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PubMed2005

Dengue vaccines: problems and prospects.

The extent of cumulative disease burden caused by dengue virus has attained an unprecedented level in recent times with sharp increase in the size of human population at risk. Dengue disease presents highly complex medical, economic and ecologic problems. The surge in publications on the development of dengue vaccines, taking advantage of new generation of biotechnology techniques indicates the profound interest and urgency in the scientific and medical communities in combating this disease. This review summarizes the importance of critical subjects like pathogenesis of dengue haemorrhagic fever and inadequacy of animal model that have adversely affected dengue vaccine development. Further, the remarkable progresses so far made in dengue vaccine research not only employing a diverse range of new strategies but also re-using old techniques to improve the existing vaccines, have been presented. The efficacy and safety of some of the new vaccine candidates have been evaluated and proven in human preclinical/clinical trials. Besides the technical advancement in vaccine development, vaccine safety and vaccine formulation have been examined.

Animals↗
PubMed2004

First case of Dengue virus infection in Nepal.

Dengue virus transmitted by Aedes mosquito is one of the important cause health problems in world. Dengue fever and more severe and often fatal forms namely dengue hemorrhagic fever and dengue shock syndrome are emerging health problems in many part of the globe. No cases of Dengue virus infection have been reported from Nepal till date and for the first time, we report a case of dengue fever from Nepal.

Adult↗
PubMed2006

Induction of neutralizing antibodies specific to dengue virus serotypes 2 and 4 by a bivalent antigen composed of linked envelope domains III of these two serotypes.

There is no vaccine to prevent dengue fever, a mosquito-borne viral disease, caused by four serotypes of dengue viruses. In this study, which has been prompted by the emergence of dengue virus envelope domain III as a promising sub-unit vaccine candidate, we have examined the possibility of developing a chimeric bivalent antigen with the potential to elicit neutralizing antibodies against two serotypes simultaneously. We created a chimeric dengue antigen by splicing envelope domain IIIs of serotypes 2 and 4. It was expressed in Escherichia coli and purified to near homogeneity. This protein retains the antigenic identities of both its precursors. It elicited antibodies that could efficiently block host cell binding of both serotypes 2 and 4 of dengue virus and neutralize their infectivity (neutralizing antibody titers approximately 1:40 and ~1:80 for dengue virus serotypes 2 and 4, respectively). This work could be a forerunner to the development of a single envelope domain III-based tetravalent antigen.

Animals↗
PubMed2006

Aedes aegypti vectorial capacity is determined by the infecting genotype of dengue virus.

Dengue viruses causing severe, hemorrhagic disease have displaced less virulent strains in the Americas during the past three decades. The American (AM) genotype of dengue serotype 2 has been endemic in the Western Hemisphere and South Pacific, causing outbreaks of dengue fever (DF), but has not been linked to dengue hemorrhagic fever (DHF). The Southeast Asian (SEA) genotype of dengue was introduced into this hemisphere in 1981, has caused outbreaks with numerous cases of DHF, and has displaced the AM genotype in several countries. We investigated the effect of viral genotype on the potential for transmission by infecting Aedes aegypti mosquitoes collected in South Texas with six viruses, representing these two genotypes. Viral replication in the midgut was significantly higher in SEA-infected mosquitoes, and virus-specific proteins could be detected in salivary glands 7 days earlier in SEA- than AM-infected mosquitoes. This much earlier appearance of dengue virus in salivary glands resulted in an estimated 2- to 65-fold increase in the vectorial capacity of these mosquitoes for the viruses that can cause DHF. This may be one of the mechanisms through which more virulent flaviviruses spread and displace others globally.

Aedes↗
PubMed1991

Outbreak of dengue fever in rural areas of Parbhani district of Maharashtra (India).

Outbreak of dengue fever in Chikalthana, Pimpalgaon and Waloor villages in Parbhani district of Maharashtra (India) were investigated. Clinically, the illness was typical of dengue fever except for the absence of maculopapular rash. A total of 42 acute, 14 late acute, 73 convalescent and 19 sera from contacts were collected. Of the 15 virus isolates, 12 were identified as dengue virus type 2 and 1 as dengue virus type 1. Serological tests confirmed the etiological role of dengue virus in the outbreak. House-to-house survey was carried out in Chikalthana and Pimpalgaon villages. Overall, 15.09 per cent of the surveyed population was affected during the outbreak and attack rate was higher at Pimpalgaon. A tendency of water storage was observed in the households and concomitant entomological studies proved Aedes aegypti breeding. Higher prevalence of dengue fever was noted among larger families and in families that had two or more patients, the commonest duration between the first and the last patient was often less than 5 days.

Antibodies, Viral↗
PubMedDate not supplied

[Dengue outbreak by virus type 4 in French Polynesia. II. Preliminary biological observations on epidemiology and physiopathology of the disease (author's transl)].

Authors report some accurate epidemiologic and physiopathologic data about dengue 4. Thanks to virus intrathoracic inoculation in Toxorhynchites amboinensis (Doleshall, 1857), 202 viral strains have been isolated from 633 sera samples. The incidence of the disease has decreased very early after immunization of the whole population and resulted in an eradication of dengue type 1 virus which was endemic in French Polynesia since 1976. Only one type of dengue virus seems to be tolerated in French Polynesian ecosystem in the same time. There is no crossing protection with dengue 1. Clinically, the picture has been the same in both new and previously infected by dengue 1 patients. Duration of viremia during the secondary dengue fever is not shorter than in the primary one. The hemagglutination inhibiting antibodies do not protect patients, but do not result in immune-complexes pathology.

Antibodies, Viral↗
PubMed1994

[Dengue 1 epidemic in the Grand Comoro Island (Federal Islamic Republic of the Comores). March-May 1993].

An epidemic of dengue fever occurred in Grande Comore island from March to May 1993. Dengue 1 virus has been isolated. The epidemic did not affect the other islands of the archipelago. No compound clinical picture, in particular hemorrhagic, was reported. A random sampling survey conducted towards the end of April showed that 26% of the population aged 5 years old or more had IgM dengue antibodies. The epidemic concerned essentially individuals under 45 years of age. The number of inhabitants of Grande Comore affected by the outbreak can be estimated between 56,000 and 75,000. The results of the sero-epidemiological survey allowed to find the serological scar of two previous epidemics of dengue: the first one around 1948, which may correspond with dengue 1, the other one in 1984, probably with dengue 2.

Adolescent↗
PubMed1993

Dengue in China: a clinical review.

Three etiologically proven outbreaks of dengue fever and one etiologically confirmed epidemic of dengue haemorrhagic fever have occurred in south China since 1978. The first of these, an epidemic of dengue due to virus type 4 took place in Shiwan town, Foshan city, Guangdong Province, in 1978; the epidemic began in May and ended in November. The clinical manifestations of 583 hospitalized patients were observed from August to October. The majority (81.3%) of patients were aged 21-50 years (male:female = 1.2:1). The course of illness was about 1 week in most cases; three patients (0.5%) died. A local outbreak of dengue due to virus type 1 occurred in Shiqi town, Zhongshan County, Guangdong Province, from September to November 1979. The majority of patients were older children and adolescents. There was no marked difference between males and females in terms of the course of the illness, and there were no complications or deaths. A large epidemic of dengue due to virus type 3 occurred on Hainan Island in 1980. The clinical manifestations of 510 hospitalized patients (mostly adolescents and adults) were observed from April to September. Some patients developed rare complications, such as loss of hair, acute intravascular haemolysis, and multiple peripheral paralysis; there were four deaths (0.78%). The first known epidemic of dengue haemorrhagic fever in China occurred among 10-29-year-olds on Hainan Island in 1985 and 1986. There were no essential differences between males and females. Some cases had rare complications such as acute intravascular haemolysis, while others had diffuse intravascular coagulation and altered mental status; 10 patients (6.5%) died.

Adolescent↗
PubMedDate not supplied

[Reflection on 2 current viral diseases: yellow fever and dengue].

Yellow fever and dengue are two current viral diseases induced by flaviviruses and usually transmitted by the same mosquito vector, Aedes aegypti. From 1987 to 1991, 18,753 cases of yellow fever, mainly from Africa, have been notified to WHO, leading to 4,522 deaths. On the other hand, WHO estimates that 2.5 billions individuals living in tropical areas are at risk to contract dengue fevers. In fact, 500,000 patients are hospitalized each year for dengue hemorrhagic fever/dengue shock syndrome and 90% of them are children. Nevertheless, the control of these two viral diseases would be reached easily in destroying mechanically the mosquito larval resting places. Although superficially similar, the two entities are in fact quite different. Relatively few is known about the pathogenesis of yellow fever whereas, for dengue fevers, it is difficult to integrate so many results accumulated to explain the occurrence of haemorrhagic phenomena according to the two main theories so far proposed which are not exclusive. The immunological one (S.B. Halstead) tries to explain the pathological events by the effect of anti-dengue enhancing antibodies acquired during a previous exposure to one of the dengue viruses, whereas that of increased virus virulence (L. Rosen) refers to fast passages between individuals during explosive epidemics.

Animals↗
PubMed1997

[Dengue in Panama, 1993].

Up to 1993, Panama was the only country in Central America where the autochthonous transmission of dengue virus had been detected without experimenting an explosive epidemic despite being reinfected with the Aedes aegypti mosquito since 1985. The characteristics of this first outbreak reported on November 19, 1993, are described in this paper. It is shown that even when there is a Program for the Surveillance and Control of Dengue, which considers low levels of Aedes aegypti infection and a system for the early detection of the virus, the epidemics appear if the community does not take an active part as it happened in 1994, 1995, and 1996. The 14 cases reported were located in an area under the responsibility of the Health Center in San Isidro, Belisario Porras, Special District of San Miguelito, in Panama City (13 cases in 4 blocks of the sector of Santa Librada and 1 case in San Isidro Valley). 3 patients were under 15 and 8 over 36, the other 3 were between 15 and 24.9 were females. The dengue type 2 virus was isolated in 3 patients. The presence of IgM and IgG antibodies to dengue was demonstrated in 11 patients, whereas in 8 over 20 it was observed a secondary type answer. According to the clinical picture, the epidemic was classified as dengue fever. The seroepidemiological survey carried out in the sector of Santa Librada and its surroundings 5 months after the appearance of the symptoms in the first case showed a prevalence of antibodies to dengue of 5.7% (46/802), mainly among individuals over 44. These results confirmed that the outbreak was geographically limited.

Adolescent↗
PubMed2026

Dengue and chikungunya vaccines past, present and future: implications for travelers.

PURPOSE OF REVIEW: Novel vaccines for dengue and chikungunya viruses offer new prevention options against two globally important arboviral diseases. This review summarizes recent developments in vaccine licensure, implementation, real-world experience and research priorities, with emphasis on implications for both endemic populations and travelers. RECENT FINDINGS: Of the three live-attenuated dengue vaccines licensed to date, TAK-003 is authorized in >40 countries and Butantan-DV in Brazil, while manufacturing of CYD-TDV is discontinued. Long-term and postmarketing data continue to refine understanding of serotype-specific protection, waning immunity, and rare adverse events.For chikungunya, two single-dose vaccines are licensed-a live-attenuated vaccine (VLA1553) and virus-like particle vaccine (PXVX0317). Uptake is guided by emerging safety and effectiveness data, with each platform offering potential advantages in different settings.Further data on long-term protection, safety, effectiveness, use in vulnerable populations and integration into outbreak management and immunization systems is anticipated. SUMMARY: Dengue and chikungunya vaccines are increasingly being used in immunization programs and pretravel consultations. Further real-world data are needed-particularly for seronegative dengue vaccine recipients and older, immunocompromised or medically at-risk adults. Research priorities include developing single-dose, nonlive dengue vaccines suitable for high-risk groups, understanding long-term chikungunya vaccine performance, and exploring broader flaviviral or pan-arboviral platforms.

Humans↗
PubMed1983

Dengue fever in the United States. A report of a cluster of imported cases and review of the clinical, epidemiologic, and public health aspects of the disease.

In the United States during 1981, fourteen state health departments reported a total of 44 imported cases of dengue fever. Most originated in the Caribbean, where dengue type 4 has reached pandemic proportions. Because the mosquito vector for dengue is abundant throughout the southeast and imported cases continue to occur, the possibility exists for indigenous dengue transmission. We report a cluster of imported dengue type 1 cases in Florida, discuss the clinical, epidemiologic, and public health aspects of the disease, and make recommendations as to how clinicians can assist public health officials in minimizing the risk of indigenous dengue transmission in the United States.

Adult↗
PubMed2000

Alteration of virus entry mode: a neutralisation mechanism for Dengue-2 virus.

Polyclonal antibodies derived from dengue virus immune sera and 3H5 monoclonal antibody showed potent neutralisation effect on dengue-2 virus in the plaque reduction neutralisation assay. This study demonstrated that antibodies present in immune human sera and 3H5 monoclonal antibody neutralised dengue-2 virus by altering the virus entry pathway into cells. In the presence of neutralising antibodies, dengue-2 virus was endocytosed by LLC-MK2 cells. The endocytosis process involved ruffling of antibody-coated virions by cellular pseudopodia and invagination of cell membrane. This mode of entry is atypical as compared to direct fusion of dengue-2 virus with cell membrane in the absence of antibody. The virions were internalised in the form of virion-antibody complexes consisting of single or clumps of virions. After 3 minutes of incubation, neutralised virions were detected in cellular vesicles, and signs of intra-endosomal penetration into cytoplasm were not evident even after a prolonged incubation of 10 minutes, suggesting that viral uncoating was compromised. Vesicle-bound virions were no longer detected after 20 minutes of incubation. In addition, no sign of viral replication was detected in cells infected with "neutralised" virions by immunofluorescence assay. This indicated that internalised virions had been degraded leading to abortive infection. In conclusion, antibodies present in 3H5 monoclonal antibody and human immune sera rendered dengue-2 virus non-infective by neutralising the viral fusion site and causing alteration of viral entry mode. Antibodies in immune sera but not 3H5 monoclonal antibody also exerted minimal inhibitory effect on virus binding and internalisation.

Antibodies, Monoclonal↗
PubMed2006

Corticosteroids for treating dengue shock syndrome.

BACKGROUND: Dengue shock syndrome is the most severe from of dengue haemorrhagic fever, one of the leading causes of death in children. Observational studies have suggested corticosteroids may benefit people with dengue shock syndrome. OBJECTIVES: To compare corticosteroids with placebo or no corticosteroids for treating dengue shock syndrome. SEARCH STRATEGY: We searched the Cochrane Infectious Disease Group Specialized Register (January 2006), CENTRAL (The Cochrane Library 2005, Issue 4), MEDLINE (1966 to January 2006), EMBASE, (1974 to January 2006), LILACS (1982 to January 2006), and reference lists. We also contacted researchers. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing corticosteroids with no corticosteroids or placebo in people diagnosed with dengue shock syndrome. DATA COLLECTION AND ANALYSIS: Two authors independently applied the inclusion criteria, extracted data, and assessed methodological quality. We calculated the relative risk (RR) for dichotomous data and weighted mean difference for continuous data, and presented them with 95% confidence intervals (CI). MAIN RESULTS: Four trials involving 284 participants met the inclusion criteria. Corticosteroids were no more effective than placebo or no treatment for reducing the number of deaths (RR 0.68, 95% CI 0.42 to 1.11; 284 participants, 4 trials), the need for blood transfusion (RR 1.08, 0.52 to 2.24; 89 participants, 2 trials), or the number of serious complications (convulsions and pulmonary haemorrhage) as reported in one trial (63 participants). AUTHORS' CONCLUSIONS: There is insufficient evidence to justify the use of corticosteroids in managing dengue shock syndrome. As corticosteroids can potentially do harm, clinicians should not use them unless they are participating in a randomized controlled trial comparing corticosteroids with placebo.

Adrenal Cortex Hormones↗
PubMed2004

Mosquito and mammalian cells grown on microcarriers for four-serotype dengue virus production: variations in virus titer, plaque morphology, and replication rate.

Dengue (DEN) viruses consisting of four distinct serotypes cause diseases such as dengue fever, dengue hemorrhagic fever, and dengue shock syndrome in humans. Most of the dengue viruses can be effectively propagated in some mosquito and mammalian cell lines. In this study, we applied microcarrier cell culture technology to study two relevant aspects involving dengue virus, one on biotechnology of cell growth and virus production, and the other on virus biology concerning genetic variation of a virus population. We investigated the growth of C6/36 mosquito cells and Vero cells grown on Cytodex 1 microcarriers. High-titer DEN virus production can be achieved in C6/36 and Vero cells infected at low cell inoculation density, in the lag-phase cell stage, and at low multiplicity of infection (MOI). The maximum titers produced for DEN-1, DEN-3, and DEN-4 viruses were approximately 10- to 10,000-fold lower than for DEN-2 virus produced in C6/36 and Vero cells grown on microcarriers. The DEN-2 virus produced in C6/36 cells displayed far more extensive plaque heterogeneity than in Vero cells. Microcarrier C6/36 mosquito cell culture appeared to be the most effective system for four-serotype DEN virus production. Interestingly, some selected variants of DEN virus may outgrow in Vero cells when using a T-flask culture. These results may provide useful information for DEN vaccine development.

Animals↗
PubMed2004

Early abdominal sonographic findings in patients with dengue fever.

PURPOSE: This study was conducted to evaluate the early sonographic findings in dengue hemorrhagic fever. METHODS: From July 2002 to September 2002, 86 patients were referred to our center with suspected dengue fever during an outbreak of the disease in Taiwan. All the patients underwent immediate abdominal sonography when they arrived at our emergency room. The diagnosis of dengue fever was subsequently confirmed by serology in 65 patients. RESULTS: All our patients had type 2 dengue fever, as confirmed by serologic tests. The sonographic features included a thickened gallbladder wall in 38 patients (59%), ascites in 24 patients (37%), splenomegaly in 22 patients (34%), and pleural effusion in 21 patients (32%); pleural effusion was either right-sided or bilateral. CONCLUSIONS: Abdominal sonography can be used as a first-line imaging modality in patients with suspected dengue fever to detect early signs suggestive of the disease prior to obtaining serologic confirmation test results, especially in a dengue fever epidemic area.

Abdomen, Acute↗
PubMed1997

Cytokine production by dengue virus antigen-responsive human T lymphocytes in vitro examined using a double immunocytochemical technique.

A number of studies suggest that cytokines may contribute to the pathogenesis of viral infections, including dengue. In this study, we developed a double immunocytochemical method and characterized cytokine-producing cells in the peripheral blood mononuclear cells (PBMC) of dengue virus-immune donors after in vitro stimulation with specific dengue antigens. We found that double immunostaining using immunoalkaline phosphatase (Vector blue) for cytokines [interferon-gamma (IFN-gamma), interleukin (IL) -2, -4, -1alpha, -1beta, and -6, tumor necrosis factor beta (TNF-beta), and TNF-alpha] and immunoperoxidase [diaminobenzidine (DAB)] for cell surface markers (CD3, CD4, CD8, CD20, and CD68) provided the best distinction of double-positive cells from single-positive or -negative cells. The number of IFN-gamma, IL-2, IL-4, and TNF-beta-positive cells increased 2 or 3 days after stimulation with specific dengue antigens. No or very few cytokine-producing cells were detected in the PBMC of non-immune donors stimulated with dengue antigens and the PBMC of immune donors stimulated with a control antigen. The analysis of cell surface markers showed that mainly CD4+ and CD8+ T cells produced these cytokines. The results obtained by immunocytochemistry were consistent with cytokine levels detected in the culture medium assayed by enzyme-linked immunosorbent assay. In conclusion, this double immunocytochemistry technique is suitable for the detection and characterization of cytokine-producing cells in PBMC. Furthermore, the results support the hypothesis that antigen-stimulated CD4+ and CD8+ T cells produce cytokines that may play a role in the pathogenesis of dengue virus infection.

Animals↗
PubMed2003

Supernatants from dengue virus type-2 infected macrophages induce permeability changes in endothelial cell monolayers.

The ability of dengue virus-infected human monocyte-derived macrophages to induce permeability changes in primary human umbilical vein endothelial cells was investigated. Supernatants from dengue virus type 2-infected monocyte-derived macrophages increased permeability in human umbilical vein endothelial cell monolayers without inducing endothelial cell infection. Production of permeabilising activity from monocyte-derived macrophages occurred after the peak of progeny virus release. TNF-alpha, a known inducer of endothelial cell permeability, was released from dengue virus infected monocyte-derived macrophages but its release did not coincide with release of endothelial cell permeabilising activity. Permeability induction was enhanced by pre-incubation with supernatants from infected monocyte-derived macrophages harvested at the time of peak release of TNF-alpha and infectious virus. Thus, supernatants from dengue virus-infected monocyte-derived macrophages contain factors that increase human umbilical vein endothelial cell permeability, but this is not accompanied by endothelial cell infection or directly correlated with release of dengue virus or TNF-alpha from monocyte-derived macrophages. This model system can be used for further in vitro analysis of mechanisms that may relate to capillary leakage and the development of dengue haemorrhagic fever/dengue shock syndrome.

Cell Membrane Permeability↗