Dengue surveillance: Building the ultimate tool

Building the ultimate dengue surveillance tool

Image courtesy of HealthMap

Today’s increasingly connected world offers us an opportunity using digital surveillance tools to gain a true, timely picture of dengue activity around the globe. Data gleaned from social media, online searches, mobile phone tracking, crowdsourcing and more have the potential to fill gaps in epidemiological surveillance information.

“We now have access to more data than ever before,” confirms Dr. Mauricio Santillana from the HealthMap team at Boston Children’s Hospital. “Transforming today’s many diverse data sources into meaningful information and knowledge will give public health officials and the public a complete picture of the current state of dengue activity.”

HealthMap aims to do just that: in addition to showing dengue-related news reports around the globe in near real-time (as it does now), it will soon centralize dengue observations from diverse sources to show multiple aspects of the disease. More than that, the recent Big Data methodological advances made by the HealthMap research team and Harvard researchers on flu activity forecasting will soon allow the system to dynamically learn about the significance of diverse data sources and take that into account in the picture it provides. That training will help ensure it offers the best possible near real-time intelligence on an outbreak.

Machine learning improves intelligence

HealthMap was originally created around a decade ago by a team of researchers, epidemiologists and software developers at Boston Children’s Hospital as a tool for tracking disease outbreaks across the U.S. Unlike similar disease tracking tools, the HealthMap Flu Trends tool, developed during the past two years now incorporates new sources of insight (including data from Google, Twitter, Wikipedia, crowd-sourced participatory disease surveillance tools and clinician’s databases) along with simulation techniques from weather forecasting and other fields such as finance.

These simulation techniques use machine learning approaches to training the system to deliver the best results. “Information from traditional flu surveillance systems, such as the Centers for Disease Control and Prevention’s ILINet flu reports, is dynamically incorporated into the flu tracking model every week,” reveals Dr. Santillana. “This allows our models to reassess the role of its various variables along with the predictive power of each data source – or even each individual input variable. It then takes that into account going forward.”

The team soon realized that the HealthMap Flu Trends could be extended to other diseases, such as dengue, and other geographic locations as a new tool to help individuals and organizations engaged in the fight against these diseases.

Google used to map dengue too

During 2008-2015, Google leveraged its technical know-how to help track infectious diseases. The technology giant explored whether data sources not designed for disease tracking could be used to map a disease. “Google introduced the notion that the search activity of flu-related terms within their search engine could be used to produce flu estimates in near real-time. Later on, and in collaboration with our team, it was shown that this approach could be extended to track Dengue. This led to the creation of Google Flu Trends and Google Dengue Trends” adds Dr. Santillana.

Public officials used the Google Flu Trends and Google Dengue Trends tools to assess the gravity of the situation. It didn’t give them precise values, but would show whether dengue was peaking or increasing. However, Google’s tools were far from ideal. In some regions the tracking was reasonably accurate; in others, it often over-predicted or failed to capture outbreaks. “While many lost faith in this use of this wealth of new information to monitor and track infectious diseases, our research team has shown in multiple peer-reviewed publications that there is still promise in these novel data sources,” says Dr. Santillana.

Google discontinued its Flu and Dengue Trends tool in the summer of 2015 and opened up its data to researchers, including the HealthMap team. As such, HealthMap is studying how to extend the method it recently developed based on Google searches to predict flu, to predict dengue activity.

Expanding sources of insight

HealthMap and Break Dengue are partnering to expand the HealthMap platform to incorporate additional novel sources including traditional clinical reporting systems, crowdsourced disease surveillance tools, internet-based services such as Twitter and Wikipedia, and even precipitation values from weather systems to take into account how flooding might increase the severity of an outbreak. Break Dengue will provide some of that social media data.

To add to the picture, the HealthMap Flu, and Dengue Trends tool may also one-day incorporate flight frequencies between countries or track mobile phones locations, for instance. The more sources the tool can combine, the closer its correlation will be with outbreaks.

After all, HealthMap’s ultimate goal is to transform any relevant information that’s already been collected for some other purpose into meaningful information for public health officials and the public in general at a local level. The team aims to provide a centralized system that delivers a single web page with electronic records that show what diverse sources of information are saying – what Twitter is saying or what Google is saying, for instance – about dengue in any specific location.

Dr. Santillana describes how, by exposing some aspects of the complex underlying dynamics, the project is contributing to efforts to contain diseases such as dengue and limit their transmission: “With HealthMap we can also assess how certain activities may be linked to transmission.”

Understanding the burden of dengue

As well as giving a near real-time picture of the current situation, the team hopes the soon-to-come HealthMap Dengue Trends tool will also act as an early warning system – estimating what might happen over the next week or two in most cases or the next month in certain countries. “We’re hoping that when we combine our alternative sources with modeling techniques well-studied in epidemiology we’ll gain a better understanding of how a dengue season is developing – whether or not it’s going to be a bad season,” Dr. Santillana says.

More than that, HealthMap also aims to give meaningful intelligence on the actual burden of the disease, as Dr. Santillana reveals: “Our ongoing research is also looking into how best to turn qualitative results that come from news reports to quantitative estimates of disease burden or disease incident.”

Testing the dengue model

The HealthMap team will use data-rich environments to appraise the viability of their model for dengue before evaluating whether the same model applies to regions where data is poorer. Ensuring the model is beneficial to local communities will require a fair amount of research as Dr. Santillana comments: “We’ve learned a lot from tracking flu in the U.S., which is a data-rich environment. Now we need to explore how our knowledge and models extend to monitor Dengue in places where epidemiologic or weather information, for instance, or internet penetration is limited.”

That research has already begun. Models are being built ready for pilots in at least four countries: Brazil, Mexico, Singapore and possibly Taiwan and/or Thailand, where Google search data will be used to track dengue activity.

By centralizing information from different data sources, dynamically learning from it and presenting multiple aspects of the disease in an easy-to-understand format, the HealthMap Dengue Trends tool may prove to be the optimum dengue surveillance tool.

Is public health headed for an ‘analytics revolution’?

Uimage trump campaigning in the US ecection.

Analysts and forecasters are sizing up data to predict future outcomes.

Predicting dengue: public health takes notes from sports and political forecasting

Will Donald Trump become the US President? Could Real Madrid win the Champions League? What is the risk that Greece could leave the Eurozone by 2020?

These questions – ranging from the serious to the trivial – are what occupy the minds of professional and amateur forecasters alike. Now the forecasters have dengue in their sights.

Information is power. The outcome of world events can have considerable economic and political ramifications which are why mathematicians and data scientists are building models designed to estimate the risk of war, famine, public health, climate change and political upheaval.

What are the odds?

Public health may be on the cusp of a revolution in epidemic forecasting that would profoundly improve our ability to deal with infectious diseases. A more informed and strategic approach could be just over the horizon.

Knowing how climate, for example, affects the risk of a dengue fever outbreak in a particular area gives public health officials a huge advantage as it allows authorities to step up vector control and vaccination efforts in at-risk regions.

Predicting the future can be hugely complex, in locations where there are multiple factors to consider, requiring increasingly sophisticated modeling.

Fortunately, the kinds of algorithms health forecasters are dealing with are primarily the same as those used by people predicting election outcomes and sports results – and the scope for mutual learning is enormous.

Add in the exponential improvement in computer power and access to an ever-increasing pool of data, and it is not difficult to see why the field is generating such excitement.

Indeed, the potential of this area has been recognized at the highest levels, prompting the launch of the White House Dengue Prediction Challenge last year. The competition challenged participants to come up with a formula for predicting outbreaks of dengue fever in San Juan, Puerto Rico and Iquitos, Peru. More about that in a moment but first, how did mathematical modeling become the next big thing?

Going mainstream

With the notable exception of weather forecasting, predictive modeling has traditionally had low public visibility. But that began to change with an explosion of interest in using data science.

One of the chief exponents of this young field was Nate Silver, a statistician who combined his love of maths with a passion for baseball and politics. He made a name for himself first by developing an algorithm called PECOTA which accurately forecast the performance of baseball players.

Image sowing the US Presidential Elections in 2008. For journalists, analysts and politicians, data science gained new appeal.

Shortly afterward, his blog FiveThirtyEight.com made him a household name in the US. The website, which takes its name from the number of delegates at stake in US Presidential Elections, became a reference point for journalists, analysts, and politicians during the 2008 election of Barack Obama. Suddenly data science was sexy.

Image: Dr Nicholas Reich, University of Massachusetts

Dr. Nicholas Reich, Department of Biostatistics and Epidemiology at the University of Massachusetts School of Public Health. “Sports is the obvious place that has seen an analytics revolution in recent years, but also finance, politics, and public health. I credit people like Nate Silver for taking terms like ‘data journalism’ and ‘predictive analytics’ into the mainstream media vocabulary.”

Dr. Reich’s team has been working to turn the power of this analytics revolution on public health problems such as flu and dengue fever. Among the big questions to be answered in translating this statistical know-how to disease modeling is whether there are near-universal approaches to forecasting all complex phenomena or does each disease requires a new algorithm to be built almost from scratch.

He says the prevailing sentiment in the infectious disease community is that models that are customized to predict disease should perform as well or better than models, not customized for disease prediction. “But the jury is still out on this. I don’t think we have enough data to support the widespread use of one type of model over another in general, yet.”

Dr. Reich has been using a general approach. A team from his lab entered the White House Dengue Prediction Challenge with a model adapted from a similar formula for predicting flu outbreaks and the trajectory of professional basketball players’ careers.

“One of the things that we learned from using this very general prediction algorithm – that has strong methodological similarities to what Nate Silver and his team a FiveThirtyEight use to project the career trajectories of NBA players – to predict dengue is that it did roughly as well as many other highly customized methods,” says Dr Reich.

Dengue’s next top model

The White House Dengue Prediction Challenge attracted ideas from over a dozen universities as well as several companies in the US and Europe. Participants were given access to dengue case counts and environmental, climatological, demographic and vegetation data.

Their challenge was to predict the timing of peak incidence, maximum weekly incidence and the total number of cases in the transmission season. In short, when will it happen, how bad will it be at its worst, and how severe will it be overall.

The winning entry came from the Johns Hopkins University Applied Physics Laboratory (APL).

“The method we developed for predictions for both locations was the same,” says Anna Buczak, who led the APL project team. “Iquitos was much more challenging to predict than San Juan because the time series were much shorter, and the data were substantially noisier. We developed an ensemble method, in which each ensemble was made from 300 best models.”

The White House-sponsored competition built on earlier US initiatives in the fields of health, the environment, and defense. For example, the US Health and Human Services ‘idea lab’ runs an Epidemic Prediction Initiative, the National Oceanic and Atmospheric Administration runs a Dengue Forecasting project and the National Science and Technology Council hosts and an interagency working group dedicated to infectious disease forecasting.

The US government plans to publish all the models submitted as part of the contest with all team leaders included as co-authors of a peer-reviewed paper on the topic.

Man spraying for mosquitos in Rio de Janeiro, Brazil

Spraying for mosquitoes in a cemetery in Niterói, Rio de Janeiro, Brazil

Room to improve

Dr. Reich believes that while the contest did not produce a perfect dengue prediction model, it helped to move the field forward. His team is currently working to refine their models in a real-world project in Thailand. The key, he says, to optimizing prediction is to get accurate, up-to-date data.

“One very complicated factor that none of the infectious disease prediction competitions have taken into account yet is complications arising from delays in case reporting,” says Dr. Reich. “We have seen that this plays a significant role in our real-time predictions of dengue in Thailand, and making adjustments for delays in case reporting makes a huge improvement in our predictive performance.”
With organizations like HealthMap, a Break Dengue partner, building real-time surveillance systems that pull data from a range of sources including social media, the prospect of real-time forecasting based on live surveillance data is coming into focus.

Intelligence gathering

Of course, it’s not just university labs and government experts that want to build better disease forecasting models. Private sector disease forecasters have been working on this problem too. Take Ascel Bio, for example. They began forecasting dengue in Asia in 2011 and had since branched out to include Brazil and Mexico.

The company works with the private sector and defense clients concerned by spikes in demand for health services, as well as other potential disruption, caused by unusual outbreaks of infectious diseases.

“Our tools create opportunities to save lives and reduce the costs of care through better planning and operational improvements,” says Patrick Wedlock, a Senior Analyst at Ascel Bio. “Disease forecasting has become more accurate with increased computational power and a better understanding of the factors that drive disease transmission.”

He says the best way to improve forecasting is to develop the baseline data. “This means more granular and routine disease surveillance worldwide. Individual nations would reap tremendous benefits by making disease data more transparent to forecasters,” says Wedlock.
As demand for accurate forecasts rises and our ability to generate real-time surveillance data grows, we can safely predict a healthy future for the field of dengue forecasting.

Watch our documentary to find out more about ‘The Lasting Effects of Dengue’

Study shows the burden of dengue in children in Asia

The burden of dengue is caused by the dengue virus (DENV), a mosquito-borne flavivirus. Image via Sanofi Pasteur

The study published in the New English Journal of Medicine (NEJM) shows that dengue is responsible for around 10% of febrile episodes recorded in children – a startling statistic that highlights the potential impact that is controlling dengue could have.

The research, based on secondary analysis of data generated through clinical trials on the world’s first dengue fever vaccine. Researchers collected data from the control groups in 10 countries from Southeast Asia and Latin America. The findings will feed into ongoing efforts to develop a robust estimate of the true global burden of dengue.

Information was collected on acute febrile illnesses and virologically-confirmed dengue (VCD) in 3,424 healthy children aged between 2 and 16 years in Indonesia, Malaysia, the Philippines, Thailand and Vietnam; and in 6,939 children aged 9 to 18 years in Brazil, Colombia, Honduras, Mexico and Peurto Rico.

VCD incidence ranged from 1.5 to 6.6 per 100 person-years

“The incidence was high which would be expected as dengue is endemic in the countries included in the study,” says Dr. Leon Ochiai, Director of Global Epidemiology at Sanofi Pasteur and corresponding author for the NEJM paper.

“What was quite surprising was the finding that 10% of all children’s fever episodes were caused by dengue. That’s an important public health story and shows that intervening against dengue could reduce fever significantly,” he told Break Dengue.

The paper turned up another eye-catching statistic: around 13% of VCD episodes in the children studied led to hospitalization. Again, this points to the potential for anti-dengue measures to curb pediatric hospitalization.

Image of a dengue mosquito feeding on a human host.

A female Aedes aegypti mosquito acquiring a blood meal from her human host, who in this instance, was actually the biomedical photographer, James Gathany, from the Centers for Disease Control. Image via Sanofi Pasteur

Standardized approach to managing dengue

The authors say their findings could make a valuable contribution to dengue fever modelling and ongoing efforts to estimate the burden of the disease. The WHO is working to estimate the incidence of dengue around the world, often relying on a broad range of individual studies.

“The data reported here uses standardized laboratory and surveillance methods,” explains Dr. Ochiai. “Instead of comparing apples and oranges we can, for the first time, analyze a comprehensive dataset using a standardized method.”

He says the data is of the highest quality because the standards employed in clinical trials is high.

“In term of quality, this is a huge asset for the WHO and others who are seeking to produce a global estimate of dengue,” Dr. Ochiai says.

The report shows that the epidemiology of dengue varies from year to year and from place to place, highlighting the need for a robust surveillance system to monitor the disease. For disease modelers and forecasters, the data is a rich source of data points on diseases severity across several age groups.

Dr. Ochiai says the findings show that the dengue vaccine, which has been approved in several countries for children aged nine and older, can play a valuable role in reducing the burden of disease. However, he noted that children below this age group are also bearing a significant burden of the disease, highlighting the importance of ongoing efforts to develop a vaccine for younger children.

In response to queries from Break Dengue, the WHO said it’s work on estimating the burden of dengue fever is ongoing. “A final report on the WHO burden project is expected in 2018,” a spokesperson said.

Big, open data

The study sets a potentially powerful precedent in how clinical trial data is used and shared.

While many large – and expensive – clinical trials are conducted to support applications for regulatory approval, taking the analysis one step further can be a tremendous service to the public health community.

“By doing this secondary analysis of the data and sharing the results we are showing our commitment to public health,” Dr. Ochiai says. “When we conduct a study of such high quality – meeting the highest standards of Good Clinical Practice – it is an opportunity to learn more about the diseases by carrying out this kind of secondary analysis.”

He says it would be “a waste” to leave the potential for this sort of analysis untapped. “We shouldn’t just sit on this data. If it can nurture scientific understanding, it needs to be shared.

This approach is in line with big data initiatives in various fields and with the more open approach that many scientists are now embracing.”

It is, he says, a win-win for all who share an interest in public health as it offers a deeper understanding of the disease, how to predict outbreaks and, ultimately, how to reduce the burden.

“Dengue burden is something of a black box so the more data we can generate and share, the better. It is a potential goldmine.”

Watch, ‘The Lingering Effect of Dengue Fever’

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World’s first dengue vaccine program begins in the Philippines

Janette Garin gives a Filipino student the world’s fist dengue vaccine. Image via Sanofi Pasteur.

Dengue becomes a vaccine preventable disease

In the Philippines, dengue fever has claimed thousands of lives and incapacitated many since the first known cases were reported in 1953, and the world’s first dengue vaccine couldn’t have arrived sooner. And so, last Monday, with much festivity and good cheer, top officials from the Department of Health, headed by Secretary Janette Garin and local government officials, launched a first-of-its-kind, school-based dengue mass vaccination program at the Parang Elementary School in Marikina, a suburb in Metro Manila. More than 600 students from Grade 4 received the first of three doses of Dengvaxia, Sanofi Pasteur’s breakthrough dengue vaccine. The vaccine is registered for use for those between the ages of 9 and 45 years old and has been approved in Mexico, the Philippines, El Salvador, and Brazil.

For school principal Marcia de Guzman and many school officials desperately pinning their hopes on it to end dengue’s long reign of terror, the dengue fever vaccine is perceived as nothing short of a miracle. De Guzman says that only in January this year, a student at the school died from the mosquito-borne viral illness, while 45 others were hospitalized by it, despite the school taking vector control measures like putting treated nets over the windows of the classrooms. Data from Marikina’s Public Information Office says there were 487 confirmed cases last year, with six deaths.

Parang Elementary is first to get the free vaccine

A fourth-grade student named Wanda Beatrice (seen at top) made history as the first child in the country’s public health program to be inoculated, with Sec. Garin herself hunkering down to administer the first dose. Doses will be given to the students in six-month intervals. The government’s health office aims to finish first dose vaccinations this June. The second dose is expected to follow the in October to December, with the last dose to be given from April to June 2017.

With Marikina a dengue hotspot in recent years (many of its communities are identified as high-risk areas), the government couldn’t have chosen a better city to kick-start its ambitious public health program of immediately vaccinating 1 million grade school children in the country.

image of children dancing for VIPs during dengue vaccine launch in Philippines

Parang Elementary School fourth graders perform a song for attendees at the dengue vaccination program kickoff.

The Department of Health has been aggressive in combating dengue as the problem continued to escalate in recent years: The Philippines has the unfortunate bragging rights of having registered the highest dengue incidence in the Western Pacific region for the years between 2013 and 2015. Last year, the country had 200, 415 confirmed cases. As of February 20, 2016, a total of 18,790 suspected dengue cases were reported nationwide. A figure 13.2 percent higher compared to the same time period last year.

Most of the cases come from Southern Tagalog with 3,182 cases (16.9 percent); Central Luzon with 2,596 cases (13.8 percent), and Metro Manila with 1,479 cases (7.9 percent).

It is with these figures in mind that the DOH is carefully appropriating its limited resources. The three regions have been selected according to burden of diseases, prevalence, and high mortality rates, based on statistics gathered from the DOH’s Epidemiology Bureau.

The Philippines Department of Health officials at the press conference. From left: Dr. Lyndon Lee Suy, DOH spokesperson; Sec. Janette Garin; Vicente Belizario, Undersecretary of Health; Dr. Rose Capeding, head of Microbiology, Research Institute for Tropical Medicine; Dr. Rontgene Solante, Philippine Society for Microbiology and Infectious Diseases chairman

The Philippines DOH and heath officials from left: Dr. Lyndon Lee Suy, DOH spokesperson; Sec. Janette Garin; Vicente Belizario, Undersecretary of Health; Dr. Rose Capeding, head of Microbiology, Research Institute for Tropical Medicine; Dr. Rontgene Solante, Philippine Society for Microbiology and Infectious Diseases chairman

A historic milestone in dengue prevention

At the press conference, Sec. Janette Garin called the program’s launch “a historic milestone”. “We are the first country to introduce, adopt, and implement the first-ever dengue vaccine through (the) public health system and under a public school setting,” she said.

The Philippine government has earmarked P3.5 billion pesos (roughly $76 million) for the administration of the vaccine. Sec. Garin says that this amount also includes “monitoring, surveillance, the whole totality.”

And yet despite the deep urgency for a dengue vaccine, especially in the Philippines, the arrival of the vaccine—and the administration to the 600 school children here in Parang—is not without controversy.

The Philippine government decided to start its vaccination program and has allowed the use of the vaccine in private clinics, ahead of the World Health Organization’s official recommendation, which is expected to be published in May.

Social media posts are circulating online warning parents of allowing their children to be vaccinated. Some doctors, led by Dr. Anthony Dans of the National Academy of Science and Technology, have questioned its safety and efficacy, strongly calling out the government for its implementation without the WHO Strategic Advisory Group of Experts’ recommendations.

But in a press briefing, four days before the mass vaccination, WHO country representative Dr. Gundo Weiler said the organization is supportive of the program. Clarifying the issues surrounding the DOH rollout, Weiler said, “It is the prerogative of a country to license the product, determine its use based on the internal scientific appraisal of the clinical research underpinning the product.”

The group only meets twice a year, he explained, which has delayed the publication of the recommendation. Weiler further stressed, “It is not the WHO’s mandate to license a medical product, to determine whether or not a product should be used in a country. This is the prerogative of the national regulatory authority in the country.”

Many agree that the Philippines’ fast approval is necessary. A new analysis published in the New England Journal of Medicine in March reported that the Philippines had the highest incidence of confirmed dengue in the 10 endemic countries that participated in the clinical efficacy studies for Dengvaxia. The analysis also reported that up to 15 percent, or about one in six children who has fever, can be attributed to dengue.

More than 40,000 individuals in 15 countries have undergone clinical trials (29,000 of them received the vaccine). In the pooled efficacy analysis in this age group, the vaccine was shown to reduce dengue due to all four serotypes in two-thirds of the participants and prevent 8 out of 10 hospitalizations and up to 93 percent of severe dengue cases.

Dengue vaccine boosts prevention arsenal for the Philippines

The Philippines delivers the first dengue vaccination.

It may have looked like a routine injection – the kind administered on a daily basis at clinics around the world – but, in fact, it was a big moment for public health.

Launching the world’s first dengue vaccine

The Philippines made history last month by delivering the first-ever dengue vaccine. “We are very proud,” says Dr Sally Gatchalian, President of the Pediatric Infectious Disease Society of the Philippines. “Doctors and patients have been waiting a long time for this vaccine and are very happy to have a new tool for preventing the disease.”

For now, the vaccine is only available to patients attending private clinics in The Philippines but Dr Gatchalian expects the government to make it available to nine-year-old school children from April in the three regions worst affected by dengue.

“Dengue fever is hyperendemic in our country, and the number of cases has been growing,” she says. “Being diagnosed with dengue is frightening for patients. When I have to tell a 10-year-old child that they have dengue they ask me if they will die – it is seen as a severe disease so parents are already asking me about the new vaccine.”

New tool against dengue for doctors

The availability of the dengue vaccine is a game-changer for doctors. Instead of treating dengue symptoms, they can now play an active role in prevention.

“Physicians always think about prevention; about protecting their patients,” says Dr Gatchalian. “We would rather provide protection to outpatients than treat their symptoms when they are admitted to hospital with dengue fever.”

She says that, until now, the only preventative measure available was to advise people on vector control. The availability of a vaccine, combined with vector control, has the potential to decrease the incidence of the disease, according to Dr Gatchalian. However, she noted that it may take some years to make a significant dent in national incidence rates because the vaccine is not yet available nationwide for the National Immunization Program.

Awareness of the vaccine is already strong thanks to media coverage surrounding the launch of the vaccine and strong interest among doctors attending medical conferences.

For the public and the medical community alike, the fact that patients in The Philippines took part in clinical trials for the vaccine is a major plus.

“I think that because children from our country participated in the trials, there is a sense of ownership – it makes the vaccine relevant to the public,” says Dr Gatchalian. “For my colleagues who were involved with the research from the start, it is a proud moment. We are all happy and thankful.”

Dengue can affect everyone

As a leading pediatrician, Dr Gatchalian has treated countless children with dengue fever. But, like many other parents in The Philippines, she has her own personal story to tell.

When her daughter, Gayle, was five years old she developed a fever after being bitten by a mosquito on holiday in the Puerto Galera. After three days, a rash developed and dengue was diagnosed, but the illness was relatively mild.

Five years later, Gayle suffered a much more serious dengue infection. She had a high fever and was feeling lethargic. “She was vomiting half a litre of blood and needed a transfusion,” Dr Gatchalian said in an interview with a Manila-based newspaper. “She was hospitalised and I donated blood.”

The fever lasted five days but Gayle made a full recovery, Dr Gatchalian told Break Dengue. “She is alive and well; a feisty young lady who knows a little too much about Aedes aegypti mosquitoes!”

If the vaccine had been available 20 years ago, things might have been different. “I would definitely have given my children the vaccine but I’m glad that many people will now have that option.”

‘Dengue mosquito’ populations plummet in Brazil trial

image of the Aedes aegypti mosquito on yellow flower

Dengue fever, Zika, chikungunya, yellow fever and other diseases are spread by the Aedes aegypti mosquito. Image courtesy of Oxitec

Releasing genetically modified Aedes aegypti sterile ‘dengue mosquitoes’ has caused the species’ population to fall by 90% in local trial sites. These results have raised expectations that this novel approach could be used to defeat dengue in combination with traditional vector control methods and vaccination in global efforts to monitor the spread of dengue and other viruses borne by this mosquito species.

The dramatic results were seen in several field trials in small Latin America towns conducted by Oxitec. The UK-based biotech company breeds male mosquitoes whose offspring are incapable of reaching maturity.

Dr. Andy McKemey, Head of Field Operations at Oxitec, told Break Dengue that the company is now set to expand into much larger towns and is planning a new facility capable of producing the necessarily large volumes of modified mosquitoes.

The production facility located in Piracicaba, Brazil, and will have the capacity to provide enough genetically modified mosquitos to protect over 300,000 people from disease-spreading mosquito bites.

Piracicaba is a natural choice for the plant. The municipality became the first public sector partner for Oxitec’s field trials which saw thousands of self-limiting mosquitoes released into the Eldorado district – home to 5,000.

During the early developmental pupal stage, Oxitec scientists separate the female mosquitoes from the males. Image courtesy of Oxitec.

“The city of Piracicaba has always sought innovative solutions to serious problems,” says Mayor Gabriel Ferrato. “In the case of Aedes aegypti, we looked for the tool that seemed most appropriate to help in the desperate battle against this mosquito that transmits dengue, Zika and chikungunya. This will bring to the city a new Oxitec factory to meet the demand for years to come and help protect the public’s health with this clean and innovative technology.”

Following approval by Brazil’s National Biosafety Committee, the trial was extended for a year and authorities have agreed to extend it to a wider area, which will cover between 35,000 and 60,000 people.

This geographic region included the city center, chosen due to the large flow of people commuting between it and surrounding neighborhoods, which may contribute to the spread of infestations and infections.

Measuring the impact on dengue transmission – a challenging task

The success of the Piracicaba trial fits with results of a series of field trials of the GM mosquito. Research published last year in the journal PLOS Neglected Tropical Diseases showed mosquito suppression of between 80%-95%, depending on how the population is estimated.

Image of Dr McKemey working in lab courtesy of Oxitec.

Previous trials in the Cayman Islands showed that the presence of the mosquito in the wild was down 96% while a small study in Mandacaru saw mosquito numbers down around 99%. In a Panama trial, suppression was 93%.

These successes have reassured local populations – some of whom had been skeptical about the idea of releasing GM-mosquitoes into their environment. “The results we have had, along with the regulatory approval for the commercial release of our mosquito strain, are huge milestones for us,” says Dr. McKemey.

The big question is how the drop in mosquito numbers will affect the spread of dengue fever and other mosquito-borne illnesses.

“We have achieved greater than 90% suppression of the Aedes population in these trials, bringing the numbers well below the level which mathematical models suggest is the dengue transmission threshold,” says Dr McKemey. However, it remains difficult to prove empirically that the trials have had an impact on dengue fever rates. “It’s hard to demonstrate a causal link in trials covering a population of a few thousand people. You cannot monitor dengue cases in a statistically significant way that accounts for seasonal variation and how people move around.”

It would, he suggests, require a study of 200,000 to 300,000 people over several years. “The best we can do at the moment is look at whether we have reduced the mosquito population and then use mathematical modeling to determine whether this is likely to be of value.”

An additional tool to control the spread of dengue and vector-borne diseases

Interest in the modified Aedes aegypti has increased with local and regional authorities from across Brazil. Faced with two pressing concerns: the 2016 Olympic Games and the rise of Zika fever, they are intensifying their efforts to control the virus-carrying mosquito population.

“It is essentially very similar to dengue regarding transmission, so the approach we have taken to control dengue can also apply to Zika…”

“Zika virus has exploded onto the scene,” says Dr McKemey. “It is essentially very similar to dengue regarding transmission, so the approach we have taken to control dengue can also apply to Zika. Cities all over Brazil are interested in this and how we can work with them.”

Image, kid in tent. Oxitec public engagement campaign, Brazil

Public engagement campaign in Brazil to educate the public on the GM mosquitoes fighting dengue outbreaks. Image courtesy of Oxitec

While the GM mosquito holds real promise as a breakthrough, Oxitec doesn’t expect it to solve the dengue fever problem on its own. “There is no silver bullet. We can achieve phenomenal suppression of the mosquito population, but it still needs to be managed with conventional tools – insecticide and clearing breeding grounds, in addition to vaccines.”

Oxitec may be adding a new weapon to the arsenal, but it is likely that a range of tools, addressing surveillance, disease management, long-term vector control and vaccination, will need to be used in synergy – meaning collaboration between various players is more important than ever.

A dengue vaccine is here – now what?

How will the new dengue vaccine be introduced to have the most impact?

Getting the most out of the new dengue vaccine investing in logistics, surveillance, and diagnostics

The world’s first dengue vaccine, introduced by Sanofi Pasteur, has been given the green light in Mexico, the Philippines, and Brazil. More countries in Latin America and South-east Asia are preparing to follow. But how can we be sure the vaccine gets to those who need it, and what needs to be done to measure its true impact?

Prof. Usa Thisyakorn

Professor Usa Thisyakorn, a consultant at the Faculty of Tropical Medicine at the Mahidol University in Thailand, says that doctors in dengue-affected areas have been crying out for a dengue vaccine for a long time and are ready to embrace it.

“For health professionals and for the general population, dengue is a high priority and the vaccine is long-awaiting,” she said.

However, while many ASEAN countries have well-developed childhood immunization programs, reaching adolescents and adults is a new challenge.

“On top of that, there are always practical challenges like safeguarding the cold chain – to keep vaccines at the appropriate temperature – when transporting them.”

In the WHO’s Global Strategy for Dengue Prevention and Control 2012-2020, the Organisation says vaccines can change how we look at dengue prevention. But the report makes the point that vaccines are only of value when they reach those who need them: “Even a perfect vaccine is only as good as our ability to deliver it.”

The strategy sets out five key elements to breaking dengue:

Diagnosis and case management
Integrated surveillance and outbreak preparedness
Sustainable vector control
Vaccine implementation
Basic, operational and implementation research

Surveillance: a mixed picture

The arrival of dengue vaccines does not mean neglecting other key elements of dengue control such as surveillance, diagnosis, and management as well as vector control. On the contrary – the vaccine is most powerful when used as part of a holistic approach to defeating the disease.

“The 10 ASEAN countries have been working together for several years, following WHO technical advice, to improve surveillance,” explains Professor Thisyakorn. “Surveillance infrastructure is not the same across the region – some countries have very strong systems, others are still developing.”

One of the big challenges is to use common case definition and surveillance criteria. This will help to show where the vaccine is most effective, potentially highlighting any differences between regions or age groups. Standard and consistent surveillance, as well as diagnostics and management, will give an accurate picture of the impact of the vaccine.

However, while some countries have access to state-of-the-art laboratory testing, others rely on clinical symptoms to diagnose the disease.

“There is great diversity from country to country. Some areas have all the modern diagnostic tests available while others rely on clinical diagnosis which is not always as accurate,” says Professor Thisyakorn.

In Bangkok, for example, surveillance systems are very advanced and public health experts use sophisticated mathematical modeling to track epidemics and predict the likely impact of health interventions. But in some countries, the lab infrastructure is significantly weaker.

Changing behaviours

One factor not causing major concern in the region is public attitudes to vaccination. While some developed nations have seen immunization rates dip due to vaccine hesitancy – perhaps due to complacency about infectious diseases – Southeast Asian countries have not had this problem.

“Everyone has been longing for an efficacious and safe vaccine against dengue,” says Professor Thisyakorn. “Confidence in existing vaccination programs is high so we don’t anticipate a problem with public acceptance.”

However, with new tools now at the disposal of health officials, the public will need to be educated about who should have the vaccine and how they can access it. Changing behavior is tricky – as vector control campaigns have shown.

“People have been educated about vector control but we are still seeing higher numbers of dengue cases every year. We have to continue to educate but also try something new, like vaccination,” Professor Thisyakorn says. “We must also communicate with other stakeholders and try to connect vaccination with existing dengue initiatives.”

While much work lies ahead to maximize the impact of dengue vaccines, public health experts are excited about writing a new chapter in the dengue story.

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