{
  "id": "dengue-fever",
  "title": "Dengue fever",
  "lang": "en",
  "source_lang": "en",
  "summary": "Dengue fever is a mosquito-borne viral disease caused by four related dengue virus serotypes, spread mainly by Aedes mosquitoes and found across tropical and subtropical regions.",
  "category": "health",
  "subcategory": "diseases",
  "type": "concept",
  "aliases": [
    "Dengue",
    "breakbone fever",
    "dengue hemorrhagic fever (historical term for severe disease)"
  ],
  "generated_at": "2026-10-15",
  "model": "pro/claude-haiku-5-5",
  "url": "https://aiwiki.page/en/dengue-fever/",
  "translations": {
    "zh-Hans": {
      "url": "https://aiwiki.page/zh/dengue-fever/",
      "json": "https://aiwiki.page/zh/dengue-fever.json"
    }
  },
  "sections": [
    {
      "heading": "",
      "text": "Dengue fever is an acute viral illness transmitted to humans mainly by female Aedes mosquitoes, above all Aedes aegypti. It is caused by dengue virus (virus), a member of the flavivirus group, and exists in four antigenically distinct serotypes (DENV-1 to DENV-4). Infection can cause no symptoms at all, a sudden and painful febrile illness, or in a minority of cases, severe plasma leakage, bleeding and shock. Because the virus depends on urban mosquito populations and warm, humid conditions, the disease is endemic across much of the tropics and subtropics and is now reported in more than 90 countries. Dengue is one of the most rapidly growing vector-borne threats to global public health, and it has become a central case study in epidemiology, vaccine development and vector control.\n\nThis entry covers the biology of the virus and its vectors, the clinical course and the WHO classification of severe disease, the immunology that explains why a second infection can be more dangerous than a first, and the methods used for diagnosis and clinical management. It then turns to the global burden of disease, including the record epidemics of recent years, the historical emergence of the disease, and the climatic and urban forces that drive its spread. The final sections examine the main prevention tools, namely vaccines, mosquito control and Wolbachia-based strategies, along with the surveillance systems, economic costs, controversies and open research questions that shape current responses."
    },
    {
      "heading": "Causative virus and serotypes",
      "text": "Dengue virus (DENV) is a member of the genus Flavivirus in the family Flaviviridae. The DENV genome is a positive (+) single-stranded RNA, approximately 11 kilobases in length. The virion has a core in which the RNA is bound to capsid protein, and this core sits inside a lipid envelope within the lipid bilayer. The genome is read as one long open reading frame that encodes a polyprotein. Viral and host proteases cut this polyprotein into three structural proteins (capsid, membrane precursor and envelope) and at least seven nonstructural proteins, including NS1 and the NS5 polymerase. The envelope (E) protein carries the sites recognized by neutralizing antibodies, and the four serotypes can differ by as much as 40% in the amino acid sequence of this protein.\n\nFour serotypes are recognized, DENV-1 to DENV-4. They possess 67–73% identity at the nucleotide level and 69–78% identity at the amino acid level. Their antigenic differences were originally established with plaque-reduction neutralization assays. Infection with one serotype produces long-lasting immunity to that serotype, while protection against the other three is only partial and temporary. Recurrent infection with a heterologous serotype only confers partial or transitory protection. Antibodies generated against one serotype can also bind a heterologous virus without neutralizing it and may instead facilitate infection, a mechanism described under immune responses and antibody-dependent enhancement. For this reason, simultaneous protection against all four serotypes is required, since an increase in disease severity can occur in persons with preexisting antibodies to a heterotypic dengue virus.\n\nWithin each serotype, viruses are grouped into genotypes. Clusters of DENV viruses with nucleotide sequence divergence not greater than 6% within a given genome region are further defined as genotypes. DENV-1 has five genotypes (I–V), among which genotypes I, IV, and V are prevalent worldwide; DENV-2 has six genotypes: Asian I, Asian II, Cosmopolitan, American, Asian-American and sylvatic; DENV-3 has four genotypes; and DENV-4 has four genotypes I-III and sylvatic. Lineage differences matter for epidemiology because they influence how efficiently a strain is transmitted by mosquitoes and how it spreads between regions. The contribution of individual lineages to clinical severity remains less clearly established, and studies on this question have not reached uniform conclusions.\n\nThe virus also has a forest-based ancestry. Sylvatic dengue virus strains are ecologically and evolutionarily distinct, ancestral DENV lineages that circulate in a forest cycle between non-human primates and arboreal canopy-dwelling mosquitoes of the genus Aedes in Southeast Asia and West Africa. Each of the four serotypes of human DENV represents an independent cross-species transmission of sylvatic DENV into humans. In a study of the Malaysian peninsula, all four DENV serotypes were found circulating between non-human primates and mosquitoes in the forest canopy, most likely among mosquitoes of the Aedes niveus group. Sources differ on how many serotypes have confirmed sylvatic lineages: one review lists sylvatic strains for at least three serotypes; DENV1, DENV2, and DENV4, showing that the evidence is still being refined. In Senegal, sylvatic DENV-2, the only one of the four DENV serotypes found to circulate in a sylvatic transmission in West Africa, is amplified cyclically at intervals of approximately eight years, and monkey serology indicated high levels of transmission in these populations.\n\nThe sylvatic and urban cycles are therefore distinct but connected. Some arboviruses, like dengue (DENV), chikungunya (CHIKV) and Zika (ZIKV), have become fully adapted to urban cycles and no longer require NHPs, forest mosquitoes and a sylvatic cycle for their maintenance. Forest cycles nevertheless matter for human disease. They may act as refugia for arboviruses which enable re-emergence once human epidemics have passed and immunity in the population (herd immunity) has waned. Sporadic spillover into people continues in parts of Southeast Asia: sporadic spillovers have been reported in Southeast Asia, including Malaysia. These events are often under-detected due to the genetic divergence of sylvatic strains from endemic urban dengue viruses."
    },
    {
      "heading": "Transmission cycle and mosquito vectors",
      "text": "Aedes aegypti is the principal urban vector of dengue. Its close association with people is unusually strong: its larvae develop mainly in water-holding containers in and around houses, and adult females feed almost exclusively on human blood. Surveys in Sri Lanka found that about 80% of larval habitats were artificial containers, and the mosquito uses a wide range of them, including water tanks, drums, flowerpots, discarded tyres, and even underground septic tanks. Aedes albopictus, the Asian tiger mosquito, is a secondary vector. It can use both artificial and natural containers, and it is generally more peridomestic than Aedes aegypti, favouring vegetated outdoor areas. Where both species coexist, their habitat preferences can determine how well a control measure works. In a Lao village study, treating domestic water containers with a larvicide sharply reduced Aedes aegypti but did not reduce Aedes albopictus, which was attributed to differences in breeding-site preferences. Adult Aedes aegypti have a limited flight range, estimated at about 200 metres, so spread over larger distances depends heavily on the movement of people, eggs, and containers.\n\nThe transmission cycle runs between humans and mosquitoes. A female mosquito acquires the virus when she takes a blood meal during a person's viraemic phase, which begins shortly before fever starts. Inside the mosquito, the virus must infect the midgut, replicate, spread through the body, and reach the salivary glands before the insect can transmit it. The interval between the infectious blood meal and the point at which the mosquito becomes infectious is the extrinsic incubation period (EIP). It is strongly temperature-dependent: model estimates suggest that at 25°C most EIPs fall between 5 and 33 days, with a mean near 15 days, whereas at 30°C they fall between 2 and 15 days, with a mean near 6.5 days. Because the EIP is shortened by warmth up to a point, the same mosquito population can be far more dangerous in a hot season than in a cool one.\n\nThe EIP matters only in combination with mosquito survival. A mosquito that dies before the virus reaches its saliva transmits nothing, and under natural conditions many mosquito-borne pathogens have an EIP that is long relative to the insect's lifespan. Studies of Aedes aegypti put its average adult lifespan at roughly two weeks, with considerable variation, while Aedes albopictus females have been estimated to live about three to eleven days. Because Aedes aegypti females seek blood meals every few days, a long-lived female that completes the EIP can bite several people, and each bite is a potential transmission event. Genetic variation among mosquitoes affects the EIP, and shorter EIPs have been linked to reduced lifespan, which shows that the two traits trade off against each other.\n\nDengue virus can also pass from an infected female to her offspring through transovarial (vertical) transmission. Laboratory work has shown that the virus can persist through several successive generations of Aedes aegypti by this route, and that infected progeny can include males, which do not feed on blood. Field studies in Brazil have detected dengue virus in naturally collected egg pools and in eggs from wild-caught females, including DENV-1, DENV-2 and DENV-4, although some field samples cannot distinguish true vertical transmission from contamination of the egg surface. Vertical transmission is generally thought to occur at low rates, and its importance is debated, but it is proposed as one mechanism for keeping the virus in a local population during interepidemic periods, when few human cases are present. Eggs can remain viable through dry spells, which is one reason why breeding sites can reseed outbreaks when the rains return.\n\nBiting and resting behaviour shape exposure risk. In the Sri Lankan study, both species showed a diurnal biting pattern with two activity peaks, one in the morning and one in the afternoon, which means that daytime protection is important, not only at dusk. Aedes aegypti is largely endophilic, resting indoors on hanging cloth, curtains, and furniture, whereas Aedes albopictus is more often found resting in outdoor vegetation. Breeding-site availability depends on climate and on household water practices. Temperature accelerates larval development and adult activity, rainfall refills containers, and intermittent water supply encourages households to store water. A Singapore surveillance dataset found that the seasonal occurrence of positive containers for Aedes aegypti tracked mean temperature, and a Colombian survey found that urban and rural households differed in water storage practices and in immature mosquito abundance. Together these findings indicate that the density of container habitats, not only the size of the mosquito population, governs local transmission potential."
    },
    {
      "heading": "Clinical course and symptoms",
      "text": "Incubation and the three clinical phases\n\nThe interval between the mosquito bite and the first symptoms is usually about a week, though it varies. One national guideline puts the average at 4 to 6 days, with a range of 3 to 14 days, while the U.S. CDC cites a typical window of 5–7 days. Illness usually begins abruptly and then moves through three phases: febrile, critical and recovery.\n\nThe febrile phase is the period of high fever, which lasts 2–7 days and is associated with viraemia. Fever in some patients is biphasic. The critical phase begins at defervescence and typically lasts 24–48 hours. This is the most dangerous stage. Most patients improve during it, but those with substantial plasma leakage can, within a few hours, develop severe dengue. The falling temperature can mislead patients into thinking they are recovering and delay hospital care. In the recovery phase, plasma is gradually reabsorbed from the interstitial tissues into the bloodstream, and vital signs normalise and appetite returns.\n\nCommon manifestations\n\nEarly findings are nonspecific. Fever with various non-specific constitutional symptoms such as headache, backache and malaise usually appear after the incubation period, which is why the early illness may be mistaken for other febrile illnesses.\n\nCharacteristic symptoms during the febrile phase include severe headache, retro-orbital pain, myalgia and arthralgia, and nausea, vomiting and diarrhoea are also common. Dehydration is common because of poor oral intake or gastrointestinal losses. The rash has a distinct timing: the second rash over face, neck, chest, and abdomen usually occurs around day 3–6 after the onset of fever and is typically maculopapular. Minor bleeding signs, including petechiae, ecchymosis, purpura, epistaxis, gingival bleeding, may also appear, and some patients have injected oropharynx and facial erythema in the first 24–48 hours after onset.\n\nPresentation varies with age. In one Asian hospital series, elderly patients at the febrile phase had significantly lower frequencies of bone pain, myalgia, headache and rash; higher frequencies of vomiting, pleural effusion and mucosal bleeding than younger adults.\n\nLaboratory findings and their use as warning signs\n\nBlood counts are often the earliest clue. Early blood counts may be normal or show leukopenia and thrombocytopenia. Reported frequencies vary widely: leukopenia and thrombocytopenia are prevalent in 25–82% and 40–89% of dengue cases, respectively, according to previous studies cited in a Nepalese cohort. In one emergency-department study in Nepal, leukopenia (< 4000 cells/mm^3) was present among 163 (64.68%) patients, and thrombocytopenia (< 150000 cells/mm^3) was present among 102 patients (40.48%). A separate Nepalese study found much lower leukopenia rates, so local conditions and definitions matter.\n\nThese findings matter because they track the transition into the critical phase. Fever resolution, progressive leukopenia with relative lymphocytosis, and a rapid decline in platelets to nadir indicate the onset of this high-risk period. Leukopenia is considered a prognostic marker, with one review noting it is often preceding severe manifestations, while thrombocytopenia is treated as a critical marker for bleeding risk and disease severity. Rising haematocrit is also common in the critical phase, alongside significantly higher incidence of ascites, mucosal bleeding, and/or gastrointestinal bleeding. The relationship is not uniform, however. One study reported that thrombocytopenia, though prevalent, was more common in milder cases, so these markers are used as triggers for closer monitoring rather than as definitive predictors of severity.\n\nAsymptomatic and mild infections\n\nA large share of infections never produce recognisable illness. A systematic review found that the mean proportion of asymptomatic infections among dengue-infected persons was 54% in 50 included studies. The term itself is ambiguous: it has been used for 'clinically undetectable infection', but also to 'undiagnosed infection' or 'mild infection'. Modelling studies that pool these categories report much higher figures, with one meta-analysis giving 82% 'asymptomatic' for primary dengue infections and 59% for secondary infections in cohort studies.\n\nSilent infections matter for transmission. Approximately half of infections are asymptomatic even though these individuals have a sufficiently high enough viral load to transmit virus back to the mosquito population. Mild cases can also remain unreported because people self-manage easily, lack access to health care, or are misdiagnosed with other febrile diseases. As a result, the proportion of inapparent infections is hard to measure precisely, and case counts based on hospital reports capture only part of the transmission in a population."
    },
    {
      "heading": "Severe dengue and disease classification",
      "text": "Most dengue infections cause no symptoms or only mild illness, but a minority progress to severe disease that can be fatal without prompt care. The way clinicians describe this spectrum has changed over time. For many years the World Health Organization used a 1997 scheme that described dengue fever (DF) and dengue hemorrhagic fever (DHF). DHF required fever together with a hemorrhagic tendency, a platelet count below 100,000 per cubic millimetre and evidence of plasma leakage, and its four grades placed the two most serious grades under the label dengue shock syndrome (DSS). Because the older categories were difficult to apply consistently, especially in busy or resource-limited hospitals, WHO issued a revised guideline in 2009. It abandoned the DF/DHF/DSS terminology and sorted suspected cases into three groups: dengue without warning signs, dengue with warning signs, and severe dengue. The 2009 scheme is built around bedside triage rather than a single defined syndrome, and a patient can be assigned to a category without laboratory confirmation. Dengue is suspected when a patient in an endemic area has fever along with at least two supporting findings, such as nausea or vomiting, rash, aches and pains, a positive tourniquet test or low white-cell counts, or when any warning sign is present.\n\nWarning signs are the features that identify patients who are likely to deteriorate. They typically appear three to seven days after the first symptoms, often as the fever subsides, which is why a falling temperature should not be taken as reassurance. The 2009 list includes abdominal pain or tenderness, persistent vomiting (commonly defined as at least three episodes in 24 hours), clinical fluid accumulation such as ascites or pleural effusion, mucosal bleeding from the gums, nose or gastrointestinal tract, lethargy or restlessness, and enlargement of the liver. Laboratory warning signs include a rising hematocrit combined with a falling platelet count. These signs indicate that the patient may be entering the critical phase, in which capillaries begin to leak plasma. Patients with warning signs are monitored closely and are usually admitted for observation, because the risk of progression is higher in this group than in those without them.\n\nSevere dengue is defined by one or more of three features: severe plasma leakage, severe bleeding, or severe organ impairment. Severe plasma leakage can cause shock, sometimes called dengue shock, or fluid accumulation with respiratory distress. Clinically, shock is recognised by a rise in hematocrit of at least 20 percent together with tachycardia, systolic hypotension below 90 mmHg, or a narrow pulse pressure below 20 mmHg. Severe bleeding is judged by the treating physician and includes significant gastrointestinal or other hemorrhage that may require transfusion. Severe organ impairment includes liver involvement, with aminotransferase levels at or above 1,000 IU/L, impaired consciousness, and heart dysfunction. Organ failure can occur without obvious plasma leakage or shock, so a patient may be severely ill even when the more familiar hemodynamic signs are absent. The 2009 framework has drawn criticism. In a study from Sri Lanka, nearly three-quarters of hospitalised patients were classified as having warning signs, yet only a small fraction showed evidence of plasma leakage, and some authors have proposed retaining the 1997 plasma-leakage criteria or refining the definitions of bleeding and organ impairment.\n\nRisk of progression depends on several factors. Age is one of the most consistent: a pooled analysis of Latin American studies associated younger children and older adults with higher risk, and an adult cohort from Singapore found that people aged 60 or older and those with diabetes, cardiac disorders, asthma or two or more pre-existing conditions had higher rates of severe organ involvement. Pre-existing diabetes, hypertension, renal disease and cardiovascular disease are also linked to progression, as are female sex and infection with serotype DENV-2 among children. Secondary infection with a different serotype is a major factor. In a population-based cohort from Taiwan, people with a second infection had roughly two to three times the risk of severe dengue compared with those experiencing a first infection, with the risk highest when more than two years separated the infections. Antibody-dependent enhancement is the proposed explanation, although not all severe cases follow a prior infection. Among infants, severity has been linked to the placental transfer of maternal IgG antibodies during the first year of life. Laboratory markers in the early febrile phase, including a lower platelet count, lower serum albumin and higher aminotransferase levels, have also been associated with later progression.\n\n参考"
    },
    {
      "heading": "Pathogenesis and immune response",
      "text": "Dengue virus enters the body through the bite of an infected mosquito and first replicates in the skin and in the local immune cells that meet it there. Dendritic cells are among the earliest targets. Monocytes, macrophages and mast cells also support infection, and in laboratory studies immature and mature dendritic cells both produce high levels of virus even without antibodies. After infection, dendritic cells carry viral antigen to draining lymph nodes and other lymphoid tissues, where the virus is amplified and where adaptive responses begin. Infected myeloid dendritic cells release cytokines such as TNF-α and interferon-α, which links the first replication stage to the later inflammatory response.\n\nAntibody-dependent enhancement (ADE) is the leading explanation for why a second infection with a different serotype is more dangerous than a first. Antibodies produced during an earlier infection bind to the new serotype but at sub-neutralizing concentrations fail to block it. The virus-antibody complexes are then taken up by cells that carry antibody receptors on their surface, especially the Fcγ receptors on monocytes, macrophages and dendritic cells, which increases the number of infected cells. In studies of primary human dendritic cells, enhancement appeared only in mature cells and depended largely on the FcγRIIa receptor, and it was inversely related to the level of the DC-SIGN attachment molecule. Infected cells exposed to patient serum at enhancing concentrations released TNF-α and IL-6 but not IL-10 or interferon-γ, which suggests that the antibody-receptor interaction also sends signals into the cell. Epidemiological evidence supports the model: infants whose maternally derived antibodies wane are at increased risk, and the risk of severe disease is highest after a heterotypic infection. The mechanism remains a central hypothesis rather than a fully proven pathway in humans, and it also shapes vaccine design, as discussed in vaccine research.\n\nThe inflammatory surge that drives plasma leakage depends on cytokines and on endothelial damage. Macrophages infected with dengue virus release large amounts of TNF, and conditioned medium from these cells disrupts endothelial monolayers in culture; much of this effect is neutralized by anti-TNF antibody, which points to TNF as a major mediator of vascular leak. Other cytokines and chemokines, including IL-6 and IL-8, rise in severe cases, and IL-10 has been associated with thrombocytopenia and with liver enzyme elevation. At the endothelial surface, the glycocalyx, a layer of proteoglycans and glycoproteins that regulates vessel permeability, is the first structure to be affected. Experimental work shows that the viral protein NS1 induces the expression of sialidases and heparanase in endothelial cells, through activation of cathepsin L, which removes sialic acid from the cell surface and sheds heparan sulfate proteoglycans. This degradation of the glycocalyx increases permeability, allowing fluid to move into the pleural and peritoneal cavities and eventually causing shock.\n\nNS1 is a glycosylated protein of about 48 kDa that is secreted from infected cells and circulates in the blood, and high circulating concentrations are associated with severe disease. In 2015, mouse experiments showed that NS1 alone can induce vascular leakage and inflammatory cytokine production, and that NS1 given with a sublethal dose of DENV-2 produced a lethal leak syndrome. NS1 from all four serotypes increased permeability in human endothelial monolayers, and anti-NS1 antibodies or NS1 immunization blocked these effects and protected mice against lethal challenge. The mechanism is contested: a later study reported that purified NS1 produced in mammalian cells did not activate Toll-like receptor 4 and had only a modest effect on endothelial integrity, much weaker than TNF. The protective role of NS1-directed antibodies is therefore better documented than its direct pathogenic role in humans.\n\nT-cell responses have a dual role. Primary infection generates CD8⁺ T cells that recognize epitopes largely located in the non-structural proteins NS3 and NS5, and many of these cells are cross-reactive across serotypes. During a secondary heterotypic infection, memory cells formed during the first infection can dominate the response, a pattern known as original antigenic sin. These cross-reactive cells often have low avidity for the new serotype, so they clear the virus less efficiently and release large amounts of inflammatory cytokines, and some studies link their activation in early convalescence to severe disease. Other studies found no correlation between the number of these cells and severity, and in mouse models cross-reactive CD8⁺ cells reduced viral burden in tissues, which suggests a protective function. Human antibody responses show a similar pattern: in a 2010–2011 study of pediatric patients in Nicaragua, a large share of circulating antibody-secreting cells during a DENV-3 infection were specific to DENV-2. Host genetics also matter, since certain HLA alleles are associated with a stronger multifunctional CD8⁺ response and a lower risk of severe disease."
    },
    {
      "heading": "Diagnosis and differential diagnosis",
      "text": "Clinical diagnosis and its limits\n\nIn endemic areas, clinicians often start with a presumptive diagnosis based on history and examination. Early symptoms, however, overlap with those of many unrelated febrile illnesses and offer no reliable sign of whether an infection will stay mild or become severe (Early dengue diagnosis based on clinical manifestations is difficult as the symptoms of the febrile phase do not differentiate from those of unrelated febrile diseases and do not distinguish between mild and severe dengue progression). For this reason, laboratory confirmation is central, and the choice of test depends on how many days have passed since symptoms began.\n\nLaboratory methods and the timing of each test\n\nDuring the first week, the CDC guidance pairs a molecular test (RT-PCR) or an NS1 antigen test with an IgM antibody test (During this period, laboratory diagnosis should be made on serum samples using either one of these test combinations). The NS1 protein is an early marker and is typically present between days 1–9 post-onset of illness but following seroconversion it can be difficult to detect in serum. A pooled analysis of reference tests found that RT-PCR and NS1 ELISA had similar accuracy in the first days of illness, with sensitivities of 95% (95% credible interval 77–99), 90% (68–98) for RT-PCR and NS1 ELISA respectively, which led its authors to suggest that the cheaper NS1 ELISA can be used where PCR is not accessible. The same analysis found that IgM ELISA should not be used alone in the first four days because of poor accuracy in that period (IgM ELISA should not be used as a single test in the first 4 days of symptom onset, due to poor diagnostic accuracy in this period.).\n\nAntibody tests become more useful later. The IgM response generally begins around day four, and IgG follows later (In primary infections, IgM is the first antibody to appear, followed by IgG.). After about a week, IgM testing is the more informative option, while NS1 may still be detectable for several more days (For patients seen more than 1 week after fever onset, IgM anti-DENV, such as the MAC-ELISA, is more useful, although NS1 may still be positive up to 12 days after fever onset.). When NS1 and molecular results are both negative, IgM testing can still indicate recent exposure (People with negative NS1 and negative or unavailable RT-PCR test results should be tested for the presence of dengue IgM antibodies to determine possible recent dengue exposure.). Combining IgG and IgM patterns can also indicate whether the infection is primary or secondary (dengue immune status can be determined using single serum samples collected during the acute phase of disease according to disease day-specific IgG:IgM ratios).\n\nCross-reactivity and differential diagnosis\n\nBecause flaviviruses share structural and sequence features, their antibodies often react with one another (these viruses show sequence and structural homology among them, which results in serological cross-reactivity). Primary dengue infection is a particular problem: primary dengue virus infections induced substantial amounts of cross-reactive IgM antibodies, which is most likely explained by structural peculiarities of dengue virus particles. Cross-reactivity is strongest within the dengue serocomplex (the extent of cross-reactivity was higher within the dengue serocomplex than in other flaviviruses.). In practice, Zika IgM responses have proved more specific, and the NS1 rapid assays used for dengue give false positives with Zika, Kunjin or yellow fever virus only at very high viral titres (substantially high viral titres of ZIKV, Kunjin virus (KUNV) and yellow fever virus (YFV) are required to give false-positive results when using DENV NS1 rapid detection assays.). Yellow fever vaccination adds further complexity in areas where it is routine; in one study, cross-reactivity with dengue IgG was seen in only one of four commercial kits tested (A cross-reactivity rate of 3.9% with DENV IgG antibodies was found only with the Dengue Virus IgG Dx Select kit (Focus Diagnostics).).\n\nDifferential diagnosis is equally demanding. Dengue shares its early picture with malaria, chikungunya and Zika, and dengue fever also overlaps significantly with similar infections of malaria, chikungunya, and the Zika virus, leading to frequent misdiagnosis. Malaria and bacterial causes such as leptospirosis must be excluded by separate testing, which is often not available in clinics where dengue is common.\n\nPoint-of-care tests and their limitations\n\nRapid diagnostic tests (RDTs) are the main option in low-resource settings. These lateral-flow devices are particularly suitable for low-resource settings because of their affordability, user friendly, and minimal storage requirements, and they can help separate primary from secondary infection (RDTs can differentiate between primary and secondary dengue infections.). Their limits are significant, however. In a Lao cohort, the NS1 rapid test was less sensitive than RT-PCR (NS1 RDT was less sensitive relative to DENV RNA RT-PCR (72.7%).), and reading results by eye depends on the operator (the visual interpretation of RDT results is operator-dependent and can be a drawback). NS1 tests also perform poorly in secondary infections, the poor performance of NS1 RDTs in diagnosing post-primary cases is attributed to the lower overall viremia post-primary cases experience during the acute phase of disease. The tourniquet test, a bedside alternative, has consistently low sensitivity, it should only be used alongside other diagnostic methods for dengue. Finally, an NS1 result confirms infection but without providing serotype information."
    },
    {
      "heading": "Clinical management and special populations",
      "text": "Dengue has no specific antiviral treatment, so management is supportive. Care aims to prevent dehydration, detect plasma leakage early, and keep the patient safe through the critical phase, which usually begins as the fever falls. Patients without warning signs can often be managed as outpatients with oral fluids and follow-up. Those with warning signs, such as persistent vomiting, severe abdominal pain, mucosal bleeding, reduced urine output or a rising hematocrit, are generally admitted to hospital. Guidelines recommend repeated checks of vital signs, urine output and complete blood counts to track the hematocrit and fluid balance.\n\nIn hospital, the main intervention is intravenous fluid replacement when plasma leakage occurs. Isotonic crystalloids such as normal saline or Ringer's lactate are the usual first choice. Fluid rates are adjusted to the patient's hematocrit trend and reduced as capillary permeability recovers, which often takes around 48 hours after defervescence. Both under-treatment and overload are hazards: excess fluid can cause pulmonary edema and respiratory distress. A falling hematocrit in a patient who is clinically improving is not, by itself, evidence of internal bleeding. Prophylactic platelet transfusions are not recommended for a low count alone, because they have not been shown to reduce severe bleeding and can add to fluid overload. Routine corticosteroids are also not advised. Transfusion is reserved for significant bleeding or a very low platelet count, and drug choice follows the same caution.\n\nMedication guidance centres on avoiding drugs that affect clotting. Paracetamol (acetaminophen) is the usual choice for fever and pain, at doses adjusted to age and body weight, and patients should check that combination cold remedies do not contain it as well. Aspirin and other salicylates, along with nonsteroidal anti-inflammatory drugs such as ibuprofen, naproxen, diclofenac and mefenamic acid, are avoided because they impair platelet function and can irritate the stomach, which raises bleeding risk in a patient whose platelet count may already be falling. People who take aspirin or anticoagulants for other conditions should consult their clinician rather than stop these drugs abruptly. Unproven herbal remedies are also discouraged.\n\nPregnant women face a higher risk of severe disease and of adverse fetal outcomes. Intravenous fluid therapy remains the cornerstone of severe dengue management in pregnancy, and close monitoring with critical-care expertise is needed when plasma leakage is present. Distinguishing dengue from pre-eclampsia can be difficult because both may involve low platelets and impaired liver function. Transmission from mother to fetus can occur around the time of delivery, and maternal infection has been linked with preterm birth and low birth weight. A cohort study in French Guiana (note: see sources) reported higher odds of low birth weight among infants of mothers with symptomatic infection during pregnancy. A study in the American Economic Journal: Applied Economics also reported higher rates of very low birth weight and hospitalisation in early childhood among children whose mothers had dengue in pregnancy.\n\nInfants and young children are among the groups at highest risk of severe illness. Their symptoms can be hard to interpret, and deterioration can be rapid once plasma leakage starts. Warning signs in young children include restlessness, excessive crying, altered responsiveness, cold clammy skin and a sudden drop in temperature. Intramuscular injections are avoided because of bleeding risk, and intravenous fluids may be needed when a child cannot keep down food or fluids.\n\nOlder adults show a different pattern. Age over 60 has been associated with a markedly higher risk of severe organ involvement, and comorbidities such as diabetes, cardiac disease, asthma and multiple chronic conditions further increase that risk. Older patients often present atypically, with fever as the main or only sign, fewer classic symptoms such as retro-orbital pain, and less frequent leukopenia. This can delay diagnosis. Bacterial co-infection and hospital-acquired infection are also more common in this group, so a low threshold for admission and close observation are generally advised.\n\nRecovery begins once plasma leakage resolves and fluid is gradually reabsorbed into the circulation. Discharge is usually considered when the patient has been afebrile for 24 hours without antipyretics, has a good appetite, produces adequate urine, shows a stable hematocrit, has recovered from any shock for at least 48 hours and has no respiratory distress. Patients are advised on warning signs that should prompt an immediate return. Weakness and fatigue can persist for weeks after the acute illness, particularly after severe episodes, and people with organ involvement or chronic disease may need follow-up of organ function and their underlying conditions."
    },
    {
      "heading": "Epidemiology and global distribution",
      "text": "Estimates of the true burden of dengue depend heavily on whether they count modelled infections or notified cases. One modelling estimate projects about 390 million infections a year, of which roughly 96 million become clinically apparent One modelling estimate indicates 390 million dengue virus infections per year, of which 96 million manifest clinically. Official counts fall far below that figure. Surveillance is thin in many endemic areas, so reported totals undercount the disease, a limitation that WHO regularly flags. The gap is also visible in the way cases are classified. In the Americas during 2025, the reported total included about 4.46 million suspected cases, of which roughly 1.68 million were laboratory-confirmed 4,459,521 and 1,682,588 confirmed dengue cases were reported to PAHO.\n\nNotifications have risen steeply over the past quarter-century. WHO figures show growth from 505 430 cases in 2000 to 14.6 million in 2024. The previous annual record had been set in 2019, with over 3.18 million cases, 28,208 severe cases, and 1,823 deaths. The 2024 total is not consistent across sources. WHO reported more than 12,000 deaths for that year a historic high of over 14.6 million cases and more than 12 000 dengue-related deaths, whereas a peer-reviewed analysis of the same surveillance system counted 14.1 million cases and 9,508 dengue-related deaths were recorded, resulting in a global case-fatality rate of 0.07%. The differences likely reflect data cut-off dates and revisions.\n\nRegionally, the Americas carry most of the reported burden. In 2024, the Region of the Americas contributed a significant proportion of the global burden, with over 13 million cases reported to WHO. Within the region, Brazil is the country most severely affected by dengue, followed by Argentina and Mexico. Southeast Asia is the second most affected region, with a total of 693,596 cases reported between January and November 2024. Africa is less affected in reported terms but has clear hotspots; in early 2024, Burkina Faso reported 72% of all cases and 89% of all deaths in the region from the beginning of 2023 to 28 April 2024. Transmission has also reached Europe, where 308 cases were reported to WHO from three European countries (France, Italy and Spain) in 2024, alongside locally acquired cases in French overseas territories.\n\nThe 2024 epidemic in Latin America and the Caribbean was followed by a marked fall in 2025. The region recorded a 66% decrease in cases and a 74% reduction in deaths compared with 2024, a year that saw a record high of over 13 million cases. The decline was uneven. The Southern Cone still reported the most cases, yet this represented a 65% decrease compared with 2024, while the Caribbean, by contrast, recorded a 7% increase over the previous year. The downward trend continued into 2026. Through the first four weeks of the year, these figures represent an 83% decrease in cases and a 98% reduction in deaths compared with the same period in 2025. By epidemiological week 36, the cumulative count was 1,695,825 suspected cases of dengue, and a decrease of 56% compared to the same period in 2025 and 63% compared to the average of the last 5 years. These 2026 figures are provisional and will be revised as reporting catches up. Declines after very large epidemics are commonly linked to the depletion of susceptible people, though weather and control measures also influence the trend.\n\nAsia presents a more mixed picture, with several countries reporting high caseloads in 2026 while others fell. By late July, Sri Lanka had become the region's hotspot with 82,007 cases, roughly 2.5 times its 2025 pace. By August 15, the country had recorded 58,079 dengue cases and 55 deaths, with cases up 56.2% compared with the same period in 2025 for Malaysia. In Vietnam, from January to May 2026, over 50 000 dengue cases, including five deaths, were recorded nationwide, representing a 2.5-fold increase in cases relative to the same months of 2025. Bangladesh reported 58,400 cases and 176 deaths (as of 17 September 2026), against 102,562 cases (412 deaths) for all of 2025. By contrast, in the Philippines the number is lower compared to the 254,137 dengue cases recorded during the same period in 2025, and a drop in the number of deaths was also observed as of early October 2026. Singapore remains a low-burden outlier.\n\nSerotype shifts shape how each epidemic unfolds. In 2025, circulation of all four dengue virus serotypes was identified in the Americas Region, and Brazil, Colombia, Costa Rica, El Salvador, Mexico, Panama, and Puerto Rico reported simultaneous circulation of all four serotypes. PAHO had earlier warned of the risk of dengue outbreaks due to increased circulation of DENV-3 in the Americas Region. The reappearance of a serotype that has been rare in a population means that many people lack neutralizing antibodies against it, so transmission can surge even when overall case numbers were falling. Individuals previously infected with a different serotype are particularly at risk of severe disease on re-exposure, which increases the clinical stakes of such shifts. In Africa, circulation of three of the four dengue serotypes (DENV-1, DENV-2, DENV-3) has been identified in the WHO African region, and in Mauritius, only DENV-2 serotype being detected to date during early 2024, illustrating how a single introduced serotype can drive a local outbreak."
    },
    {
      "heading": "Historical emergence and spread",
      "text": "Dengue-like illnesses appear in Chinese medical sources from the Jin dynasty onward, but the disease became clearly recognizable only in the late eighteenth century. Three epidemics mark its arrival: two in 1779, in Cairo and in Batavia (now Jakarta) in the Dutch East Indies, and one in Philadelphia in 1780. Benjamin Rush treated patients in Philadelphia and published the first clinical description in 1789. The English name \"breakbone fever\" came from the severe bone and joint pain that patients reported. Spanish-language sources used a similar phrase in Puerto Rico in 1771, so the name was not confined to one city. The word \"dengue\" is generally traced to Swahili phrases such as ka dinga pepo, and it was in use in Spanish by 1801. Its etymology is still debated.\n\nThe mosquito vector is thought to have originated in Africa. Genomic work suggests that a human-adapted subspecies of Aedes aegypti emerged in the Americas after the Atlantic slave trade and then spread worldwide. Historians regard the eighteenth and nineteenth centuries as a period in which dengue moved along shipping routes. Infected people and mosquitoes arrived in port cities, including Philadelphia, through Caribbean trade. A global wave of outbreaks from 1779 to 1916 is often described as the first dengue pandemic. Because only one serotype circulated at a time, these outbreaks tended to be brief and local to particular cities. Before the mid-twentieth century, Aedes aegypti was the dominant day-biting mosquito in most Asian cities. As shipping expanded, it displaced Aedes albopictus, which is better suited to gardens and vegetated edges than to dense urban areas. By the mid-twentieth century, the two species coexisted in most Asian cities, with albopictus largely confined to vegetated spaces.\n\nThe twentieth century brought a sharper change. The movement of troops and war materials during the Second World War carried the virus and its mosquito to most parts of Asia and the Pacific. Once the war ended, rapid economic growth and urbanization in Southeast Asia created crowded neighborhoods with unreliable water supplies and poor waste disposal, which favored mosquito breeding and transmission. By the end of the war, many Asian countries already had all four serotypes circulating together. Severe dengue was first recognized in this setting. The first documented epidemics of dengue hemorrhagic fever occurred in Manila in 1953–1954, followed by Bangkok in 1958. Outbreaks then appeared in Singapore, Malaysia and Vietnam in the 1960s, and in Indonesia and Burma in the 1970s. Serotypes 2, 3 and 4 were identified during the 1956 Philippine epidemic, and serotype 1 during the 1958 Thai epidemic. Before 1970, only nine countries had experienced severe epidemics. Severe disease became a leading cause of hospitalization and death among children in many Southeast Asian countries by 1975. In the 1980s the disease spread again into South Asia, including Sri Lanka, India and the Maldives. Severe dengue was first recorded in the Americas during an epidemic in Cuba in 1981.\n\nReinfestation after eradication is a recurring theme in this history. In the Americas, regional campaigns from the late 1940s removed Aedes aegypti from many countries. Funding for these campaigns declined, and the mosquito returned in many places in the following decades. Southern Europe had lost the species by the middle of the twentieth century, but later saw its return, which made Europe susceptible again to dengue. Some Pacific islands, including Guam, Saipan and Hawaii, eliminated the mosquito through intensive urban control, aided by competition from albopictus in vegetated areas. Northern Taiwan also remained free of the species, while southern Taiwan had been infested since the nineteenth century. These patterns show that local eradication could reduce transmission for decades, but it did not remove the underlying risk when the mosquito could re-enter from neighboring areas through trade and travel."
    },
    {
      "heading": "Climate, urbanization and ecological drivers",
      "text": "Temperature acts on dengue at several points in the transmission cycle at once. Warmth speeds up the development of the virus inside the Aedes mosquito: one modelling review notes that the average extrinsic incubation period is about 6.5 days at 30°C but about 15 days at 25°C, so even a small shortening can markedly increase the share of mosquitoes that live long enough to become infectious Average extrinsic incubation period is shorter at 30°C (6.5 days) than at 25°C (15 days). Even a small reduction in this period can markedly boost pathogen transmission by increasing the number of mosquitoes that live long enough to become infectious. Warmer conditions also quicken the mosquito's feeding rhythm, since the time between blood meals and egg-laying falls as temperature rises Biting rate is related to the gonotrophic cycle (the time between a mosquito taking a blood meal and laying eggs), which accelerates as temperature increases.\n\nThe relationship is not a simple upward line. Modelling studies describe an inverted-U curve in which changing temperature significantly alters dengue risk in an inverted U-shape, with temperatures in the range 27-31°C producing the highest risk. Above that range, mosquito survival becomes the limiting factor: transmission requires that the mosquito's lifespan exceed the extrinsic incubation period, and lifespan shortens as heat increases beyond a certain point for transmission to take place, the mosquito lifespan, which declines with increasing temperature after a certain point, must exceed the EIP. Field analyses in Singapore similarly report increased risk of dengue at a maximum temperature of 32 °C and at intermediately wet conditions, with decreasing risk in very hot and very dry conditions. This means that continued warming could shift risk in hot regions away from mosquito biting and toward other factors, such as the length of the human infectious period, rather than simply raising transmission everywhere As temperatures increase beyond 31°C, the determinants of dengue risk begin to shift from mosquito biting rate and carrying capacity to the duration of the human infectious period.\n\nRainfall and water availability shape where and when mosquitoes can breed. Because the aquatic stages depend on standing water, precipitation has a crucial influence on mosquito development, because it provides a suitable habitat for the stages of the mosquito life cycle that are water-dependent. The effect is not uniformly positive, however. Temperature increases associated with El Niño events superimposed on long-term increases in ambient temperature may alter dengue transmission when heavy precipitation events wash away breeding sites. Dry spells create a different problem: limited access to clean water has been shown to increase dengue risk in dry settings by promoting water collection and storage in small containers outside of homes. In many cities, household water storage thus links dengue risk to the reliability of municipal supply.\n\nEl Niño–Southern Oscillation (ENSO) is the most important source of multi-year variability. Its warm phase is associated with higher temperatures and altered rainfall in several dengue-affected regions, and its influence is visible in local records. In Venezuela, four out of seven dengue epidemics at national level and in the two studied regions coincided with El Niño events, including a long and extreme dengue outbreak from 2009–2010. Analyses of Ecuador's record show a recurring two-year periodicity, and two to three-year cycles of dengue transmission have been reported in other parts of the world, particularly in years associated with El Niño events. The impact of ENSO varies by region and season. During the 2015–2016 event, dengue activity in Southeast Asia and Brazil tracked land surface temperature more closely than rainfall dengue was significantly associated with LST anomaly but not with rainfall anomaly. Recent attribution work suggests that climate change is amplifying these effects: one multicountry model estimated that ACC could explain 48·64% (95% eCI 38·01 to 60·19) of EP-El Niño-attributable increment in dengue cases. In Peru, a cyclone combined with a coastal El Niño in 2023 produced an outbreak in a normally dry region, in which researchers traced Peru's 2023 dengue outbreak to cyclone conditions, finding that 60% of cases stemmed from extreme rainfall and heat.\n\nUrbanization determines whether climatic conditions translate into large outbreaks. Dengue is an emerging vector borne disease due to rapid urbanization, scarcity of water and changing climatic conditions all over the globe. Dense urban districts with intermittent piped water, irregular waste collection and crowded housing offer abundant containers, shaded corners and human hosts close together, all of which favour the domestic mosquito. Urban heat islands can add to these conditions by raising local temperatures above regional averages, which can push transmission toward the favourable range described above, although the net effect depends on how hot a particular city already is.\n\nClimate change is also expanding the geographic range of dengue vectors. Aedes albopictus is currently established in 16 countries and 369 regions – up from 114 regions about a decade ago. Locally acquired dengue has followed this expansion in southern Europe, where 304 cases of locally acquired dengue were reported in Europe, an increasing trend compared with previous years (130 cases in 2023 and 71 cases in 2022). The largest recent event was in Italy, where Italy had the largest recorded dengue outbreak in Europe, with more than 200 confirmed autochthonous cases in October 2024. Transmission has not been confined to peak summer conditions: an event in Madeira in early 2025 was confirmed during a period of low mosquito abundance and low climatic suitability. Projections for temperate regions are more uncertain. A modelling study of the United States suggested that climate change may lead to dengue transmission in currently naïve populations. Climate change could create suitable conditions for dengue transmission year-round. Taken together, these studies indicate that warming will likely expand the zone of risk and lengthen the season, while local rainfall, water storage and vector control will continue to determine how many of those potential introductions become outbreaks."
    },
    {
      "heading": "Vector control and Wolbachia-based strategies",
      "text": "Source reduction, larval control and community mobilization\n\nSource reduction targets the water-holding containers where Aedes aegypti breeds: households empty, cover or discard them, and larvicides such as temephos are applied to water that cannot be removed. These measures work only while they are maintained. Once households stop emptying containers or communities stop participating, breeding resumes quickly, so programs depend on continuous mobilization rather than one-off campaigns. Community engagement also determines whether biological interventions can start at all. In Yogyakarta, Wolbachia mosquito releases within Yogyakarta City began after two years of engagement with communities and approval by the provincial government. Field teams have reported very high community acceptability in the sites where they ran releases.\n\nInsecticides, resistance and the limits of space spraying\n\nAdult control in outbreaks relies mainly on pyrethroid space spraying with vehicle-mounted foggers. Outdoor spraying often fails because droplets do not penetrate into houses, where the mosquitoes rest, a failure of insecticide droplets to penetrate indoors where Ae. aegypti rest. A review concluded that, although the method is the standard outbreak response and is recommended by the WHO, there is scant evidence available from studies to evaluate this method sufficiently.\n\nResistance compounds these limits. Resistance to pyrethroids is linked to kdr mutations, V1016G and F1534C, identified in some provinces and showed a strong association with pyrethroid resistance. In Martinique, where resistance was detected in the 1990s, treatments with resistant populations produced very low mortality among resistant mosquitoes, and there was no reduction of either larval or adult Ae. aegypti population densities after treatments. The problem is also driven by use: in Boa Vista, Brazil, intensified spraying pushed resistance ratios up sharply within months. Resistance is geographically uneven, with resistance levels generally lower in Asia, Africa and the USA, and higher in Latin America, although there are exceptions. For these reasons, the insecticide resistance problem has pushed programs toward biological and genetic tools.\n\nWolbachia: mechanism, spread and field results\n\nWolbachia is an intracellular bacterium that is maternally transmitted via the egg and manipulates insect reproduction to favour its own population dissemination via cytoplasmic incompatibility (CI). The spread mechanism is simple: when female mosquitoes with Wolbachia mate with males without Wolbachia, all of their offspring will carry Wolbachia. Strains introduced into Aedes aegypti also block dengue virus transmission. The wAlbB strain maintains higher density than wMel at high larval rearing temperatures.\n\nEstablishment is the key variable. In Campo Grande, Brazil, a stable wMel prevalence of at least 60% was associated with a 63.2% reduction in dengue incidence, while areas with unstable or partial Wolbachia establishment did not show statistically significant reductions in dengue incidence. In Rio de Janeiro, invasion has been difficult, with Wolbachia frequencies often failing to reach 50% in populations and averaging 32% in release areas. The World Mosquito Program describes the method as self-sustaining, over 6-12 months, Wolbachia is established throughout the local mosquito population. Whether it needs ongoing maintenance in all settings remains debated.\n\nEfficacy estimates from larger studies are substantial. The randomized trial in Yogyakarta reported a 77% reduction in dengue incidence and 86% reduction in dengue hospitalisations, and protective efficacy was similar across serotypes. In Malaysia, releases of wAlbB were associated with an average reduction in dengue fever of 62.4% (confidence intervals 50–71%) in 20 releases sites when compared to 76 control sites. In Niterói, Brazil, a quasi-experimental study linked wMel deployments to a 69% reduction in dengue incidence relative to a control area.\n\nMale-release and female-replacement approaches\n\nTwo strategies are commonly distinguished. Male-release (suppression) programs release Wolbachia-infected males, which mate with wild females that do not carry the bacterium. Because such matings produce no viable offspring, the wild population declines. A large cluster-randomized trial in Singapore found that releasing sterile male Wolbachia-infected mosquitoes greatly reduced dengue infections by suppressing local mosquito populations. The average mosquito index fell to 0.041 in intervention clusters, compared with 0.277 in control clusters. The trial reported that the intervention achieved a protective efficacy of 71% to 72% after at least three months of exposure. A separate synthetic-control analysis of the same Singapore program estimated an aggregate intervention efficacy of 56.88% (2242 of 3941, 95% CI 55.18–58.46) for total cases.\n\nFemale-replacement, or population-replacement, approaches release both sexes so that Wolbachia spreads through the wild population over generations and reduces its capacity to transmit virus. Rather than reducing numbers, this strategy aims to change the population's vector competence, and it is designed to persist without repeated releases. The field trials summarized above are mostly of this type. Results depend on establishment, which is why the frequency of Wolbachia in local mosquitoes is monitored alongside case data."
    },
    {
      "heading": "Vaccines and their development",
      "text": "Early efforts and the first licensed vaccine\n\nA dengue vaccine has to protect against four antigenically distinct serotypes at once without harming people who have never been infected. The first licensed product, Dengvaxia (CYD-TDV) from Sanofi Pasteur, was approved in Mexico on 8 December 2015 and later licensed in 22 countries in total, though it was not registered in every one of them. Its two large phase 3 trials met their primary efficacy endpoints, but longer follow-up revealed a safety signal in seronegative recipients, meaning people without prior dengue exposure. In the Philippines, a 2016 mass campaign vaccinated more than 830,000 schoolchildren without serostatus screening. Sanofi reported in December 2017 that vaccination of previously uninfected people could mimic a first dengue infection and so set up later antibody-dependent enhancement. Subsequent analyses showed that seronegative vaccinees had a 1.75-fold higher risk of dengue hospitalization and severe dengue than unvaccinated seronegative controls. The product was then restricted to people with confirmed prior infection, and WHO advised serostatus testing before vaccination in most settings. The Philippines halted its school program, imposed a permanent ban in February 2019, and Sanofi stopped production in January 2024. The final batches expired in August 2024.\n\nTAK-003 (Qdenga)\n\nTAK-003 is a live-attenuated tetravalent vaccine developed by Takeda. It uses a DENV-2 backbone carrying recombinant surface-protein elements for DENV-1, DENV-3 and DENV-4, and unlike Dengvaxia it can be given to people who have not had dengue. The European Medicines Agency granted market authorization in November 2022, and the first doses were distributed in February 2023. At 4.5 years, its vaccine efficacy was 61% against virologically confirmed dengue and 84% against dengue-related hospitalization, but efficacy data for people over 16 are lacking. Its effect is predominantly against DENV-2, and protection against DENV-3 and DENV-4 in seronegative people is not yet clearly established. In September 2023 WHO's SAGE recommended its use for children aged 6–16 in high-transmission settings without pre-screening. WHO does not recommend routine use in children under 6, where efficacy is lower and seropositivity is generally low, nor in low- to moderate-transmission settings until the DENV-3 and DENV-4 risk profile in seronegative people is better characterized. The schedule is two doses at least three months apart. In Brazil, many recipients did not return for the second dose and remained only partly protected. Because WHO favors targeted subnational introduction, available doses are typically concentrated in selected high-transmission areas, which limits how widely the vaccine can be deployed.\n\nButantan-DV\n\nButantan-DV is a single-dose tetravalent live-attenuated vaccine developed by the Instituto Butantan in São Paulo. It originated from a platform developed at the US National Institutes of Health and was optimized and advanced clinically in Brazil. In a phase 3 trial of 16,235 participants, two-year vaccine efficacy against symptomatic, virologically confirmed dengue was 79.6%, with 73.6% among people without previous exposure and 89.2% among those with prior exposure. A separate phase 3 trial reported 67.3% efficacy against DENV-1 and DENV-2, but not against DENV-3 or DENV-4. Anvisa's technical evaluation gave an overall efficacy of 74.7% in people aged 12–59, so published figures differ depending on the analysis. Anvisa approved the vaccine on 26 November 2025 for people aged 12 to 59, making Brazil the first country to launch a single-dose tetravalent dengue vaccine. Rollout began on 9 February 2026, when about 1.1 million primary health-care workers were scheduled to receive it. Butantan has also partnered with the Chinese company WuXi to expand production, with approximately 30 million doses expected in the second half of 2026.\n\nChallenges and post-licensure monitoring\n\nProtection across all four serotypes remains uneven across current candidates. TAK-003 acts mainly on DENV-2, and Butantan-DV has weaker documented efficacy against DENV-3 and DENV-4. Safety in people without prior infection remains the central constraint, because the mechanisms of antibody-dependent enhancement are still under investigation. Post-approval data on efficacy, safety and uptake for Dengvaxia were limited, which made its long-term public-health impact hard to assess. Passive surveillance systems also varied in their ability to detect vaccine-associated dengue. WHO recommends post-introduction studies to clarify long-term safety and efficacy, and national travel guidance for Qdenga has been more restrictive than the regulatory approvals, especially for travelers without documented prior infection."
    },
    {
      "heading": "Surveillance, outbreak response and public-health systems",
      "text": "In most endemic countries, dengue surveillance relies on passive notification: clinicians and laboratories report cases to health authorities, which compile them into national databases. Laboratory confirmation is the weak point. Latin American countries tried to confirm nearly every suspected case, mostly with IgM/IgG ELISA and increasingly NS1 testing, but during large outbreaks only a fraction was tested, at least 10% in Brazil and 30% in Mexico. Asian countries used the same tests, but laboratory confirmation was applied to a small sample, usually fewer than 10% of patients. Several countries have added sentinel sites that actively collect data from selected clinics and hospitals. In Puerto Rico, the long-standing passive system depended on clinical suspicion followed by laboratory confirmation, and it struggled with underreporting and limited testing, which led to an enhanced sentinel system covering 2012 to 2022.\n\nSentinel laboratory systems and the limits of clinical diagnosis\n\nSentinel sites produce data that passive reporting cannot. In Colombo, Sri Lanka, a study enrolled up to 60 patients per week who presented with undifferentiated fever at three outpatient clinics and three government hospitals. Their acute blood samples were tested by dengue-specific PCR, NS1 ELISA and IgM ELISA. Of the 3,127 febrile patients, 43.6% were PCR and/or NS1 positive for dengue, and the positivity rate differed sharply by care setting: the share of lab-confirmed dengue was 53.9% among inpatients compared with 7.6% among outpatients. The same study found that clinicians' presumptive diagnoses had a sensitivity of 84% but a specificity of only 34%, which means that clinical notifications alone overstate the number of dengue cases. Laboratory-based systems do have a cost: sentinel laboratory surveillance yields high-quality virological and serological data and is useful for detecting introduced dengue, but results that are not linked to clinical and epidemiological information must be interpreted with caution.\n\nEarly warning systems and forecasting\n\nForecasting models are increasingly used to convert surveillance data into advance warnings. In Singapore, a set of statistical models based on LASSO regression was updated weekly with recent case data, meteorological data, vector surveillance data, and population-based national statistics, and it produced operationally useful forecasts at a 3-month lag. A later Singapore model added serotype information. A climate-informed model improved predictive power by 54% compared with a seasonal baseline, and including serotype information raised this to 60%. Model developers in Bangladesh have taken a similar route, using tree-based machine learning models built on sociodemographic, climate, landscape, and dengue surveillance epidemiological data. Models for Brazil have gone further by adding historical dengue cases, lagged climate variables, and human mobility-adjusted imported cases to a deep-learning forecast. An earlier analysis suggested that a dengue early warning issued about 3 months in advance could provide enough time for effective mitigation.\n\nOutbreak response and reporting speed\n\nOutbreak response depends on how quickly suspected cases reach the authorities, not only on confirmed ones. Many health providers do not report dengue activity until they receive a positive laboratory result, because they are unaware that prompt vector control can begin as soon as suspected cases are notified. Some physicians also skip testing during outbreaks because they feel confident in clinical diagnosis, and others are unfamiliar with the timing of tests or the difficulties of interpreting results when several flaviviruses circulate. Human-resource planning for surges and the training of health-care workers in laboratory testing and case notification are therefore part of preparedness. Reporting speed also depends on infrastructure. In Sri Lanka, a paper-based notification process took approximately 12 days to complete the whole cycle, which delayed the response to outbreaks. Some national guidelines set tighter deadlines: Timor-Leste's guideline requires that, in urban areas, the sub-district vector-control supervisor submit an epidemiological and entomological investigation report within 24 hours, and it allows penalties for non-reporting of notifiable disease.\n\nInternational reporting and inconsistent data\n\nAt the global level, the World Health Organization collects and analyzes official dengue and severe dengue records from more than 100 Member States. These records are not directly comparable. WHO has stated that because of differences in surveillance methods and reporting practices, comparing trends between countries and areas is not possible, although national trends can be observed over time. Coverage also varies from period to period: the European Centre for Disease Prevention and Control reported that 78 countries or territories reported dengue cases between January and March 2026, and its figures drew on publicly available information rather than uniform notification. Regional totals are shaped by the same differences. The Pan American Health Organization reported that in epidemiological week 12 of 2026 a total of 624,085 suspected cases of dengue were reported in the Americas, but because these are suspected rather than confirmed cases, the figure reflects local testing practices as much as true incidence."
    },
    {
      "heading": "Socioeconomic burden and health-system strain",
      "text": "Dengue's economic cost is large but difficult to measure, because much of it falls outside formal health budgets. A widely cited global analysis, which used 2013 incidence data for 141 countries and territories, estimated the annual cost of dengue illness at about US$8.9 billion, with a 95% uncertainty interval of US$3.7 billion to US$19.7 billion. The same analysis split cases by care setting: 18% were admitted to hospital, 48% were treated as ambulatory cases, and 34% were classed as non-medical, meaning they never reached formal care. Productivity losses form a major share of the total. Roughly 40–42% of the global figure is attributed to them, and combined indirect and out-of-pocket costs often exceed direct medical costs, representing 50–75% of total per-episode spending across several low- and middle-income studies. Households therefore carry much of the burden through lost wages, caregiver time and private payments. More recent work has noted that there is no recent comprehensive assessment of the global economic impact, so the 2013 figure remains the common reference point.\n\nNational estimates vary with epidemic conditions and methods. India's annual burden has been put at about USD 1.1 billion, while Brazil's estimates range from USD 300 million to over USD 1 billion depending on epidemic conditions. For Indonesia, the burden was estimated at USD 300–500 million annually. Unit costs differ widely. The average cost per case ranged from USD 200 to 1,500, depending on severity, access to healthcare and national income level. Among public-sector inpatients, the average total cost ranged from $30.1 in Burkina Faso to $1,855.3 in Mexico, a gap that reflects differences in hospital stays, supplies and wage structures.\n\nEpidemic peaks place acute pressure on hospitals. In Bangladesh in 2026, hospitals recorded 19,317 dengue admissions for September 1–15 alone, and the rising caseload strained bed capacity, clinical staff, diagnostic services, blood transfusion systems, and essential medicines. Triage is a key bottleneck: patients without warning signs are usually managed as outpatients, those with warning signs are generally admitted, and severe cases go to intensive care, so a surge can overwhelm each step. Hospitals respond by cancelling elective procedures; during Singapore's 2005 outbreak, hospitals cancelled some elective surgery to free beds for dengue patients. Admission policy can ease the load. After the 2004–2005 epidemic, Singapore tightened its criteria, and the share of dengue cases hospitalized fell from 93.2% in the 2004–2005 epidemic to 28.9% in 2013–2014, with no accompanying rise in adverse outcomes.\n\nThe burden is unevenly distributed. In Bangladesh, densely populated areas faced critical shortages of hospital beds, which may have affected fatality rates. Dengue also feeds back into poverty: diseases of this kind reduce workforce productivity, hinder educational achievement, and drain health resources in settings that already have limited resources. Beyond the figures in the available sources, the pattern is well documented: crowded housing, unreliable water supply and inadequate waste collection concentrate transmission in informal settlements, while residents there have less access to timely clinical care, sick leave and private treatment. Poorer households are thus more likely to face delayed diagnosis and catastrophic out-of-pocket costs.\n\nEconomic evaluations of prevention are relatively few. One review noted that few cost-effectiveness analyses of dengue interventions have been reported, despite the disease's importance in Asia and Latin America. In Colima, Mexico, community participation in vector control was estimated at $3,952.84 per DALY avoided, and ultra-low-volume spraying at $4,472.09 per DALY avoided, and the authors concluded that both were cost-effective. Wolbachia releases have attracted more modelling work. An Indonesian study projected that Wolbachia releases in high-density urban areas would be highly cost-effective, with gross costs below $1,500 per DALY averted, and that over 10-year horizons such programmes could become cost-saving. A scoping review of nine studies reached a similar conclusion for large urban settings, while calling for more work on how variation in effectiveness affects long-term projections and how Wolbachia would combine with other measures such as vaccination. For vaccination, a Colombian model found that the costs of diagnostic testing and vaccination would need to fall before dengue vaccination could be considered cost-effective, and insecticide-based measures ranked higher. Early warning systems have also been assessed: in Brazil, an early warning system was judged very cost-effective in 25 of 27 states, under the modelled assumptions."
    },
    {
      "heading": "Travel, imported cases and blood safety",
      "text": "Imported cases and travel medicine\n\nTravel is the main way dengue reaches places where it does not circulate year-round. During 2024, a record 3,798 dengue cases were reported in the United States, and 97.2% of cases were travel associated, and 2.8% were locally acquired. In the EU/EEA and the United Kingdom, the reported numbers of travel-associated cases per year since 2012 generally surpass 1,000, reaching a maximum of 4,900 for the year 2023. Because many infections produce no symptoms, these counts are probably low. Infections are frequently asymptomatic, at about 50% according to a meta-analysis, so reports likely underestimate the number of imported cases each year.\n\nImported dengue is also easy to miss in clinics. A returning traveller from Bangladesh had fever, rash, nausea, vomiting, myalgia and conjunctivitis, and no laboratory confirmation of prior dengue infection was available, so he was discharged with a diagnosis of viral fever and the possibility of a secondary infection after dengue. Travel medicine clinics therefore give pre-departure advice on mosquito bite prevention and a clear plan for when to seek care after returning. For example, in 2026 the Hawaiʻi Department of Health reported that all eight dengue cases in the state that year involved travel to Pacific Island countries and territories. Its guidance is that people returning from areas with dengue risk should take precautions against mosquito bites for three weeks, and should seek medical evaluation if symptoms develop within two weeks of returning.\n\nIntroduction into non-endemic areas\n\nWhen an infected traveller arrives where competent vectors are present, local transmission can follow. When environmental conditions are favourable and dengue vectors are present, viraemic travel-associated cases can occasionally pass the virus to people living nearby, producing limited clusters. Aedes albopictus is established in a large part of Europe, which makes this pathway relevant there. In Italy, six locally acquired dengue virus 1 infections were detected in Lodi province, Lombardy Region, in August 2023, and genomic analysis placed the viruses alongside Peruvian and Brazilian strains collected between 2021 and 2023, which pointed to an imported origin. Across Europe, 304 cases of locally acquired dengue were reported in 2024, an increasing trend compared with previous years (130 cases in 2023 and 71 cases in 2022).\n\nIntroductions also occur in regions with little prior dengue. Rwanda reported two imported mild dengue cases detected in travelers returning to Rwanda from Brazil and the Central African Republic. In the Caribbean, when controlling for gross domestic product, population, and year, the risk associated with local cases of dengue increases by 96% for every one unit increase in the log of travel infection rates from the Dominican Republic, Jamaica, and Puerto Rico. Genomic and surveillance data can also show where a virus came from. In Guinea, a traveller's case was serotyped as DENV-1 two days after symptom onset, and in-country phylogenetic analysis linked the virus with urban dengue viruses known to circulate in West Africa.\n\nTransfusion and organ donation\n\nTransfusion transmission is uncommon but documented. There have been rare cases of dengue virus spreading through blood transfusions. The main difficulty is that donors are usually well. DENV, like many other arboviruses, can cause asymptomatic infections in up to 80% of infected individuals. Antibody tests, although useful for diagnosis, are unsuitable for blood screening because the infectious viremic stage precedes seroconversion. For this reason, NAT targeting DENV RNA has been considered the most appropriate approach for blood screening. A 2026 report from mainland China described a platelet donor who was asymptomatic, tested positive for DENV RNA, and negative for anti-DENV IgM/IgG antibodies at donation, and the recipient's infection was confirmed molecularly. Screening practice varies widely. The United States does not screen for dengue virus in blood donations or apply dengue-specific deferrals, because the risk for donors in the continental United States is very low. Endemic countries usually combine several safeguards, including geographical donor deferrals, traveling deferrals, donation testing, pathogen reduction techniques, and lookback programs. Some studies also suggest that a joint test for DENV RNA, NS1, and IgG/IgM antibodies may be essential to increase the likelihood of detection and reduce transfusion risk. Organ donation is screened using donor history and laboratory testing in a similar way, though the evidence base there is thinner.\n\nPublic-health measures for travellers and affected areas\n\nPublic-health responses to imported cases combine rapid laboratory work with vector control. In Madeira in 2025, following two suspected dengue cases, increased entomological surveillance efforts were implemented to confirm local transmission. Authorities complemented a network of mosquito traps with targeted surveillance using traps placed near suspected human cases. European guidance for locally acquired Aedes-borne diseases outlines surveillance, prevention, and control measures tailored to four risk levels based on vector presence, environmental conditions, and recent transmission. Clinical awareness remains the weakest link. In Spain's 2024 outbreak, case detection was largely dependent on clinical suspicion, which underlines the need for clinicians to consider dengue in returning patients with compatible symptoms."
    },
    {
      "heading": "Research history and key discoveries",
      "text": "The dengue virus was first isolated in 1943. Ren Kimura and Susumu Hotta worked with blood samples from patients during an epidemic in Nagasaki, Japan, and passed the material through laboratory mice, which showed that the agent was a filterable virus. Albert Sabin and Walter Schlesinger isolated the virus independently a year later. The early isolates were soon linked to other outbreaks: DENV-1 appeared in Japan, Hawaii, Singapore and French Polynesia in 1943–1944, and DENV-2 was recovered from New Guinea in 1944, where it had infected American soldiers. Researchers came to see that these were not one virus. Neutralization tests using patients' sera revealed antigenic differences, so the group was understood as four distinct serotypes, DENV-1 to DENV-4. Dates for the last serotype vary between accounts: some sources place its first identification in Thailand and the Philippines around 1953, while others date its isolation in the Philippines to 1956. Because infection with one serotype confers lasting immunity only to that serotype, the serotype concept became central to later work on immunity, vaccines and surveillance.\n\nThe link between dengue and Aedes aegypti was established through transmission experiments rather than through a single discovery. In 1925, Joseph Siler and colleagues set up a mosquito colony in Manila for experiments on dengue transmission, and a further group carried out dengue transmission work in Amsterdam in 1930. These studies, together with later historical reviews of the disease in tropical Asia, supported the view that Aedes aegypti, a mosquito that lives close to people and breeds in household containers, was the principal vehicle of urban epidemics. The mosquito's behaviour, which favours feeding on humans and indoor breeding, made it an unusually efficient carrier of the virus between people. Later work confirmed that Aedes albopictus can also transmit dengue, especially in areas where the other species is absent. For background on the vector itself, see Aedes aegypti.\n\nThe severe form of the disease was first recognized in the 1950s. In 1953–1954, Quintos and colleagues described a group of children in and around Manila with high fever, abdominal pain, a positive tourniquet test, low platelet counts, narrow pulse pressure, shock and gastrointestinal bleeding, and they initially named it Philippine hemorrhagic fever. In 1956 about 1,200 further cases were recorded in the Philippines, and William Hammon, who was in the country that year, helped establish the viral cause. Similar epidemics were reported in Bangkok and Manila in 1954, and during the 1960s Thai researchers and the U.S. Army's SEATO Medical Research Laboratory in Bangkok described the clinical physiology of dengue shock syndrome. Later studies in Vietnam and elsewhere documented the disease in other countries of Southeast Asia. This body of clinical work led to the four-grade system of the period (grades I–IV, with shock in grades III and IV), which was the framework used before the 2009 WHO reclassification.\n\nThe concept of antibody-dependent enhancement emerged from the observation that some patients with a previous dengue infection developed more severe disease during a second infection with a different serotype. Investigators in Thailand and Vietnam in the 1960s, notably Scott Halstead, documented this pattern in epidemiological and clinical studies, and the immunological explanation was refined in subsequent decades. The proposed mechanism is that antibodies from an earlier infection bind to a new serotype without neutralizing it, and instead help the virus enter cells that carry Fc receptors, particularly macrophages and monocytes. This increases viral load and triggers an intense inflammatory response. The recognition of this mechanism had direct consequences for vaccine design: a useful vaccine must induce balanced protection against all four serotypes, because partial or uneven immunity could in principle increase the risk of severe disease in people who were later exposed to a different serotype. This requirement has shaped the development of the vaccines discussed in later sections."
    },
    {
      "heading": "Controversies in prevention policy",
      "text": "Dengue prevention has been shaped by three overlapping disputes: the safety of the first licensed vaccine, the question of whether vaccination should depend on prior infection, and the acceptance of genetically modified or bacteria-based mosquito releases. Each dispute has affected public trust as much as the underlying science.\n\nThe most consequential case is Dengvaxia (CYD-TDV), a live tetravalent vaccine that was introduced in 2015 as the first licensed dengue vaccine. In the Philippines, a 2016 campaign aimed at more than 830,000 schoolchildren went ahead without screening for prior infection, even though warnings about ADE risks in seronegative individuals had been raised. In late 2017 the manufacturer's review found that, in rare cases, the vaccine could raise the risk of severe dengue in people who had never had the disease and were infected later (so-called seronegative patients). The WHO then advised that the vaccine be used only in people previously infected. The Philippine Department of Health suspended the programme in December 2017, and the Philippines revoked Sanofi's product licence for Dengvaxia in February 2019. Production was halted in January 2024.\n\nThe suspension also produced a wider loss of confidence. Despite nationally televised dialogues, the creation of hotlines and close monitoring of Dengvaxia recipients, a broad vaccine scare spread across the country. Parents' fear of the dengue vaccine led some to refuse vaccination for other vaccine-preventable diseases. Analysts have also framed the episode as an ethical problem: giving a vaccine to healthy seronegative people means that the vaccine prevents serious disease in some while at the same time it places others at risk of severe dengue. Some vaccine experts have continued to affirm the scientific basis of the interim safety report, so the dispute is over how the risk was communicated and managed as much as over the signal itself.\n\nThe same question of prior infection returns with Qdenga (TAK-003), the vaccine that was developed to protect people whether or not they had dengue before. In September 2023, WHO officially recommended that countries should consider introducing TAK-003 vaccine into their routine immunization programmes for age 6-16 years but only in settings with dengue transmission intensity. The use of a pre-vaccination screening strategy to limit vaccination to seropositive persons is not recommended in settings with high dengue transmission. In low- and moderate-transmission settings, WHO does not recommend the programmatic use of this vaccine until the risk profile in seronegative people infected with DENV-3 and DENV-4 is better defined. Guidance for travellers illustrates the divergence. Guidance was generally more restrictive than regulatory authorization, and while there was broad agreement in recommending vaccination for travellers with laboratory-confirmed prior dengue infection, recommendations for those without documented infection varied widely.\n\nCommunity acceptance of mosquito releases raises a related set of concerns. Programmes that use genetically modified mosquitoes or the Sterile Insect Technique aim to suppress populations and require continuous, large-scale releases of male mosquitoes to maintain their effect. The Wolbachia approach used by the World Mosquito Program is presented as not involving any genetic modification, but the release of any organism into the environment requires local consent and engagement. A risk assessment of Wolbachia releases lists community opposition with the community not engaged, formal regulatory oversight among the factors that can stop a programme from proceeding, and it treats non-acceptance of release because of political and/or community opposition as a distinct barrier. Public engagement, transparency and the perceived trustworthiness of the sponsoring institution are therefore central to whether these interventions can be deployed.\n\nThe debate over whether Wolbachia can be self-sustaining is largely scientific, but it also has policy consequences. Proponents note that the replacement of populations with Wolbachia-infected females is self-sustaining and can greatly reduce local dengue transmission, whereas suppression approaches depend largely on decreasing the population density of mosquitoes driven by infertility and require continued mosquito release. Trial results from Yogyakarta, Niterói and Medellín are cited by the developer as evidence of effectiveness, with dengue reductions of 77 per cent in Yogyakarta, Indonesia, 89% in Niterói, Brazil, and by more than 90 per cent in Medellín, Colombia. Critics point to durability. Long-term data from Rio de Janeiro reported that introgression of the wMel strain never exceeded suboptimal levels (~32%), even after massive releases, and following the interruption of releases, Wolbachia frequency declined sharply, reaching <10% within less than two years. A separate Vietnamese release saw the Wolbachia frequency fall to 20% roughly 40 to 60 weeks later, suggesting that the strain's high fitness cost renders it unsustainable in the absence of regular re-introduction. A 2025 perspective therefore argues that Wolbachia should not be framed as a self-sustaining or stand-alone solution, but rather as a maintenance-dependent, context-sensitive intervention. Because the outcome also depends on Wolbachia, viruses and their mosquito hosts can evolve, leading to uncertainty around the long-term effectiveness of a given Wolbachia strain, the disagreement is unlikely to be settled by any single trial."
    },
    {
      "heading": "Current research frontiers and unresolved questions",
      "text": "Dengue still has no approved specific antiviral, so most current work is at early clinical stages. A Vietnamese program, led by the National Hospital for Tropical Diseases with the Korean company Hyundai Bioscience, began testing an oral agent called XAFTY in March 2026. The formulation raises the bioavailability of niclosamide more than fivefold, so that enough of the drug reaches the blood to act. Its proposed mechanism is indirect: it does not attack the virus itself but activates autophagy in the host's own cells. Other candidates target viral enzymes. Mosnodenvir, a compound that Johnson & Johnson developed, reduced DENV-3 infection and viral RNA in a phase 2a trial in which volunteers were given a weakened DENV-3 challenge strain, but no clinical trial results in dengue patients have been published for this class of compound. The authors of the challenge study also noted that its small sample size and controlled timing of exposure limit generalizability to real-world settings, where several serotypes circulate and exposure is unpredictable. Newer studies are testing other agents in patients. The Oxford University Clinical Research Unit in Vietnam started an adaptive phase 2 platform trial in April 2026 for people with early symptomatic dengue, and a Hyundai Bioscience phase 2/3 study plans to enrol patients with NS1-positive dengue within 72 hours of fever onset. Research groups in Brazil and Novartis have also registered early-phase studies of other compounds.\n\nBiomarkers are the second major gap. Clinicians still cannot reliably tell, at admission, which patient will develop plasma leakage or shock, and most candidate markers have been validated only in small, single-site cohorts. A Thai study of 265 patients found that serum cortisol offered only modest discrimination on its own, with an AUC of 0.62, but the AUC increased to 0.76 when cortisol was combined with persistent vomiting and the day of fever. A circulating microRNA study began with a discovery cohort of only 19 patients, and its two leading candidates reached an AUC of 0.83 in a larger validation group. Urinary markers have been examined as a non-invasive alternative: urinary neutrophil gelatinase-associated lipocalin reached an AUC of 0.88 in one adult cohort. Inflammatory and endothelial proteins, including IL-6, soluble TNF receptor 1, angiopoietin-2 and thrombomodulin, have also been proposed as prognostic markers. Projects now aim to combine such molecular data with clinical records, serotype information and climate data in AI-driven prognostic tools. The main unresolved issue is external validation across populations, serotypes and healthcare settings.\n\nVaccine research is focused on the problem of protecting against all four serotypes at once without increasing the risk of severe disease in people with prior infection. Merck's V181 is a live attenuated quadrivalent vaccine that has been developed with Instituto Butantan, and its phase 3 MOBILIZE-1 trial is designed for a single dose. The study plans to enrol approximately 12,000 healthy individuals 2 to 17 years of age, randomized to vaccine or placebo across several Asia-Pacific countries. Its primary endpoint is protection against symptomatic, virologically confirmed dengue of any severity, and severe disease is a secondary endpoint. The trial's inclusion of participants regardless of prior exposure means that data on seronegative and seropositive groups will be needed before the balance of benefit and risk can be judged. Post-licensure monitoring will also be required to detect any change in severe disease patterns after the vaccine has been used widely.\n\nThe long-term ecological consequences of vector control are less well characterized. Wolbachia releases and other mosquito-suppression methods alter local Aedes populations, but the durability of these effects, the responses of non-target insects, and the possibility that other vectors fill the vacated niche remain open questions that require sustained, multi-year monitoring. Climate is a parallel uncertainty. Warmer and wetter conditions can lengthen the transmission season and expand the range of Aedes mosquitoes, while El Niño-related variability produces sharp multi-year swings in case numbers. Forecasting models therefore need to represent both the biology of the vector and the socio-ecological conditions that shape exposure, and their accuracy over decades remains to be tested."
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    }
  ],
  "license": "https://creativecommons.org/licenses/by/4.0/"
}