Health inequities in SARS-CoV-2 infection, seroprevalence, and COVID-19 vaccination: Results from the East Bay COVID-19 study.

Comprehensive data on transmission mitigation behaviors and both SARS-CoV-2 infection and serostatus are needed from large, community-based cohorts to identify COVID-19 risk factors and the impact of public health measures. We conducted a longitudinal, population-based study in the East Bay Area of Northern California. From July 2020-March 2021, approximately 5,500 adults were recruited and followed over three data collection rounds to investigate the association between geographic and demographic characteristics and transmission mitigation behavior with SARS-CoV-2 prevalence. We estimated the populated-adjusted prevalence of antibodies from SARS-CoV-2 infection and COVID-19 vaccination, and self-reported COVID-19 test positivity. Population-adjusted SARS-CoV-2 seroprevalence was low, increasing from 1.03% (95% CI: 0.50-1.96) in Round 1 (July-September 2020), to 1.37% (95% CI: 0.75-2.39) in Round 2 (October-December 2020), to 2.18% (95% CI: 1.48-3.17) in Round 3 (February-March 2021). Population-adjusted seroprevalence of COVID-19 vaccination was 21.64% (95% CI: 19.20-24.34) in Round 3, with White individuals having 4.35% (95% CI: 0.35-8.32) higher COVID-19 vaccine seroprevalence than individuals identifying as African American or Black, American Indian or Alaskan Native, Asian, Hispanic, two or more races, or other. No evidence for an association between transmission mitigation behavior and seroprevalence was observed. Despite >99% of participants reporting wearing masks individuals identifying as African American or Black, American Indian or Alaskan Native, Asian, Hispanic, two or more races, or other, as well as those in lower-income households, and lower-educated individuals had the highest SARS-CoV-2 seroprevalence and lowest vaccination seroprevalence. Results demonstrate that more effective policies are needed to address these disparities and inequities.

Cost-effectiveness of community mobilization (Camino Verde) for dengue prevention in Nicaragua and Mexico: A cluster randomized controlled trial.

BACKGROUND: We assessed the cost-effectiveness of Camino Verde, a community-based mobilization strategy to prevent and control dengue and other mosquito-borne diseases. A cluster-randomized controlled trial in Managua, Nicaragua, and in three coastal regions in Guerrero, Mexico (75 intervention and 75 control clusters), Camino Verde used non-governmental community health workers, called brigadistas, to support community mobilization. This donor-funded trial demonstrated reductions of 29.5% (95% confidence interval, CI: 3.8%-55.3%) on dengue infections and 24.7% (CI: 1.8%-51.2%) on self-reported cases. METHODS: We estimated program costs through a micro-costing approach and semi-structured questionnaires. We show results as incremental cost-effectiveness ratios (ICERs) for costs per disability-adjusted life-year (DALYs) averted and conducted probabilistic sensitivity analyses. FINDINGS: The Camino Verde trial spent US$16.72 in Mexico and $7.47 in Nicaragua per person annually. We found an average of 910 (CI: 487-1 353) and 500 (CI: 250-760) dengue cases averted annually per million population in Mexico and Nicaragua, respectively, compared to control communities. The ICER in Mexico was US$29 618 (CI: 13 869-66 898) per DALY averted, or 3.0 times per capita GDP. For Nicaragua, the ICER was US$29 196 (CI: 14294-72181) per DALY averted, or 16.9 times per capita GDP. INTERPRETATION: Camino Verde, as implemented in the research context, was marginally cost-effective in Mexico, and not cost-effective in Nicaragua, from a healthcare sector perspective. Nicaragua's low per capita GDP and the use of grant-funded management personnel weakened the cost-effectiveness results. Achieving efficiencies by incorporating Camino Verde activities into existing public health programs would make Camino Verde cost-effective.

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.

Global Assessment of Dengue Virus-Specific CD4+ T Cell Responses in Dengue-Endemic Areas.

BACKGROUND: Dengue is a major public health problem worldwide. Assessment of adaptive immunity is important to understanding immunopathology and to define correlates of protection against dengue virus (DENV). To enable global assessment of CD4+ T cell responses, we mapped HLA-DRB1-restricted DENV-specific CD4+ T cell epitopes in individuals previously exposed to DENV in the general population of the dengue-endemic region of Managua, Nicaragua. METHODS: HLA class II epitopes in the population of Managua were identified by an in vitro IFNγ ELISPOT assay. CD4+ T cells purified by magnetic bead negative selection were stimulated with HLA-matched epitope pools in the presence of autologous antigen-presenting cells, followed by pool deconvolution to identify specific epitopes. The epitopes identified in this study were combined with those previously identified in the DENV endemic region of Sri Lanka, to generate a "megapool" (MP) consisting of 180 peptides specifically designed to achieve balanced HLA and DENV serotype coverage. The DENV CD4MP180 was validated by intracellular cytokine staining assays. RESULTS: We detected responses directed against a total of 431 epitopes, representing all 4 DENV serotypes, restricted by 15 different HLA-DRB1 alleles. The responses were associated with a similar pattern of protein immunodominance, overall higher magnitude of responses, as compared to what was observed previously in the Sri Lanka region. Based on these epitope mapping studies, we designed a DENV CD4 MP180 with higher and more consistent coverage, which allowed the detection of CD4+ T cell DENV responses ex vivo in various cohorts of DENV exposed donors worldwide, including donors from Nicaragua, Brazil, Singapore, Sri Lanka, and U.S. domestic flavivirus-naïve subjects immunized with Tetravalent Dengue Live-Attenuated Vaccine (TV005). This broad reactivity reflects that the 21 HLA-DRB1 alleles analyzed in this and previous studies account for more than 80% of alleles present with a phenotypic frequency ≥5% worldwide, corresponding to 92% phenotypic coverage of the general population (i.e., 92% of individuals express at least one of these alleles). CONCLUSION: The DENV CD4 MP180 can be utilized to measure ex vivo responses to DENV irrespective of geographical location.

Community cost-benefit discussions that launched the Camino Verde intervention in Nicaragua.

BACKGROUND: Recent literature on community intervention research stresses system change as a condition for durable impact. This involves highly participatory social processes leading to behavioural change. METHODS: Before launching the intervention in the Nicaraguan arm of Camino Verde, a cluster-randomised controlled trial to show that pesticide-free community mobilisation adds effectiveness to conventional dengue controls, we held structured discussions with leaders of intervention communities on costs of dengue illness and dengue control measures taken by both government and households. These discussions were the first step in an effort at Socialising Evidence for Participatory Action (SEPA), a community mobilisation method used successfully in other contexts. Theoretical grounding came from community psychology and behavioural economics. RESULTS: The leaders expressed surprise at how large and unexpected an economic burden dengue places on households. They also acknowledged that large investments of household and government resources to combat dengue have not had the expected results. Many were not ready to see community preventive measures as a substitute for chemical controls but all the leaders approved the formation of "brigades" to promote chemical-free household control efforts in their own communities. CONCLUSIONS: Discussions centred on household budget decisions provide a good entry point for researchers to engage with communities, especially when the evidence showed that current expenditures were providing a poor return. People became motivated not only to search for ways to reduce their costs but also to question the current response to the problem in question. This in turn helped create conditions favourable to community mobilisation for change. TRIAL REGISTRATION: ISRCTN27581154 .

Informed community mobilization for dengue prevention in households with and without a regular water supply: Secondary analysis from the Camino Verde trial in Nicaragua.

BACKGROUND: Studies in different countries have identified irregular water supply as a risk factor for dengue virus transmission. In 2013, Camino Verde, a cluster-randomised controlled trial in Managua, Nicaragua, and Mexico's Guerrero State, demonstrated impact of evidence-based community mobilisation on recent dengue infection and entomological indexes of infestation by Aedes aegypti mosquitoes. This secondary analysis of data from the trial impact survey asks: (1) what is the importance of regular water supply in neighbourhoods with and without the trial intervention and (2) can community interventions like Camino Verde reasonably exclude households with adequate water supply? METHODS: Entomological data collected in the dry season of 2013 in intervention and control communities allow contrasts between households with regular and irregular water supplies. Indicators of entomological risk included the House Index and pupa positive household index. Generalised linear mixed models with cluster as a random effect compared households with and without regular water, and households in intervention and control communities. RESULTS: For the House Index, regular water supply was associated with a protection in both intervention households (OR 0.7, 95%CI 0.6-0.9) and control households (OR 0.6, 95%CI 0.5-0.8). For the pupa positive household index, we found a similar protection from regular water supply in intervention households (OR 0.6, 95%CI 0.4-0.8) and control households (OR 0.7, 95%CI 0.5-0.9). The Camino Verde intervention had a similar impact on House Index in households with regular water supply (OR 0.7, 95%CI 0.5-1.0) and irregular water supply (OR 0.6, 95%CI 0.4-0.8); for the pupa positive household index, the effect of the intervention was very similar in households with regular (OR0.5, 95%CI 0.3-0.8) and irregular (OR 0.5, 95%CI 0.3-0.9) water supply. CONCLUSION: While Aedes aegypti control efforts based on informed community mobilisation had a strong impact on households without a regular water supply, this intervention also impacted entomological indices in households with a regular water supply. These households should not be excluded from community mobilisation efforts to reduce the Aedes aegypti vector. TRIAL REGISTRATION: ISRCTN27581154 .

Camino Verde (The Green Way): evidence-based community mobilisation for dengue control in Nicaragua and Mexico: feasibility study and study protocol for a randomised controlled trial.

BACKGROUND: Since the Aedes aegypti mosquitoes that transmit dengue virus can breed in clean water, WHO-endorsed vector control strategies place sachets of organophosphate pesticide, temephos (Abate), in household water storage containers. These and other pesticide-dependent approaches have failed to curb the spread of dengue and multiple dengue virus serotypes continue to spread throughout tropical and subtropical regions worldwide. A feasibility study in Managua, Nicaragua, generated instruments, intervention protocols, training schedules and impact assessment tools for a cluster randomised controlled trial of community-based approaches to vector control comprising an alternative strategy for dengue prevention and control in Nicaragua and Mexico. METHODS/DESIGN: The Camino Verde (Green Way) is a pragmatic parallel group trial of pesticide-free dengue vector control, adding effectiveness to the standard government dengue control. A random sample from the most recent census in three coastal regions of Guerrero state in Mexico will generate 90 study clusters and the equivalent sampling frame in Managua, Nicaragua will generate 60 clusters, making a total of 150 clusters each of 137-140 households. After a baseline study, computer-driven randomisation will allocate to intervention one half of the sites, stratified by country, evidence of recent dengue virus infection in children aged 3-9 years and, in Nicaragua, level of community organisation. Following a common evidence-based education protocol, each cluster will develop and implement its own collective interventions including house-to-house visits, school-based programmes and inter-community visits. After 18 months, a follow-up study will compare dengue history, serological evidence of recent dengue virus infection (via measurement of anti-dengue virus antibodies in saliva samples) and entomological indices between intervention and control sites. DISCUSSION: Our hypothesis is that informed community mobilisation adds effectiveness in controlling dengue. TRIAL REGISTRATION: ISRCTN27581154 .

Yes we can! The Raffles Dialogue on Human Wellbeing and Security.

The future of human wellbeing and security depends on our ability to deal with the multiple effects of globalisation and on adoption of a new paradigm and philosophy for living and for health that emphasises people's wellbeing and social justice. Such was the topic of the inaugural Raffles Dialogue on Human Wellbeing and Security held in Singapore on Feb 2-3, 2015. Participants agreed that, to achieve these goals, four conditions must be met. First, equity must be integral to the implementation of technology. Second, there is an urgent need for innovations within our global institutions to make them "fit for purpose" in a rapidly changing world. Third, we must find the right balance between the roles of government and markets so that all those in need can access affordable medicine and health care. Finally, we must realise that we live in a small and interdependent "global village", where Asian countries need to assume greater leadership of our global village councils. This is the great imperative of our times.

Economic and disease burden of dengue in Mexico.

BACKGROUND: Dengue imposes a substantial economic and disease burden in most tropical and subtropical countries. Dengue incidence and severity have dramatically increased in Mexico during the past decades. Having objective and comparable estimates of the economic burden of dengue is essential to inform health policy, increase disease awareness, and assess the impact of dengue prevention and control technologies. METHODS AND FINDINGS: We estimated the annual economic and disease burden of dengue in Mexico for the years 2010-2011. We merged multiple data sources, including a prospective cohort study; patient interviews and macro-costing from major hospitals; surveillance, budget, and health data from the Ministry of Health; WHO cost estimates; and available literature. We conducted a probabilistic sensitivity analysis using Monte Carlo simulations to derive 95% certainty levels (CL) for our estimates. Results suggest that Mexico had about 139,000 (95%CL: 128,000-253,000) symptomatic and 119 (95%CL: 75-171) fatal dengue episodes annually on average (2010-2011), compared to an average of 30,941 symptomatic and 59 fatal dengue episodes reported. The annual cost, including surveillance and vector control, was US$170 (95%CL: 151-292) million, or $1.56 (95%CL: 1.38-2.68) per capita, comparable to other countries in the region. Of this, $87 (95%CL: 87-209) million or $0.80 per capita (95%CL: 0.62-1.12) corresponds to illness. Annual disease burden averaged 65 (95%CL: 36-99) disability-adjusted life years (DALYs) per million population. Inclusion of long-term sequelae, co-morbidities, impact on tourism, and health system disruption during outbreaks would further increase estimated economic and disease burden. CONCLUSION: With this study, Mexico joins Panama, Puerto Rico, Nicaragua, and Thailand as the only countries or areas worldwide with comprehensive (illness and preventive) empirical estimates of dengue burden. Burden varies annually; during an outbreak, dengue burden may be significantly higher than that of the pre-vaccine level of rotavirus diarrhea. In sum, Mexico's potential economic benefits from dengue control would be substantial.

Approaches to refining estimates of global burden and economics of dengue.

Dengue presents a formidable and growing global economic and disease burden, with around half the world's population estimated to be at risk of infection. There is wide variation and substantial uncertainty in current estimates of dengue disease burden and, consequently, on economic burden estimates. Dengue disease varies across time, geography and persons affected. Variations in the transmission of four different viruses and interactions among vector density and host's immune status, age, pre-existing medical conditions, all contribute to the disease's complexity. This systematic review aims to identify and examine estimates of dengue disease burden and costs, discuss major sources of uncertainty, and suggest next steps to improve estimates. Economic analysis of dengue is mainly concerned with costs of illness, particularly in estimating total episodes of symptomatic dengue. However, national dengue disease reporting systems show a great diversity in design and implementation, hindering accurate global estimates of dengue episodes and country comparisons. A combination of immediate, short-, and long-term strategies could substantially improve estimates of disease and, consequently, of economic burden of dengue. Suggestions for immediate implementation include refining analysis of currently available data to adjust reported episodes and expanding data collection in empirical studies, such as documenting the number of ambulatory visits before and after hospitalization and including breakdowns by age. Short-term recommendations include merging multiple data sources, such as cohort and surveillance data to evaluate the accuracy of reporting rates (by health sector, treatment, severity, etc.), and using covariates to extrapolate dengue incidence to locations with no or limited reporting. Long-term efforts aim at strengthening capacity to document dengue transmission using serological methods to systematically analyze and relate to epidemiologic data. As promising tools for diagnosis, vaccination, vector control, and treatment are being developed, these recommended steps should improve objective, systematic measures of dengue burden to strengthen health policy decisions.

From construction workers to architects: developing scientific research capacity in low-income countries.

Solving global health challenges in a sustainable manner depends on explicitly addressing scientific capacity-building needs, as well as establishing long-term, meaningful partnerships with colleagues in the developing world.

The Nicaraguan pediatric dengue cohort study: study design, methods, use of information technology, and extension to other infectious diseases.

Dengue is a mosquito-borne viral disease that is a major public health problem worldwide. In 2004, the Pediatric Dengue Cohort Study was established in Managua, Nicaragua, to study the natural history and transmission of dengue in children. Here, the authors describe the study design, methods, and results from 2004 to 2008. Initially, 3,721 children 2-9 years of age were recruited through door-to-door visits. Each year, new children aged 2 years are enrolled in the study to maintain the age structure. Children are provided with medical care through the study, and data from each medical visit are recorded on systematic study forms. All participants presenting with suspected dengue or undifferentiated fever are tested for dengue by virologic, serologic, and molecular biologic assays. Yearly blood samples are collected to detect inapparent dengue virus infections. Numerous information and communications technologies are used to manage study data, track samples, and maintain quality control, including personal data assistants, barcodes, global information systems, and fingerprint scans. Close collaboration with the Nicaraguan Ministry of Health and use of almost entirely local staff are essential components for success. This study is providing critical data on the epidemiology and transmission of dengue in the Americas needed for future vaccine trials.

Quantitative assessment of the benefits of specific information technologies applied to clinical studies in developing countries.

Clinical studies and trials require accessibility of large amounts of high-quality information in a timely manner, often daily. The integrated application of information technologies can greatly improve quality control as well as facilitate compliance with established standards such as Good Clinical Practice (GCP) and Good Laboratory Practice (GLP). We have customized and implemented a number of information technologies, such as personal data assistants (PDAs), geographic information system (GIS), and barcode and fingerprint scanning, to streamline a pediatric dengue cohort study in Managua, Nicaragua. Quantitative data was obtained to assess the actual contribution of each technology in relation to processing time, accuracy, real-time access to data, savings in consumable materials, and time to proficiency in training sessions. In addition to specific advantages, these information technologies benefited not only the study itself but numerous routine clinical and laboratory processes in the health center and laboratories of the Nicaraguan Ministry of Health.

Sustainable transfer of biotechnology to developing countries: fighting poverty by bringing scientific tools to developing-country partners.

Poverty and social inequalities have powerfully sculpted not only the distribution of infectious and other diseases but also the course of disease in those affected. The lack of proper diagnosis and access to adequate health services only compounds the problem. In low-resource settings, the burden of disease can be reduced if the basic human and material resources exist to support the use of low-cost interventions by appropriately trained personnel. For 20 years, the Sustainable Sciences Institute has built scientific capacity in developing countries to recognize, prevent, and respond to the threats posed by disease.

Short report: assessment of the World Health Organization scheme for classification of dengue severity in Nicaragua.

The World Health Organization (WHO) scheme for classification of dengue severity was evaluated in a three-year study of 1,671 confirmed dengue cases in three Nicaraguan hospitals. The WHO classification of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) was compared with the presence of hemorrhagic manifestations, signs of vascular permeability, marked thrombocytopenia, and shock in 114 infants, 1,211 children, and 346 adults. We found that strict application of the WHO criteria fails to detect a significant number of patients with severe manifestations of dengue, especially in adults.

Differences in dengue severity in infants, children, and adults in a 3-year hospital-based study in Nicaragua.

To investigate age-related differences in dengue severity, 114 infants, 1,211 children, and 346 adults with laboratory-confirmed dengue virus (DEN) infections presenting to three hospitals in major urban centers in Nicaragua were recruited from 1999 to 2001. The age distribution of dengue cases and the circulating serotype (predominantly DEN2) were representative of national data. Similar results were obtained when either dengue hemorrhagic fever/dengue shock syndrome or its principal manifestations (vascular permeability, internal hemorrhage, marked thrombocytopenia, and/or shock) were analyzed in relation to age and immune status. The burden of disease and of severe dengue was found predominantly in infants 4-9 months of age and in children 5-9 years old, and secondary DEN infection was a risk factor for severity in children. Age-related differences were identified in the prevalence of specific clinical manifestations as well as in their association with a confirmed DEN diagnosis. This represents one of the few comprehensive studies to analyze characteristics of dengue in infants, children, and adults in the same population and highlights age-related differences in dengue severity.