Neglected tropical diseases: Action on all fronts
A relatively new term, neglected tropical diseases (NTDs), is raising awareness of the numerous infectious diseases it encompasses, the burden they place on the world’s poorest people, and the need to do more to control them. While each NTD will require specific research, treatment and prevention strategies, common to all is the need for a variety of approaches. In his latest post in our NTDs series, Michael Regnier investigates how multiple strategies are being pursued to combat dengue fever.
Dengue is a mosquito-borne viral infection that causes fluid to leak out of the blood vessels into the abdomen and other cavities, in some cases causing severe shock. While less than 1 per cent of people infected with dengue virus will die from the disease, it is endemic in many countries where it is a constant problem.
On top of this ‘background’ level of infection, there are peaks of infectious outbreaks – epidemics – that can produce three to five times the normal number of cases. Professor Gavin Screaton, a Wellcome Trust Senior Investigator and Head of the Department of Medicine at Imperial College London, says dengue has the potential to spread through communities like wildfire.
“Dengue is predominantly a disease of urbanisation,” he says. “It poses major challenges to healthcare systems in developing countries because of its epidemic potential causing explosive outbreaks in some major cities. In endemic countries they’re good at treating it with excellent support management – which consists of giving patients large quantities of replacement fluid – but you don’t know who will get severe disease, so many cases will require hospitalisation.”
No drugs, no vaccines
Because the majority of patients recover, dengue doesn’t receive the same attention as infections such as HIV, malaria and tuberculosis, or even some other neglected tropical diseases (NTDs). But there are currently no drugs or vaccines at all for dengue. A drug that could be used in the early stages of dengue would help to prevent severe disease, while a vaccine would prevent many infections and reduce hospital admissions.
Screaton studies the immunopathology of dengue – how it causes disease through its interactions with the immune system – in order to help the development of effective vaccines. He started his research into dengue when Juthathip Mongkolsapaya, then a PhD student in his lab, told him about her work in Thailand. “Ju told me it was fascinating epidemiologically and immunologically,” Screaton recalls. “And, of course, it was a very important pathogen with no vaccine.
“It’s actually four viruses, or serotypes, which differ from each other by about 30 per cent. You can be infected more than once and the majority of cases that get very sick are secondary infections.”
This is because the body generates specific antibodies against the dengue virus during the first infection. If the same serotype comes back, these antibodies quickly bind to it and neutralise it.
If a different dengue serotype enters the body, however, the previously generated antibodies bind to it less strongly because of the variation between serotypes. Weak binding means they are unable to neutralise the second serotype. The functioning virus is then able to infect more cells in the body, triggering serious disease.
The challenge in developing a vaccine, therefore, is to work against all four serotypes at the same time. “It’s extremely difficult to get vaccines that are not too hot that they cause febrile illness themselves and not too cold, that is, ineffective,” explains Screaton. In true Goldilocks fashion, the vaccine has to be just right: “The aim is a balanced immune response against four targets that are in some aspects very different but at the same time rather similar.”
Approaching the problem from all angles
Trials of dengue vaccines are in progress, as are antiviral drug trials, including one sponsored by Roche. Professor Cameron Simmons, a Wellcome Trust Senior Fellow at the University of Oxford, has been working on this trial and says much has been learned as a result: “It’s different running trials in acute disease interventions,” he explains. “The timing of intervention is crucial, and needs careful follow-up. It’s a different sort of approach to trials in hepatitis or HIV.” The results of the trial will be published soon but whatever the results, says Simmons, the experience will help to provide a toolbox of how and what should be done in future trials.
Simmons is also involved in the development of new diagnostic and prognostic tests for dengue. “We’d like to give clinicians a tool to predict who’s at risk of getting severe disease,” he explains. “Then the doctor may make a different triage decision.” Identifying which patients are at most risk would help to ease the burden on healthcare systems during an outbreak of dengue. With the right tests, doctors could make a more accurate assessment of patients when they come to the hospital and admit only those people at high risk of severe disease.
Another approach is vector control: preventing the transmission of the virus from mosquitoes to people. For example, Simmons is working on a project, in collaboration with researchers in Australia, to infect mosquitoes with a bacterium called Wolbachia. This makes them partially resistant to dengue, which could help reduce the number of infections in humans.
“The science has developed quickly and gone into the field very quickly,” says Simmons. “Vector control really struggled for a good research base for a long while but now we’re seeing scientifically robust work coming in. These approaches have emerged in the last five years or so, whereas vaccine research has been grinding away in the background for the last 20.
“The important point,” he adds, “is that all these approaches can be complementary. We’re not going to eradicate the virus any time soon, so we need a swag of tools to control dengue.”
This is true for most NTDs. Drug development and vaccine research take a long time; in the meantime, other approaches can be pursued to reduce the burden of disease. Ultimately, a combination of approaches will be the most successful.
Simmons is based in Vietnam, where he and his team work closely with local partners who have first-hand experience of the disease. He believes this contributes to the strength of their research: “There are very few research groups based in countries where dengue is endemic. At the Wellcome Trust Major Overseas Programme in Vietnam, we can take a long-term view and tackle the research on the ground, taking into account the priorities of the local community.
“A lot of our work is hospital-based and, importantly, we do training at the hospital, building research capacity in the clinical setting. Hospital clinicians see dengue patients every day – they understand the strain in health systems during epidemics.”
Dengue was not included in the first list of NTDs but Simmons is clear that it fits the criteria: “Dengue is neglected in the sense that the true scale of the disease burden is poorly understood and certainly underestimated.
“The research community is pretty small but in the last five years it has been growing. We could well have a vaccine in the next ten years, there are novel approaches in vector control, and there is interest from both academics and industry in developing antiviral drugs. We’re building momentum.”
Controlling dengue fever, improving lives: an alternative approach to dengue vector control in this Wellcome Trust video.