Achieving global equity for COVID-19 vaccines: Stronger international partnerships and greater advocacy and solidarity are needed.

Peter Figueroa and co-authors advocate for equity in the worldwide provision of COVID-19 vaccines.

Global public health security and justice for vaccines and therapeutics in the COVID-19 pandemic.

A Lancet Commission for COVID-19 task force is shaping recommendations to achieve vaccine and therapeutics access, justice, and equity. This includes ensuring safety and effectiveness harmonized through robust systems of global pharmacovigilance and surveillance. Global production requires expanding support for development, manufacture, testing, and distribution of vaccines and therapeutics to low- and middle-income countries (LMICs). Global intellectual property rules must not stand in the way of research, production, technology transfer, or equitable access to essential health tools, and in context of pandemics to achieve increased manufacturing without discouraging innovation. Global governance around product quality requires channelling widely distributed vaccines through WHO prequalification (PQ)/emergency use listing (EUL) mechanisms and greater use of national regulatory authorities. A World Health Assembly (WHA) resolution would facilitate improvements and consistency in quality control and assurances. Global health systems require implementing steps to strengthen national systems for controlling COVID-19 and for influenza vaccinations for adults including pregnant and lactating women. A collaborative research network should strive to establish open access databases for bioinformatic analyses, together with programs directed at human capacity utilization and strengthening. Combating anti-science recognizes the urgency for countermeasures to address a global-wide disinformation movement dominating the internet and infiltrating parliaments and local governments.

Implementation strategies for the first licensed dengue vaccine: A meeting report.

Dengue vaccination would enhance the control of dengue, one of the most frequent vector-borne viral diseases globally. CYD-TDV is the first dengue vaccine to be licensed, but global uptake has been hampered due to its use being limited to seropositive persons aged 9 years and above, and the need for a 3-dose schedule. The Partnership for Dengue Control (PDC) organized a meeting with key opinion leaders and stakeholders to deliberate on implementation strategies for the use of CYD-TDV. New data have emerged that support the shortening of the primary schedule from a 3 to 2 dose schedule, extending the age range below 9 to 6 years of age, and expanding the indication from endemic populations to also include travelers to endemic areas. Cost-effectiveness may improve with the modified 2-dose regimen and with multiple testing. Strategies to implement a dengue vaccination program have been developed, in particular school-based strategies. A range of delivery scenarios can then be considered, using various settings for each step of the intervention. However, several challenges remain, including communication about limiting the use of this vaccine to seropositive individuals only. Affordability will vary from country to country, as will government commitment and community acceptance. Well-tailored communication strategies that target key stakeholders are expected to make up a significant part of any future dengue vaccination program.

Household and Hospitalization Costs of Pediatric Dengue Illness in Colombo, Sri Lanka.

Dengue, a mosquito-borne viral infection that affects millions around the world, poses a substantial economic burden in endemic countries. We conducted a prospective costing study in hospitalized pediatric dengue patients at the Lady Ridgeway Hospital for Children (LRHC), a public pediatric hospital in Colombo district, Sri Lanka, to assess household out-of-pocket and hospitalization costs of dengue in pediatric patients during peak dengue transmission season. Between August and October 2013, we recruited 216 hospitalized patients (aged 0-3 years, 27%; 4-7 years, 29%; 8-12 years, 42%) who were clinically or laboratory diagnosed with dengue. Using 2013 US dollars, household out-of-pocket spending, on average, was US$59 (SD 49) per episode and increased with disease severity (DF, US$52; DHF/DSS, US$78). Pediatric dengue patients received free-of-charge medical care during hospitalization at LRHC, and this places a high financial burden on hospitals. The direct medical cost of hospitalization was US$68 (SD 31.4) for DF episode, and US$122.7 (SD 65.2) for DHF/DSS episode. Yet a hospitalized dengue illness episode still accounted for 20% to 35% of household monthly income due to direct and indirect costs. Additionally, a majority of caregivers (70%) sought outpatient care before hospitalization, most of whom (81%) visited private health facilities. Our findings indicate that hospitalized pediatric dengue illness poses a nontrivial cost burden to households and healthcare systems, emphasizing the importance of preventing and controlling the transmission of dengue in endemic countries.

COVID-19 healthcare demand and mortality in Sweden in response to non-pharmaceutical mitigation and suppression scenarios.

BACKGROUND: While the COVID-19 outbreak in China now appears suppressed, Europe and the USA have become the epicentres, both reporting many more deaths than China. Responding to the pandemic, Sweden has taken a different approach aiming to mitigate, not suppress, community transmission, by using physical distancing without lockdowns. Here we contrast the consequences of different responses to COVID-19 within Sweden, the resulting demand for care, intensive care, the death tolls and the associated direct healthcare related costs. METHODS: We used an age-stratified health-care demand extended SEIR (susceptible, exposed, infectious, recovered) compartmental model for all municipalities in Sweden, and a radiation model for describing inter-municipality mobility. The model was calibrated against data from municipalities in the Stockholm healthcare region. RESULTS: Our scenario with moderate to strong physical distancing describes well the observed health demand and deaths in Sweden up to the end of May 2020. In this scenario, the intensive care unit (ICU) demand reaches the pre-pandemic maximum capacity just above 500 beds. In the counterfactual scenario, the ICU demand is estimated to reach ∼20 times higher than the pre-pandemic ICU capacity. The different scenarios show quite different death tolls up to 1 September, ranging from 5000 to 41 000, excluding deaths potentially caused by ICU shortage. Additionally, our statistical analysis of all causes excess mortality indicates that the number of deaths attributable to COVID-19 could be increased by 40% (95% confidence interval: 0.24, 0.57). CONCLUSION: The results of this study highlight the impact of different combinations of non-pharmaceutical interventions, especially moderate physical distancing in combination with more effective isolation of infectious individuals, on reducing deaths, health demands and lowering healthcare costs. In less effective mitigation scenarios, the demand on ICU beds would rapidly exceed capacity, showing the tight interconnection between the healthcare demand and physical distancing in the society. These findings have relevance for Swedish policy and response to the COVID-19 pandemic and illustrate the importance of maintaining the level of physical distancing for a longer period beyond the study period to suppress or mitigate the impacts from the pandemic.

Need for sustainable biobanking networks for COVID-19 and other diseases of epidemic potential.

Outbreaks of infectious diseases are occurring with increasing frequency and unpredictability. The rapid development and deployment of diagnostics that can accurately and quickly identify pathogens as part of epidemic preparedness is needed now for the COVID-19 pandemic. WHO has developed a global research and innovation forum to facilitate, accelerate, and deepen research collaboration among countries and funders. Great progress has been made in the past decade, but access to specimens remains a major barrier for the development and evaluation of needed quality diagnostics. We present a sustainable model for a global network of country-owned biobanks with standardised methods for collection, characterisation, and archiving of specimens and pathogens to facilitate and accelerate diagnostics development and evaluation for COVID-19 and other diseases of epidemic potential. The biobanking network should be run on the guiding principles of transparency, equitable access, ethics, and respect for national laws that support country ownership and sustainability. Adapting the Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits, sharing of specimens from national biobanks can be rewarded through mechanisms such as equitable access to diagnostics at negotiated prices. Such networks should be prepared for any pathogen of epidemic potential.

ZikaPLAN: addressing the knowledge gaps and working towards a research preparedness network in the Americas.

Zika Preparedness Latin American Network (ZikaPLAN) is a research consortium funded by the European Commission to address the research gaps in combating Zika and to establish a sustainable network with research capacity building in the Americas. Here we present a report on ZikaPLAN`s mid-term achievements since its initiation in October 2016 to June 2019, illustrating the research objectives of the 15 work packages ranging from virology, diagnostics, entomology and vector control, modelling to clinical cohort studies in pregnant women and neonates, as well as studies on the neurological complications of Zika infections in adolescents and adults. For example, the Neuroviruses Emerging in the Americas Study (NEAS) has set up more than 10 clinical sites in Colombia. Through the Butantan Phase 3 dengue vaccine trial, we have access to samples of 17,000 subjects in 14 different geographic locations in Brazil. To address the lack of access to clinical samples for diagnostic evaluation, ZikaPLAN set up a network of quality sites with access to well-characterized clinical specimens and capacity for independent evaluations. The International Committee for Congenital Anomaly Surveillance Tools was formed with global representation from regional networks conducting birth defects surveillance. We have collated a comprehensive inventory of resources and tools for birth defects surveillance, and developed an App for low resource regions facilitating the coding and description of all major externally visible congenital anomalies including congenital Zika syndrome. Research Capacity Network (REDe) is a shared and open resource centre where researchers and health workers can access tools, resources and support, enabling better and more research in the region. Addressing the gap in research capacity in LMICs is pivotal in ensuring broad-based systems to be prepared for the next outbreak. Our shared and open research space through REDe will be used to maximize the transfer of research into practice by summarizing the research output and by hosting the tools, resources, guidance and recommendations generated by these studies. Leveraging on the research from this consortium, we are working towards a research preparedness network.

Model-based assessment of public health impact and cost-effectiveness of dengue vaccination following screening for prior exposure.

The tetravalent dengue vaccine CYD-TDV (Dengvaxia) is the first licensed vaccine against dengue, but recent findings indicate an elevated risk of severe disease among vaccinees without prior dengue virus (DENV) exposure. The World Health Organization currently recommends CYD-TDV only for individuals with serological confirmation of past DENV exposure. Our objective was to evaluate the potential health impact and cost-effectiveness of vaccination following serological screening. To do so, we used an agent-based model to simulate DENV transmission with and without vaccination over a 10-year timeframe. Across a range of values for the proportion of vaccinees with prior DENV exposure, we projected the proportion of symptomatic and hospitalized cases averted as a function of the sensitivity and specificity of serological screening. Scenarios about the cost-effectiveness of screening and vaccination were chosen to be representative of Brazil and the Philippines. We found that public health impact depended primarily on sensitivity in high-transmission settings and on specificity in low-transmission settings. Cost-effectiveness could be achievable from the perspective of a public payer provided that sensitivity and the value of a disability-adjusted life-year were both high, but only in high-transmission settings. Requirements for reducing relative risk and achieving cost-effectiveness from an individual perspective were more restricted, due to the fact that those who test negative pay for screening but receive no benefit. Our results predict that cost-effectiveness could be achieved only in high-transmission areas of dengue-endemic countries with a relatively high per capita GDP, such as Panamá (13,680 USD), Brazil (8,649 USD), México (8,201 USD), or Thailand (5,807 USD). In conclusion, vaccination with CYD-TDV following serological screening could have a positive impact in some high-transmission settings, provided that screening is highly specific (to minimize individual harm), at least moderately sensitive (to maximize population benefit), and sufficiently inexpensive (depending on the setting).

Evaluation of intensified dengue control measures with interrupted time series analysis in the Panadura Medical Officer of Health division in Sri Lanka: a case study and cost-effectiveness analysis.

BACKGROUND: Dengue has become a major public health problem in Sri Lanka with a considerable economic burden. As a response, in June, 2014, the Ministry of Health initiated a proactive vector control programme in partnership with military and police forces, known as the Civil-Military Cooperation (CIMIC) programme, that was targeted at high-risk Medical Officer of Health (MOH) divisions in the country. Evaluating the effectiveness and cost-effectiveness of population-level interventions is essential to guide public health planning and resource allocation decisions, particularly in resource-limited health-care settings. METHODS: Using an interrupted time series design with a non-linear extension, we evaluated the impact of vector control interventions from June 22, 2014, to Dec 29, 2016, in Panadura, a high-risk MOH division in Western Province, Sri Lanka. We used dengue notification and larval survey data to estimate the reduction in Breteau index and dengue incidence before and after the intervention using two separate models, adjusting for time-varying confounding variables (ie, rainfall, temperature, and the Oceanic Niño Index). We also assessed the cost and cost-effectiveness of the CIMIC programme from the perspective of the National Dengue Control Unit under the scenarios of different levels of hospitalisation of dengue cases (low [25%], medium [50%], and high [75%]) in terms of cost per disability-adjusted life-year averted (DALY). FINDINGS: Vector control interventions had a significant impact on combined Breteau index (relative risk reduction 0·43, 95% CI 0·26 to 0·70) and on dengue incidence (0·43, 0·28 to 0·67), the latter becoming prominent 2 months after the intervention onset. The mean number of averted dengue cases was estimated at 2192 (95% CI 1741 to 2643), and the total cost of the CIMIC programme at 2016 US$271 615. Personnel costs accounted for about 89% of the total cost. In the base-case scenario of moderate level of hospitalisation, the CIMIC programme was cost-saving with a probability of 70% under both the lowest ($453) and highest ($1686) cost-effectiveness thresholds, resulting in a net saving of $20 247 (95% CI -57 266 to 97 790) and averting 176 DALYs (133 to 226), leading to a cost of -$98 (-497 to 395) per DALY averted. This was also the case for the scenario with high hospitalisation levels (cost per DALY averted -$512, 95% CI -872 to -115) but with a higher probability of 99%. In the scenario with low hospitalisation levels (cost per DALY averted $690, 143 to 1379), although the CIMIC programme was cost-ineffective at the lowest threshold with a probability of 77%, it was cost-effective at the highest threshold with a probability of 99%. INTERPRETATION: This study suggests that communities affected by dengue can benefit from investments in vector control if interventions are implemented rigorously and coordinated well across sectors. By doing so, it is possible to reduce the disease and economic burden of dengue in endemic settings. FUNDING: None.

A Prospective Study on the Impact and Out-of-Pocket Costs of Dengue Illness in International Travelers.

Although the costs of dengue illness to patients and households have been extensively studied in endemic populations, international travelers have not been the focus of costing studies. As globalization and human travel activities intensify, travelers are increasingly at risk for emerging and reemerging infectious diseases, such as dengue. This exploratory study aims to investigate the impact and out-of-pocket costs of dengue illness among travelers. We conducted a prospective study in adult travelers with laboratory-confirmed dengue and recruited patients at travel medicine clinics in eight different countries from December 2013 to December 2015. Using a structured questionnaire, we collected information on patients and their health-care utilization and out-of-pocket expenditures, as well as income and other financial losses they incurred because of dengue illness. A total of 90 patients participated in the study, most of whom traveled for tourism (74%) and visited countries in Asia (82%). Although 22% reported hospitalization and 32% receiving ambulatory care while traveling, these percentages were higher at 39% and 71%, respectively, after returning home. The out-of-pocket direct and indirect costs of dengue illness were US$421 (SD 744) and US$571 (SD 1,913) per episode, respectively, averaging to a total out-of-pocket cost of US$992 (SD 2,052) per episode. The study findings suggest that international travelers incur important direct and indirect costs because of dengue-related illness. This study is the first to date to investigate the impact and out-of-pocket costs of travel-related dengue illness from the patient's perspective and paves the way for future economic burden studies in this population.

Clinical development and regulatory points for consideration for second-generation live attenuated dengue vaccines.

Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines. Subsequently, efficacy and longer-term follow-up data have become available from two Phase 3 trials of a dengue vaccine, conducted in parallel, and the vaccine was licensed in December 2015. The findings and interpretation of the results from these trials released both before and after licensure have highlighted key complexities for tetravalent dengue vaccines, including concerns vaccination could increase the incidence of dengue disease in certain subpopulations. This report summarizes clinical and regulatory points for consideration that may guide vaccine developers on some aspects of trial design and facilitate regulatory review to enable broader public health recommendations for second-generation dengue vaccines.

Household costs of hospitalized dengue illness in semi-rural Thailand.

BACKGROUND: Dengue-related illness is a leading cause of hospitalization and death in Thailand and other Southeast Asian countries, imposing a major economic burden on households, health systems, and governments. This study aims to assess the economic impact of hospitalized dengue cases on households in Chachoengsao province in eastern Thailand. METHODS: We conducted a prospective cost-of-illness study of hospitalized pediatric and adult dengue patients at three public hospitals. We examined all hospitalized dengue cases regardless of disease severity. Patients or their legal guardians were interviewed using a standard questionnaire to determine household-level medical and non-medical expenditures and income losses during the illness episode. RESULTS: Between March and September 2015, we recruited a total of 224 hospitalized patients (<5 years, 4%; 5-14 years, 20%, 15-24 years, 36%, 25-34 years, 15%; 35-44 years, 10%; 45+ years, 12%), who were clinically diagnosed with dengue. The total cost of a hospitalized dengue case was higher for adult patients than pediatric patients, and was US$153.6 and US$166.3 for pediatric DF and DHF patients, respectively, and US$171.2 and US$226.1 for adult DF and DHF patients, respectively. The financial burden on households increased with the severity of dengue illness. CONCLUSIONS: Although 74% of the households reported that the patient received free medical care, hospitalized dengue illness cost approximately 19-23% of the monthly household income. These results indicated that dengue imposed a substantial financial burden on households in Thailand where a great majority of the population was covered by the Universal Coverage Scheme for health care.

Epidemic arboviral diseases: priorities for research and public health.

For decades, arboviral diseases were considered to be only minor contributors to global mortality and disability. As a result, low priority was given to arbovirus research investment and related public health infrastructure. The past five decades, however, have seen an unprecedented emergence of epidemic arboviral diseases (notably dengue, chikungunya, yellow fever, and Zika virus disease) resulting from the triad of the modern world: urbanisation, globalisation, and international mobility. The public health emergency of Zika virus, and the threat of global spread of yellow fever, combined with the resurgence of dengue and chikungunya, constitute a wake-up call for governments, academia, funders, and WHO to strengthen programmes and enhance research in aedes-transmitted diseases. The common features of these diseases should stimulate similar research themes for diagnostics, vaccines, biological targets and immune responses, environmental determinants, and vector control measures. Combining interventions known to be effective against multiple arboviral diseases will offer the most cost-effective and sustainable strategy for disease reduction. New global alliances are needed to enable the combination of efforts and resources for more effective and timely solutions.

Costs of Dengue Control Activities and Hospitalizations in the Public Health Sector during an Epidemic Year in Urban Sri Lanka.

BACKGROUND: Reported as a public health problem since the 1960s in Sri Lanka, dengue has become a high priority disease for public health authorities. The Ministry of Health is responsible for controlling dengue and other disease outbreaks and associated health care. The involvement of large numbers of public health staff in dengue control activities year-round and the provision of free medical care to dengue patients at secondary care hospitals place a formidable financial burden on the public health sector. METHODS: We estimated the public sector costs of dengue control activities and the direct costs of hospitalizations in Colombo, the most heavily urbanized district in Sri Lanka, during the epidemic year of 2012 from the Ministry of Health's perspective. The financial costs borne by public health agencies and hospitals are collected using cost extraction tools designed specifically for the study and analysed retrospectively using a combination of activity-based and gross costing approaches. RESULTS: The total cost of dengue control and reported hospitalizations was estimated at US$3.45 million (US$1.50 per capita) in Colombo district in 2012. Personnel costs accounted for the largest shares of the total costs of dengue control activities (79%) and hospitalizations (46%). The results indicated a per capita cost of US$0.42 for dengue control activities. The average costs per hospitalization ranged between US$216-609 for pediatric cases and between US$196-866 for adult cases according to disease severity and treatment setting. CONCLUSIONS: This analysis is a first attempt to assess the economic burden of dengue response in the public health sector in Sri Lanka. Country-specific evidence is needed for setting public health priorities and deciding about the deployment of existing or new technologies. Our results suggest that dengue poses a major economic burden on the public health sector in Sri Lanka.

A simple and powerful method for the estimation of intervention effects on serological endpoints using paired interval-censored data.

Clinical trials often use a binary "fold increase" endpoint defined according to the ratio of interval-censored measurement at end-of-study to that at baseline. We propose a simple yet principled analytic approach based on the linear mixed-effects model for interval-censored data for the analysis of such paired measurements. Having estimated the model parameters, the risk ratio can be estimated by explicit composite estimand and the variance is estimated using the delta method. The estimation can be implemented using the existing procedures in popular statistical software. We use antibody data from the Chloroquine for Influenza Prevention Trial for illustration.

The potential for a controlled human infection platform in Singapore.

For over 100 years, controlled human infection (CHI) studies have been performed to advance the understanding of the pathogenesis, treatment and prevention of infectious diseases. This methodology has seen a resurgence, as it offers an efficient model for selecting the most promising agents for further development from available candidates. CHI studies are utilised to bridge safety and immunogenicity testing and phase II/III efficacy studies. However, as this platform is not currently utilised in Asia, opportunities to study therapeutics and vaccines for infections that are important in Asia are missed. This review examines the regulatory differences for CHI studies between countries and summarises other regulatory differences in clinical trials as a whole. We found that the regulations that would apply to CHI studies in Singapore closely mirror those in the United Kingdom, and conclude that the regulatory and ethical guidelines in Singapore are compatible with the conduct of CHI studies.