Background

Causative agents. Dengue fever (DF), dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) are progressively more severe clinical manifestations of dengue infection caused by four, single-strand RNA flaviviruses known as DEN-1–4. Virus transmission occurs through the infective bite of Aedes aegypti, a mosquito with high biting frequencies and readily interrupted feeding behaviour. The virus replicates in lymph nodes, spleen, liver and mononuclear phagocytic cells in other tissue systems.

Current global status. Dengue is the most important arboviral disease of humans. An estimated 50 million dengue infections and 500,000 DHF cases occur annually, particularly in south-east Asia, the western Pacific and the Americas1 (Fig. 1).

Figure 1
figure 1

Areas where there is a risk of dengue transmission

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Recent developments

New basic knowledge. Dengue viruses encode three structural proteins — capsid (C), membrane (M) and envelope (E) proteins — and seven non-structural (NS) proteins.

In the Americas, the transition from DF to DHF and DSS occurred in Cuba in 1981, when an Asian genotype virus (DEN-2) was introduced into a DEN-1-immune population2. By contrast, when the American genotype DEN-2 infected a DEN-1-immune population in Iquitos, Peru, only mild disease resulted3,4. Differences in the outcome of secondary infection seem to be due to the high level of cross-neutralization between DEN-1 antibodies and the DEN-2 virus5. It is hypothesized that Asian dengue strains that successfully circulate in highly dengue-immune populations have lost cross-reactive epitopes, as a mechanism of immune escape. Important for the development of DHF/DSS is enhanced viral replication during the early stage of infection6, which is apparently mediated by non-neutralizing antibodies that are residual from an earlier dengue infection and is known as antibody-dependent enhancement (ADE)7. So, early infection, the time interval between first and second infection8, virus strain and host genetic factors are involved in severity of the disease outcome. Plasma leakage, the main patho-physiological feature of DHF, seems to be particularly correlated with blood concentrations of cytokines (such as IFN-γ, IL-2 and TNF-α) and infected cell lysis, owing to dengue-specific T lymphocytes9. The ultimate causes of haemorrhage due to vasculopathy, platelet reduction or dysfunction and prothrombin-complex deficiency are even less clear, although platelet-activating factors and, potentially, platelet-destroying mechanisms have been described10,11.

New tools and intervention methods. An effective dengue vaccine should protect against the four serotypes and should be long-lasting to avoid antibody titres dropping to sub-neutralizing levels. Six live attenuated vaccines are in various stages of development12. Two live attenuated vaccines have reached Phase II evaluation, and 3–4-year follow-up data for one vaccine show protection against disease and no increase in severe dengue. In preparation for Phase III trials, there is still considerable need for field site development and epidemiological characterization of study populations. A dengue vaccine could be highly cost-effective, as the cost per disability-adjusted life year has been estimated as US $50 (Ref. 13). In addition, both the WHO-based Initiative for Vaccine Research (IVR) and the Paediatric Dengue Vaccine Initiative (PDVI) are working to facilitate vaccine development.

Current dengue diagnostic tools include anti-dengue immunoglobulin M (IgM) detection, which indicates a recent infection, and the use of PCR, which allows detection of the dengue virus genome in serum, mosquitoes and tissues. Improved tests that allow early diagnosis, including clinical prognosis, are urgently needed; one such test which targets the NS1 protein is currently under development.

Discovery of a drug that reduces viral load in dengue patients has been initiated at the Novartis Institute for Tropical Diseases in Singapore. A library of more than 1 million compounds is being tested against a cloned fraction of the NS3 viral enzyme so that a candidate lead molecule can be identified. A rapid-acting compound with minimal side effects might also be effective as a chemoprophylactic component, potentially preventing the occurrence of large outbreaks. However, successful antiviral therapy will depend on rapid early diagnosis.

At present, the only methods for reducing dengue transmission are reduction of human–vector contact and control of the mosquito populations. New tools are under development, such as insecticide-treated curtains and improved formulations of larvicides that are safe for use in drinking water.

In addition, implementation of DengueNet — a global system for standardized epidemiological and virological surveillance — will allow a continually updated database to be maintained for timely control measures and epidemiological research.

New strategies, policies and partnerships. New vector-control measures and new partnerships with, for example, municipal authorities are needed. Given that mosquito habitat management or treatment methods rely on the involvement of individuals, communities and governments, a manual using the COMBI approach (Communication for Behavioural Impact) has been developed to assist programme planners in developing sustained community action plans for dengue prevention and control14. Transgenic technology to interupt pathogen transmission has been developed for A. aegypti15, using the introduction of exogenous DNA into the germ line. Completion of the A. aegypti genome sequence will facilitate the research process.

Conclusions and future outlook

The pipeline of vaccine candidates looks promising, but their use for disease control will require careful safety follow-up to assure that no sensitization to severe disease occurs. An improved understanding of the molecular mechanisms of pathogenesis of severe disease will help to overcome this threat. Monitoring the molecular structure of circulating virus exposed to selective pressure from vaccine-induced immunity will be important. Vector control will also be needed. Capacity building will be essential for the sustained delivery of vector control measures to protect high-risk populations and respond to epidemics or the threat of epidemics.