Dengue Virus
Dengue is caused by Dengue virus (DENV), a mosquito-borne flavivirus. DENV is an single stranded RNA positive-strand virus of the family Flaviviridae, genus Flavivirus. This genus includes also the West Nile virus, Tick-borne Encephalitis Virus, Yellow Fever Virus, and several other viruses which may cause encephalitis. DENV causes a wide range of diseases in humans, from a self limited Dengue Fever (DF) to a life-threatening syndrome calledDengue Hemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS).
There are four antigenically different serotypes of the virus:
| DENV-1 | |
| DENV-2 | |
| DENV-3 | |
| DENV-4 |
Here, a serotype is a group of viruses classified together based on their antigens on the surface of the virus. These four subtypes are different strains of dengue virus that have 60-80% homology between each other. The major difference for humans lies in subtle differences in the surface proteins of the different dengue subtypes. Infection induces long-life protection against the infecting serotype, but it gives only a short time cross protective immunity against the other types. The first infection cause mostly minor disease, but secondary infections has been reported to cause severe diseases (DHF or DSS) in both children and adults. This fenomenon is called Antibody-Dependent Enhancement.
Figure 1. Dengue virus particle and microscopic picture of dengue viruses
DENV is a 50-nm virus enveloped with a lipid membrane (see figure 1). There are 180 identical copies of the envelope (E) protein attached to the surface of the viral membrane by a short transmembrane segment. The virus has a genome of about 11000 bases that encodes a single large polyprotein that is subsequently cleaved into several structural and non-structural mature peptides. The polyprotein is divided into three structural proteins, C, prM, E; seven nonstructural proteins, NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5; and short non-coding regions on both the 5' and 3' ends (see figure 2). The structural proteins are the capsid (C) protein, the envelope (E) glycoprotein and the membrane (M) protein, itself derived by furine-mediated cleavage from a prM precursor. The E glycoprotein is responsible for virion attachment to receptor and fusion of the virus envelope with the target cell membrane and bears the virus neutralization epitopes. In addition to the E glycoprotein, only one other viral protein, NS1, has been associated with a role in protective immunity. NS3 is a protease and a helicase, whereas NS5 is the RNA polymerase in charge of viral RNA replication.
Figure 2. Dengue virus genome structure with the structural and nonstructural genes
The life cycle of dengue involves endocytosis via a cell surface receptor (see video 1 and figure 3). The virus uncoats intracellularly via a specific process. In the infectious form of the virus, the envelope protein lays flat on the surface of the virus, forming a smooth coat with icosahedral symmetry. However, when the virus is carried into the cell and into lysozomes, the acidic environment causes the protein to snap into a different shape, assembling into trimeric spike. Several hydrophobic amino acids at the tip of this spike insert into the lysozomal membrane and cause the virus membrane to fuse with lysozome. This releases the RNA into the cell and infection starts.
Video 1. Dengue virus entry in cell
Figure 3. Dengue virus life cycle.
The DENV RNA genome is in the infected cell translated by the host ribosomes. The resulting polyprotein is subsequently cleaved by cellular and viral proteases at specific recognition sites. The viral nonstructural proteins use a negative-sense intermediate to replicate the positive-sense RNA genome, which then associates with capsid protein and is packaged into individual virions. Replication of all positive-stranded RNA viruses occurs in close association with virus-induced intracellular membrane structures. DENV also induces such extensive rearrangements of intracellular membranes, called replication complex (RC). These RCs seem to contain viral proteins, viral RNA and host cell factors. The subsequently formed immature virions are assembled by budding of newly formed nucleocapsids into the lumen of the endoplasmic reticulum (ER), thereby acquiring a lipid bilayer envelope with the structural proteins prM and E. The virions mature during transport through the acidic trans-Golgi network, where the prM proteins stabilize the E proteins to prevent conformational changes. Before release of the virions from the host cell, the maturation process is completed when prM is cleaved into a soluble pr peptide and virion-associated M by the cellular protease furin. Outside the cell, the virus particles encounter a neutral pH, which promotes dissociation of the pr peptides from the virus particles and generates mature, infectious virions. At this point the cycle repeats itself.
Antibody-Dependent Enhancement
After a person is infected with dengue, they develop an immune response to that dengue subtype. The immune response produced specific antibodies to that subtype specific surface proteins that prevents the virus from binding to macrophage cells (the target cell that dengue viruses infect) and gaining entry. However, if another subtype of dengue virus infects the individual, the virus will activate the immune system to attack it as if it was the first subtype. The immune system is tricked because the four subtypes have very similar surface antigens. The antibodies bind to the surface proteins but do not inactivate the virus. The immune response attracts numerous macrophages, which the virus proceeds to infect because it has not been inactivated. This situation is referred to as Antibody-Dependent Enhancement (ADE) of a viral infection. This makes the viral infection much more acute. The body releases cytokines that cause the endothelial tissue to become permeable which results in Dengue Haemorrhagic Fever (DHF) and fluid loss from the blood vessels.
There are several possibilities to explain the phenomenon:
1. A viral surface protein laced with antibodies against a virus of one serotype binds to a similar virus with a different serotype. The binding is meant to neutralize the virus surface protein from attaching to the cell, but the antibody bound to virus also binds to the receptor of the cell, the Fc-region antibody receptor FcγR. This brings the virus into close proximity to the virus-specific receptor, and the cell endocytoses the virus through the normal infection route.
2. A virus surface protein may be attached to antibodies of a different serotype, activating the classical pathway of the complement system. The complement cascade system instead binds C1q attached to the virus surface protein via the antibodies, which in turn bind C1q receptor found on cells, bringing the virus and the cell close enough for a specific virus receptor to bind the virus, beginning infection. This mechanism as not been shown specifically for the dengue virus infection, but is supposed to occur with Ebola virus infection in vitro.
3. When an antibody to a virus is present for a different serotype, it is unable to neutralize the virus, which is then ingested into the cell as a sub-neutralized virus particle. These viruses are phagocytosed as antigen-antibody complexes, and degraded by macrophages. Upon ingestion the antibodies no longer even sub-neutralize the body due to the denaturing condition at the step for acidification of phagosome before fusion with lysosome. The virus becomes active and begins its proliferation within the cell.
In 1997, 205 cases of DHF/DSS occurred in Cuba, all in people older than 15 years, after an infection with DENV-2 serotype. All but three cases were shown to have been previously infected by DENV-1 virus, during the epidemic of 1977–1979. Two outbreaks of the disease occurred after the first epidemic in 1977-1979, one in 1981 and one in 1997. People who had been infected with DENV-1 during the 1977-79 outbreak and secondarily infected with DENV-2 in 1997 had 3 to 4 more chances to develop a severe disease than those secondarily infected with DENV-2 in 1981. While heterotypic antibody titers decrease, homotypic antibody titers increase during long time periods (4 to 20 years). This could be due to the preferential survival of long-lived B memory cells producing homotypic antibodies, thanks to their bigger affinity. This cross-reactive protection does not persist more than 3 months. The decrease of cross-reactive neutralizing antibodies titers in the serum could be the reason for more severe secondarily infections.
History of Dengue
The origins of the word dengue are not clear, but one theory is that it is derived from the Swahili phrase "Ka-dinga pepo", meaning "cramp-like seizure caused by an evil spirit". The Swahili word "dinga" may possibly have its origin in the Spanish word "dengue" meaning fastidious or careful, which would describe the gait of a person suffering the bone pain ofdengue fever. Alternatively, the use of the Spanish word may derive from the similar-sounding Swahili. Slaves in the West Indies who contracted dengue were said to have the posture and gait of a dandy, and the disease was known as "Dandy Fever".
The first record of a case of probable dengue fever is in a Chinese medical encyclopedia from the Jin Dynasty (265–420 AD) which referred to a “water poison” associated with flying insects. The first recognized Dengue epidemics occurred almost simultaneously in Asia, Africa, and North America in the 1780s, shortly after the identification and naming of the disease in 1779. The first confirmed case report dates from 1789 and is by Benjamin Rush, who coined the term "breakbone fever" because of the symptoms of myalgia and arthralgia.
The viral etiology and the transmission by mosquitoes were only deciphered in the 20th century. The socioeconomic impact of World War II resulted in increased spread globally (see also Dengue epidemiology). Nowadays, about 2.5 billion people, or 40% of the world’s population, live in areas where there is a risk of dengue transmission (see figure 1). Dengue spread to more than 100 countries in Asia, the Pacific, the Americas, Africa, and the Caribbean.
Figure 1. Average annual number of dengue fever (DF) and dengue hemorrhagic fever (DHF) cases reported to WHO and average annual number of countries reporting dengue (Source:World Health Organization).
Possible factors for dengue fever spread include:
| Unplanned urban overpopulation of areas leading to inadequate housing and public health systems (water, sewerage and waste management) | |
| Poor vector control, e.g., stagnant pools of water for mosquito breeding | |
| Climate change and viral evolution (increased virus transmission has been linked to El Nino conditions) | |
| Increased international travel (recreational, business or military) to endemic areas |
All of these factors must be addressed to control the spread of dengue. Unplanned urbanization is believed to have had the largest impact on disease amplification in individual countries, whereas travel is believed to have had the largest impact on global spread.
Vaccine Research
There is no vaccine to protect against dengue. Although progress is underway, developing a vaccine against the disease is challenging. With four different serotypes of the dengue virusthat can cause the disease, the vaccine must immunize against all four types to be effective. Vaccination against only one serotype could possible lead to severe DHS when infected with another serotype due to Antibody-Dependent Enhancement. There is still limited knowledge of how the disease typically behaves and how the virus interacts with the immune system. Another difficulty is that there is no reliable animal model for DHF and thus also not a suitable animal model to test immune responses to potential vaccines. In addition, progress in vaccine development is slow mainly because dengue viruses grow poorly in cell culture (see alsoClinical Trials).
As there is no cross-protection between the four dengue serotypes, and because of the possibility of immune enhancement by monotypic antibody leading to DHF with subsequent natural infections, the control of dengue will be possible only after an efficient tetravalent vaccine has been developed. This means a vaccine that protects against all four dengue serotypes. The most favored strategy is to develop a live vaccine. Attenuation was obtained by repeated passage of wild-type strains of dengue viruses in cell culture. The difficulty in this approach has been to find the correct balance between insufficient attenuation and over-attenuation of the candidate vaccine strains, as criteria of virus attenuation in vitro, such as small plaque phenotype and temperature-sensitive growth, do not appear to be predictive of attenuation in vivo. In addition, whereas monovalent attenuated vaccine lots showed good immunogenicity, their combination into a tetravalent vaccine initially generated disappointing immunogenicity results, due to a phenomenon of interference between strains.
Other approaches for vaccine development include inactivated and subunit vaccines, DNA vaccines and recombinant vaccinia virus (MVA) vectors. Most advanced are efforts to develop a subunit, tetravalent vaccine using a mixture of the E protein from the four dengue serotypes and the nonstructural NS1 protein of DV-2 as immunogens in a proprietary adjuvant.
Video 1: Scientists Seek Better Treatment for Dengue Fever | Video 2: Vaccine for Dengue Fever Near |
New and Updated Clinical Dengue Vaccine Trials
Dengue vaccine studies updated or received in the last year at ClinicalTrials.gov. Only open studies, recruiting or not yet recruiting are shown.
- Condition: DengueInterventions: Biological: TetraVax-DV Vaccine - Admixture TV003; Biological: TetraVax-DV Vaccine - Admixture TV005; Biological: PlaceboSponsor: National Institute of Allergy and Infectious Diseases (NIAID)Recruiting - verified September 2011
- Conditions: Dengue; Dengue Hemorrhagic Fever; Yellow FeverInterventions: Biological: Live, attenuated dengue serotype 1, 2, 3, and 4 virus; Biological: Yellow fever vaccine; Biological: Measles, mumps, and rubella vaccine; Biological: Pneumococcal Conjugated Vaccine; Biological: Hepatitis A Pediatric Vaccine; Biological: Diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae vaccine; Biological: Live, attenuated dengue serotype 1, 2, 3, and 4 virus; Biological: Yellow Fever Vaccine; Biological: Placebo (NaCl); Biological: Measles, mumps, and rubella vaccine; Biological: Pneumococcal Conjugated Vaccine; Biological: Diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae vaccineSponsor: Sanofi-AventisRecruiting - verified September 2011
- Condition: Dengue FeverIntervention:Sponsors: Oxford University Clinical Research Unit, Vietnam; Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam; Children's Hospital No.1, Ho Chi Minh City, Viet Nam; Children's Hospital No.2, Ho Chi Minh City, Viet Nam; Tien Giang Provincial Hospital, Tien Giang, Viet Nam; District 8 Hospital, Ho Chi Minh City, Viet NamRecruiting - verified August 2011
- Conditions: Dengue; Dengue Hemorrhagic FeverInterventions: Biological: Live, attenuated, recombinant dengue serotype 1, 2, 3, and 4 virus; Biological: DTaP IPV//Hib vaccine; Biological: Placebo; Biological: Measles, mumps, and rubella vaccine; Biological: Pneumococcal vaccine; Biological: Live, attenuated, recombinant dengue serotype 1, 2, 3, and 4 virus; Biological: DTaP IPV//Hib vaccine; Biological: Placebo; Biological: Measles, mumps, and rubella vaccine; Biological: Pneumococcal vaccineSponsor: Sanofi-AventisRecruiting - verified August 2011
- Condition: Dengue Virus InfectionInterventions: Other: Data collection; Procedure: Blood sample collectionSponsor: GlaxoSmithKlineNot yet recruiting - verified August 2011
- Conditions: Dengue Fever; Dengue Hemorrhagic Fever; DengueInterventions: Biological: Live, attenuated, dengue serotype 1, 2, 3, 4 virus; Biological: Placebo: NaCl 0.9% solutionSponsor: Sanofi-AventisRecruiting - verified June 2011
- Conditions: Dengue; Dengue Fever; Dengue Hemorrhagic FeverInterventions: Biological: Live, attenuated, dengue serotype 1, 2, 3, 4 virus; Biological: Placebo: NaCl 0.9%Sponsor: Sanofi-AventisRecruiting - verified June 2011
- Conditions: Dengue Fever; FeverIntervention:Sponsor: Sanofi-AventisRecruiting - verified August 2011
- Condition: Mass ScreeningIntervention:Sponsors: Bio-Rad Laboratories; American National Red Cross; Centers for Disease Control and PreventionRecruiting - verified June 2011
- Conditions: Fever; DengueInterventions: Other: biological sample collection; Other: quality of life questionnaire EuroQol®Sponsors: Centre Hospitalier Universitaire de Fort-de-France; Institut National de la Santé Et de la Recherche Médicale, France; Centre d'Investigation Clinique - Epidémiologie Clinique CIE 802Recruiting - verified March 2011
- Condition: Dengue FeverInterventions: Procedure: Platelet transfusion; Procedure: Supportive careSponsors: Tan Tock Seng Hospital; Singapore General Hospital; Changi General Hospital; National University Hospital, SingaporeRecruiting - verified July 2011
Dengue Literature - Latest PubMed Articles
Overview of latest articles and publications on dengue in PubMed. PubMed is a service of the US National Library of Medicine that includes over 18 million citations from MEDLINE and other life science journals.
- Alphey N, Alphey L, Bonsall MB | | |
- Chuansumrit A, Chaiyaratana W, Tangnararatchakit K, et al. | | |
- Machain-Williams C, Mammen MP, Zeidner NS, et al. | |
- Gebhard LG, Filomatori CV, Gamarnik AV | |
- Chen R, Vasilakis N | |
- Heaton NS, Randall G | |
- Guzman MG, Vazquez S | |
- Ciota AT, Kramer LD | |
- Prashanth GP, Mugali SB |
- Dai J, Pan W, Wang P | | |
WHO Dengue Guidelines and Documents
Overview of the World Health Organization (WHO) guidelines, manuals and resources for prevention, control and outbreak response for Dengue and Dengue Haemorrhagic fever. Please visit also the WHO website to check for recent updates of the documents.
Guidelines and manuals on prevention and control
| Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2nd edition. Geneva, 1997. A practical guide to the diagnosis, treatment, prevention and control of dengue and dengue haemorrhagic fever. The book has been revised to reflect considerable recent gains in knowledge, particularly concerning methods of laboratory diagnosis and strategies for vector surveillance and control. All dimensions of the global dengue problem - from the characteristics of epidemics to the complexities of diagnosis - are addressed in this concise, yet comprehensive guide. | |
| Prevention and Control of Dengue and Dengue Haemorrhagic Fever - Comprehensive Guidelines. The Guidelines for Prevention and Control of Dengue/DHF focus on the South-East Asia Region. While the key roles of Ministries of Health as well as the non-health sectors have been highlighted, emphasis has also been placed on community involvement particularly of students, welfare and civic organizations and NGOs. | |
| Dengue Haemorrhagic Fever: early recognition, diagnosis and hospital management.An audiovisual guide for health care workers responding to outbreaks. Downloadtranscript | |
| Infection control for viral haemorrhagic fevers in the African health care setting. This manual describes a system for using viral haemorrhagic fever (VHF) isolation precautions to reduce the risk of transmission of VHF in the health care setting. It is intended primarily for health officers who implement infection control in the health care setting, and can be used as a rapid reference when one or two cases of a VHF appear in a health facility and no previous preparations for VHF isolation precautions have been done. The information can also be used to set up an isolation area quickly and make adaptations from local materials so that an effective system of infection control can be implemented as soon as possible. | |
| Guidelines for Treatment of Dengue Fever or Dengue Haemorrhagic Fever in Small Hospitals. This guidelines is developed in 1999 by WHO, in consultation with the leading experts in the field of clinical management of DHF. These guidelines will be a proper tool for physicians working in small hospitals to conduct appropriate treatment of patients with DF/DHF, and would help in achieving our common target to reduce case fatality rate of DHF to less than one per cent in all endemic countries. | |
| WHO report on global surveillance of epidemic-prone infectious diseases - Dengue and dengue haemorrhagic fever. The chapter on dengue and dengue haemorrhagic fever contains a background of dengue and dengue haemorrhagic fever including a brief history, a short description of the transmission process, clinical features, and number of cases reported to WHO and countries reporting, 1955-1998 | |
| Planning Social Mobilization and Communication for Dengue Fever Prevention and Control: A Step-by-Step Guide. This guide presents the basic steps and underlying principles of COMBI (Communication-for-Behavioural-Impact). It is intended for health planners, dengue or vector control programme managers and individuals, nongovernmental organizations (NGOs) and other agencies with interests and/or expertise in developing biological, chemical, environmental and communication interventions to prevent and control dengue fever. | |
| Dengue: Guidelines for diagnosis, treatment, prevention and control. Edition 2009. This publication is intended to contribute to prevention and control of the morbidity and mortality associated with dengue and to serve as an authoritative reference source for health workers and researchers. These guidelines are not intended to replace national guidelines but to assist in the development of national or regional guidelines. | |
| Manual for Indoor Residual Spraying: Application of Residual Sprays for Vector Control. The objective of this illustrated manual (aimed at pest-control workers) is to ensure the safe and correct application of a residual insecticide to indoor surfaces on which malaria vectors may rest. However, it also applicable for any other vector-borne diseases where indoor residual spraying would be an appropriate means of vector control | |
| Guidelines for Integrated Vector Management. Trial edition, 2003. Setup for the African Region. |
Vaccine Research and Production
Strategies and Best Practices
| Strengthening implementation of the global strategy for dengue fever/dengue haemorrhagic fever prevention and control. Report of the Informal Consultation, 18-20 October 1999. | |||||||||||||
| The International Dengue Task Force: Dedicated to the Fight against Dengue | |||||||||||||
Best Practices for Dengue Control in the Americas - Environmental Health ProjectCDC Dengue Guidelines and DocumentsOverview of the Centers for Disease Control and Prevention (CDC) guidelines, manuals and documents for prevention, control, clinical handling for Dengue and Dengue Haemorrhagic fever. Please visit also the CDC website to check for recent updates of the documents.
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