Dengue is caused by Dengue virus (DENV), a mosquito-borne flavivirus. DENV is a 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 called Dengue Hemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS).
There are four antigenically different serotypes of the virus (although there is report of 2013 that a fifth serotype has been found): 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.
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
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.
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.
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 of dengue 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 Caribbe
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 virus that 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 also Clinical 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. Live attenuated vaccine candidates are the furthest along in development. See also dengue vaccine researchwebsite of the WHO.
CYD-TDV is a live attenuated tetravalent chimeric vaccine made using recombinant DNA technology by replacing the PrM (pre-membrane) and E (envelope) structural genes of the yellow fever attenuated 17D strain vaccine with those from each of the four dengue serotypes. Ongoing phase III trials in Latin America and Asia involve over 31,000 children between the ages of 2 and 14 years. In the first reports from the trials, vaccine efficacy was 56.5% in the Asian study and 64.7% in the Latin American study in patients who received at least one injection of the vaccine. Efficacy varied by serotype. In both trials vaccine reduced by about 80% the number of severe dengue cases. An analysis of both the Latin American and Asian studies at the 3rd year of follow-up showed that the efficacy of the vaccine was 65.6% in preventing hospitalization in children older than 9 years of age, but considerably greater (81.9%) for children who were seropositive (indicating previous dengue infection) at baseline. The vaccination series consists of three injections at 0, 6 and 12 months. The vaccine was approved in Mexico, Philippines, and Brazil in December 2015, expected to be the first among the 20 countries in the coming weeks. Tradenamed Dengvaxia, it is approved for use for those aged nine and older and can prevent all four serotypes.
DEN-Vax is a recombinant chimeric vaccine with DENV1, DENV3, and DENV4 components on a dengue virus type 2 (DENV2) backbone developed at Mahidol University in Bangkok. Phase I and II trials are ongoing in the United States, Colombia, Puerto Rico, Singapore and Thailand.
TetraVax-DV is a tetravalent admixture of monovalent vaccines that were tested separately for safety and immunogenicity. The vaccine passed phase I trials and is being tested in phase II studies in Thailand and Brazil.
TDEN PIV is inactivated tetravalent vaccine undergoing phase I trials as part of a collaboration between GSK and the Walter Reed Army Institute of Research. A synergistic formulation with another live attenuated candidate vaccine (prime-boost strategy) is also being evaluated in a phase II study. In prime-boosting, one type of vaccine is followed by a boost with another type in an attempt to improve immunogenicity.(DVNet)