Dengue vaccine development. How close are we to a dengue vaccine?

How close are we to a dengue vaccine?

Dengue vaccine development is well underway and Sanofi Pasteur is not the only pharmaceutical company making progress in the development of a dengue vaccine. GlaxoSmithKline, Merck, and Takeda are each at different stages of development of vaccines of their own, as are other nonprofit organizations. Here’s how a few of them are getting on.

In May 2013, Japanese pharma firm Takeda underlined its support for the development of a dengue vaccine with the acquisition of a US start-up, Inviragen. The vaccine candidate, DENVax is currently in phase II clinical trials (according to Takeda’s August 2014 pipeline report.) It’s being tested in Colombia, Puerto Rico, Singapore, and Thailand. The vaccine candidate aims to offer protection against all four strains of dengue.

GlaxoSmithKline, meanwhile, entered into a partnership with Brazil’s Oswaldo Cruz Foundation to develop and manufacturer a dengue vaccine that originally came out of military research – from the US army’s Walter Reed Army Institute of Research. It’s currently in phase I clinical trials.

Merck began dengue vaccine development in 2010 when it acquired the dengue vaccine research unit at Hawaii Biotech. It is currently in phase I clinical trials, which are due to close at the end of 2014.

Could a shift in vaccine confidence towards other vaccines affect dengue vaccination rates?

Other organizations include Brazil’s Instituto Butantan, which is currently recruiting participants for phase II of its clinical trials. This is a public initiative, as Instituto Butantan is affiliated with São Paulo’s state health secretary. The US-government funded National Institute of Allergy and Infectious Diseases is also testing dengue vaccines in phase I clinical trials.

It is encouraging to see that so many firms and organizations are working to come up with a vaccine against one of the fastest growing neglected tropical diseases.

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Working together to understand vectors in Europe

VectorNet infographic on the dengue vector

Images courtesy of EFSA

Vector-borne disease is on the rise worldwide. More people are traveling than ever before, global trade is increasing and climate change is altering our environment. Combined with modern agriculture methods and animal movement, these factors are increasing the risk from vector-borne diseases across the Europe Union (EU) – including the risk from dengue.

Increasing the capacity to respond to outbreaks

A collaboration between the European Food Safety Authority (EFSA) and the European Centre for Disease Prevention and Control (ECDC) aims to increase understanding of these diseases and improve the EU’s capacity to respond to new outbreaks. The project is collecting data on the distribution and abundance of vectors and pathogens that carry diseases that can affect both animals and humans, and analyzing their spread in the EU.

Built by the two agencies and their partners, the database will enable EFSA and ECDC to provide independent scientific advice on vector-borne diseases to decision-makers in the European Commission, European Parliament, and other competent authorities in EU member states.This in turn, will assist authorities in making better-informed decisions that will help prevent the spread of these diseases and reduce their impact on public health and the EU economy.

Preventing diseases from establishing and spreading

Franck Berthe, Head of EFSA’s Animal and Plant Health Unit, says that: “We are seeing certain vector-borne diseases rising in public health priorities in the EU member states. Over the past few years we have seen outbreaks of diseases outside their expected geographical range, along with diseases newly emerging. All this has created the awareness and the will to work together on the issue of vector-borne diseases.”

Known as VectorNet, the database will extend the coverage of existing databases that have previously been built by specific EFSA and ECDC research projects. One of its important features will be details on the abundance of vectors. “Abundance of vectors is key for the disease to establish or spread. This issue of abundance is very important and challenging,” added Dr. Berthe.

Is low-cost travel spurring dengue outbreaks?

First steps for VectorNet

The project started earlier this year and will run for a total of four years, with the next project meeting scheduled in autumn. A kick-off meeting in June identified the project’s five major tasks:

Development of the database – its structure, its access and its housekeeping.
Creation of a broad network – the success of this project is dependent on a very broad network of experts and institutions.
Collection and assessment of the quality of data – working with partners across the UK, Turkey, the Netherlands, Belgium, Denmark, Italy and Sweden.
Delivery of ad hoc scientific technical advice by the two agencies.
Overall project management.

The meeting also looked at how the two agencies would work together: a framework contract clarifies the deliverables, timelines and activities for each phase of the project. “It is not a one shot thing but a step by step unfolding project,” elaborates Dr. Berthe. “At each step we sign specific contracts under the umbrella of the framework contract.”

Initial challenges

One of the first major challenges the project faces is the identification of disease priorities. “Many vector-borne diseases exist,” explains Dr. Berthe. “We will need to prioritize the diseases, the vector species, and regionalize across the EU – which is very diverse in terms of climate and habitat.”
Other early challenges include:

Establishing a comprehensive network of top experts in medical and animal entomology and in public and animal health.
Working out the practicalities of sampling and surveillance of vectors.
Building a strategy for identifying the different diseases in the different regions, each with its own unique environment that must also be fully understood.

Extending VBORNET

VectorNet is not being built from scratch; previously ECDC ran VBORNET. “Our intention with VectorNet is to broaden the basis of the VBORNET network,” Dr. Berthe reveals, “bringing together the community of medical entomology and the community of animal expertise with their knowledge on surveillance, modelling and so on.”

Is artificial intelligence key to dengue prevention?

The long term aims of the project are to establish a sustained and non-compartmentalized network of expertise. “We expect to have a positive long term impact: adding value to individual databases, avoiding duplication in efforts, and strengthening the collaboration,” concludes Dr. Brethe.

Isn’t it time that all regions tackle the threat of vector-borne diseases in a holistic manner?

Learn more about combating the ‘dengue mosquito’ and its growing insecticide resistance

One step closer to a dengue vaccine

Dengue virus. All images courtesy of Sanofi Pasteur.

Are we one step closer to a dengue vaccine?

In September 2014, pharmaceutical firm Sanofi Pasteur announced the results of the second wave of its Phase III clinical trials. The news builds on the positive results of the first half of its Phase III clinical trials in Asia. In the first trial involving 10,275 children aged 2-14 years across Malaysia, the Philippines, Thailand, and Vietnam, Sanofi Pasteur reported that the vaccine candidate was 57% effective against symptomatic dengue.

More importantly, the trial found the vaccine candidate to be 89% effective against severe dengue and reduced hospitalizations by 67%.

The second trial involved a three-dose vaccination schedule in 20,875 children aged 9-16 years across Brazil, Colombia, Mexico, Honduras, and Puerto Rico. Sanofi Pasteur reported that the vaccine candidate showed overall efficacy of 60.8% against symptomatic dengue, and reduced hospitalizations by 80.3%.

According to the pharmaceutical firm, in both trials the level of efficacy varied between each dengue serotype: ranging from 50% for type one, 35% for type two, 78% for type three, and 75% for type four in the Asian trial.

The results were consistent, with a little less variation, in the Latin American trial: 50% for type one, 42% for type two, 74% for type three, and 77% for type four. These results indicate that the vaccine could bring a good contribution in reaching the World Health Organization (WHO) objectives for the Global strategy for dengue prevention and control, 2012–2020, which aims to reduce dengue mortality by 50% and morbidity by at least 25% by 2020.

Reducing the severity of dengue

dengue2 “Dengue is so unpredictable and you really don’t know if a patient with dengue will go into shock or just have a mild case,” reveals Dr. Rosario Capeding, head of the dengue vaccine group at the Research Institute for Tropical Medicine in the Philippines.

“The vaccine will have a major impact because the efficiency is good enough. But the most important finding was that the vaccine candidate reduced the severity of the disease. As a mother and a clinician, that is what we are looking for.

If you have a child with dengue, it gives you more confidence that their dengue will just be mild.” “It took 20 years for Sanofi Pasteur to develop the vaccine because it’s different,” notes Dr. Capeding.

“It protects the individual against all four serotypes, any or all of which may be circulating in a region at any time. In the early years, the 1940s, dengue vaccine only protected against one serotype.” “The development was complicated further because, unlike other vaccines, you can’t test it on animals,” she continues. “Monkeys can get the disease, but its manifestation in monkeys is different to humans.”

Impact where it is needed the most

dengue3 Confirming the positive results from Asia, the results from Latin America are welcome news at Sanofi Pasteur. “We’re really pleased with the results with the second trial as they show consistent results across the two phase III studies,” says Melanie Saville, chief medical and clinical officer (CMCO), Dengue at Sanofi Pasteur.

“We are continuing to complete the analysis and share that with experts in the field and with the regulators, with a view to submitting for approval in some key countries in endemic areas.”

Melanie hopes a vaccine could be available in some key endemic countries in the second half of 2015. “With 100 countries at risk, there is an unmet medical need with no vaccine and no treatment at the moment. This is very important for the fight against dengue.” Dr. Capeding anticipates that she, like other experts on the dengue vaccine around the world, will be invited to participate in discussions around priorities for the vaccine in her local region – the Philippines – and possibly around integrating the vaccine into the national immunization program.

This isn’t the only dengue vaccine in development. Other firms working on a dengue vaccine include Takeda, GlaxoSmithKline, and Merck (all in collaboration with other organizations). None of these are at Phase III of clinical trials, but we’ll be creating a separate post about what they are working on soon.

Mobile brings new opportunities to dengue prevention

dengue0 An innovative research program at the Nanyang Technological University (NTU) in Singapore is using digital communication technologies to boost efforts by authorities and citizens in the fight against dengue.

Known as Mo-Buzz, the system uses modern mobile technologies to improve the efficiency of dengue surveillance techniques through crowd-sourced data, warns of impending outbreaks and enhances knowledge about dengue and how to prevent it.

Mo-Buzz for public health inspectors

Equipped with tablets, health inspectors can send instantaneous updates on potential breeding sites and hot spots from out in the field. Associate Professor May O. Lwin, the principal investigator of the program adds: “It is a huge step for health authorities because their traditionally manual process typically took a number of days, but now they can collate that information in a day.”
At the back end, the dynamic monitoring system uses a computer simulation to forewarn health authorities about impending disease outbreaks. “This technology is very efficient at identifying potential hot spots and breeding sites that can be targeted for clean up,” notes Professor May.
The tablets also allow health inspectors to disseminate knowledge. Digitized health promotion materials are always close at hand and can easily be circulated in zones facing dengue problems.

dengue prevention chart for the system flow

Mo-Buzz for the public

The multiple functions of the Mo-Buzz public smartphone app:

– Alerts warn of potential hot spots and encourage people living near them to take preventative measures.
– Reporting tools allow the general public to aid health authorities by reporting mosquito bites, dengue symptoms, and breeding sites.
– Tailored detailed and graphical health communications aim to build knowledge and awareness.

“If members of the public see a breeding spot or they are experiencing a large number of bites, for example, they can provide a video or image with their smartphone and that information is tagged with geographic location,” adds Professor May. “And although smartphone users are increasing, a small minority still have normal phones, so we need a text based system in place too.”
The system’s health communications are also aimed at increasing civic engagement and participation. “We also use the system as a health education and communication platform to target various groups with health information and encourage them to upload information,” Professor May elaborates.

Rolling out across Sri Lanka

Pilots run in conjunction with Colombo Municipal Council’s Public Health Department and Sri Lanka mobile operator Mobitel across university settings and with public health inspectors using the iPads out in the field have provided some source data and insight into public response.

dengueprevention in Singapore

Field-testing through a larger six-month pilot to be rolled out across Sri Lanka later this summer will provide a better understanding of adoption and usage. “The municipal authorities and the Colombo mayor’s office and the Telcos are supporting this and we are working in conjunction with the University of Colombo,” adds Professor May.
The unceasing wave of new technologies in recent years is bringing many new opportunities in the fight against dengue. We have seen other tools, such as the winner of our India prize X-Dengue, contribute to the fight in innovative ways.
In an earlier blog post we asked if digital tools could help control dengue. We are hoping for positive outcomes from the research and pilots generated by projects such as Mo-Buzz.
What’s your favorite digital tool helping to combat dengue fever outbreaks?

How Singapore is using social technologies to combat dengue

dengue_1 For the people of Singapore, 2013 was the worst year on record for dengue with more than 22,000 cases reported throughout the year. At its peak in June more than 800 cases were being reported each week, and though this came down to around 400 each week in the later months of the year, this was still four times more than normally expected. The 2013 outbreak is thought to have been brought on by the reemergence of the dengue serotype one, which accounts for 85% of cases. Unfortunately, Singapore’s success in controlling the vector over the past decade may have led to low immunity to dengue among the population. This outbreak continued into 2014, with an unseasonal 400 cases reported each week for the first weeks of the year. Though this has now dropped to a plateau of around 250 a week, the Singaporean government is continuing to fight back by using the latest mobile and social technologies to the fullest.

Images taken from Google play

The National Environment Agency’s (NEA) myENV app provides an overview and detailed maps of local dengue clusters, and will soon include push notifications and more location-specific features. The Stop Dengue Now Facebook page has some 13,000 followers, and provides weekly updates of dengue clusters, highlighting neighborhoods most at risk, and showing the number of cases. Meanwhile, the “We are Dengue Fighters” Facebook app provides a wealth of information in video and poster formats about how to combat the disease. This smart use of the latest technologies will help keep dengue infections down during Singapore’s peak dengue season.

2013: Asia Pacific’s worst year for dengue

Across the Asia Pacific region, 2013 was one of the worst years for dengue, with a number of countries seeing a more than two-fold increase in reported cases and deaths compared to 2012 in some nations. All four serotypes are now circulating in many countries – including Malaysia, Singapore, Thailand and Vietnam.

Trends vary across the region but, most notably, some nations have reported an increase in adolescent and adult cases, and a spread to rural and other low dengue transmission areas.

Hover over the image to find out more.

How efforts in Fiji stopped dengue in its tracks

87558867 Just a month after declaring March National Clean-Up Campaign month, Fiji’s Health Ministry reported that the number of suspected cases had leveled off, whereas a single week in February had seen 1,200 new cases.
Fiji’s dengue outbreak began in December 2013 and by the end of that month, 283 cases had been recorded. When 123 new cases were recorded in the first three days of January, the World Health Organization quickly raised concerns about the risk posed by the rare strain of dengue fever affecting Fiji – one which hadn’t been seen there for 20 years.
By the end of February there had been 3,802 confirmed cases and eight deaths. To make matters worse, Fiji was hit by Tropical Cyclone Kofi, bringing with it heavy rains and extensive flooding.
To deal with the situation, community groups, government, and stakeholders were mobilized to help in the clean-up campaign. Extensive planning brought task forces together to systematically remove any rubbish that might provide a breeding place for the dengue mosquitoes. 45 tons of tires, 268 kilos of drums, 24.5 tons of other containers, and 77.15 tons of other kinds of waste were collected between March 8-22.
Elsewhere, fliers and continual media reporting on dengue raised awareness, advocating prevention and precaution.

if-they-breed-they-will-kill-dengue-mosquitos

Image from Fiji Ministry of Information

Numbers continued to rise during March with over 15,446 suspected cases notified by the end of the month. But the pace was beginning to slow. The last week in March saw 400 fewer cases.
Then on World Health Day, April 7, Health Minister, Dr. Neil Sharma, was able to announce: “We have 12 deaths recorded from mid-March and the number of clinically suspected cases remains at 20,204.” He attributes the decline to the massive clean-up drive.
Fiji has shown how communities are not helpless in the face of dengue. Its clean-up campaign made a real difference, stopping dengue in its tracks.
What are you doing in your community to prevent the spread of dengue?

GM mosquitoes: from field trials to operational use in Brazil

dengue1 In our earlier blog post we described how a laboratory in the UK has developed a genetically modified male mosquito which could help stop the spread of dengue. With extensive research in the lab and numerous field trials, this technology is now in operational use in one city in Brazil – where it has already achieved 79% suppression of the Aedes aegypti mosquito population.

Field trials in Brazil

Field trials, which involved the release of millions of the modified males, began in Brazil in 2011 with the Itaberaba neighborhood of Juazeiro seeing its mosquito population plummet by over 80% compared to an adjacent area.

dengue2 A second trial, in the Mandacaru neighborhood, saw populations plummet by 96% within six months. “It typically takes about six months to achieve that level of control because it works on a generation by generation approach,” revealed Dr. McKemey, Head of Field Operations at Oxitec. “If half the wild females mate with Oxitec males, that means half of the next generation won’t develop. If you carry on releasing, then the same happens again. A mosquito generation is roughly a month, so you won’t see any immediate effect for at least that period of time and then there is a drop in numbers as each subsequent generation becomes affected by the males released.”

dengue3 Six months into the trial the number of mosquitoes released was reduced four-fold. Dr. McKemey explained why. “For the initial phase you need to release large numbers, but once the population has dropped you continue releasing, but at a very low level, just enough to ensure that any remaining females mate with the modified males.”

Operational use in Brazil

2013 saw field trials move to operational use in the Brazilian city of Jacobina – a city of 79,000 inhabitants that, according to Oxitec, saw 1,647 dengue cases and two deaths due to it in the first half of 2012. “Our approach in Jacobina is to treat an area and then as we gain control in that area we move onto the next area,” Dr. McKemey told us. “In the first area, Pedra Branca, we have already achieved 79% suppression.”

dengue4 Adequate production is key to the successful operational use of the modified mosquitoes. Social nonprofit organization Moscamed has increased production in their mass-rearing facility, meaning the area being treated can be increased. Once control is achieved in one area, the team can reduce the release rate and the extra capacity can be put to treating new areas.

In April 2014, Brazil became the first country to grant biosafety approval for the commercial release of these mosquitoes. The approval process assesses the safety of the technology and this regulatory conformation means a specific safety permit is no longer needed for each project. Oxitec is now working with the national health authorities in Brazil to obtain approval to sell it commercially.

dengue5 Oxitec has recently set up its own mass-rearing facility in a city called Campinas, near São Paulo in south Brazil. The company is currently in negotiations with local authorities and vector control teams to launch new projects in the region.

Field trials in Panama, talks in Florida

Meanwhile field trials started in Panama earlier this year following approval for open release in the country. “We have been working with the Gorgas Institute in Panama tracking populations in two villages for two or three years to use as our baseline. From there we selected a further village that we are now working in,” says Dr. McKemey. According to Health Minister Javier Diaz, Panama reported 3,124 dengue cases in 2013, up from 899 in 2012.

Elsewhere in the Americas, the Florida Keys Mosquito Control District is evaluating the Oxitec technology. Dr. McKemey says that “despite having the top experts and best resources – helicopters and planes – the Keys have been really struggling to get on top of the Aedes aegypti mosquito. There have been a couple of outbreaks and they are highly concerned that it might get hold. We are working with the US Food and Drug Administration to get approval for a trial in an area of between 500 and 1,000 people.”

The company hopes that continuing field tests and increased operational usage will increase awareness of this technology and help them make a significant contribution to the fight against dengue.

What might be the risks in using GM mosquitoes in the fight against dengue and would the potential benefits outweigh these?

World Mosquito Day: Understanding the tiny, dangerous invaders

August 20 is World Mosquito Day, a celebration of the work of British doctor Sir Ronald Ross who discovered that female mosquitoes (of the Anopheles genus) were responsible for transmitting the malarial parasite. His pioneering work is marked every year by a series of events around the world, led by the London School of Hygiene and Tropical Medicine (LSHTM).

Martin Hibberd, Professor Emerging Infectious Disease at the LSHTM, says a century of mosquito research has improved understanding of vector-borne diseases. He explains there are important differences between how malaria and dengue fever are spread.

Night and day

For starters, malaria and dengue are transmitted by different types of mosquito which tend to bite at different times of the day. This has major implications for vector control.

“For malaria, bed nets can be used to protect you from being bitten by mosquitoes at night. For dengue it’s trickier. The mosquito carrying dengue bites during the day when you are outdoors and active,” says Professor Hibberd.

“They can bite you anywhere – your hand, your foot, your face – so avoiding contact is difficult.”

This has led to widespread use of insect repellents. While some are proven to be effective, the evidence for others is questionable.

A story that (literally) made the headlines recently told of a newspaper in Sri Lanka which was partly printed in ink that contained citronella – a natural substance often associated with dengue prevention.

“There is a worldwide industry selling products such as citronella but there is almost no science behind it. When you do controlled experiments, you find that these natural inhibitors work particularly poorly,” says Professor Hibberd.

The question for effective mosquito repellents remains an active area of research at the London school but other, more sophisticated, ways to contain mosquitoes are also in the works.

“There’s no treatment for dengue fever right now so vector control is the only way of controlling it,” says Professor Hibberd, recalling his time in Singapore where mosquito control is quite advanced.

“The only really effective approach is source reduction. This means identifying egg location and removing these. The mosquito that spreads dengue usually lives inside houses so egg-laying is typically in flower pots or other places with a water source.”

London’s insectarium

Back at the LSHTM’s insectarium, scientists are exploring other ways of controlling the mosquito population. The insectarium has several rooms buzzing with low-risk mosquitoes, which can be used to study biting and reproduction, and other mosquitoes (kept in contained areas) which are infected with dengue, malaria or other diseases.

Careful study of infected mosquitoes could lead to new ways of blocking transmission.

“One hot area of research is looking to infect mosquitoes with parasitic bacteria which make it more resistant to infection by the dengue virus,” explains Professor Hibberd.

The idea is to release thousands of these bacteria-infected mosquitoes, which would then mate with wild mosquitoes. If this makes the general mosquito population less susceptible to picking up dengue fever, it reduces the chances that dengue will be spread to humans.

Gaining momentum?

Despite the leaps forward made since the first World Mosquito Day in 1897, there are plenty of remaining gaps in scientific knowledge. But Professor Hibberd feels the area is gaining momentum.

“Dengue is still classed as a neglected tropical disease which means it probably doesn’t receive the attention it should – and the number of cases worldwide is still huge and growing. But over the past decade or so since I’ve been working in this area, interest in dengue has risen slowly.”

As we mark another World Mosquito Day, there is reason to hope that research on dengue transmission could deliver new answers to a stubborn problem.

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How a 19th century mosquito expert helped break dengue

In 1897, a British doctor named Sir Ronald Ross made a game-changing discovery which ultimately led to smarter ways to prevent dengue fever – even if that wasn’t his primary intention at the time.

Born in India, Ross had become fascinated by malaria, a disease he had seen kill thousands of people during his 25 years in the Indian Medical Service.

At the time, it was unclear how malaria was spread. It was Ross who found that female mosquitoes (of the Anopheles genus) were to blame for transmitting the malarial parasite. That flash of insight changed how we think about mosquitoes, disease transmission, and prevention.

Ross won the Nobel Prize for Physiology or Medicine in 1902. (He was, incidentally, a bit of an all-rounder: he was a doctor, a poet, a novelist, and a songwriter. And an artist. And mathematician!)

This was an exciting time for medical research. Just a few years later in 1906, it was confirmed that dengue fever was spread by the Aedes aegypti mosquito. The following year, dengue became the second disease (after yellow fever) that was shown to be caused by a virus.

It must have seemed as though scientists were on the verge of figuring out mosquito-borne illnesses once and for all. But, alas, it wasn’t so simple.

Happy anniversary?

Winning the Nobel Prize meant that Ronald Ross’ contribution to medicine would never be forgotten. But, just in case, he made sure his discovery would be celebrated every year by declaring August 20 to be World Mosquito Day.

The day is marked with a series of events, led by the London School of Hygiene and Tropical Medicine. This year, the school is even hosting a play about Ross and his work.

So where are we today? Far more is known about how vector-borne diseases like dengue and malaria are transmitted, yet millions of people still suffer from them.

Perhaps reflecting on how far we’ve come in a little over a century will inspire new breakthroughs – just like the moment Ronald Ross discovered that those tiny mosquitoes were causing some of our biggest problems.

On August 20, we’ll be posting an interview with a leading dengue researcher at the London School of Hygiene and Tropical Medicine.

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Got a smartphone? Click the link below to join the global effort to map dengue fever?

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