Researchers cover all bases to stop dengue fever spread
Dengue fever kills around 25 000 people every year and infects 50-100 million, according to the WHO. With incidences rising, there is a new urgency to predict where it will strike (is Europe at risk?) and who is vulnerable. Doctors also need the tools to diagnose the disease quickly, while gaining the upper hand over the mosquitoes that carry the virus would limit its spread in the first place. Between them, three EU-funded projects are approaching Dengue Fever from each of these angles in the race to save lives.
The symptoms of Dengue fever range from a high temperature, severe headache, muscle and joint pain and rash to bleeding and life-threatening shock syndrome. In the absence of good hospital care, severe dengue can be lethal, and although a vaccine has been recently developed, it is not suitable for children under the age of 9, and is under scrutiny for efficacy.
Prediction – where?
Scientists already know how the disease is spread – by mosquitoes carrying one of four virus serotypes. To bring the disease fully under control, they also need to understand the conditions likely to lead to an outbreak.
This is complicated by the fact that a large percentage of those carrying the virus are actually asymptomatic, but can nonetheless be bitten by mosquitoes that then go on to bite others, so passing on the disease. “People with symptoms are really the tip of the iceberg,” says Anavaj Sakuntabhai, coordinator of the DENFREE project.
In a quest to reduce the spread of the disease, the DengueTools project set up a surveillance system in Sri Lanka, where reliable confirmation of dengue fever was previously impossible. After establishing a laboratory where dengue could be diagnosed reliably, the team put in place an active surveillance system to document the burden of disease and its evolution over time. The system is still up and running after the end of DengueTools, project coordinator Annelies Wilder-Smith says proudly.
As we don’t know who is carrying the virus, there is no system in place that could stop carriers travelling and spreading the disease. Mobility patterns together with climate and weather conditions,have the greatest impact on spread, says Sakuntabhai.
Unfortunately, predicting an outbreak is not as simple as checking the weather forecast. The DengueTools project trained a local team to develop predictive models. Its research showed that climate data alone are not sufficient to predict an outbreak. “Dengue fever has a very focal distribution and is very hard to map. Where dengue moves next depends largely on the introduction of new serotypes, socioeconomic behaviour and herd immunity, in addition to weather variables,” explains Wilder-Smith.
The work done in the project has nonetheless laid the ground for future research – as have the maps created by the IDAMS and DengueTools projects that project the future dengue burden.
While understanding the future burden of dengue fever obviously involves prediction, having a clear view of the current burden in some regions also requires projection. This is partly because the number of asymptomatic carriers is unknown, and partly because cases are often underreported in most countries. This has important implications, for example in understanding vaccine efficacy.
The IDAMS project estimates there to be 390 million infections globally each year. Many of the cases are in Africa, where the team finds that the burden is masked by illnesses with similar symptoms, under-reporting and a tendency to not always seek treatment. Whether Africa has more cases than other regions, or whether the cases there are perhaps less serious, are interesting questions that project coordinator Thomas Jänisch would like to pursue in the future.
Prediction – who?
In its research on predicting the clinical course of dengue fever, the IDAMS project is looking at the development of the disease within the individual. “We might be able to predict clinical evolution with reasonable accuracy,” says Jänisch.
Knowing who is likely to be more seriously ill from the disease will ensure that those who need to be monitored are admitted to hospital, while others are monitored as outpatients, thereby freeing up hospital beds.
The IDAMS team is analysing blood samples from nearly 7 500 patients to identify clinical and laboratory markers that could predict an individual developing a severe case of dengue fever.
Diagnosing dengue fever must currently be done in a laboratory, by trained experts using expensive equipment. Both the DENFREE and DengueTools projects worked on cheaper, portable alternatives. DENFREE has a prototype that needs further development, while DengueTools developed a diagnostic assay in Malaysia that can also be used in the field. The test can be done within 10 minutes and is a “breakthrough” for DengueTools, according to Wilder-Smith – it does however still require the purchase of certain equipment.
Protection by vaccine
The human body has several weapons that it can use to fight against disease. Antibodies are one option, and it is on these that most research to date has focused. But some individuals with a high level of antibodies still get dengue fever, explains Sakuntabhai. “We were able to show that people without symptoms have higher cellular immunity activity.”
So while previous attempts to develop vaccines have focused on the induction of antibody production (and were not satisfactory, failing to protect 40 % of the population, and offering little protection against certain strains), the DENFREE team is looking at stimulating cellular immunity, and is working with companies interested in developing a vaccine using this approach.
Protection from mosquitoes
In the absence of a vaccine, protection from mosquito bites is the only way to be sure that the disease does not spread.
As Aedes mosquitoes mostly bite during the day, DengueTools researchers had the hypothesis that impregnated school uniforms could reduce mosquito bites in school-aged children. To test the hypothesis, the team conducted a large randomised controlled school-based trial; children from half of the schools wore impregnated school uniforms while the other half wore their usual (unimpregnated) uniforms. Although the repellent ‘permethrin’ worked very well in the laboratory, the trial showed that protection in field conditions was minimal over the school term. The team noted that permethrin washes out of clothes very quickly in field conditions in the tropics which could explain the lack of protection.
Still, Wilder-Smith is not discouraged. “I still believe in this idea, but we need repellents that are more resistant to washing, ultraviolet light and ironing,” she says. The concept will be taken forward in an EU-funded project focused on the Zika disease – ZikaPLAN– which will investigate improved technologies for impregnating maternity clothes and wristbands, among other garments with repellents and insecticides.
The DENFREE project has meanwhile been testing its own mosquito control system. In Madeira it trapped mosquitoes, then coated their legs in an insect hormone that prevents larvae from turning into adult mosquitos. The trial proved effective in Madeira and is now being trialled at a larger scale in Asian endemic settings where dengue is rife.
Dengue in Europe?
“The mosquito that transmits dengue likes cities; its main food source is humans,” says Sakuntabhai. Although primarily abundant in the tropics and sub-tropics, mosquitoes found in Europe have already infected people there. France has already seen a small outbreak, and the DENFREE project confirmed that the mosquitoes found in southern France are indeed able to transmit a virus usually found in South East Asia.
The DengueTools project developed a predictive model for the climate dependent transmission capacity of the Aedes mosquito, which is the main vector for dengue viruses. The model helps assess where and when dengue would most likely hit Europe.
“In southern Europe there is definitely a possibility for transmission,” concludes Wilder-Smith. Nice, for example, has already documented transmission of dengue. But the seasonal window for mosquitoes is short. Furthermore, as infected humans carry the virus in their blood for only one week, an infected person entering a dengue-free country would need to be bitten within that timeframe, placing some limit on the risk of introduction and establishment of dengue in Europe. To help policy-makers assess the risk of dengue epidemic potential in Europe, DengueTools created seasonal window maps for various European cities.
All of these findings have been passed onto the European Centre for Disease Prevention and Control (ECDC), which has published the information on its website.
When the DENFREE, IDAMS and Dengue Tools projects were conceived, the researchers involved had little idea that Zika – also spread by mosquitoes – was about to become a public health emergency of international concern.
The IDAMS project has been recruiting patients with a high temperature in the north east of Brazil, where the Zika epidemic has hit the hardest, and will therefore be able to produce valuable data on Zika virus infections as the outbreak evolves. These data are now helping to answer open questions regarding the natural history and case definitions of Zika versus dengue and chikungunya – three parallel epidemics in Latin America and the Caribbean.
Several EU-funded projects are now looking for ways to combat the Zika virus, while many of the groups involved in these three EU-funded dengue consortia are already working on Zika within one such project.
But dengue fever research has certainly not been abandoned in the light of Zika. The three projects have been – and continue to be – in regular contact, and have established a strong network in this important field. This network is a “treasure for future studies of various kinds” and has already led to a “substantial upgrade in research capacity in participating groups,” according to Thomas Jänisch.