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Background: Sri Lanka experienced its largest dengue outbreak in 2017 with more than 185,000 dengue cases including at least 250 fatalities., Objectives: Our study aimed to characterize the clinical, immunological and virological features of confirmed dengue patients in Sri Lanka during the outbreak in 2017 when unusual manifestations of severe dengue were observed., Study Design: Sera from 295 patients who were admitted to Teaching Hospital Kandy, Kandy, Sri Lanka between March 2017- January 2018 were subjected to NS1 antigen, IgM and IgG ELISAs, virus isolation, conventional and real time RT-PCR and next generation sequencing., Results: Primary and secondary infections were detected in 48.5 % and 51.5 % of the study population, respectively. Two hundred twenty five DENV strains were isolated (219 DENV-2, one DENV-3, two DENV-4, two mixed infections of DENV-2 and -3 and one mixed infection of DENV-2 and -4). Unusual and severe manifestations such as encephalitis, encephalopathy, liver failure, kidney failure, myocarditis, Guillain-Barré syndrome and multi-organ failure were noted in 44 dengue patients with 11 deaths. The viraemia levels in patients with primary infection and unusual manifestations were significantly higher compared to those in patients with secondary infection. A new clade of DENV-2 Cosmopolitan genotype strains was observed with the strains closely related to those from China, Malaysia, Indonesia, Singapore and Taiwan., Conclusions: The new clade of DENV-2 cosmopolitan genotype observed in Sri Lanka in 2017 caused an unprecedented, severe dengue outbreak. The emergence of DENV-3 and DENV-4 in the 2017 outbreak might cause future outbreaks in Sri Lanka., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Dengue is a serious global burden. Unreported and unrecognised apparent dengue virus infections make it difficult to estimate the true extent of dengue and current estimates of the incidence and costs of dengue have substantial uncertainty. Objective, systematic, comparable measures of dengue burden are needed to track health progress, assess the application and financing of emerging preventive and control strategies, and inform health policy. We estimated the global economic burden of dengue by country and super-region (groups of epidemiologically similar countries)., Methods: We used the latest dengue incidence estimates from the Institute for Health Metrics and Evaluation's Global Burden of Disease Study 2013 and several other data sources to assess the economic burden of symptomatic dengue cases in the 141 countries and territories with active dengue transmission. From the scientific literature and regressions, we estimated cases and costs by setting, including the non-medical setting, for all countries and territories., Findings: Our global estimates suggest that in 2013 there were a total of 58·40 million symptomatic dengue virus infections (95% uncertainty interval [95% UI] 24 million-122 million), including 13 586 fatal cases (95% UI 4200-34 700), and that the total annual global cost of dengue illness was US$8·9 billion (95% UI 3·7 billion-19·7 billion). The global distribution of dengue cases is 18% admitted to hospital, 48% ambulatory, and 34% non-medical., Interpretation: The global cost of dengue is substantial and, if control strategies could reduce dengue appreciably, billions of dollars could be saved globally. In estimating dengue costs by country and setting, this study contributes to the needs of policy makers, donors, developers, and researchers for economic assessments of dengue interventions, particularly with the licensure of the first dengue vaccine and promising developments in other technologies., Funding: Sanofi Pasteur., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Dengue is the most common arbovirus infection globally, but its burden is poorly quantified. We estimated dengue mortality, incidence, and burden for the Global Burden of Disease Study 2013., Methods: We modelled mortality from vital registration, verbal autopsy, and surveillance data using the Cause of Death Ensemble Modelling tool. We modelled incidence from officially reported cases, and adjusted our raw estimates for under-reporting based on published estimates of expansion factors. In total, we had 1780 country-years of mortality data from 130 countries, 1636 country-years of dengue case reports from 76 countries, and expansion factor estimates for 14 countries., Findings: We estimated an average of 9221 dengue deaths per year between 1990 and 2013, increasing from a low of 8277 (95% uncertainty estimate 5353-10 649) in 1992, to a peak of 11 302 (6790-13 722) in 2010. This yielded a total of 576 900 (330 000-701 200) years of life lost to premature mortality attributable to dengue in 2013. The incidence of dengue increased greatly between 1990 and 2013, with the number of cases more than doubling every decade, from 8·3 million (3·3 million-17·2 million) apparent cases in 1990, to 58·4 million (23·6 million-121·9 million) apparent cases in 2013. When accounting for disability from moderate and severe acute dengue, and post-dengue chronic fatigue, 566 000 (186 000-1 415 000) years lived with disability were attributable to dengue in 2013. Considering fatal and non-fatal outcomes together, dengue was responsible for 1·14 million (0·73 million-1·98 million) disability-adjusted life-years in 2013., Interpretation: Although lower than other estimates, our results offer more evidence that the true symptomatic incidence of dengue probably falls within the commonly cited range of 50 million to 100 million cases per year. Our mortality estimates are lower than those presented elsewhere and should be considered in light of the totality of evidence suggesting that dengue mortality might, in fact, be substantially higher., Funding: Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests LEC, CJLM, and JDS, have received grants from Bill & Melinda Gates Foundation, during the study; KBG received a 2011 Gustav Nossal Postgraduate Scholarship sponsored by CSL Behring. EAU and DSS have received grants from Sanofi Pasteur. The other authors declare no competing interests., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Formulations of chimeric dengue vaccine (DENVax) viruses containing the pre-membrane (prM) and envelope (E) genes of serotypes 1-4 expressed in the context of the attenuated DENV-2 PDK-53 genome were tested for safety, immunogenicity and efficacy in interferon receptor knock-out mice (AG129). Monovalent formulations were safe and elicited robust neutralizing antibody responses to the homologous virus and only limited cross-reactivity to other serotypes. A single dose of monovalent DENVax-1, -2, or -3 vaccine provided eighty or greater percent protection against both wild-type (wt) DENV-1 (Mochizuki strain) and DENV-2 (New Guinea C strain) challenge viruses. A single dose of monovalent DENVax-4 also provided complete protection against wt DENV-1 challenge and significantly increased the survival times after challenge with wt DENV-2. In studies using tetravalent mixtures, DENVax ratios were identified that: (i) caused limited viremia, (ii) induced serotype-specific neutralizing antibodies to all four DENV serotypes with different hierarchies, and (iii) conferred full protection against clinical signs of disease following challenge with either wt DENV-1 or DENV-2 viruses. Overall, these data highlight the immunogenic profile of DENVax, a novel candidate tetravalent dengue vaccine and the advantage of sharing a common attenuated genomic backbone among the DENVax monovalent vaccines that confer protection against homologous or heterologous virus challenge., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The dengue virus non-structural 1 (NS1) protein contributes to evasion of host immune defenses and represents a target for immune responses. Evidences generated in experimental models, as well as the immune responses elicited by infected individuals, showed that induction of anti-NS1 immunity correlates with protective immunity but may also result in the generation of cross-reactive antibodies that recognize platelets and proteins involved in the coagulation cascade. In the present work, we evaluated the immune responses, protection to type 2 dengue virus (DENV2) challenges and safety parameters in BALB/c mice vaccinated with a recombinant NS1 protein in combination with three different adjuvants: aluminum hydroxide (alum), Freund's adjuvant (FA) or a genetically detoxified derivative of the heat-labile toxin (LT(G33D)), originally produced by some enterotoxigenic Escherichia coli (ETEC) strains. Mice were subcutaneously (s.c.) immunized with different vaccine formulations and the induced NS1-specific responses, including serum antibodies and T cell responses, were measured. Mice were also subjected to lethal challenges with the DENV2 NGC strain. The results showed that maximal protective immunity (50%) was achieved in mice vaccinated with NS1 in combination with LT(G33D). Analyses of the NS1-specific immune responses showed that the anti-virus protection correlated mainly with the serum anti-NS1 antibody responses including higher avidity to the target antigen. Mice immunized with LT(G33D) elicited a prevailing IgG2a subclass response and generated antibodies with stronger affinity to the antigen than those generated in mice immunized with the other vaccine formulations. The vaccine formulations were also evaluated regarding induction of deleterious side effects and, in contrast to mice immunized with the FA-adjuvanted vaccine, no significant hepatic damage or enhanced C-reactive protein levels were detected in mice immunized with NS1 and LT(G33D.) Similarly, no detectable alterations in bleeding time and hematological parameters were detected in mice vaccinated with NS1 and LT(G33D). Altogether, these results indicate that the combination of a purified recombinant NS1 and a nontoxic LT derivative is a promising alternative for the generation of safe and effective protein-based anti-dengue vaccine., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Key symptoms observed during the febrile phase of dengue may identify patients who are likely to progress to severe disease., Objectives: To test this hypothesis, we examined the relationships between symptoms reported by patients at presentation and the development of severe outcomes., Study Design: Retrospective analysis of data recorded prospectively in 560 adult dengue patients admitted to an emergency department. A logistic regression analysis was used to quantify the association between symptoms reported at presentation and outcome., Results: Plasma leakage was observed in 95 patients (17%), severe thrombocytopenia (platelet counts <20 x 10(9)/L) in 93 patients (16.6%) and acute hepatitis in 42 patients (7.5%). Severe thrombocytopenia developed in 57% of patients with plasma leakage and 40.5% of patients with hepatitis. Patients who developed a plasma leakage syndrome were older, mainly male, and reported more often an abdominal pain and a cough. Diarrhea and taking paracetamol >60 mg/kg/day before admission were associated with the development of acute hepatitis. Seven patients died. The mortality rate was 6/95 (6.3%) in patients who developed plasma leakage, 3/42 (7.1%) in patients who developed hepatitis, 5/93 (5.4%) in patients with severe thrombocytopenia, and 3/12 (25%) in the patients who demonstrated together all these severe manifestations., Conclusion: Plasma leakage, severe thrombocytopenia and acute hepatitis identified subgroups of adult dengue patients with increased mortality rates. Key symptoms reported by the patients at presentation such as abdominal pain, cough or diarrhea were significantly associated with the development of severe manifestations and should be considered as warning signs., (Copyright 2010 Elsevier B.V. All rights reserved.)

A survey of policymakers and other influential professionals in four southeast Asian countries (Cambodia, Indonesia, Philippines and Vietnam) was conducted to determine policymakers' views on the public health importance of dengue fever and dengue haemorrhagic fever (DHF), the need for a vaccine and the determinants influencing its potential introduction. The survey, which involved face-to-face interviews with policymakers, health programme managers, researchers, opinion leaders and other key informants, revealed an almost uniformly high level of concern about dengue fever/DHF and a high perceived need for a dengue vaccine. Several characteristics of the disease contribute to this high sense of priority, including its geographic spread, occurrence in outbreaks, the recurrent risk of infection each dengue season, its severity and the difficulty in diagnosis and management, its urban predominance, its burden on hospitals, and its economic toll on governments and families. Research felt to be key to future decision-making regarding dengue vaccine introduction include: disease surveillance studies, in-country vaccine trials or pilot projects, and studies on the economic burden of dengue and the cost-effectiveness of dengue vaccines. The results suggest favourable conditions for public and private sector markets for dengue vaccines and the need for creative financing strategies to ensure their accessibility to poor children in dengue-endemic countries.

Despite efforts to elucidate the pathogenesis of dengue fever, the progression into severe disease remains poorly understood. In-vitro findings suggest that coagulopathy and disturbances in fibrinolysis have a pivotal role in the pathophysiology. If disturbances in these processes are predictive of clinical outcome in this disease, there could be important consequences for both diagnosis and treatment. We have critically reviewed publications on this topic to assess whether there is an association between activation of coagulation and fibrinolysis and clinical outcome of dengue-virus infections. In general, the selected studies showed activation of both the coagulation and fibrinolytic systems in this infection. The activation was more pronounced in severe infections and in cases with a poor clinical outcome. However, the findings were not consistent, and owing to a lack of detailed information on characteristics of patients, disease, and study design, we could not ascertain whether inconsistencies were caused by differences in these characteristics, selection bias, or confounding factors. We conclude that an association between activation of coagulation and fibrinolysis and clinical outcome of dengue-virus infections is conceivable but has been inadequately assessed and that methodologically sound studies, complemented with complete and reliable reporting, are needed to show whether there is a true association.

This review is an update of dengue and dengue haemorrhagic fever (DHF) based on international and Cuban experience. We describe the virus characteristics and risk factors for dengue and DHF, and compare incidence and the case fatality rates in endemic regions (southeast Asia, western Pacific, and the Americas). The clinical picture and the pathogenesis of the severe disease are explained. We also discuss the viral, individual, and environmental factors that determine severe disease. Much more research is necessary to clarify these mechanisms. Also reviewed are methods for viral isolation and the serological, immunohistochemical, and molecular methods applied in the diagnosis of the disease. We describe the status of vaccine development and emphasise that the only alternative that we have today to control the disease is through control of its vector Aedes aegypti.