Showing papers on "Dengue fever published in 2015"

First report of autochthonous transmission of Zika virus in Brazil

Abstract: In the early 2015, several cases of patients presenting symptoms of mild fever, rash, conjunctivitis and arthralgia were reported in the northeastern Brazil. Although all patients lived in a dengue endemic area, molecular and serological diagnosis for dengue resulted negative. Chikungunya virus infection was also discarded. Subsequently, Zika virus (ZIKV) was detected by reverse transcription-polymerase chain reaction from the sera of eight patients and the result was confirmed by DNA sequencing. Phylogenetic analysis suggests that the ZIKV identified belongs to the Asian clade. This is the first report of ZIKV infection in Brazil.

Efficacy of a Tetravalent Dengue Vaccine in Children in Latin America

Abstract: Background In light of the increasing rate of dengue infections throughout the world despite vector-control measures, several dengue vaccine candidates are in development. Methods In a phase 3 efficacy trial of a tetravalent dengue vaccine in five Latin American countries where dengue is endemic, we randomly assigned healthy children between the ages of 9 and 16 years in a 2:1 ratio to receive three injections of recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) or placebo at months 0, 6, and 12 under blinded conditions. The children were then followed for 25 months. The primary outcome was vaccine efficacy against symptomatic, virologically confirmed dengue (VCD), regardless of disease severity or serotype, occurring more than 28 days after the third injection. Results A total of 20,869 healthy children received either vaccine or placebo. At baseline, 79.4% of an immunogenicity subgroup of 1944 children had seropositive status for one or more dengue serotypes. In the per-protocol population, there were 176 VCD cases (with 11,793 person-years at risk) in the vaccine group and 221 VCD cases (with 5809 person-years at risk) in the control group, for a vaccine efficacy of 60.8% (95% confidence interval [CI], 52.0 to 68.0). In the intention-to-treat population (those who received at least one injection), vaccine efficacy was 64.7% (95% CI, 58.7 to 69.8). Serotype-specific vaccine efficacy was 50.3% for serotype 1, 42.3% for serotype 2, 74.0% for serotype 3, and 77.7% for serotype 4. Among the severe VCD cases, 1 of 12 was in the vaccine group, for an intention-to-treat vaccine efficacy of 95.5%. Vaccine efficacy against hospitalization for dengue was 80.3%. The safety profile for the CYD-TDV vaccine was similar to that for placebo, with no marked difference in rates of adverse events. Conclusions The CYD-TDV dengue vaccine was efficacious against VCD and severe VCD and led to fewer hospitalizations for VCD in five Latin American countries where dengue is endemic. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01374516.)

Leptospirosis in Humans

Abstract: Leptospirosis is a widespread and potentially fatal zoonosis that is endemic in many tropical regions and causes large epidemics after heavy rainfall and flooding. Infection results from direct or indirect exposure to infected reservoir host animals that carry the pathogen in their renal tubules and shed pathogenic leptospires in their urine. Although many wild and domestic animals can serve as reservoir hosts , the brown rat (Rattus norvegicus) is the most important source of human infections. Individuals living in urban slum environments characterized by inadequate sanitation and poor housing are at high risk of rat exposure and leptospirosis. The global burden of leptospirosis is expected to rise with demographic shifts that favor increases in the number of urban poor in tropical regions subject to worsening storms and urban flooding due to climate change. Data emerging from prospective surveillance studies suggest that most human leptospiral infections in endemic areas are mild or asymptomatic. Development of more severe outcomes likely depends on three factors: epidemiological conditions, host susceptibility, and pathogen virulence (Fig. 1). Mortality increases with age, particularly in patients older than 60 years of age. High levels of bacteremia are associated with poor clinical outcomes and, based on animal model and in vitro studies, are related in part to poor recognition of leptospiral LPS by human TLR4. Patients with severe leptospirosis experience a cytokine storm characterized by high levels of IL-6, TNF-alpha, and IL-10. Patients with the HLA DQ6 allele are at higher risk of disease, suggesting a role for lymphocyte stimulation by a leptospiral superantigen. Leptospirosis typically presents as a nonspecific, acute febrile illness characterized by fever, myalgia, and headache and may be confused with other entities such as influenza and dengue fever. Newer diagnostic methods facilitate early diagnosis and antibiotic treatment. Patients progressing to multisystem organ failure have widespread hematogenous dissemination of pathogens. Nonoliguric (high output) renal dysfunction should be supported with fluids and electrolytes. When oliguric renal failure occurs, prompt initiation of dialysis can be life saving. Elevated bilirubin levels are due to hepatocellular damage and disruption of intercellular junctions between hepatocytes, resulting in leaking of bilirubin out of bile caniliculi. Hemorrhagic complications are common and are associated with coagulation abnormalities. Severe pulmonary hemorrhage syndrome due to extensive alveolar hemorrhage has a fatality rate of >50 %. Readers are referred to earlier, excellent summaries related to this subject (Adler and de la Pena-Moctezuma 2010; Bharti et al. 2003; Hartskeerl et al. 2011; Ko et al. 2009; Levett 2001; McBride et al. 2005).

Discovery of fifth serotype of dengue virus (DENV-5): A new public health dilemma in dengue control.

Abstract: Dengue fever is a re-emerging public health problem with two-fifths of the world population being at risk of infection. Till now, dengue fever was believed to be caused by four different serotypes. The fifth variant DENV-5 has been isolated in October 2013. This serotype follows the sylvatic cycle unlike the other four serotypes which follow the human cycle. The likely cause of emergence of the new serotype could be genetic recombination, natural selection and genetic bottlenecks. There is no indication of the presence of DENV-5 in India. Recent clinical trials with the promising Chimerivax tetravalent vaccine suffered a setback. Discovery of DENV-5 and more such sylvatic strains in future may further impede the Dengue Vaccine Initiative. Integrated Vector Management holds the key to sustainable dengue control. Further epidemiological and ecological studies are needed to detect additional sylvatic dengue strains.

Impact of human mobility on the emergence of dengue epidemics in Pakistan

Abstract: The recent emergence of dengue viruses into new susceptible human populations throughout Asia and the Middle East, driven in part by human travel on both local and global scales, represents a significant global health risk, particularly in areas with changing climatic suitability for the mosquito vector. In Pakistan, dengue has been endemic for decades in the southern port city of Karachi, but large epidemics in the northeast have emerged only since 2011. Pakistan is therefore representative of many countries on the verge of countrywide endemic dengue transmission, where prevention, surveillance, and preparedness are key priorities in previously dengue-free regions. We analyze spatially explicit dengue case data from a large outbreak in Pakistan in 2013 and compare the dynamics of the epidemic to an epidemiological model of dengue virus transmission based on climate and mobility data from ∼40 million mobile phone subscribers. We find that mobile phone-based mobility estimates predict the geographic spread and timing of epidemics in both recently epidemic and emerging locations. We combine transmission suitability maps with estimates of seasonal dengue virus importation to generate fine-scale dynamic risk maps with direct application to dengue containment and epidemic preparedness.

A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus

Abstract: Dengue is a rapidly emerging, mosquito-borne viral infection, with an estimated 400 million infections occurring annually. To gain insight into dengue immunity, we characterized 145 human monoclonal antibodies (mAbs) and identified a previously unknown epitope, the envelope dimer epitope (EDE), that bridges two envelope protein subunits that make up the 90 repeating dimers on the mature virion. The mAbs to EDE were broadly reactive across the dengue serocomplex and fully neutralized virus produced in either insect cells or primary human cells, with 50% neutralization in the low picomolar range. Our results provide a path to a subunit vaccine against dengue virus and have implications for the design and monitoring of future vaccine trials in which the induction of antibody to the EDE should be prioritized.

Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination

Abstract: The four dengue virus serotypes (DENV1 to DENV4) are mosquito-borne flaviviruses that cause up to ~100 million cases of dengue annually worldwide. Severe disease is thought to result from immunopathogenic processes involving serotype cross-reactive antibodies and T cells that together induce vasoactive cytokines, causing vascular leakage that leads to shock. However, no viral proteins have been directly implicated in triggering endothelial permeability, which results in vascular leakage. DENV nonstructural protein 1 (NS1) is secreted and circulates in patients' blood during acute infection; high levels of NS1 are associated with severe disease. We show that inoculation of mice with DENV NS1 alone induces both vascular leakage and production of key inflammatory cytokines. Furthermore, simultaneous administration of NS1 with a sublethal dose of DENV2 results in a lethal vascular leak syndrome. We also demonstrate that NS1 from DENV1, DENV2, DENV3, and DENV4 triggers endothelial barrier dysfunction, causing increased permeability of human endothelial cell monolayers in vitro. These pathogenic effects of physiologically relevant amounts of NS1 in vivo and in vitro were blocked by NS1-immune polyclonal mouse serum or monoclonal antibodies to NS1, and immunization of mice with NS1 from DENV1 to DENV4 protected against lethal DENV2 challenge. These findings add an important and previously overlooked component to the causes of dengue vascular leak, identify a new potential target for dengue therapeutics, and support inclusion of NS1 in dengue vaccines.

Asymptomatic humans transmit dengue virus to mosquitoes

Abstract: Three-quarters of the estimated 390 million dengue virus (DENV) infections each year are clinically inapparent. People with inapparent dengue virus infections are generally considered dead-end hosts for transmission because they do not reach sufficiently high viremia levels to infect mosquitoes. Here, we show that, despite their lower average level of viremia, asymptomatic people can be infectious to mosquitoes. Moreover, at a given level of viremia, DENV-infected people with no detectable symptoms or before the onset of symptoms are significantly more infectious to mosquitoes than people with symptomatic infections. Because DENV viremic people without clinical symptoms may be exposed to more mosquitoes through their undisrupted daily routines than sick people and represent the bulk of DENV infections, our data indicate that they have the potential to contribute significantly more to virus transmission to mosquitoes than previously recognized.

Standard operating procedures for standardized mass rearing of the dengue and chikungunya vectors Aedes aegypti

Abstract: BackgroundManagement of large quantities of eggs will be a crucial aspect of the efficient and sustainable mass production of mosquitoes for programmes with a Sterile Insect Technique component. The efficiency of different hatching media and effectiveness of long term storage methods are presented here.MethodsThe effect on hatch rate of storage duration and three hatching media was analysed: deionized water, boiled deionized water and a bacterial broth, using Two-way ANOVA and Post hoc Tukey tests, and the Pearson correlation coefficient was used to find the effect on the proportion of collapsed eggs. Two long term storage methods were also tested: conventional storage (egg paper strips stored in zip lock bags within a sealed plastic box), and water storage (egg papers in a covered plastic cup with deionized water). Regression analyses were used to find the effect of water storage and storage duration on hatch rate.ResultsBoth species hatched most efficiently in bacterial broth. Few eggs hatched in deionized water, and pre-boiling the water increased the hatch rate of Ae. aegypti, but not Ae. albopictus. A hatch rate greater than 80 % was obtained after 10 weeks of conventional storage in Ae. aegypti and 11 weeks in Ae. albopictus. After this period, hatching decreased dramatically; no eggs hatched after 24 weeks. Storing eggs in water produced an 85 % hatch rate after 5 months in both species. A small but significant proportion of eggs hatched in the water, probably due to combined effects of natural deoxygenation of the water over time and the natural instalment hatching typical of the species.ConclusionsThe demonstrated efficiency of the bacterial broth hatching medium for both Ae. albopictus and Ae. aegypti facilitates mass production of these two important vector species in the same facility, with use of a common hatching medium reducing cost and operational complexity. Similarly the increased hatch rate of eggs stored in water would allow greater flexibility of egg management in a large programme over the medium term, particularly if oxygenation of the water by bubbling oxygen through the storage tray could be applied to prevent hatching during storage.

Co-infection with Zika and Dengue Viruses in 2 Patients, New Caledonia, 2014

Abstract: To the Editor: Dengue is the most prevalent arthropod-borne viral disease in tropical and subtropical countries. Every year, dengue virus (DENV) infections cause more than 50 million cases, 500,000 hospitalizations, and 12,500 deaths worldwide (1). DENV belongs to the genus Flavivirus and is transmitted by Aedes spp. mosquitoes. There are 4 distinct serotypes (DENV-1 to DENV-4), and infection with 1 serotype does not provide long-term, cross-protective immunity against the other 3 serotypes. In New Caledonia, DENV outbreaks have occurred since World War II and have been caused mainly by 1 serotype/genotype introduced from a country to which dengue is hyperendemic. Since 2000, New Caledonia has had recurrent DENV-1 outbreaks (2). In 2014, circulation of DENV-1 and DENV-3 was still reported in this country (3). Zika virus (ZIKV) is an emerging mosquito-borne virus that belongs to the genus Flavivirus and was first isolated in Uganda (4). ZIKV is believed to be transmitted to humans by Aedes spp. mosquitoes. Before 2007, few human cases of infection had been reported. In 2007, the first Zika epidemic occurred in Yap, Federated States of Micronesia (5). In October 2013, a ZIKV outbreak was reported in French Polynesia (6). In New Caledonia, the first cases of ZIKV infection imported from French Polynesia were confirmed at the end of November 2013, and the first autochthonous cases were reported by mid-January 2014. Early in February 2014, the New Caledonia Health Authority declared an outbreak situation. Since February 2014, a total of 1,385 ZIKV laboratory-confirmed cases have been detected, including 35 imported cases (32 from French Polynesia, 2 from Vanuatu, and 1 from the Cook Islands). Concomitant with this ZIKV outbreak, circulation of DENV-1 and DENV-3 was reported; >150 cases were biologically confirmed during January–September 2014 (3). Thus, New Caledonia currently has 3 arboviruses co-circulating. In recent years, co-circulation of multiple DENV serotypes or DENV and chikungunya virus has been reported. Although rare co-infections have been identified (7,8), given the similar clinical features and lack of concurrent testing, co-infections might not be identified. We report detection of ZIKV and DENV genomes in serum of a traveler (patient 1) who returned from French Polynesia where ZIKV and DENV were co-circulating (6,9) and in serum of a person (patient 2) in New Caledonia who had no travel history. The traveler was co-infected with ZIKV and DENV-3, and the local patient was co-infected with ZIKV and DENV-1. Patient 1 was a 14-year-old boy who had fever (39.5°C), headache, arthralgia, asthenia, and myalgia. No hemorrhagic or neurologic findings were reported, and the patient recovered within 3 days. A complete blood count showed mild thrombocytopenia (platelet count 129 × 109 platelets/L; reference range 150–400 × 109 platelets/L), leukopenia (leukocyte count 2.75 × 109 cells/L; reference range 4–10 × 109 cells/L) with associated stimulated lymphocytes, and discreet hepatic cytolysis (aspartate aminotransferase 55 IU/L; reference value <34 UI/L, and alanine aminotransferase 51 IU/L; reference value <55 IU/L). Serum was analyzed by using real-time reverse transcription PCR (RT-PCR) and was positive for ZIKV as recommended by Lanciotti et al. (5) and DENV-3. Patient 2 was a 38-year-old woman who had fever (40°C), headache, arthralgia, asthenia, myalgia, retroorbital pain, conjunctivitis, diarrhea, nausea, and a diffuse pruritic maculopapular rash. No hemorrhagic or neurologic findings were reported, but signs of illness lasted ≈1 week. The patient had mild thrombocytopenia (platelet count 123 × 109 platelets/L) and leukopenia (leukocyte count 2.65 × 109 cells/L). Serum was analyzed by using RT-PCR (5) and was positive for ZIKV and DENV-1. Co-infections were assessed by sequencing partial ZIKV membrane–envelope gene regions for isolates (GenBank accession nos. {"type":"entrez-nucleotide","attrs":{"text":"KM212963","term_id":"746873133","term_text":"KM212963"}}KM212963 and {"type":"entrez-nucleotide","attrs":{"text":"KM212967","term_id":"746873141","term_text":"KM212967"}}KM212967) from both patients, partial DENV-1 envelope gene for an isolate ({"type":"entrez-nucleotide","attrs":{"text":"KM212960","term_id":"746873127","term_text":"KM212960"}}KM212960) from patient 2, and partial DENV-3 nonstructural protein 5 gene for an isolate ({"type":"entrez-nucleotide","attrs":{"text":"KM212962","term_id":"746873131","term_text":"KM212962"}}KM212962) from patient 1. Sequencing was conducted at La Plateforme du Vivant (Noumea, New Caledonia). DENV-1 sequence obtained belonged to genotype I and clustered with DENV-1 sequences isolated in New Caledonia (2). DENV-3 sequence obtained belonged to genotype III, similar to DENV-3 recently isolated in French Polynesia (9). ZIKV sequences obtained belonged to the Asian lineage and had 99% identity with sequences of ZIKV isolated in French Polynesia in 2013 (10). Serum specimens from both patients were cultured on Vero cells, and supernatants were evaluated by RT-PCR. Each specimen was positive only for DENV, which was probably caused by low viral loads for ZIKV. We report co-infection of 2 patients with DENV and ZIKV; each patient was infected with a different DENV serotype. No synergistic effects of the 2 viral infections were observed because both patients were not hospitalized and recovered after a mild clinical course. During this outbreak, patients in New Caledonia were tested for DENV, chikungunya virus, and ZIKV within the framework of the arboviruses sentinel network, which enabled detection of co-infections. Thus, clinicians should be aware of infections with multiple pathogens in the differential diagnosis of dengue-like illness, especially in patients who returned from tropical regions. This diagnostic procedure could be improved by using multiplex RT-PCR for travelers, given the frequent co-circulation of multiple arboviruses in tropical regions.

New insights into the immunopathology and control of dengue virus infection

Abstract: Dengue virus poses a major threat to global public health: two-thirds of the world's population is now at risk from infection by this mosquito-borne virus. Dengue virus causes a range of diseases with a small proportion of infected patients developing severe plasma leakage that leads to dengue shock syndrome, organ impairment and bleeding. Infection with one of the four viral serotypes results in the development of homotypic immunity to that serotype. However, subsequent infection with a different serotype is associated with an increased risk of developing severe disease, which has led to the suggestion that severe disease is triggered by immunopathology. This Review outlines recent advances in the understanding of immunopathology, vaccine development and human monoclonal antibodies produced against dengue virus.

Recognition determinants of broadly neutralizing human antibodies against dengue viruses

Abstract: Dengue disease is caused by four different flavivirus serotypes, which infect 390 million people yearly with 25% symptomatic cases and for which no licensed vaccine is available. Recent phase III vaccine trials showed partial protection, and in particular no protection for dengue virus serotype 2 (refs 3, 4). Structural studies so far have characterized only epitopes recognized by serotype-specific human antibodies. We recently isolated human antibodies potently neutralizing all four dengue virus serotypes. Here we describe the X-ray structures of four of these broadly neutralizing antibodies in complex with the envelope glycoprotein E from dengue virus serotype 2, revealing that the recognition determinants are at a serotype-invariant site at the E-dimer interface, including the exposed main chain of the E fusion loop and the two conserved glycan chains. This 'E-dimer-dependent epitope' is also the binding site for the viral glycoprotein prM during virus maturation in the secretory pathway of the infected cell, explaining its conservation across serotypes and highlighting an Achilles' heel of the virus with respect to antibody neutralization. These findings will be instrumental for devising novel immunogens to protect simultaneously against all four serotypes of dengue virus.

Outbreak of Exanthematous Illness Associated with Zika, Chikungunya, and Dengue Viruses, Salvador, Brazil.

Abstract: To the Editor: Zika virus (ZIKV) has been recognized as an emerging mosquito-borne flavivirus since outbreaks were reported from Yap Island in 2007 (1), French Polynesia in 2013 (2), and Cook Island and New Caledonia in 2014 (3). It has joined dengue virus (DENV) and chikungunya virus (CHIKV) as global public health threats (4). ZIKV infection typically causes a self-limited dengue-like illness characterized by exanthema, low-grade fever, conjunctivitis, and arthralgia, and an increase in rates of Guillain-Barre syndrome have been observed during ZIKV outbreaks (5). In Brazil, clusters of cases of acute exanthematous illness have been reported from various regions since late 2014, and in April 2015, ZIKV was identified as the etiologic agent (6). In May 2015, the Brazilian Ministry of Health recognized circulation of ZIKV in Brazil. We report epidemiologic findings for an ongoing outbreak of acute exanthematous illness in the population of Salvador, the third largest city in Brazil. The Salvador Epidemiologic Surveillance Office (ESO) was first alerted to cases of an acute exanthematous illness early in 2015. Reporting of cases increased during March, and in April the ESO established 10 public emergency health centers in Salvador as sentinel units for systematic surveillance of patients with acute exanthematous illness of unknown cause. The units searched retrospectively for suspected cases by review of medical charts of patients treated since February 15, continued with prospective case detection, and submitted weekly reports of identified cases to the ESO. During February 15−June 25, a total of 14,835 cases of an indeterminate acute exanthematous illness were reported from the 12 sanitary districts in Salvador. The overall attack rate was 5.5 cases/1,000 persons (4.6 cases/1,000 men and 6.3 cases/1,000 women, 8.2 cases/1,000 children 40 years of age). The epidemic curve peaked in the first week of May, which was 1 week after molecular diagnosis of ZIKV in 8 patients residing ≈50 km from Salvador and during a period of intense media coverage of the outbreak (Figure) (6). Reporting of suspected dengue cases in Salvador did not vary substantially from that in other years and was >5 times lower: 2,630 cases, of which 165/366 (45.1%) were positive for dengue IgM, 20/590 (3.4%) positive for dengue virus nonstructural protein 1, and 1/11 (9.1%) positive for dengue virus by reverse transcription PCR (Figure). During the same period, 58 cases of suspected chikungunya were reported and 24 patients with suspected Guillain-Barre syndrome were hospitalized. Figure Reported cases of indeterminate acute exanthematous illness and suspected dengue fever in Salvador, Brazil, by date of medical care, February 15−June 25, 2015. Letters indicate specific events. A) February 15: systematic reporting of cases of ... The median age of case-patients was 26 years (interquartile range 11–39 years), but all age groups were affected, which is a pattern typical of spread of new microorganisms (or subtypes) in a susceptible population. Median duration of symptoms at time of medical attention was 1 day (interquartile range 0–3 days). All patients had exanthema and most (12,711/14,093 [90.2%]) had pruritus. Fever (4,841/13,786, 35.1%), arthralgia (278/1,048 [26.5%]), headache (3,446/13,503 [25.6%]), and myalgia (223/1,033 [21.6%]) were less common. Serum samples from some patients were examined for rubella IgM (2/200, 1.0% positive), rubella IgG (15/18, 83.3% positive), measles IgM (0/11, 0% positive), dengue nonstructural protein 1 (3/185, 1.6% positive), dengue IgM (17/80, 21.3% positive), parvovirus B19 IgM (0/1, 0% positive), and parvovirus B19 IgG (1/1, 100% positive). Reverse transcription PCR was performed on 58 serum samples stored at −20°C and confirmed ZIKV in 3 (5.2%) samples, CHIKV in 3 (5.2%) samples, DENV type 3 in 1 (1.7%) sample, and DENV type 4 in 1 (1.7%) sample. Identification of ZIKV, CHIKV and DENV as etiologic agents of acute exanthematous illness suggests that these 3 Aedes spp. mosquito−transmitted viruses were co-circulating in Salvador and highlights the challenge in clinically differentiating these infections during outbreaks. Although we were not able to determine the specific incidence of each virus, the low frequency of fever and arthralgia, which are indicators of dengue and chikungunya, point to ZIKV as the probable cause of several of the reported cases. Furthermore, laboratory-confirmed cases of infection with ZIKV were simultaneously identified in other cities within metropolitan Salvador (6,7) and in other states in Brazil (8). Low diagnosis of ZIKV infection is likely because viremia levels among infected patients appear to be low (9). The spread of ZIKV represents an additional challenge for public health systems, particularly because of the risk for concurrent transmission of DENV and CHIKV by the same vectors, Ae. aegypti and Ae. albopictus mosquitoes, which are abundant throughout tropical and subtropical regions. To date, the largest outbreak of chikungunya in Brazil occurred in 2014 in Feira de Santana, Bahia, ≈100 km from Salvador, where dengue is also prevalent (10). This report illustrates the potential for explosive simultaneous outbreaks of ZIKV, CHIKV, and DENV in the Western Hemisphere and the increasing public health effects of Aedes spp. mosquitoes as vectors. The apparent increase in reports of Guillain-Barre syndrome during the outbreak deserves further investigation to elucidate whether this syndrome is associated with ZIKV infection. Public health authorities in Brazil and neighboring countries should plan accordingly.

Dengue virus infection elicits highly polarized CX3CR1+ cytotoxic CD4+ T cells associated with protective immunity.

Abstract: Dengue virus (DENV) is a rapidly spreading pathogen with unusual pathogenesis, and correlates of protection from severe dengue disease and vaccine efficacy have not yet been established. Although DENV-specific CD8+ T-cell responses have been extensively studied, the breadth and specificity of CD4+ T-cell responses remains to be defined. Here we define HLA-restricted CD4+ T-cell epitopes resulting from natural infection with dengue virus in a hyperepidemic setting. Ex vivo flow-cytometric analysis of DENV-specific CD4+ T cells revealed that the virus-specific cells were highly polarized, with a strong bias toward a CX3CR1+ Eomesodermin+ perforin+ granzyme B+ CD45RA+ CD4 CTL phenotype. Importantly, these cells correlated with a protective HLA DR allele, and we demonstrate that these cells have direct ex vivo DENV-specific cytolytic activity. We speculate that cytotoxic dengue-specific CD4+ T cells may play a role in the control of dengue infection in vivo, and this immune correlate may be a key target for dengue virus vaccine development.

Zika virus in Brazil and the danger of infestation by Aedes (Stegomyia) mosquitoes

Abstract: Zika virus, already widely distributed in Africa and Asia, was recently reported in two Northeastern Brazilian: State of Bahia and State of Rio Grande do Norte, and one Southeastern: State of Sao Paulo. This finding adds a potentially noxious virus to a list of several other viruses that are widely transmitted by Aedes (Stegomyia) aegypti and Aedes (Stegomyia) albopictus in Brazil. The pathology and epidemiology, including the distribution and vectors associated with Zika virus, are reviewed. This review is focused on viruses transmitted by Aedes (Stegomyia) mosquitoes, including dengue, Chikungunya, Zika, Mayaro, and yellow fever virus, to emphasize the risks of occurrence for these arboviruses in Brazil and neighboring countries. Other species of Aedes (Stegomyia) are discussed, emphasizing their involvement in arbovirus transmission and the possibility of adaptation to environments modified by human activities and introduction in Brazil.

Modeling the impact on virus transmission of Wolbachia-mediated blocking of dengue virus infection of Aedes aegypti

Abstract: Dengue is the most common arboviral infection of humans and is a public health burden in more than 100 countries. Aedes aegypti mosquitoes stably infected with strains of the intracellular bacterium Wolbachia are resistant to dengue virus (DENV) infection and are being tested in field trials. To mimic field conditions, we experimentally assessed the vector competence of A. aegypti carrying the Wolbachia strains wMel and wMelPop after challenge with viremic blood from dengue patients. We found that wMelPop conferred strong resistance to DENV infection of mosquito abdomen tissue and largely prevented disseminated infection. wMel conferred less resistance to infection of mosquito abdomen tissue, but it did reduce the prevalence of mosquitoes with infectious saliva. A mathematical model of DENV transmission incorporating the dynamics of viral infection in humans and mosquitoes was fitted to the data collected. Model predictions suggested that wMel would reduce the basic reproduction number, R0, of DENV transmission by 66 to 75%. Our results suggest that establishment of wMelPop-infected A. aegypti at a high frequency in a dengue-endemic setting would result in the complete abatement of DENV transmission. Establishment of wMel-infected A. aegypti is also predicted to have a substantial effect on transmission that would be sufficient to eliminate dengue in low or moderate transmission settings but may be insufficient to achieve complete control in settings where R0 is high. These findings develop a framework for selecting Wolbachia strains for field releases and for calculating their likely impact.

The changing epidemiology of dengue in China, 1990-2014: a descriptive analysis of 25 years of nationwide surveillance data

Abstract: Dengue has been a notifiable disease in China since 1 September 1989. Cases have been reported each year during the past 25 years of dramatic socio-economic changes in China, and reached a historical high in 2014. This study describes the changing epidemiology of dengue in China during this period, to identify high-risk areas and seasons and to inform dengue prevention and control activities. We describe the incidence and distribution of dengue in mainland China using notifiable surveillance data from 1990-2014, which includes classification of imported and indigenous cases from 2005-2014. From 1990-2014, 69,321 cases of dengue including 11 deaths were reported in mainland China, equating to 2.2 cases per one million residents. The highest number was recorded in 2014 (47,056 cases). The number of provinces affected has increased, from a median of three provinces per year (range: 1 to 5 provinces) during 1990-2000 to a median of 14.5 provinces per year (range: 5 to 26 provinces) during 2001-2014. During 2005-2014, imported cases were reported almost every month and 28 provinces (90.3%) were affected. However, 99.8% of indigenous cases occurred between July and November. The regions reporting indigenous cases have expanded from the coastal provinces of southern China and provinces adjacent to Southeast Asia to the central part of China. Dengue virus serotypes 1, 2, 3, and 4 were all detected from 2009-2014. In China, the area affected by dengue has expanded since 2000 and the incidence has increased steadily since 2012, for both imported and indigenous dengue. Surveillance and control strategies should be adjusted to account for these changes, and further research should explore the drivers of these trends. Please see related article: http://dx.doi.org/10.1186/s12916-015-0345-0

Thrombocytopenia in Dengue: Interrelationship between Virus and the Imbalance between Coagulation and Fibrinolysis and Inflammatory Mediators

Abstract: Dengue is an infectious disease caused by dengue virus (DENV). In general, dengue is a self-limiting acute febrile illness followed by a phase of critical defervescence, in which patients may improve or progress to a severe form. Severe illness is characterized by hemodynamic disturbances, increased vascular permeability, hypovolemia, hypotension, and shock. Thrombocytopenia and platelet dysfunction are common in both cases and are related to the clinical outcome. Different mechanisms have been hypothesized to explain DENV-associated thrombocytopenia, including the suppression of bone marrow and the peripheral destruction of platelets. Studies have shown DENV-infected hematopoietic progenitors or bone marrow stromal cells. Moreover, anti-platelet antibodies would be involved in peripheral platelet destruction as platelets interact with endothelial cells, immune cells, and/or DENV. It is not yet clear whether platelets play a role in the viral spread. Here, we focus on the mechanisms of thrombocytopenia and platelet dysfunction in DENV infection. Because platelets participate in the inflammatory and immune response by promoting cytokine, chemokine, and inflammatory mediator secretion, their relevance as “immune-like effector cells” will be discussed. Finally, an implication for platelets in plasma leakage will be also regarded, as thrombocytopenia is associated with clinical outcome and higher mortality.

Dengue Serotype-Specific Differences in Clinical Manifestation, Laboratory Parameters and Risk of Severe Disease in Adults, Singapore

Abstract: Studies on serotype-specific features of dengue and disease severity on adults are limited. We prospectively recruited adult febrile patients without alternate diagnosis to dengue from April 2005 to December 2011. Outcomes were defined using both the World Health Organization (WHO) 1997 and 2009 criteria; Dengue hemorrhagic fever (DHF) and severe dengue (SD). Infecting serotype was identified in 469 dengue-confirmed patients comprising 22.0% dengue virus serotype 1 (DENV-1), 57.1% DENV-2, 17.1% DENV-3, and 3.8% DENV-4. Cases infected with DENV-1 were more likely to present with red eyes whereas presence of joint pain and lower platelet count was associated with DENV-2 cases. After adjusting for potential confounders, DENV-1 was associated with both DHF (adjusted Relative Risk (aRR) = 1.74) and SD (aRR = 2.1) whereas DENV-2 had a lower risk of DHF (aRR = 0.5). DENV-1 genotype 1 and DENV-2 cosmopolitan were the predominant genotypes identified. Infecting dengue serotype and possibly genotype may play an important role in disease severity among adult dengue patients in Singapore.

Dengue and its effects on liver.

Abstract: Dengue has emerged as an important arboviral disease with significant impact on the disease burden in population residing in tropical countries. Dengue is spread by the bite of Aedes mosquito. The virus seems to have some hepatotoxic effects. Affliction of liver in form of derangements in the liver function tests is common and may include mild elevations in serum bilirubin, elevated transaminases and derangements in serum albumin. Although asymptomatic in most cases, clinical manifestations like jaundice, and acute liver failure (ALF) may occasionally complicate the clinical picture. Indeed, dengue has been implicated as an important cause of ALF in endemic countries. The present review focuses on the hepatic manifestations and the pathogenesis of the liver injury in dengue.

Reappearance of Chikungunya, Formerly Called Dengue, in the Americas

Abstract: After an absence of ≈200 years, chikungunya returned to the American tropics in 2013. The virus is maintained in a complex African zoonotic cycle but escapes into an urban cycle at 40- to 50-year intervals, causing global pandemics. In 1823, classical chikungunya, a viral exanthem in humans, occurred on Zanzibar, and in 1827, it arrived in the Caribbean and spread to North and South America. In Zanzibar, the disease was known as kidenga pepo, Swahili for a sudden cramp-like seizure caused by an evil spirit; in Cuba, it was known as dengue, a Spanish homonym of denga. During the eighteenth century, dengue (present-day chikungunya) was distinguished from breakbone fever (present-day dengue), another febrile exanthem. In the twentieth century, experiments resulted in the recovery and naming of present-day dengue viruses. In 1952, chikungunya virus was recovered during an outbreak in Tanzania, but by then, the virus had lost its original name to present-day dengue viruses.

The human CD8+ T cell responses induced by a live attenuated tetravalent dengue vaccine are directed against highly conserved epitopes

Abstract: The incidence of infection with any of the four dengue virus serotypes (DENV1 to -4) has increased dramatically in the last few decades, and the lack of a treatment or vaccine has contributed to significant morbidity and mortality worldwide. A recent comprehensive analysis of the human T cell response against wild-type DENV suggested an human lymphocyte antigen (HLA)-linked protective role for CD8+ T cells. We have collected one-unit blood donations from study participants receiving the monovalent or tetravalent live attenuated DENV vaccine (DLAV), developed by the U.S. National Institutes of Health. Peripheral blood mononuclear cells from these donors were screened in gamma interferon enzyme-linked immunosorbent spot assays with pools of predicted, HLA-matched, class I binding peptides covering the entire DENV proteome. Here, we characterize for the first time CD8+ T cell responses after live attenuated dengue vaccination and show that CD8+ T cell responses in vaccinees were readily detectable and comparable to natural dengue infection. Interestingly, whereas broad responses to structural and nonstructural (NS) proteins were observed after monovalent vaccination, T cell responses following tetravalent vaccination were, dramatically, focused toward the highly conserved NS proteins. Epitopes were highly conserved in a vast variety of field isolates and able to elicit multifunctional T cell responses. Detailed knowledge of the T cell response will contribute to the identification of robust correlates of protection in natural immunity and following vaccination against DENV. IMPORTANCE The development of effective vaccination strategies against dengue virus (DENV) infection and clinically significant disease is a task of high global public health value and significance, while also being a challenge of significant complexity. A recent efficacy trial of the most advanced dengue vaccine candidate, demonstrated only partial protection against all four DENV serotypes, despite three subsequent immunizations and detection of measurable neutralizing antibodies to each serotype in most subjects. These results challenge the hypothesis that seroconversion is the only reliable correlate of protection. Here, we show that CD8+ T cell responses in vaccinees were readily detectable and comparable to natural dengue virus infection. Detailed knowledge of the T cell response may further contribute to the identification of robust correlates of protection in natural immunity and vaccination against DENV.

Economic Impact of Dengue: Multicenter Study across Four Brazilian Regions

Abstract: Dengue is an increasing public health concern in Brazil. There is a need for an updated evaluation of the economic impact of dengue within the country. We undertook this multicenter study to evaluate the economic burden of dengue in Brazil.

Wolbachia Reduces the Transmission Potential of Dengue-Infected Aedes Aegypti

Abstract: Background Dengue viruses (DENV) are the causative agents of dengue, the world's most prevalent arthropod-borne disease with around 40% of the world's population at risk of infection annually. Wolbachia pipientis, an obligate intracellular bacterium, is being developed as a bio-control strategy against dengue because it limits replication of the virus in the mosquito. The Wolbachia strain wMel, which has been introduced into the mosquito vector, Aedes aegypti, has been shown to invade and spread to near fixation in field releases. Standard measures of Wolbachia's efficacy for blocking virus replication focus on the detection and quantification of virus in mosquito tissues. Examining the saliva provides a more accurate measure of transmission potential and can reveal the extrinsic incubation period (EIP), that is, the time it takes virus to arrive in the saliva following the consumption of DENV viremic blood. EIP is a key determinant of a mosquito's ability to transmit DENVs, as the earlier the virus appears in the saliva the more opportunities the mosquito will have to infect humans on subsequent bites.