-related quality of life associated with HFMD in China., Method: A telephone survey of caregivers were conducted in 31 provinces across China. Caregivers of laboratory-confirmed HFMD patients who were registered in the national HFMD enhanced surveillance database during 2012-2013 were invited to participate in the survey. Total costs included direct medical costs (outpatient care, inpatient care and self-medication), direct non-medical costs (transportation, nutrition, accommodation and nursery), and indirect costs for lost income associated with caregiving. Health utility weights elicited using EuroQol EQ-5D-3L and EQ-Visual Analogue Scale (VAS) were used to calculate associated loss in quality adjusted life years (QALYs)., Results: The subjects comprised 1136 mild outpatients, 1124 mild inpatients, 1170 severe cases and 61 fatal cases. The mean total costs for mild outpatients, mild inpatients, severe cases and fatal cases were $201 (95%CI $187, $215), $1072 (95%CI $999, $1144), $3051 (95%CI $2905, $3197) and $2819 (95%CI $2068, $3571) respectively. The mean QALY losses per HFMD episode for mild outpatients, mild inpatients and severe cases were 3.6 (95%CI 3.4, 3,9), 6.9 (95%CI 6.4, 7.4) and 13.7 (95%CI 12.9, 14.5) per 1000 persons. Cases who were diagnosed with EV-A71 infection and had longer duration of illness were associated with higher total cost and QALY loss., Conclusion: HFMD poses a high economic and health burden in China. Our results provide economic and health utility data for cost-effectiveness analysis for HFMD vaccination in China.

Heterogeneities in contact networks have a major effect in determining whether a pathogen can become epidemic or persist at endemic levels. Epidemic models that determine which interventions can successfully prevent an outbreak need to account for social structure and mixing patterns. Contact patterns vary across age and locations (e.g. home, work, and school), and including them as predictors in transmission dynamic models of pathogens that spread socially will improve the models' realism. Data from population-based contact diaries in eight European countries from the POLYMOD study were projected to 144 other countries using a Bayesian hierarchical model that estimated the proclivity of age-and-location-specific contact patterns for the countries, using Markov chain Monte Carlo simulation. Household level data from the Demographic and Health Surveys for nine lower-income countries and socio-demographic factors from several on-line databases for 152 countries were used to quantify similarity of countries to estimate contact patterns in the home, work, school and other locations for countries for which no contact data are available, accounting for demographic structure, household structure where known, and a variety of metrics including workforce participation and school enrolment. Contacts are highly assortative with age across all countries considered, but pronounced regional differences in the age-specific contacts at home were noticeable, with more inter-generational contacts in Asian countries than in other settings. Moreover, there were variations in contact patterns by location, with work-place contacts being least assortative. These variations led to differences in the effect of social distancing measures in an age structured epidemic model. Contacts have an important role in transmission dynamic models that use contact rates to characterize the spread of contact-transmissible diseases. This study provides estimates of mixing patterns for societies for which contact data such as POLYMOD are not yet available.

Background: Large Phase III trials across Asia and Latin America have recently demonstrated the efficacy of a recombinant, live-attenuated dengue vaccine (Dengvaxia) over the first 25 mo following vaccination. Subsequent data collected in the longer-term follow-up phase, however, have raised concerns about a potential increase in hospitalization risk of subsequent dengue infections, in particular among young, dengue-naïve vaccinees. We here report predictions from eight independent modelling groups on the long-term safety, public health impact, and cost-effectiveness of routine vaccination with Dengvaxia in a range of transmission settings, as characterised by seroprevalence levels among 9-y-olds (SP9). These predictions were conducted for the World Health Organization to inform their recommendations on optimal use of this vaccine., Methods and Findings: The models adopted, with small variations, a parsimonious vaccine mode of action that was able to reproduce quantitative features of the observed trial data. The adopted mode of action assumed that vaccination, similarly to natural infection, induces transient, heterologous protection and, further, establishes a long-lasting immunogenic memory, which determines disease severity of subsequent infections. The default vaccination policy considered was routine vaccination of 9-y-old children in a three-dose schedule at 80% coverage. The outcomes examined were the impact of vaccination on infections, symptomatic dengue, hospitalised dengue, deaths, and cost-effectiveness over a 30-y postvaccination period. Case definitions were chosen in accordance with the Phase III trials. All models predicted that in settings with moderate to high dengue endemicity (SP9 ≥ 50%), the default vaccination policy would reduce the burden of dengue disease for the population by 6%-25% (all simulations: -3%-34%) and in high-transmission settings (SP9 ≥ 70%) by 13%-25% (all simulations: 10%- 34%). These endemicity levels are representative of the participating sites in both Phase III trials. In contrast, in settings with low transmission intensity (SP9 ≤ 30%), the models predicted that vaccination could lead to a substantial increase in hospitalisation because of dengue. Modelling reduced vaccine coverage or the addition of catch-up campaigns showed that the impact of vaccination scaled approximately linearly with the number of people vaccinated. In assessing the optimal age of vaccination, we found that targeting older children could increase the net benefit of vaccination in settings with moderate transmission intensity (SP9 = 50%). Overall, vaccination was predicted to be potentially cost-effective in most endemic settings if priced competitively. The results are based on the assumption that the vaccine acts similarly to natural infection. This assumption is consistent with the available trial results but cannot be directly validated in the absence of additional data. Furthermore, uncertainties remain regarding the level of protection provided against disease versus infection and the rate at which vaccine-induced protection declines., Conclusions: Dengvaxia has the potential to reduce the burden of dengue disease in areas of moderate to high dengue endemicity. However, the potential risks of vaccination in areas with limited exposure to dengue as well as the local costs and benefits of routine vaccination are important considerations for the inclusion of Dengvaxia into existing immunisation programmes. These results were important inputs into WHO global policy for use of this licensed dengue vaccine., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: LC is employed by Sanofi Pasteur. KV is a staff member of the World Health Organization. TAP and GE receive support from GlaxoSmithKline for unrelated work on dengue vaccine modelling. IL, TJH, and CABP have received travel support from Sanofi Pasteur to present other work on dengue vaccine modelling. Sanofi Pasteur has not funded any of their research and was not involved in any research decisions related to their work presented. NF gave advice to Sanofi-Pasteur and the World Health Organization on the efficacy profile and potential public health impact of Dengvaxia. He is also collaborating with Sanofi-Pasteur on secondary analyses of Dengvaxia clinical trial data. He has received no remuneration, grant income, expense payments or in-kind benefit from Sanofi-Pasteur. DATC and IRB have advised WHO on the use of the Sanofi vaccine in a number of meetings and as part of a consortium of modelers who estimated the potential impact of the vaccine. On occasion they received travel expenses for visits to WHO. They have also advised Sanofi Pasteur Ltd. on the implications their work has for use of their vaccine. They have not received any financial or in-kind payment from Sanofi. All other authors have declared that no competing interests exist.

A semi-circle looped vertically omnidirectional radiation (VOR) patterned tag antenna for UHF (919-923 MHz for Malaysia) frequency is designed to overcome the impedance mismatch issue in this paper. Two impedance matching feeding strips are used in the antenna structure to tune the input impedance of the antenna. Two dipole shaped meandered lines are used to achieve a VOR pattern. The proposed antenna is designed for 23-j224 Ω chip impedance. The antenna is suitable for 'place and tag' application. A small size of 77.68×35.5 mm2 is achieved for a read range performance of 8.3 meters using Malaysia regulated maximum power transfer of 2.0 W effective radiated power (ERP).

Background: The epidemiology of oral human papillomavirus (HPV) infection in men who have sex with men (MSM) differs from anogenital HPV infection. The impact of HPV vaccination has, to date, largely focussed on anogenital outcomes. Vaccination of MSM in the UK has been recommended and, if implemented, baseline estimates of oral HPV prevalence will be useful., Methods: We searched Medline, Embase and psycINFO databases for studies reporting prevalence, incidence, and clearance of oral HPV infection in MSM. We performed a random-effects meta-analysis and meta-regression on prevalence estimates and summarised within-study risk factors for oral HPV DNA detection and incidence/clearance rates. We also performed a meta-analysis of the effect of MSM on oral HPV prevalence compared to heterosexual men., Results: 26 publications were identified. The pooled prevalence of oral HPV16 from twelve estimates was 3.0% (95%CI 0.5-5.5) in HIV-negative and 4.7% (95%CI 2.1-7.3) in HIV-positive MSM. Median age of study participants explained 38% of heterogeneity (p<0.01) in HPV prevalence estimates (pooled = 17% and 29% in HIV-negative and HIV-positive, respectively; 22 estimates). Nine studies compared MSM to heterosexual men and found no difference in oral HPV prevalence (pooled OR 1.07 (95%CI 0.65-1.74)). The clearance rate was higher than incidence within studies. Type-specific concordance between oral and anogenital sites was rare., Conclusion: There was substantial heterogeneity between estimates of oral HPV prevalence in MSM populations that was partly explained by HIV status and median age.

Background: China accounted for 87% (9.8 million/11.3 million) of all hand, foot, and mouth disease (HFMD) cases reported to WHO during 2010-2014. Enterovirus 71 (EV71) is responsible for most of the severe HFMD cases. Three EV71 vaccines recently demonstrated good efficacy in children aged 6-71 mo. Here we assessed the cost-effectiveness of routine pediatric EV71 vaccination in China., Methods and Findings: We characterized the economic and health burden of EV71-associated HFMD (EV71-HFMD) in China using (i) the national surveillance database, (ii) virological surveillance records from all provinces, and (iii) a caregiver survey on the household costs and health utility loss for 1,787 laboratory-confirmed pediatric cases. Using a static model parameterized with these data, we estimated the effective vaccine cost (EVC, defined as cost/efficacy or simply the cost of a 100% efficacious vaccine) below which routine pediatric vaccination would be considered cost-effective. We performed the base-case analysis from the societal perspective with a willingness-to-pay threshold of one times the gross domestic product per capita (GDPpc) and an annual discount rate of 3%. We performed uncertainty analysis by (i) accounting for the uncertainty in the risk of EV71-HFMD due to missing laboratory data in the national database, (ii) excluding productivity loss of parents and caregivers, (iii) increasing the willingness-to-pay threshold to three times GDPpc, (iv) increasing the discount rate to 6%, and (v) accounting for the proportion of EV71-HFMD cases not registered by national surveillance. In each of these scenarios, we performed probabilistic sensitivity analysis to account for parametric uncertainty in our estimates of the risk of EV71-HFMD and the expected costs and health utility loss due to EV71-HFMD. Routine pediatric EV71 vaccination would be cost-saving if the all-inclusive EVC is below US$10.6 (95% CI US$9.7-US$11.5) and would remain cost-effective if EVC is below US$17.9 (95% CI US$16.9-US$18.8) in the base case, but these ceilings could be up to 66% higher if all the test-negative cases with missing laboratory data are EV71-HFMD. The EVC ceiling is (i) 10%-14% lower if productivity loss of parents/caregivers is excluded, (ii) 58%-84% higher if the willingness-to-pay threshold is increased to three times GDPpc, (iii) 14%-19% lower if the discount rate is increased to 6%, and (iv) 36% (95% CI 23%-50%) higher if the proportion of EV71-HFMD registered by national surveillance is the same as that observed in the three EV71 vaccine phase III trials. The validity of our results relies on the following assumptions: (i) self-reported hospital charges are a good proxy for the opportunity cost of care, (ii) the cost and health utility loss estimates based on laboratory-confirmed EV71-HFMD cases are representative of all EV71-HFMD cases, and (iii) the long-term average risk of EV71-HFMD in the future is similar to that registered by national surveillance during 2010-2013., Conclusions: Compared to no vaccination, routine pediatric EV71 vaccination would be very cost-effective in China if the cost of immunization (including all logistical, procurement, and administration costs needed to confer 5 y of vaccine protection) is below US$12.0-US$18.3, depending on the choice of vaccine among the three candidates. Given that the annual number of births in China has been around 16 million in recent years, the annual costs for routine pediatric EV71 vaccination at this cost range should not exceed US$192-US$293 million. Our results can be used to determine the optimal vaccine when the prices of the three vaccines are known.

This paper addresses the performance evaluation of a modified square loop antenna design for UHF RFID applications that is excited through a narrow feed line connected to a square loop, an impedance matching network. The square loop dimensions are modified to reach a conjugate impedance matching. A gap is fixed between the feed-lines to link the chip. To achieve impedance matching, the structures of the feed-line are optimized accordingly. In addition, the antenna consists of a straightforward geometry. An 11.9-meter maximum read range is achieved using a compact size of 80 × 44 mm2 and 3.2 W for the effective isotropic radiated power. Additional findings reveal that the proposed tag antenna is able to provide a stable resonance response in the near field of a large metallic surface.

The burden of severe pneumonia in terms of morbidity and mortality is unknown in India especially at sub-national level. In this context, we aimed to estimate the number of severe pneumonia episodes, pneumococcal pneumonia episodes and pneumonia deaths in children younger than 5 years in 2010. We adapted and parameterized a mathematical model based on the epidemiological concept of potential impact fraction developed CHERG for this analysis. The key parameters that determine the distribution of severe pneumonia episode across Indian states were state-specific under-5 population, state-specific prevalence of selected definite pneumonia risk factors and meta-estimates of relative risks for each of these risk factors. We applied the incidence estimates and attributable fraction of risk factors to population estimates for 2010 of each Indian state. We then estimated the number of pneumococcal pneumonia cases by applying the vaccine probe methodology to an existing trial. We estimated mortality due to severe pneumonia and pneumococcal pneumonia by combining incidence estimates with case fatality ratios from multi-centric hospital-based studies. Our results suggest that in 2010, 3.6 million (3.3-3.9 million) episodes of severe pneumonia and 0.35 million (0.31-0.40 million) all cause pneumonia deaths occurred in children younger than 5 years in India. The states that merit special mention include Uttar Pradesh where 18.1% children reside but contribute 24% of pneumonia cases and 26% pneumonia deaths, Bihar (11.3% children, 16% cases, 22% deaths) Madhya Pradesh (6.6% children, 9% cases, 12% deaths), and Rajasthan (6.6% children, 8% cases, 11% deaths). Further, we estimated that 0.56 million (0.49-0.64 million) severe episodes of pneumococcal pneumonia and 105 thousand (92-119 thousand) pneumococcal deaths occurred in India. The top contributors to India's pneumococcal pneumonia burden were Uttar Pradesh, Bihar, Madhya Pradesh and Rajasthan in that order. Our results highlight the need to improve access to care and increase coverage and equity of pneumonia preventing vaccines in states with high pneumonia burden.

Background: While healthcare costs for rotavirus gastroenteritis requiring hospitalization may be burdensome on households in Malaysia, exploration on the distribution and catastrophic impact of these expenses on households are lacking., Objectives: We assessed the economic burden, levels and distribution of catastrophic healthcare expenditure, the poverty impact on households and inequities related to healthcare payments for acute gastroenteritis requiring hospitalization in Malaysia., Methods: A two-year prospective, hospital-based study was conducted from 2008 to 2010 in an urban (Kuala Lumpur) and rural (Kuala Terengganu) setting in Malaysia. All children under the age of 5 years admitted for acute gastroenteritis were included. Patients were screened for rotavirus and information on healthcare expenditure was obtained., Results: Of the 658 stool samples collected at both centers, 248 (38%) were positive for rotavirus. Direct and indirect costs incurred were significantly higher in Kuala Lumpur compared with Kuala Terengganu (US$222 Vs. US$45; p<0.001). The mean direct and indirect costs for rotavirus gastroenteritis consisted 20% of monthly household income in Kuala Lumpur, as compared with only 5% in Kuala Terengganu. Direct medical costs paid out-of-pocket caused 141 (33%) households in Kuala Lumpur to experience catastrophic expenditure and 11 (3%) households to incur poverty. However in Kuala Terengganu, only one household (0.5%) experienced catastrophic healthcare expenditure and none were impoverished. The lowest income quintile in Kuala Lumpur was more likely to experience catastrophic payments compared to the highest quintile (87% vs 8%). The concentration index for out-of-pocket healthcare payments was closer to zero at Kuala Lumpur (0.03) than at Kuala Terengganu (0.24)., Conclusions: While urban households were wealthier, healthcare expenditure due to gastroenteritis had more catastrophic and poverty impact on the urban poor. Universal rotavirus vaccination would reduce both disease burden and health inequities in Malaysia.

Background: Recent evidence suggests that less than one-quarter of patients with symptomatic nosocomial Clostridium difficile infections (CDI) are linked to other in-patients. However, this evidence was limited to one geographic area. We aimed to investigate the level of symptomatic CDI transmission in hospitals located across England from 2008 to 2012., Methods: A generalized additive mixed-effects Poisson model was fitted to English hospital-surveillance data. After adjusting for seasonal fluctuations and between-hospital variation in reported CDI over time, possible clustering (transmission between symptomatic in-patients) of CDI cases was identified. We hypothesised that a temporal proximity would be reflected in the degree of correlation between in-hospital CDI cases per week. This correlation was modelled through a latent autoregressive structure of order 1 (AR(1))., Findings: Forty-six hospitals (33 general, seven specialist, and six teaching hospitals) located in all English regions met our criteria. In total, 12,717 CDI cases were identified; seventy-five per cent of these occurred >48 hours after admission. There were slight increases in reports during winter months. We found a low, but statistically significant, correlation between successive weekly CDI case incidences (phi = 0.029, 95%CI: 0.009-0.049). This correlation was five times stronger in a subgroup analysis restricted to teaching hospitals (phi = 0.104, 95%CI: 0.048-0.159)., Conclusions: The results suggest that symptomatic patient-to-patient transmission has been a source of CDI-acquisition in English hospitals in recent years, and that this might be a more important transmission route in teaching hospitals. Nonetheless, the weak correlation indicates that, in line with recent evidence, symptomatic cases might not be the primary source of nosocomial CDI in England.

Background: The current generation of Human Papillomavirus (HPV) vaccines, Cervarix® and Gardasil®, exhibit a high degree of efficacy in clinical trials against the two high-risk (HR) genotypes represented in the vaccines (HPV16 and HPV18). High levels of neutralizing antibodies are elicited against the vaccine types, consistent with preclinical data showing that neutralizing antibodies can mediate type-specific protection in the absence of other immune effectors. The vaccines also confer protection against some closely related non-vaccine HR HPV types, although the vaccines appear to differ in their degree of cross-protection. The mechanism of vaccine-induced cross-protection is unknown. This study sought to compare the breadth and magnitudes of neutralizing antibodies against non-vaccine types elicited by both vaccines and establish whether such antibodies could be detected in the genital secretions of vaccinated individuals., Methods and Findings: Serum and genital samples were collected from 12-15 year old girls following vaccination with either Cervarix® (n = 96) or Gardasil® (n = 102) HPV vaccine. Serum-neutralizing antibody responses against non-vaccine HPV types were broader and of higher magnitude in the Cervarix®, compared to the Gardasil®, vaccinated individuals. Levels of neutralizing and binding antibodies in genital secretions were closely associated with those found in the serum (r = 0.869), with Cervarix® having a median 2.5 (inter-quartile range, 1.7-3.5) fold higher geometric mean HPV-specific IgG ratio in serum and genital samples than Gardasil® (p = 0.0047). There was a strong positive association between cross-neutralizing antibody seropositivity and available HPV vaccine trial efficacy data against non-vaccine types., Conclusions: These data demonstrate for the first time that cross-neutralizing antibodies can be detected at the genital site of infection and support the possibility that cross-neutralizing antibodies play a role in the cross-protection against HPV infection and disease that has been reported for the current HPV vaccines., Trial Registration: ClinicalTrials.gov NCT00956553.

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.

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.

Background: The UK introduced the 7-valent pneumococcal conjugate vaccine (PCV7) into the national vaccination program in September 2006. Previous modelling assumed that the likely impact of PCV7 on invasive pneumococcal disease (IPD) would be similar to the US experience with PCV7. However, recent surveillance data show a more rapid replacement of PCV7 IPD cases by non-PCV7 IPD cases than was seen in the US., Methods and Findings: A previous model of pneumococcal vaccination was re-parameterised using data on vaccine coverage and IPD from England and Wales between 2006 and 2009. Disease incidence was adjusted for the increasing trend in reported IPD cases prior to vaccination. Using this data we estimated that individuals carrying PCV7 serotypes have much higher protection (96%;95% CI 72%-100%) against acquisition of NVT carriage than the 15% previously estimated from US data, which leads to greater replacement. However, even with this level of replacement, the annual number of IPD cases may be 560 (95% CI, -100 to 1230) lower ten years after vaccine introduction compared to what it may have been without vaccination. A particularly marked fall of 39% in children under 15 years by 2015/6 is predicted., Conclusion: Our model suggests that PCV7 vaccination could result in a decrease in overall invasive pneumococcal disease, particularly in children, even in an environment of rapid replacement with non-PCV7 serotypes within 5 years of vaccine introduction at high coverage.

Background: Mathematical modelling of infectious diseases transmitted by the respiratory or close-contact route (e.g., pandemic influenza) is increasingly being used to determine the impact of possible interventions. Although mixing patterns are known to be crucial determinants for model outcome, researchers often rely on a priori contact assumptions with little or no empirical basis. We conducted a population-based prospective survey of mixing patterns in eight European countries using a common paper-diary methodology., Methods and Findings: 7,290 participants recorded characteristics of 97,904 contacts with different individuals during one day, including age, sex, location, duration, frequency, and occurrence of physical contact. We found that mixing patterns and contact characteristics were remarkably similar across different European countries. Contact patterns were highly assortative with age: schoolchildren and young adults in particular tended to mix with people of the same age. Contacts lasting at least one hour or occurring on a daily basis mostly involved physical contact, while short duration and infrequent contacts tended to be nonphysical. Contacts at home, school, or leisure were more likely to be physical than contacts at the workplace or while travelling. Preliminary modelling indicates that 5- to 19-year-olds are expected to suffer the highest incidence during the initial epidemic phase of an emerging infection transmitted through social contacts measured here when the population is completely susceptible., Conclusions: To our knowledge, our study provides the first large-scale quantitative approach to contact patterns relevant for infections transmitted by the respiratory or close-contact route, and the results should lead to improved parameterisation of mathematical models used to design control strategies.