A emergência da dengue como desafio virológico: de doença-fantasma à endemia "de estimação", 1986-1987 / The emergence of dengue as a virological challenge: from phantom disease to "pet" endemic, 1986-1987

Resumo O artigo analisa como a dengue se apresentou como desafio virológico na década de 1980. O objetivo é entender o papel dos estudos virológicos na compreensão da doença e a construção de uma expertise em arboviroses. Embora surtos da doença já tivessem sido relatados ao longo do século XX, a dengue era pouco conhecida nas Américas até a epidemia de dengue hemorrágica em Cuba, em 1981. Quando em 1986 a doença atingiu a cidade de Nova Iguaçu (RJ), a equipe de virologistas liderada por Hermann Schatzmayr tomaria a doença como objeto, mobilizando esforços a partir da criação do Laboratório de Flavivírus do Instituto Oswaldo Cruz.

Abstract This article analyzes how dengue presented a virological challenge during the 1980s in order to explore the role of virological studies in understanding this disease and constructing expertise in arboviral diseases. Although outbreaks were reported throughout the twentieth century, dengue was barely known in the Americas until the epidemic of dengue fever in Cuba in 1981. When the disease reached the Brazilian city of Nova Iguaçu (RJ) in 1986, it became the focus of attention for a team of virologists led by Hermann Schatzmayr, who mobilized efforts after the creation of the Flavivirus Laboratory at the Oswaldo Cruz Institute.

Emergence of a Novel Dengue Virus 3 (DENV-3) Genotype-I Coincident with Increased DENV-3 Cases in Yangon, Myanmar between 2017 and 2019.

Dengue fever, caused by the mosquito-borne dengue virus (DENV), has been endemic in Myanmar since 1970 and it has become a significant public health burden. It is crucial that circulating DENV strains are identified and monitored, and that their transmission efficiency and association with disease severity is understood. In this study, we analyzed DENV-1, DENV-2, DENV-3, and DENV-4 serotypes in 1235 serum samples collected in Myanmar between 2017 and 2019. Whole-genome sequencing of DENV-1-4 demonstrated that most DENV-1-4 strains had been circulating in Myanmar for several years. We also identified the emergence of DENV-3 genotype-I in 2017 samples, which persisted through 2018 and 2019. The emergence of the strain coincided with a period of increased DENV-3 cases and marked changes in the serotype dynamics. Nevertheless, we detected no significant differences between serum viral loads, disease severity, and infection status of individuals infected with different DENV serotypes during the 3-year study. Our results not only identify the spread of a new DENV-3 genotype into Yangon, Myanmar, but also support the importance of DENV evolution in changing the epidemic dynamics in endemic regions.

Historical discourse on the development of the live attenuated tetravalent dengue vaccine candidate TV003/TV005.

Dengue is the most important arboviral disease world-wide with an estimated 400 million annual infections. Dengvaxia™ is a live attenuated tetravalent vaccine recently licensed for dengue seropositive individuals aged 9-45 years. There is great need for a dengue vaccine that could be given to dengue-naïve individuals and very young children. To that end, the U.S. NIH developed a live attenuated tetravalent dengue vaccine using an iterative approach evaluating the safety, infectivity, and immunogenicity of different candidates. This approach identified poor candidates who were then discarded from further evaluation. Each of the components of the tetravalent vaccine formulation is able to replicate to very low titer, inducing a homotypic immune response to each. The immune response elicited by the tetravalent vaccine is balanced, without immunodominance of one component. The vaccine was licensed by several manufacturers for development, including the Instituto Butantan which initiated a Phase 3 efficacy trial.

Dengue fever in the Corpus Hippocraticum.

Dengue fever (DF) is a globally significant infection which causes a range of severe and non-severe clinical manifestations. It is transmitted by mosquitoes of the Aedes genus (primarily Aedes aegypti, but also Aedes albopictus). In this letter, a possible DF epidemic on Thasos Island in Greece, which is described in the Book of Epidemics I of the Corpus Hippocraticum, is presented and analyzed. To my knowledge, it is the first report of DF in the history of medicine.

Phantom Menace: Dengue and Yellow Fever in Asia.

This article explores the entangled histories of dengue and yellow fever. It traces how historical conflations of these diseases deepened at the start of the twentieth century in the context of rising fears that yellow fever might spread to Asia. Advances in biomedicine, I suggest, reinforced notions of their kinship and generated competing theories that dengue either foreshadowed yellow fever in Asia or inoculated the region against it. This history in which the language and science of dengue and yellow fever shadowed one another offers a nonlinear narrative of scientific progress. Furthermore, as the so-called neglected tropical diseases resurge in the present, it elucidates how disease threats are read against one another. Thus, the article offers a historical context to ongoing discussions on disease emergence and pandemic preparedness.

The evolutionary dynamics of DENV 4 genotype I over a 60-year period.

Dengue virus serotype 4 (DENV 4) has had a relatively low prevalence worldwide for decades; however, likely due to data paucity, no study has investigated the epidemiology and evolutionary dynamics of DENV 4 genotype I (DENV 4-I). This study aims to understand the diversity, epidemiology and dynamics of DENV 4-I. We collected 404 full length DENV4-1 envelope (E) gene sequences from 14 countries using two sources: Yunnan Province in China (15 strains during 2013-2016) and GenBank (489 strains up to 2018-01-11). Conducting phylogenetic and phylogeographical analyses, we estimated the virus spread, population dynamics, and selection pressures using different statistical analysis methods (substitution saturation, likelihood mapping, Bayesian coalescent inference, and maximum likelihood estimation). Our results show that during the last 60 years (1956-2016), DENV 4-I was present in mainland and maritime Southeast Asia, the Indian subcontinent, the southern provinces of China, parts of Brazil and Australia. The recent spread of DENV 4-I likely originated in the Philippines and later spread to Thailand. From Thailand, it spread to adjacent countries and eventually the Indian subcontinent. Apparently diverging around years 1957, 1963, 1976 and 1990, the different Clades (Clade I-V) were defined. The mean overall evolution rate of DENV 4-I was 9.74 (95% HPD: 8.68-10.82) × 10-4 nucleotide substitutions/site/year. The most recent common ancestor for DENV 4-I traces back to 1956. While the demographic history of DENV 4-I fluctuated, peaks appeared around 1982 and 2006. While purifying selection dominated the majority of E-gene evolution of DENV 4-I, positive selection characterized Clade III (Vietnam). DENV 4-I evolved in situ in Southeast Asia and the Indian subcontinent. Thailand and Indian acted as the main and secondary virus distribution hubs globally and regionally. Our phylogenetic analysis highlights the need for strengthened regional cooperation on surveillance and sharing of sample sequences to improve global dengue control and cross-border transmission prevention efforts.

Asymptomatic Dengue Virus Infections, Cambodia, 2012-2013.

We investigated dengue virus (DENV) and asymptomatic DENV infections in rural villages of Kampong Cham Province, Cambodia, during 2012 and 2013. We conducted perifocal investigations in and around households for 149 DENV index cases identified through hospital and village surveillance. We tested participants 0.5-30 years of age by using nonstructural 1 rapid tests and confirmed DENV infections using quantitative reverse transcription PCR or nonstructural 1-capture ELISA. We used multivariable Poisson regressions to explore links between participants' DENV infection status and household characteristics. Of 7,960 study participants, 346 (4.4%) were infected with DENV, among whom 302 (87.3%) were <15 years of age and 225 (65.0%) were <9 years of age. We identified 26 (7.5%) participants with strictly asymptomatic DENV infection at diagnosis and during follow-up. We linked symptomatic DENV infection status to familial relationships with index cases. During the 2-year study, we saw fewer asymptomatic DENV infections than expected based on the literature.

Joint Estimation of Relative Risk for Dengue and Zika Infections, Colombia, 2015-2016.

We jointly estimated relative risk for dengue and Zika virus disease (Zika) in Colombia, establishing the spatial association between them at the department and city levels for October 2015-December 2016. Cases of dengue and Zika were allocated to the 87 municipalities of 1 department and the 293 census sections of 1 city in Colombia. We fitted 8 hierarchical Bayesian Poisson joint models of relative risk for dengue and Zika, including area- and disease-specific random effects accounting for several spatial patterns of disease risk (clustered or uncorrelated heterogeneity) within and between both diseases. Most of the dengue and Zika high-risk municipalities varied in their risk distribution; those for Zika were in the northern part of the department and dengue in the southern to northeastern parts. At city level, spatially clustered patterns of dengue high-risk census sections indicated Zika high-risk areas. This information can be used to inform public health decision making.

Cross-Protection of Dengue Virus Infection against Congenital Zika Syndrome, Northeastern Brazil.

The Zika virus outbreak in Latin America resulted in congenital malformations, called congenital Zika syndrome (CZS). For unknown reasons, CZS incidence was highest in northeastern Brazil; one potential explanation is that dengue virus (DENV)-mediated immune enhancement may promote CZS development. In contrast, our analyses of historical DENV genomic data refuted the hypothesis that unique genome signatures for northeastern Brazil explain the uneven dispersion of CZS cases. To confirm our findings, we performed serotype-specific DENV neutralization tests in a case-control framework in northeastern Brazil among 29 Zika virus-seropositive mothers of neonates with CZS and 108 Zika virus-seropositive control mothers. Neutralization titers did not differ significantly between groups. In contrast, DENV seroprevalence and median number of neutralized serotypes were significantly lower among the mothers of neonates with CZS. Supported by model analyses, our results suggest that multitypic DENV infection may protect from, rather than enhance, development of CZS.

Seroprevalence of Zika and Dengue Virus Antibodies among Migrant Workers, Taiwan, 2017.

A serosurvey of 600 workers newly arrived in Taiwan from 4 Southeast Asia countries showed that 18 (3%) were positive for Zika virus IgM; 6 (1%) fulfilled the World Health Organization criteria for laboratory-confirmed recent Zika virus infection. The incidence of Zika virus infection in Southeast Asia might be underestimated.

Dengue vaccine: WHO position paper, September 2018 - Recommendations.

This article presents the World Health Organization's (WHO) recommendations on the use of dengue vaccine excerpted from the WHO position paper on dengue vaccine - September 2018, published in the Weekly Epidemiological Record [1]. This position paper replaces the July 2016 WHO position paper concerning the first licensed dengue vaccine, CYD-TDV [2]. The position paper presents new evidence that became available in November 2017. A retrospective analysis of data from clinical trials, using a new serological assay classified trial participants according to their dengue serostatus prior to receipt of the first vaccine dose. The analysis revealed an excess risk of severe dengue in seronegative vaccine recipients compared to seronegative non-vaccinated individuals, while confirming long-term protection in seropositive individuals [3]. The paper provides revised guidance on dengue vaccination strategies from a population health perspective. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence-to-recommendation table. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. Recommendations on the use of dengue vaccine CYD-TDV were discussed by SAGE in April 2018; evidence presented at the meeting can be accessed at: http://www.who.int/immunization/sage/meetings/2018/april/presentations_background_docs/en/.

Emergence of dengue virus type 1 and type 3 as dominant serotypes during 2017 in Pune and Nashik regions of Maharashtra, Western India.

India witnessed dengue outbreaks during 2017 in different parts with more than 180000 cases. There is no data on the serotypes/genotypes of dengue virus (DENV) associated with the 2017 outbreak season. The present study investigated DENV circulating in Pune and Nashik regions of Maharashtra, Western India at molecular level. IgM negative samples that were collected before 6th post onset days of illness were tested for DENV RNA and serotyped by real time RT-PCR based methods. Representative samples of each serotype were processed for virus isolation and envelope (E) gene sequencing. Among the 472 samples tested for DENV serotypes from Nashik, DENV-1 was observed in 36.2%, DENV-2 in 12.9%, DENV-3 in 35.4%, DENV-4 in 8.0%, and multiple serotypes in 7.4% of the samples respectively. In Pune region, among the 109 samples tested for DENV serotypes, DENV-1 was observed in 27.5%, DENV-2 in 11.0%, DENV-3 in 52.3%, DENV-4 in 4.6%, and multiple serotypes in 4.6% of the samples respectively. Comparison of serotype distribution from 2009 to 2017 from the Pune region revealed the emergence of DENV-3 as the dominant serotype followed by DENV-1 in 2017. In the Nashik region, both DENV-1 and DENV-3 were predominant in 2017. Phylogenetic analyses revealed co-circulation of American African (AM/AF) and Asian genotypes of DENV-1. DENV-1 Asian genotype was detected for the first time in the region. No genotype changes were observed for DENV-2 (cosmopolitan genotype), DENV-3 (genotype III) and DENV-4 (genotype I). For DENV-3, a unique amino acid substitution (I380T) was observed in the domain III of E protein of 2017 isolates and was not observed in earlier DENV-3 genotype III isolates. To conclude, the results suggest the emergence of DENV-1 with circulation of both Asian and AM/AF genotypes and DENV-3 with unique amino acid substitutions in Pune and Nashik regions. The study underscores the need for continuous molecular monitoring at a large scale to detect the changes in DENV serotypes/genotypes that might have implications for earlier prediction of dengue outbreaks and designing dengue vaccines and predicting its efficacy.

History, epidemiology and diagnostics of dengue in the American and Brazilian contexts: a review.

Dengue virus (DENV), an arbovirus transmitted by mosquitoes, has become a major threat to American human life, reaching approximately 23 million cases from 1980 to 2017. Brazil is among the countries most affected by this terrible viral disease, with 13.6 million cases. DENV has four different serotypes, DENV1-4, which show a broad clinical spectrum. Dengue creates a staggering epidemiological and economic burden for endemic countries. Without a specific therapy and with a commercial vaccine that presents some problems relative to its full effectiveness, initiatives to improve vector control strategies, early disease diagnostics and the development of vaccines and antiviral drugs are priorities. In this study, we present the probable origins of dengue in America and the trajectories of its spread. Overall, dengue diagnostics are costly, making the monitoring of dengue epidemiology more difficult and affecting physicians' therapeutic decisions regarding dengue patients, especially in developing countries. This review also highlights some recent and important findings regarding dengue in Brazil and the Americas. We also summarize the existing DENV polymerase chain reaction (PCR) diagnostic tests to provide an improved reference since these tests are useful and accurate at discriminating DENV from other flaviviruses that co-circulate in the Americas. Additionally, these DENV PCR assays ensure virus serotyping, enabling epidemiologic monitoring.

Seroprevalence of Dengue and Chikungunya Virus Antibodies, French Polynesia, 2014-2015.

We investigated dengue and chikungunya virus antibody seroprevalence in French Polynesia during 2014-2015. Dengue virus seroprevalence was ≈60% among schoolchildren and >83% among the general population; chikungunya virus seroprevalence was <3% before and 76% after Zika virus emergence (2013). Dengue virus herd immunity may affect Zika virus infection and pathogenesis.

Innovative and New Approaches to Laboratory Diagnosis of Zika and Dengue: A Meeting Report.

Epidemics of dengue, Zika, and other arboviral diseases are increasing in frequency and severity. Current efforts to rapidly identify and manage these epidemics are limited by the short diagnostic window in acute infection, the extensive serologic cross-reactivity among flaviviruses, and the lack of point-of-care diagnostic tools to detect these viral species in primary care settings. The Partnership for Dengue Control organized a workshop to review the current landscape of Flavivirus diagnostic tools, identified current gaps, and developed strategies to accelerate the adoption of promising novel technologies into national programs. The rate-limiting step to bringing new diagnostic tools to the market is access to reference materials and well-characterized clinical samples to facilitate performance evaluation. We suggest the creation of an international laboratory-response consortium for flaviviruses with a decentralized biobank of well-characterized samples to facilitate assay validation. Access to proficiency panels are needed to ensure quality control, in additional to in-country capacity building.

Dengue in Rio Grande do Sul, Brazil: 2014 to 2016.

The first autochthonous dengue case in Rio Grande do Sul (RS), Southern Brazil, occurred in 2007. In 2008 and 2009, only imported cases were reported in RS, but from 2010 to 2013, reports of autochthonous infections increased significantly. This study analyzes and discusses laboratory, demographic, and clinical data regarding dengue cases in RS, from 2014 to 2016. This study analyzed 13,420 serum samples from notified patients with suspicion of dengue fever in RS from 2014 to 2016. Seasonality of positive cases, viral serotypes, and clinical and epidemiological aspects were analyzed. There was no difference in gender (P = .4); dengue fever occurred mainly in adults, with similar distribution among age groups. The number of dengue virus (DENV) cases increased from 89 cases in 2014 to 2518 in 2016. Dengue virus 1 was the most prevalent circulating serotype during this period (97.5% of cases). Dengue virus infections show peaks in March and April (late summer and early autumn), after periods of high temperatures and rainfall. In 2014, dengue cases were concentrated in the northwestern and eastern regions of RS, and in 2015 and 2016, the northern region also confirmed a high number of cases. With increase in DENV circulation in RS, a rise in the number of autochthonous infections was also observed, mainly in highly urbanized areas. This study revealed that circulation of DENV in RS increased significantly in 2015 and 2016, with a rise in the number of autochthonous infections and cocirculation with Chikungunya and Zika viruses, recently introduced into RS.

Circulating Genotypes of Dengue-1 Virus in South West India, 2014-2015.

Dengue is the most prevalent arboviral disease affecting humans, with tropical and subtropical regions having the highest risk of dengue virus infections. The clinical symptoms often range from mild fever to fever with hemorrhagic manifestations and shock. Since 2010, India has been witnessing a marked increase in the number of dengue virus serotype 1 (DENV-1) infections, apart from those of serotypes 2 (DENV-2) and 3 (DENV-3). The present study was undertaken to understand the circulating genotypes of DENV-1 in South West India, by sequencing the envelope gene of DENV-1 samples representative of the 2014-2015 time period. The extracted RNAs from dengue NS1 antigen ELISA-positive samples, archived at the APEX Referral Laboratory for Arboviruses (National Vector Borne Disease Control Programme, Manipal Centre for Virus Research), were used for the study. The currently circulating genotypes of DENV-1 identified from the study area belong to genotypes V and I. Multicentric laboratory-based studies analyzing the envelope gene of all dengue serotypes are required from endemic countries like India.

Características del virus del dengue y su pronóstico bioclimático en el Departamento de Cortés / Characteristic of the dengue virus and its bioclimatic prognosis in Cortés Department

Se efectuó un estudio observacional, descriptivo y transversal en el Departamento de Cortés, en Honduras, durante el período de 2003 a 2013, con vistas a determinar las características del dengue en esta región, describir su historicidad y desarrollar un modelo matemático de pronóstico basado en variables bioclimáticas. En la serie el sexo no constituyó un factor predisponente, mientras que los grupos etarios de 5-9 y de 20-49 años, el ser habitante en Choloma, Villanueva y Puerto Cortés, resultaron elementos importantes en la aparición del dengue. Asimismo las formas graves de la enfermedad en niños y jóvenes indicaron una baja memoria inmunológica y/o varias exposiciones a serotipos del virus. Se obtuvo un patrón definido, cíclico-epidémico (de 4 a 5 años) y estacional, pues correspondía al período lluvioso de la región. Finalmente, se concluyó que las condiciones climáticas de Cortés están condicionando la transmisión del dengue, de manera que puede ser posible la predicción de los acontecimientos epidémicos

An observational, descriptive and cross-sectional study was carried out in Cortés Department, Honduras, during the period of 2003 at 2013, aimed at determining the characteristics of dengue in this region, describing its history and developing a prognosis mathematical model based on bioclimatic variables. In the series, sex didn't constitute a predisposing factor, while the age groups 5-9 and 20-49 years, being inhabitant in Choloma, Villanueva and Puerto Cortés were important elements in the emergence of dengue. Also the severe forms of the disease in children and young persons indicated a low immunologic memory and/or several exposures to serotypes of the virus. A defined, seasonal recurrent-epidemic pattern was obtained (of 4 to 5 years), because it corresponded to the rainy period of the region. Finally, it was concluded that the climate conditions of Cortés are conditioning the transmission of dengue, so that the prognosis of the epidemic events can be possible