Uncovering the Burden of Dengue in Africa: Considerations on Magnitude, Misdiagnosis, and Ancestry.

Dengue is a re-emerging neglected disease of major public health importance. This review highlights important considerations for dengue disease in Africa, including epidemiology and underestimation of disease burden in African countries, issues with malaria misdiagnosis and co-infections, and potential evidence of genetic protection from severe dengue disease in populations of African descent. The findings indicate that dengue virus prevalence in African countries and populations may be more widespread than reported data suggests, and that the Aedes mosquito vectors appear to be increasing in dissemination and number. Changes in climate, population, and plastic pollution are expected to worsen the dengue situation in Africa. Dengue misdiagnosis is also a problem in Africa, especially due to the typical non-specific clinical presentation of dengue leading to misdiagnosis as malaria. Finally, research suggests that a protective genetic component against severe dengue exists in African descent populations, but further studies should be conducted to strengthen this association in various populations, taking into consideration socioeconomic factors that may contribute to these findings. The main takeaway is that Africa should not be overlooked when it comes to dengue, and more attention and resources should be devoted to this disease in Africa.

Knowledge gaps in the epidemiology of severe dengue impede vaccine evaluation.

The most severe consequences of dengue virus infection include shock, haemorrhage, and major organ failure; however, the frequency of these manifestations varies, and the relative contribution of pre-existing anti-dengue virus antibodies, virus characteristics, and host factors (including age and comorbidities) are not well understood. Reliable characterisation of the epidemiology of severe dengue first depends on the use of consistent definitions of disease severity. As vaccine trials have shown, severe dengue is a crucial interventional endpoint, yet the infrequency of its occurrence necessitates the inclusion of thousands of study participants to appropriately compare its frequency among participants who have and have not been vaccinated. Hospital admission is frequently used as a proxy for severe dengue; however, lack of specificity and variability in clinical practices limit the reliability of this approach. Although previous infection with a dengue virus is the best characterised risk factor for developing severe dengue, the influence of the timing between dengue virus infections and the sequence of dengue virus infections on disease severity is only beginning to be elucidated. To improve our understanding of the diverse factors that shape the clinical spectrum of disease resulting from dengue virus infection, prospective, community-based and clinic-based immunological, virological, genetic, and clinical studies across a range of ages and geographical regions are needed.

After the honeymoon, the divorce: Unexpected outcomes of disease control measures against endemic infections.

The lack of effective vaccines for many endemic diseases often forces policymakers to rely on non-immunizing control measures, such as vector control, to reduce the massive burden of these diseases. Controls can have well-known counterintuitive effects on endemic infections, including the honeymoon effect, in which partially effective controls cause not only a greater initial reduction in infection than expected, but also large outbreaks during control resulting from accumulation of susceptibles. Unfortunately, many control measures cannot be maintained indefinitely, and the results of cessation are poorly understood. Here, we examine the results of stopped or failed non-immunizing control measures in endemic settings. By using a mathematical model to compare the cumulative number of cases expected with and without control, we show that deployment of control can lead to a larger total number of infections, counting from the time that control started, than without any control-the divorce effect. This result is directly related to the population-level loss of immunity resulting from non-immunizing controls and is seen in a variety of models when non-immunizing controls are used against an infection that confers immunity. Finally, we examine three control plans for minimizing the magnitude of the divorce effect in seasonal infections and show that they are incapable of eliminating the divorce effect. While we do not suggest stopping control programs that rely on non-immunizing controls, our results strongly argue that the accumulation of susceptibility should be considered before deploying such controls against endemic infections when indefinite use of the control is unlikely. We highlight that our results are particularly germane to endemic mosquito-borne infections, such as dengue virus, both for routine management involving vector control and for field trials of novel control approaches, and in the context of non-pharmaceutical interventions aimed at COVID-19.

Avian anti-NS1 IgY antibodies neutralize dengue virus infection and protect against lethal dengue virus challenge.

Dengue is the most prevalent arboviral disease in humans and a continually increasing global public health burden. To date, there are no approved antiviral therapies against dengue virus (DENV) and the only licensed vaccine, Dengvaxia, is exclusively indicated for individuals with prior DENV infection. Endothelial hyperpermeability and vascular leak, pathogenic hallmarks of severe dengue disease, can be directly triggered by DENV non-structural protein 1 (NS1). As such, anti-NS1 antibodies can prevent NS1-triggered endothelial dysfunction in vitro and pathogenesis in vivo. Recently, goose-derived anti-DENV immunoglobulin Y (IgY) antibodies were shown to neutralize DENV and Zika virus (ZIKV) infection without adverse effects, such as antibody-dependent enhancement (ADE). In this study, we used egg yolks from DENV-immunized geese to purify IgY antibodies specific to DENV NS1 epitopes. We determined that 2 anti-NS1 IgY antibodies, NS1-1 and NS1-8, were capable of neutralizing DENV infection in vitro. In addition, these antibodies did not cross-react with the DENV Envelope (E) protein nor enhance DENV or ZIKV infection in vitro. Intriguingly, NS1-8, but not NS1-1, partially blocked NS1-induced endothelial dysfunction in vitro while neither antibody blocked binding of soluble NS1 to cells. Finally, prophylactic treatment of mice with NS1-8 conferred significant protection against lethal DENV challenge. Although further research is needed to define the mechanism of action of these antibodies, our findings highlight the potential of anti-NS1 IgY as a promising prophylactic approach against DENV infection.

Dengue hemorrhagic fever - A systemic literature review of current perspectives on pathogenesis, prevention and control.

BACKGROUND: Dengue is an arboviral disease caused by dengue virus. Symptomatic dengue infection causes a wide range of clinical manifestations, from mild dengue fever (DF) to potentially fatal disease, such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). We conducted a literature review to analyze the risks of DHF and current perspectives for DHF prevention and control. METHODS: According to the PRISMA guidelines, the references were selected from PubMed, Web of Science and Google Scholar database using search strings containing a combination of terms that included dengue hemorrhagic fever, pathogenesis, prevention and control. Quality of references were evaluated by independent reviewers. RESULTS: DHF was first reported in the Philippines in 1953 and further transmitted to the countries in the region of South-East Asia and Western Pacific. Plasma leakages is the main pathophysiological hallmark that distinguishes DHF from DF. Severe plasma leakage can result in hypovolemic shock. Various factors are thought to impact disease presentation and severity. Virus virulence, preexisting dengue antibodies, immune dysregulation, lipid change and host genetic susceptibility are factors reported to be correlated with the development of DHF. However, the exact reasons and mechanisms that triggers DHF remains controversial. Currently, no specific drugs and licensed vaccines are available to treat dengue disease in any of its clinical presentations. CONCLUSION: This study concludes that antibody-dependent enhancement, cytokine dysregulation and variation of lipid profiles are correlated with DHF occurrence. Prompt diagnosis, appropriate treatment, active and continuous surveillance of cases and vectors are the essential determinants for dengue prevention and control.

Secondary Analysis of the Efficacy and Safety Trial Data of the Tetravalent Dengue Vaccine in Children and Adolescents in Colombia.

BACKGROUND: The efficacy of the recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) against virologically-confirmed dengue (VCD) has been documented in a phase 3 trial in Latin America (CYD15, NCT01374516). This is a descriptive secondary analysis of the efficacy and safety of CYD-TDV in participants from Colombia. METHODS: Data from 9740 Colombian participants 9-16 years of age who were randomized 2:1 to receive CYD-TDV or placebo were assessed to describe the vaccine efficacy of CYD-TDV against VCD and severe VCD. Estimation was made of the relative risk (RR) for hospitalized VCD cases and severe hospitalized VCD cases after the first dose of CYD-TDV, as well as a description of the incidence of hospitalized dengue from the start of the study and per year of the study until study completion. RESULTS: During the active phase of the trial in Colombia, the efficacy of CYD-TDV was 67.5% [95% confidence interval (CI): 58.3-74.7] against symptomatic VCD due to any serotype from injection 1 (month 0) to 25 months postinjection 1. Over 6 years, the RR across all 4 serotypes was 0.166 (95% CI: 0.09-0.29) in hospitalized VCD patients and 0.154 (95% CI: 0.04-0.50) in patients with severe hospitalized VCD. CONCLUSIONS: Analysis of the data from Colombia mimics the efficacy observed in CYD15 during the active surveillance follow-up (25 months), but with a sustained beneficial RR for dengue hospitalizations on the subsequent years of follow-up. In Colombia, where seroprevalence has been demonstrated to be high in several regions of the country, CYD-TDV is a useful tool to consider as part of an integrated control strategy against endemic dengue, a disease with a high economic impact on the health system.

The small molecule AZD6244 inhibits dengue virus replication in vitro and protects against lethal challenge in a mouse model.

Dengue virus (DENV) is the most common mosquito-borne viral disease. The World Health Organization estimates that 400 million new cases of dengue fever occur every year. Approximately 500,000 individuals develop severe and life-threatening complications from dengue fever, such as dengue shock syndrome (DSS) and dengue hemorrhagic fever (DHF), which cause 22,000 deaths yearly. Currently, there are no specific licensed therapeutics to treat DENV illness. We have previously shown that the MEK/ERK inhibitor U0126 inhibits the replication of the flavivirus yellow fever virus. In this study, we demonstrate that the MEK/ERK inhibitor AZD6244 has potent antiviral efficacy in vitro against DENV-2, DENV-3, and Saint Louis encephalitis virus (SLEV). We also show that it is able to protect AG129 mice from a lethal challenge with DENV-2 (D2S20). The molecule is currently undergoing phase III clinical trials for the treatment of non-small-cell lung cancer. The effect of AZD6244 on the DENV life cycle was attributed to a blockade of morphogenesis. Treatment of AG129 mice twice daily with oral doses of AZD6244 (100 mg/kg/day) prevented the animals from contracting dengue hemorrhagic fever (DHF)-like lethal disease upon intravenous infection with 1 × 105 PFU of D2S20. The effectiveness of AZD6244 was observed even when the treatment of infected animals was initiated 1-2 days postinfection. This was also followed by a reduction in viral copy number in both the serum and the spleen. There was also an increase in IL-1ß and TNF-α levels in mice that were infected with D2S20 and treated with AZD6244 in comparison to infected mice that were treated with the vehicle only. These data demonstrate the potential of AZD6244 as a new therapeutic agent to treat DENV infection and possibly other flavivirus diseases.

The potential impact of dengue vaccination with, and without, pre-vaccination screening.

BACKGROUND: The World Health Organization defined a 'screen and vaccinate' strategy as its recommended policy for the licensed dengue vaccine (Dengvaxia, Sanofi Pasteur), so that only individuals with previous dengue infection are vaccinated. The objectives of the present study were to build upon a recently published analysis of the benefits and risks associated with dengue vaccination to evaluate the public health impact and cost-effectiveness of a screen and vaccinate strategy. METHODS: The current analysis was based on a previously reported transmission model and added, for the screening part, three rapid diagnostic tests with identical specificity (99%) but alternative sensitivities (50-70-90%) in the detection of prior dengue infection. The impact of a screen-and-vaccinate strategy considered nine settings representing different levels of transmission intensity. Outcomes (dengue-related hospitalizations, severe dengue, and symptomatic dengue) were assessed according to the level of transmission setting. The cost-effectiveness of vaccination in 10 endemic countries was also assessed. RESULTS: Although associated, in most cases, with a lower population impact than a 'no-screening' approach, a screen and vaccinate strategy is more effective in reducing the number of hospitalized and severe cases prevented per vaccination performed and generates positive health benefits for individuals screened and subsequently vaccinated. As a result, this intervention is cost-effective in all countries considered except for very low transmission settings. The overall population impact of a screen and vaccinate approach is also likely to be improved by the use of several rounds of screening (up to 48% reduction in dengue hospitalization over 10 years with 5 rounds). CONCLUSIONS: WHO recommended option of a screen and vaccinate policy is likely to have a positive impact both at the individual and population level across a wide range of transmission settings and has the potential to be as, if not more, cost-effective than a no screening strategy.

The Role of Reference Materials in the Research and Development of Diagnostic Tools and Treatments for Haemorrhagic Fever Viruses.

Following the Ebola outbreak in Western Africa in 2013-16, a global effort has taken place for preparedness for future outbreaks. As part of this response, the development of vaccines, treatments and diagnostic tools has been accelerated, especially towards pathogens listed as likely to cause an epidemic and for which there are no current treatments. Several of the priority pathogens identified by the World Health Organisation are haemorrhagic fever viruses. This review provides information on the role of reference materials as an enabling tool for the development and evaluation of assays, and ultimately vaccines and treatments. The types of standards available are described, along with how they can be applied for assay harmonisation through calibration as a relative potency to a common arbitrary unitage system (WHO International Unit). This assures that assay metrology is accurate and robust. We describe reference materials that have been or are being developed for haemorrhagic fever viruses and consider the issues surrounding their production, particularly that of biosafety where the viruses require specialised containment facilities. Finally, we advocate the use of reference materials at early stages, including research and development, as this helps produce reliable assays and can smooth the path to regulatory approval.

The effectiveness of health education using audiovisual media on increasing family behavior in preventing dengue hemorrhagic fever (DHF)

Objective: This study aims to determine the effectiveness of health education through audiovisual media on improving family knowledge in the prevention of dengue fever (DHF). Method: This study used a Quasi Experiment research design with a research design of Non-Equivalent Control Group. The study was conducted in the community with a sample of 40 people, consisting of 20 for experimental group and 20 for control group. The samples were selected using purposive sample collection method. The measuring instrument used is a questionnaire that has been tested for validity and reliability. The analysis was done through univariate analysis and bivariate analysis using t-independent test. Result: This study found that the showed a significant increase in changes in the level of attitudes and actions of families in the prevention of dengue fever by using audiovisual media, (p = 0.000), (p = 0.000). Conclusion: It is recommended that the health workers should provide health education by using audiovisual media in the prevention of dengue fever

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Deliberations of the Strategic Advisory Group of Experts on Immunization on the use of CYD-TDV dengue vaccine.

The Strategic Advisory Group of Experts (SAGE) on Immunization advises WHO on global policies for vaccines. In April, 2016, SAGE issued recommendations on the use of the first licenced dengue vaccine, CYD-TDV. In November, 2017, a retrospective analysis of clinical trial data, stratifying participants according to their dengue serostatus before the first vaccine dose, showed that although in high seroprevalence settings the vaccine provides overall population benefit, there was an excess risk of severe dengue in seronegative vaccinees. SAGE's working group on dengue vaccines met to discuss the new data and mainly considered two vaccination strategies: vaccination of populations with dengue seroprevalence rates above 80% or screening of individuals before vaccination, and vaccinating only seropositive individuals. We report on the deliberations that informed the recommendation of the pre-vaccination screening strategy, in April, 2018. Important research and implementation questions remain for CYD-TDV, including the development of a highly sensitive and specific rapid diagnostic test to determine serostatus, simplified immunisation schedules, and assessment of the need for booster doses.

Virus-inclusive single-cell RNA sequencing reveals the molecular signature of progression to severe dengue.

Dengue virus (DENV) infection can result in severe complications. However, the understanding of the molecular correlates of severity is limited, partly due to difficulties in defining the peripheral blood mononuclear cells (PBMCs) that contain DENV RNA in vivo. Accordingly, there are currently no biomarkers predictive of progression to severe dengue (SD). Bulk transcriptomics data are difficult to interpret because blood consists of multiple cell types that may react differently to infection. Here, we applied virus-inclusive single-cell RNA-seq approach (viscRNA-Seq) to profile transcriptomes of thousands of single PBMCs derived early in the course of disease from six dengue patients and four healthy controls and to characterize distinct leukocyte subtypes that harbor viral RNA (vRNA). Multiple IFN response genes, particularly MX2 in naive B cells and CD163 in CD14+ CD16+ monocytes, were up-regulated in a cell-specific manner before progression to SD. The majority of vRNA-containing cells in the blood of two patients who progressed to SD were naive IgM B cells expressing the CD69 and CXCR4 receptors and various antiviral genes, followed by monocytes. Bystander, non-vRNA-containing B cells also demonstrated immune activation, and IgG1 plasmablasts from two patients exhibited clonal expansions. Lastly, assembly of the DENV genome sequence revealed diversity at unexpected sites. This study presents a multifaceted molecular elucidation of natural dengue infection in humans with implications for any tissue and viral infection and proposes candidate biomarkers for prediction of SD.

Economic impact of dengue in Mexico considering reported cases for 2012 to 2016.

BACKGROUND: Given that dengue disease is growing and may progress to dengue hemorrhagic fever (DHF), data on economic cost and disease burden are important. However, data for Mexico are limited. METHODOLOGY/PRINCIPAL FINDINGS: Burden of dengue fever (DF) and DHF in Mexico was assessed using official databases for epidemiological information, disabilities weights from Shepard et al, the reported number of cases and deaths, and costs. Overall costs of dengue were summed from direct medical costs to the health system, cost of dengue to the patient (out-of-pocket expenses [medical and non-medical], indirect costs [loss of earnings, patient and/or caregiver]), and other government expenditures on prevention/surveillance. The first three components, calculated as costs per case by a micro-costing approach (PAATI; program, actions, activities, tasks, inputs), were scaled up to overall cost using epidemiology data from official databases. PAATI was used to calculate cost of vector control and prevention, education, and epidemiological surveillance, based on an expert consensus and normative construction of an ideal scenario. Disability-adjusted life years (DALYs) for Mexico in 2016 were calculated to be 2283.46 (1.87 per 100,000 inhabitants). Overall economic impact of dengue in Mexico for 2012 was US$144 million, of which US$44 million corresponded to direct medical costs and US$5 million to the costs from the patient's perspective. The estimated cost of prevention/surveillance was calculated with information provided by federal government to be US$95 million. The overall economic impact of DF and DHF showed an increase in 2013 to US$161 million and a decrease to US$133, US$131 and US$130 million in 2014, 2015 and 2016, respectively. CONCLUSIONS/SIGNIFICANCE: The medical and economic impact of dengue were in agreement with other international studies, and highlight the need to include governmental expenditure for prevention/surveillance in overall cost analyses given the high economic impact of these, increasing the necessity to evaluate its effectiveness.

Assessment of benefits and risks associated with dengue vaccination at the individual and population levels: a dynamic modeling approach.

BACKGROUND: A case-cohort study, using a novel assay and data from three dengue vaccine efficacy trials, highlighted differences in vaccination outcomes according to baseline serostatus. Based on these results, we explored, with a model, the benefits and risks associated with vaccination. RESEARCH DESIGN AND METHODS: Parameters of a previously developed transmission model were estimated with subject-level data from a case-cohort study. The model was used to assess vaccination outcomes for a range of transmission settings over 5-30 years, with or without indirect protection. MAIN OUTCOME MEASURES: Symptomatic dengue cases, dengue hospitalizations, and severe dengue cases. RESULTS: The model is consistent with previous results indicating a transitory period at increased risk for dengue-seronegative vaccine recipients (setting-dependent duration) and long-term benefits for dengue-seropositive recipients. At the population level, benefits to seropositive individuals over 10 years outweighed the risk to those seronegative in moderate to high transmission settings (≥50% seropositivity at age 9), especially in high transmission settings (no excess hospitalizations in dengue-seronegative for ≥80% seropositivity at age 9). Results were more favorable when longer time horizons or indirect protection were considered. CONCLUSIONS: Results indicate a public health benefit associated with dengue vaccination especially in high-transmission settings, even with the initial excess risks to dengue-seronegative patients which diminish over time.

Synergism between the tyrosine kinase inhibitor sunitinib and Anti-TNF antibody protects against lethal dengue infection.

Dengue virus (DENV) currently circulates in more than 100 countries and causes an estimated 390 million infections per year. While most cases manifest as a self-resolving fever, ∼1.5% of infections develop into a more severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), which causes ∼20,000 deaths annually. The underlying pathological feature of DHF/DSS, also known as Severe Dengue, is an acute increase in vascular permeability leading to hypovolemia and shock. Angiogenic factors and cytokines, such as vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF), have been implicated in the increased vascular permeability, suggesting a potential therapeutic strategy for Severe Dengue. Here, we employed a mouse model of antibody-dependent enhancement of DENV infection, which recapitulates the fatal capillary leakage and shock of human Severe Dengue, to investigate the effects of approved VEGF- and TNF-targeting drugs. DENV infection caused a significant increase in serum VEGF levels within 2 days and resulted in ∼80% mortality within 8 days of infection. Treatment of mice with sunitinib, a VEGF receptor tyrosine kinase inhibitor, once (day 2) or twice (days 1 and 2) post-infection reduced mortality by 50-80% compared with untreated mice. Notably, sunitinib treatment decreased serum TNF levels, white blood cell counts, and hematocrit levels relative to untreated mice, but had only marginal effects on tissue viral burden. Combination therapy with anti-TNF antibody and sunitinib significantly reduced vascular leakage and synergized to provide superior protection from lethal DENV infection compared with either agent alone. These data suggest that a two-pronged anti-angiogenic and anti-inflammatory approach may be useful for the rapid treatment of DHF/DSS.

Dengue virus non-structural protein 1: a pathogenic factor, therapeutic target, and vaccine candidate.

Dengue virus (DENV) infection is the most common mosquito-transmitted viral infection. DENV infection can cause mild dengue fever or severe dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS). Hemorrhage and vascular leakage are two characteristic symptoms of DHF/DSS. However, due to the limited understanding of dengue pathogenesis, no satisfactory therapies to treat nor vaccine to prevent dengue infection are available, and the mortality of DHF/DSS is still high. DENV nonstructural protein 1 (NS1), which can be secreted in patients' sera, has been used as an early diagnostic marker for dengue infection for many years. However, the roles of NS1 in dengue-induced vascular leakage were described only recently. In this article, the pathogenic roles of DENV NS1 in hemorrhage and vascular leakage are reviewed, and the possibility of using NS1 as a therapeutic target and vaccine candidate is discussed.

Experimental in vitro and in vivo systems for studying the innate immune response during dengue virus infections.

Dengue is the most prevalent arboviral disease in humans and leads to significant morbidity and socioeconomic burden in tropical and subtropical areas. Dengue is caused by infection with any of the four closely related serotypes of dengue virus (DENV1-4) and usually manifests as a mild febrile illness, but may develop into fatal dengue hemorrhagic fever and shock syndrome. There are no specific antiviral therapies against dengue because understanding of DENV biology is limited. A tetravalent chimeric dengue vaccine, Dengvaxia, has finally been licensed for use, but its efficacy was significantly lower against DENV-2 infections and in dengue-naïve individuals. The identification of mechanisms underlying the interactions between DENV and immune responses will help to determine efficient therapeutic and preventive options. It has been well established how the innate immune system responds to DENV infection and how DENV overcomes innate antiviral defenses, however further progress in this field remains hampered by the absence of appropriate experimental dengue models. Herein, we review the available in vitro and in vivo approaches to study the innate immune responses to DENV.

A tetravalent virus-like particle vaccine designed to display domain III of dengue envelope proteins induces multi-serotype neutralizing antibodies in mice and macaques which confer protection against antibody dependent enhancement in AG129 mice.

BACKGROUND: Dengue is one of the fastest spreading vector-borne diseases, caused by four antigenically distinct dengue viruses (DENVs). Antibodies against DENVs are responsible for both protection as well as pathogenesis. A vaccine that is safe for and efficacious in all people irrespective of their age and domicile is still an unmet need. It is becoming increasingly apparent that vaccine design must eliminate epitopes implicated in the induction of infection-enhancing antibodies. METHODOLOGY/PRINCIPAL FINDINGS: We report a Pichia pastoris-expressed dengue immunogen, DSV4, based on DENV envelope protein domain III (EDIII), which contains well-characterized serotype-specific and cross-reactive epitopes. In natural infection, <10% of the total neutralizing antibody response is EDIII-directed. Yet, this is a functionally relevant domain which interacts with the host cell surface receptor. DSV4 was designed by in-frame fusion of EDIII of all four DENV serotypes and hepatitis B surface (S) antigen and co-expressed with unfused S antigen to form mosaic virus-like particles (VLPs). These VLPs displayed EDIIIs of all four DENV serotypes based on probing with a battery of serotype-specific anti-EDIII monoclonal antibodies. The DSV4 VLPs were highly immunogenic, inducing potent and durable neutralizing antibodies against all four DENV serotypes encompassing multiple genotypes, in mice and macaques. DSV4-induced murine antibodies suppressed viremia in AG129 mice and conferred protection against lethal DENV-4 virus challenge. Further, neither murine nor macaque anti-DSV4 antibodies promoted mortality or inflammatory cytokine production when passively transferred and tested in an in vivo dengue disease enhancement model of AG129 mice. CONCLUSIONS/SIGNIFICANCE: Directing the immune response to a non-immunodominant but functionally relevant serotype-specific dengue epitope of the four DENV serotypes, displayed on a VLP platform, can help minimize the risk of inducing disease-enhancing antibodies while eliciting effective tetravalent seroconversion. DSV4 has a significant potential to emerge as a safe, efficacious and inexpensive subunit dengue vaccine candidate.

Contribución de Cuba y del Instituto de Medicina Tropical "Pedro Kourí" para evitar las muertes por dengue / Contribution of Cuba and Pedro Kouri Tropical Medicine Institute to preventing mortality from dengue

El dengue es una enfermedad viral transmitida por mosquitos que puede ser causa de gravedad y muerte. No existe droga antiviral reconocida como eficaz. Sin embargo, las regularidades de esta enfermedad han permitido la identificación de signos de alarma que anuncian extravasación de plasma e inminencia del choque. El inicio precoz del tratamiento de los pacientes mediante la reposición de líquidos cristaloides por vía intravenosa ha demostrado ser una medida efectiva y salvadora. Se necesita capacitación sistemática y acciones de reorganización de la atención médica en función de la epidemia. Se expone la contribución de los profesionales del Instituto de Medicina Tropical Pedro Kourí y otras instituciones cubanas a ese empeño(AU)

Dengue is a viral disease transmitted by mosquitoes which may be severe and cause death. No antiviral drug has been recognized as effective. However, the regularities of this condition have made it possible to identify warning signs announcing plasma leakage and the imminence of shock. Early start of treatment with intravenous crystalloid fluid replacement has proven to be an effective, life-saving measure. Systematic training actions and reorganization of medical care are required during an epidemic. The paper describes the contribution of professionals from Pedro Kouri Tropical Medicine Institute and other Cuban institutions to this effort(AU)

Immune correlates of protection for dengue: State of the art and research agenda.

Dengue viruses (DENV1-4) are mosquito-borne flaviviruses estimated to cause up to ∼400 million infections and ∼100 million dengue cases each year. Factors that contribute to protection from and risk of dengue and severe dengue disease have been studied extensively but are still not fully understood. Results from Phase 3 vaccine efficacy trials have recently become available for one vaccine candidate, now licensed for use in several countries, and more Phase 2 and 3 studies of additional vaccine candidates are ongoing, making these issues all the more urgent and timely. At the "Summit on Dengue Immune Correlates of Protection", held in Annecy, France, on March 8-9, 2016, dengue experts from diverse fields came together to discuss the current understanding of the immune response to and protection from DENV infection and disease, identify key unanswered questions, discuss data on immune correlates and plans for comparison of results across assays/consortia, and propose a research agenda for investigation of dengue immune correlates, all in the context of both natural infection studies and vaccine trials.