Author: Alison

Has coronavirus brought the world together to fight deadly viruses?

COVID-19 brought the 2020 New Year in with a bang. Almost immediately, scientists started experiments, shared data and revealed the secrets of the pathogen. Will we apply what we learn from working together to contain this novel virus to halt dengue?

Just eight weeks into 2020, the novel strain of coronavirus not previously seen in humans had infected tens of thousands of people in China. Fatalities had reached several thousand.

Meanwhile, 2019 was one of the worst years on record for dengue, according to WHO. There was an unprecedented surge in epidemics across the globe: in Asia, Africa and the Americas.

So, how do the COVID-19 and dengue outbreaks compare?

Coronavirus as of 18th February 2020 Dengue in 2019
Year discovered 2019 1943
Suspected cases Not known 100 million
Confirmed cases 75,000 >4 million
Average new cases per day 1,500 ~10,000
Asymptomatic rate Not known 40-80%
Mild rate 80% 95%
Severe rate 14% <5%
Fatality rate 2.3% 1-2.5%
Fatalities 1,870 >40,000
Average daily fatalities 38 ~100
Countries 25 >125
Country worst affected China Brazil
Transmission Person-person Person-mosquito and mosquito-person
Complications Severe pneumonia causing shortness of breath and breathing difficulties Severe dengue that can result in shock, internal bleeding, and even death

Coronavirus: A global emergency

The global response to the coronavirus outbreak has been phenomenal, boosted by a call to action from the World Health Organization.

On 30th January, WHO declared the coronavirus outbreak a “Public Health Emergency of International Concern” (PHEIC). Its International Health Regulations (2005) Emergency Committee felt a global coordinated effort was needed to combat the virus and asked the global community to “provide support to low- and middle-income countries to enable their response to this event, as well as to facilitate access to diagnostics, potential vaccines and therapeutics”.

Collaboration achieves results

So, what have their COVID-19 efforts achieved?

  • By January 9, Chinese researchers had recovered the virus from an infected individual and generated a full genetic sequence of it.

 

  • By January 11, scientists had developed tests capable of detecting genetic sequences that distinguish the new agent from other coronaviruses circulating in humans.

 

  • By January 28, China’s National Medical Products Administration had approved diagnostic test kits from five companies.
  • On February 15, Nature announced more than 80 clinical trials had launched to test coronavirus treatments.

If nothing else positive, the coronavirus outbreak has shown we can work together to achieve results – and rapidly.

Combatting dengue

Will the world take what it has learnt from working together to combat COVID-19 and apply it to dengue? Does it have the motivation to act to combat a virus that isn’t hitting manufacturers, supply chains and, ultimately, stock markets in the West? Or do we have to wait until climate change brings dengue to developed countries before it acts decisively?

On 14th November 2019, the WHO announced that it was scaling up its response to the worldwide surge in dengue. Will the world sit up and listen? Will the world respond?

Mosquito-eating spiders: coming to a town near you?

Insecticide resistance is growing; ‘biological control’ of mosquitoes is becoming more commonplace in response. Communities are increasingly employing small creatures to help in their fight against dengue. Previously, we’ve looked at how people in Cambodia have used guppy fish, and also tried using crustaceans, to help reduce Aedes mosquito numbers.

A recent study decided to review a completely new type of biological mosquito control: mosquito-eating spiders!

Spiders as mosquito predators

You may well be asking yourself why the team from the Bindura University of Science Education in Zimbabwe specifically chose to examine this particular creature. Their research paper explains: “Spiders have a wide insect host range and thus can act as biological control agents of insect pests.”

With various species of spider known to prey on different species of mosquito, the paper goes on to note: “Spiders have largely been overlooked as predators of mosquitoes and its larvae in various ecosystems, yet they play an important role as stabilizing agents or regulators of insect populations in agro-forest and other terrestrial ecosystems.”

Aiming to get a better understanding of how spiders and mosquitoes interact, the team examined previous research into mosquito-eating spiders. They looked at both web-building spiders and hunting spiders, some of which actively search and chase mosquitoes as well as ones that lie in wait and seize their prey.

Mosquito hunters

The East African mosquito-eating jumping Evarcha culicivora spider targets its prey based on their last meal. Commonly known as the ‘vampire spider,’ it has a distinct liking for adult female mosquitoes with a belly full of human blood.

To decide whether a particular mosquito is worth pursuing, the spider uses its unique, complex eyes to “see prey in remarkably fine detail” along with olfaction (sense of smell) to work out whether a mosquito “has just taken a blood meal based on the tilt of their abdomens.” If the prey looks interesting, it “pounces,” the researchers reveal.

For these particular mosquito-eating spiders, eating blood-filled mosquitoes isn’t just about nutrition – it’s also about sex. According to the study, eating blood-filled mosquitoes gives them a “perfume” that makes them more attractive to a potential mate.

Also from the same Salticidae spider family but this time found in Southeast Asia, the Paracyrba wanlessi “lives in the hollow internodes of fallen bamboo,” note the team. Unlike E. culicivora, P. wanlessi doesn’t have a preference for the age or sex of its prey – or what’s in its belly.

Weaving a mosquito trap

The team also looked at mosquito-eating spiders from the Pholcidae family. The long-legged Crossopriza lyoni is a common inhabitant of homes in the rural villages of Thailand “where dengue fever, transmitted by the Aedes aegypti mosquito is endemic,” states the report.

After moulting, young spiderlings are already able to overpower the adult Aedes aegypti mosquito, even though it is “many times their own size”. The spiders use their hind legs to throw silk, immobilising the mosquitoes by “entangling them in the standing web”. The report suggests “C. lyoni could be an important component of integrated control of Aedes aegypti and help reduce dengue transmission.”

The review concludes that “spider predation could be of great ecological significance in suppressing mosquito populations. Management of spider populations could provide the

additional control of adult mosquitoes needed to reduce the transmission of mosquito-borne diseases.” Its final recommendation is rather startling: “Perhaps, it would behove human communities to foster

spiders in and around their homes.”

Would you introduce spiders or other biological mosquito controls in your area?

The Takeda dengue vaccine: Promising results bring hope for the future

Professor Duane Gubler is one of the world’s leading experts on dengue vaccines. He has supported the development of all three of today’s leading vaccines: Sanofi’s Dengvaxia, the Takeda dengue vaccine and the NIH (US National Institutes of Health) dengue vaccine, both currently in clinical trials. We caught up with him to learn about the history and complexity of developing a vaccine to protect against a virus with four serotypes.  

 

The Takeda dengue vaccine has a long history. Where did it all begin?

 

Back in the 1970s, dengue haemorrhagic fever was increasing dramatically in Southeast Asia, and dengue had started to appear in the American region as well. Dr Scott Halstead at the University of Hawaii had begun researching dengue vaccines and was using dog kidney cells to attenuate (weaken) the four serotypes of the dengue virus.

 

In 1977, SEARO (the Southeast Asia Regional Office of the World Health Organization) agreed to support the development of a dengue vaccine at a WHO meeting in Singapore. SEARO then awarded a grant to Professor Natth Bhamarapravati at Mahidol University in Thailand to develop the first tetravalent dengue vaccine in early the 1980s.

 

Dr Scott Halstead shared his work with Professor Natth. By the early 1990s, Professor Natth had what he considered to be four attenuated monovalent (for only one serotype) dengue vaccines – one for each of the dengue serotypes. He had based the vaccines for the first three serotypes on Thai viruses and used an Indonesian virus for the fourth.

 

I was a member of the WHO peer review that reviewed Professor Natth’s work every year and made recommendations. By 1993, we were confident that Professor Natth had a tetravalent (for all four serotypes) vaccine that was ready for further clinical trials.

 

Professor Natth then signed a licensing contract with Pasteur Mérieux, now Sanofi Pasteur, handing over all four monovalent vaccine candidates. Professor Natth kept the right to use those vaccine candidates to develop second-generation vaccines.

 

What happened next?

 

The four monovalent vaccines were then combined to create a tetravalent dengue vaccine. Sanofi ran their first clinical trial in 1995 in collaboration with the US Army programme at the Walter Reed Institute of Research in Washington DC, inoculating volunteer dengue naïve US soldiers. It did not go well; DENV-3 overgrew the other three serotypes.

 

A new attenuated DENV-3 monovalent vaccine was then derived by CDC under contract from Sanofi and trialled in medical students in Hong Kong. That did not progress either as the virus was not attenuated.

 

Sanofi Pasteur decided to shelve Professor Natth’s vaccine and pursued a vaccine based on the yellow fever 17D vaccine backbone. That was the origin of the Dengvaxia vaccine.

 

What are the origins of the Takeda dengue vaccine?

 

During the mid-1990s, Professor Natth gave me his four monovalent vaccines to take back to Fort Collins with the agreement that we would work with him to develop second-generation dengue vaccines. My molecular virologists, Rich Kinney and Claire Wong, constructed a clone of the best of the four monovalent vaccines: the DENV-2 vaccine, also known as PDK 53. They inserted the structural genes from the DENV-1, DENV-3 and DENV-4 viruses into the clone to create a tetravalent vaccine. We called it the CDC Mahidol vaccine, and myself, Rich Kinney, Claire Wong and Professor Natth in Thailand filed a patent on it.

 

We licensed it to a small biotech vaccine company in Fort Collins called Inviragen. We continued to collaborate with Inviragen to develop the vaccine. First trials were on mice and primates were followed by Phase 1 trials in 2010 and Phase 2 trials in 2011.

 

Takeda bought Inviragen in 2013, and that’s how Takeda’s Tetravalent Dengue Vaccine (TDV) came into existence. Takeda then repeated Inviragen’s trials, following the Phase 1 and 2 trials more recently with Phase 3 trials.

 

What were some of the key challenges you faced along the way?

 

It takes a lot of time and effort and money to bring the vaccines to a stage where you’re confident that they’re going to work in humans. The pre-clinical trials take several years; then there is a period of getting the results you need to go on to the next step. You can only move onto human clinical trials once the results from these laboratory trials were good. The initial safety trials were primarily in the US but were then moved to dengue endemic countries for the Phase 2 and Phase 3 trials.

 

There were a lot of ups and downs, particularly in the early days when we were trying to get the right formulations. But we were persistent because we had a strong belief that we desperately needed vaccines for dengue.

 

The four different dengue serotypes made developing this vaccine particularly challenging; we still don’t fully understand their interactions. We know the vaccines induce antibodies for all four dengue serotypes, but we don’t know whether they’re enhancing antibodies (antibodies that help the dengue virus) or protecting antibodies (antibodies that fight the dengue virus).

 

But a lack of funding was one of the main challenges that delayed this whole process. In the early days, the funding agencies never really thought that dengue was a high priority for funding, and so a lot of the development work was done on a shoestring. We developed the Takeda vaccine at CDC out of my own budget and a small grant from the Rockefeller Foundation to Mahidol University. There was no major funding from CDC – or any other funding agency – earmarked for dengue vaccine development.

 

We should also mention the dengue vaccine being developed by the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, out of their own budget. It’s following right behind Takeda. The NIH vaccine was developed independently by Steve Whitehead and Brian Murphy. I gave them a lot of my viruses and some of those are used in the NIH vaccine.

 

What are the next steps for the Takeda vaccine?

 

Takeda will be looking at the data that comes in over the next year or two as well as acquiring longer-term data. If the data are consistent, then the Takeda vaccine is going to make a big impact. And the preliminary data suggests it can be used as a single dose. The NIH vaccine will also be probably used as a single dose.

 

I am concerned that it may be difficult for us to get a perfect tetravalent dengue vaccine that provides equal protection against all four dengue serotypes. If a vaccine doesn’t protect people against all four serotypes, we need to decide how, where and when we use it. That’s the next big challenge. We desperately need dengue vaccines, and I think we can use them effectively even if they are not perfect– if we do it properly.

 

I don’t see a vaccine that we can confidently use in a national immunisation programme for at least another three or four years.

 

While the Takeda story has taken a while to unfold, successes from recent trials regardless of previous exposure to dengue are bringing hope.

 

International travellers: Beware the cost of dengue!

Studies into the burden of dengue have primarily focused on the costs borne by patients and healthcare systems in endemic countries. But with today’s world more connected than ever, the burden of dengue is now being felt right across the globe. We spoke with Professor Yesim Tozan, lead author of ‘A Prospective Study on the Impact and Out-of-Pocket Costs of Dengue Illness in International Travellers’ to learn more.

 

“More people from countries not affected by dengue are travelling to endemic countries,” says the Professor. “If they contract the disease, it can have a significant impact, both during their travels and once they’ve returned home. We need to start thinking about all populations – not just people living in endemic countries – when it comes to dengue treatment, prevention and control.”

 

How travellers are affected by dengue

 

Professor Tozan’s research was a spinoff of the DengueTools project, a European-backed initiative hosted at Sweden’s Umeå University, investigating how to prevent the spread of dengue through better diagnosis, prevention and prediction. The project had three core areas of study, one of which explored how dengue is moving across the globe.

 

“After DengueTools, leveraging the partnerships we’d built to understand how international travellers were affected by dengue was a natural next step,” says Professor Tozan. “We reached out to travel and tropical medicine clinics in eight countries to learn about the burden of dengue on travellers returning home with a confirmed diagnosis.”

 

The study explored costs incurred by 90 travellers returning to their home countries of Australia, Austria, Germany, Israel, Italy, the Netherlands, Switzerland and the US. Two-thirds of the travellers were tourists, with the remainder primarily travelling on business or visiting friends or family. All were adults and almost all reported experiencing their first bout of dengue. They reported having a fever, fatigue, pain and a headache, with the fever lasting nearly a week on average.

 

Burden of dengue on travellers

 

Only 20 of the travellers stayed in hospital while they were abroad; they stayed for an average of 3.7 days. Of the remainder, 29 visited a pharmacy or doctor’s office. The majority – 64 in total – visited an outpatients department, doctor or healthcare clinic on their return home, and 35 spent an average of 3.1 days in hospital in their home country. One returning traveller spent seven nights in intensive care.

 

The researchers estimated that each traveller incurred out-of-pocket costs averaging $993. “We looked at it from the patient’s perspective, what they paid,” says Professor Tozan. “They told us about both direct and indirect costs at home and abroad, including drug, hospital and other medical costs, along with the cost of cutting travel or staying for extra days. Some paid for family to come and spend time with them – or even to evacuate them.”

 

The study opened the door to a larger piece of research looking into the burden of dengue, chikungunya and malaria across more countries for a longer period. Entitled ‘Monitoring long-term consequences of chikungunya, dengue, Zika and falciparum malaria in travellers’ and with the identity ‘CHIDEZIMA’, the study – which is currently recruiting participants – aims to “describe and compare the symptoms, functional activities, healthcare consumption and quality of life” of travellers who are “at the acute state of infection”. A sub-study will look at “the economic burden of illness due to these travel-associated, tropical febrile infections by international travellers”.

 

Burden of dengue on society

 

Besides this more extensive study, there is still more to explore. After all, the out-of-pocket costs incurred by travellers are just one piece of the puzzle. “We’re missing the healthcare component,” says Professor Tozan. “We need to drill into one country and match the patients’ out-of-pocket costs with the treatment they received in their home country to get a more comprehensive picture of what one traveller’s dengue illness episode could cost society.”

 

While the costs are likely to be different in each country, the researchers estimated they could amount to more than US$7k, US$8k and just short of US$3.5k per patient for the US, Australian and Italian healthcare systems, respectively. They derived these ballpark estimates from average national costs for healthcare.

 

If we add together the almost US$1k cost to the patient and the US$7k cost to the US healthcare system, that’s a potential cost of US$8k for each episode of uncomplicated dengue – which is significant. Costs for an episode of severe dengue would be far, far higher. And if enough of those travellers were to bring dengue back to a region with a population of Aedes mosquitoes capable of transmitting the disease, it could lead to an outbreak.

 

Europe now has mosquito populations capable of transmitting the disease. Just imagine the financial burden of a dengue outbreak!

 

Dengue prevention essential

 

“We now have the financial argument that shows why preventative measures are so important for travellers. We need to tell people what they need to do when they are travelling to dengue-endemic regions, let them know that the burden of dengue is high. Once a vaccine is available for travellers, getting a shot before you travel will be a no-brainer,” concludes Professor Tozan.

 

Have you experienced an episode of dengue while travelling abroad? Please tell us your story. How were you diagnosed? What treatment did you receive? How are you now?

Dengue research in Europe: Are we doing enough?

Dengue is becoming a real threat for Europe. Scientists believe dengue vectors Aedes aegypti and Aedes albopictus could soon spread as far north as Stockholm and Berlin respectively if we don’t curb greenhouse gas levels. In 2018, we saw the threat of dengue in Europe come to life with cases reported in Spain and France, and the vector Aedes albopictus reaching Eindhoven. With dengue already on its way to Europe, scientists from Sweden feared that dengue could become a regular problem for the continent. Are policymakers taking the threat seriously?

 

To understand how Europe is grappling with this growing challenge, let’s take a look at some of the ongoing dengue-related research projects the European Commission is backing under its Horizon 2020 programme:

 

  • BluSense Diagnostics is developing a simple test for diagnosing dengue fever. The nanotechnology-based point-of-care blood testing tool can determine whether a patient has dengue in just a few minutes and with a single drop of blood. The project, which runs until the end of July 2020, aims to enable BluSense to move their tool from a low-volume product to a full diagnostic dengue platform that can be produced on a high-throughput automated line.

 

  • NOVIRUSES2BRAIN is developing a ‘one size fits all’ drug to simultaneously eradicate multiple viruses from the central nervous system of individuals infected with a combination of Zika, dengue and chikungunya along with HIV and measles. The project, which began in the summer of 2019 and will run for four years, aims to identify candidates for the drug.

 

  • The FIghtiNg DEngue viRus project hopes to disrupt the interactions between two enzymes that the virus needs to replicate. The project, which runs until the end of April 2020, could lead to the development of effective anti-dengue drugs.

 

  • PiQiMosqBite is exploring how mosquito-borne pathogens, such as dengue, are transmitted during blood feeding. The project, which began in October and will run for two years, will use quantitative imaging, computer vision and an engineered human skin to study blood-feeding behaviour in detail. It will compare the behaviours leading up to blood feeding and the dynamics of biting between infected and healthy mosquitoes.

 

  • INFRAVEC2 aims to prepare Europe for vector-borne diseases. The four-year project, which concludes early in 2021, is building a durable European infrastructure able to predict and prevent the inevitable next epidemic outbreak.

 

  • MetAeAvIm hopes to gain a better understanding of mosquito immunity to dengue by investigating the gene expression profile of mosquitoes that are immune to the virus. The two-year project, which will conclude in 2021, is studying how immune mechanisms and metabolic pathways interact to control viruses at different stages of infection.

 

  • SuperCol aims to train scientists to develop super-selective biosensors for dengue and cholera along with particles that will allow biomolecules to be captured and released on demand. The project will begin in January 2020 and run for four years.

 

  • VECTRACK is combining cost-efficient sampling strategies, remote sensing and spatial modelling techniques to build risk maps for targeted surveillance and risk assessment. Running until October 2022, its earth observation satellite service promises to be the first transnational and automated vector surveillance system for preventive control of insect disease vectors.

 

  • DRmov is looking to decipher the replication dynamics of viruses such as dengue. By identifying host factors that play essential roles in infection, the project, which will run for two years from next January, hopes to identify new targets for antivirals.

 

Climate change and globalisation are increasing the spread and impact of dengue around the globe. Diseases that have historically been a problem of tropical regions now represent a threat for temperate regions of the world, including Europe. We’re already seeing the dengue vector moving further into Europe. Added to that, recent research findings suggest international travellers incur important direct and indirect costs because of dengue-related illness.

 

Are you in Europe? Have you experienced dengue-related illness or has the Aedes dengue vector reached your region? We’d be really interested to hear your story.

Oxitec field trial: Brazil tests crash mosquito population by up to 96%

In the first of our two-part series looking at Oxitec’s 2nd generation Friendly™ Mosquito technology, Grey Frandsen, Oxitec’s CEO, explained their self-limiting mosquitoes potential to fight dengue. In this second part, Frandsen shares news on developments in Brazil, explains why public engagement is so important and reveals two new strains of their mosquito technology designed to stop the spread of vector-borne diseases.

Oxitec has been working in Brazil with its 1st generation Friendly Aedes aegypti technology for some time. Aedes aegypti is the main vector for dengue fever – reducing the mosquito population could play a vital role in curbing global dengue outbreaks. “Over the past eight years, we have achieved great Aedes aegypti control across multiple cities, project sizes and project types,” says Frandsen. “Our four-year partnership with the Brazilian city of Piracicaba has shown sustained performance over time, achieving significant suppression year-after-year.”

Brazil trials

New study raises questions

Researchers at Yale University have published a study in Nature: Scientific Reports showing that genes from genetically-modified mosquitoes have been passed on to subsequent generations.
The scientists examined mosquitoes in the Bahia region where Oxitec had released almost 450,000 male mosquitoes in the city of Jacobina over a 27-week period. The mosquitoes are designed in a way that should ensure their offspring cannot reach adult stage.

This should have meant that the GM-mosquitoes could not reproduce. However, the study found that the Oxitec mosquitoes’ genes were present in the population, leading critics to claim that the experiment had failed.

The biotech company has selected Indaiatuba, a municipality in the state of São Paulo, for the first field trial of its 2nd generation technology, a pilot project aimed at demonstrating the new strain’s effectiveness in suppressing populations of the Aedes aegypti mosquito. In partnership with the city’s municipal vector control authorities and under approval issued by Brazil’s national biosafety authority, CTNBio, Oxitec released Friendly Aedes aegypti in a year-long trial starting in May 2018.

The results for the first field trial, which covers four separate densely populated urban communities across the city, are now in. “The pilot was a success,” says Frandsen. “Relative to the untreated control area, releases of Friendly male mosquitoes achieved an average of 89% peak suppression across the two communities treated with a low release rate of mosquitoes and an average of 93% across the two communities treated with a higher release rate. At peak, one of the communities with a high release rate achieved a 96% suppression across four weeks.”

Plans are afoot for further field trials in Brazil in 2019 and 2020. These trials will more broadly evaluate the performance of the 2nd generation strain, including its deployment as eggs and the strain’s potential as an insecticide resistance management tool.

Public engagement crucial to success

“Engaging stakeholders collaboratively and transparently is a large part of successfully ushering a new technology to market, which is precisely what we’ve tried to do in every country and with every partner,” says Frandsen. Oxitec is continuing with its previous public engagement approach for its new technology. Frandsen explains: “We treat public engagement as an integrated element of our technology, not just a prerequisite for deployments in a given locale. We take a dedicated and thoughtful approach to education and information sharing, and we always rely on transparency, openness and direct dialogue with our key stakeholders.”

In every area that Oxitec works, it does so in partnership with governments and communities. “We’ve had exceptionally high levels of support at local, national and international levels,” says Frandsen. “And with more than 100 Oxitec-authored peer-reviewed publications, communication of our technology to the public is founded on strong science. Any stakeholder can evaluate our technology, our projects and our results at any time.”

Expanding to the fight against malaria

Alongside progress on its 2nd generation Aedes aegypti strains, Oxitec has partnered with the Bill & Melinda Gates Foundation to develop new Friendly Mosquito strains to combat two malaria-carrying mosquitoes:

  • Anopheles albimanus, one of the most important vectors of malaria in Central America, and
  • Anopheles stephensi, a malaria vector in Asia and the Middle East that has, in recent years, invaded the Horn of Africa, presenting a growing public health threat to the African continent.

The new ‘Friendly Anopheles’ strains will also incorporate Oxitec’s 2nd generation technology.

Endorsements and approvals around the globe

 

At a global level, the World Health Organization has endorsed Oxitec’s technology, joining a long list of national and regional regulatory bodies and organisations:

  • a positive recommendation from the World Health Organization’s Vector Control Advisory Group for use in pilot efforts against Zika during the global Zika crisis;
  • Findings of No Significant Impact from the US Food and Drug Administration and US Department of Agriculture;
  • approvals for release into the environment in the Cayman Islands, Panama and Malaysia;
  • positive technical opinions from regulatory agencies in the Netherlands and France; and
  • approvals for contained studies in the UK, India, Morocco and Australia.

New mosquito control tools are sorely needed to support vector management efforts around the world. “We broke the mould with the first release of genetically engineered mosquitoes in 2010, and we’re proud to advance once again the next generation of self-limiting insect technology designed to solve for the precise challenges of cost, safety, targeted suppression, and insecticide resistance,” concludes Frandsen.

Dengue epidemic in the Philippines: Is the worst still to come?

The Philippines Department of Health (DOH) declared a National Dengue Epidemic on 6th August 2019. Dengue cases in the country had almost doubling compared with the first seven months of 2018 – a year that was itself considered an extreme year for dengue. With the only licensed dengue vaccine banned, what’s behind this year’s worrying dengue epidemic?

By 27th July, the number of dengue cases recorded in the Philippines in 2019 had reached

167,607, with 720 fatalities, according to a World Health Organization (WHO) situation report. While all four serotypes are circulating, laboratory tests have confirmed that DENV 3 is the biggest culprit, responsible for 72% of cases. The average age of people infected is 12 years old with just under a quarter (23%) of cases and more than half (52%) of fatalities in children between the ages of five and nine.

Dengue case numbers expected to rise

Dengue is endemic in the Philippines, occurring throughout the year. Transmission is generally highest between June and October, peaking in August, which tends to be the rainiest month of the year. But a weak El Niño has delayed the rains this year, pushing back the peak of the dengue season.

We spoke with Lulu Bravo, Professor of Pediatric Infectious and Tropical Diseases at the University of the Philippines in Manila, to understand what’s behind the current dengue epidemic in the Philippines.

“In the Philippines, we expect to see increased incidence of dengue every two to three years,” said Professor Bravo. “This has been happening for the past 50 years. But this year we have already seen nearly 200,000 cases when we are only eight months into the year; so we can expect something nearer 250,000 cases in 2019. It will be a record high.”

Indeed, data from the nation’s DOH shows how peaks in dengue case numbers have been rising, and that 2018 has been the worse year this decade with just over 216,000 dengue cases reported throughout the year.

How is the country reacting?

The DOH declared a National Dengue Epidemic on 6th August. It has urged all regional DOH offices to increase dengue surveillance, case management and outbreak response. It is also encouraging clean-up drives along with vector control in health facilities and communities. “There are lots of radio and TV announcements and interviews by the health officials to raise awareness on dengue prevention and better control,” she says. “The Aedes mosquito breeds in moderately clean water, not the dark or stream water; it’s mostly stagnant rainwater, clean water on the roof.”

People are acting on the advice given, removing mosquito breeding sites by taking away water containers that are not covered, changing the water in flower vases, and generally keeping the environment clean.

Professor Bravo emphasises the importance of knowing the warning signs and getting medical attention quickly: “We need to be conscious of the warning signs that dengue could present. If you see any of these signs, seek consultation early because that’s the only way to prevent severe dengue and progress to a shock syndrome.”

Is the Dengvaxia ban to blame?

Media reports are blaming the government for banning the sale and distribution of Dengvaxia, a dengue vaccine made by Sanofi Pasteur, in February. The Guardian claims: “[Dengue] cases have gone up 98% after the government banned a vaccine widely blamed for causing the deaths of children.”

The Professor has a very different perspective. She explains: “The epidemic is not due to the banning of the vaccine. Dengvaxia has been stopped from being used in the Philippines since December 2017, that’s more than a year and a half ago. It had been administered to almost 800 children and adults.”

Scientists, Professor Bravo tells us, believe urbanisation has brought about the increasing incidence of dengue. She explains: “People are clustering in urban areas. Transmission is going to be high in places where there are lots of people.”

She also reveals how and why climate change has been blamed. “Mosquitoes want to breed where there are wet and humid places. The Aedes aegypti mosquito that is responsible for the dengue virus transmission can now survive in places that may not have been affected by dengue before – even in temperate countries.”

Read: Double dengue: Why a second dengue infection is worst than the first – and what it means for vaccination

Will the dengue ban be lifted?

Dengvaxia, she notes, is licensed in at least 21 countries, including the United States and the European Union. “The vaccine has been withdrawn in the Philippines for an administrative, not a safety, reason,” says Professor Bravo.

A recent DOH press release announcing the outcome of Sanofi Pasteur’s appeal against the Dengvaxia ban states that the DOH “has upheld the Food and Drug Administration’s (FDA) permanent revocation” because of “the continued failure of manufacturer Sanofi Pasteur to submit post-approval requirements.” Interestingly, it also notes that “the efficacy of the Dengvaxia itself is not an issue in this case.”

There is still hope in the Philippines that the Dengvaxia ban may one day be lifted. “People here are still trying to figure out how to make this vaccine available again so that it can be made useful for those who have had the dengue before,” says Professor Bravo. “The WHO has recommended that if you are already positive for dengue, then the vaccine is for you.”

Read: Wanted – a simple test for dengue fever 

People travelling to dengue-endemic areas are also showing interest in the vaccine. Professor Bravo has advice for travellers looking for a dengue vaccine: “This first generation dengue vaccine is not for travellers or a rapid response to an outbreak. It has a maximised duration for effectivity of about one year, and it requires three doses over six months. Scientists are working on developing something better.”

Dengue is a complicated disease. For every person with symptomatic or severe dengue, there will be four who have mild or no symptoms at all. With dengue not only on the rise in the Philippines but also spreading across the globe, more needs to be done to protect people from dengue.

If you’re currently in the Philippines, share your experience of the current dengue epidemic.

Dengue in the Brazil: A surge in cases in 2019

What’s behind Brazil’s 2019 dengue?

Brazil is facing one of its worst dengue outbreaks in recent years. During the first six months of 2019, case numbers have risen to seven times those seen during the same period in 2018. Fatalities, meanwhile, are six times higher. So, exactly what is happening in Brazil?

 Brazil looked to be winning the battle against dengue. Case numbers had fallen six-fold from around 1.5 million in 2016 and 2015 to around 250,000 in 2018 and 2017. Deaths had fallen too, from nearly 900 in 2015 to around 600 in 2016, then around 150 in both 2017 and 2018.

Dengue fights back in Brazil

But dengue has hit back hard in 2019, with already more than 1.2 million suspected cases and more than 400 confirmed fatalities in the first six months of 2019, according to the official Aedes monitoring report from the country’s Ministry of Health. That’s a jump of almost 600 per cent in suspected cases from the same period last year when there were just over 180,000 suspected cases and 129 fatalities.

The epidemic looks to have peaked. The majority of cases were recorded between the end of March and early May, tying in with Brazil’s rainy season which, according to the International Association for Medical Assistance to Travellers (IAMAT), runs from January through to May.

Dengue hits Brazilian cities the hardest

Minas Gerais and São Paulo in the south-east of Brazil reported the most cases, around 400,000 each, according to the official report from the Brazilian Health Ministry. While incidence rates are highest in Minas Gerais, case numbers are highest in São Paulo.

Dengue is suspected of striking down almost two per cent of the inhabitants of Minas Gerais, that’s one in every 50 people. Next hardest hit is Goiás in the mid-west where the virus has infected 1.3 per cent of inhabitants. Located in the western limits of the northern region of Brazil, the rural state of Acre we reported on last year is seeing an incident rate of just over 0.5 per cent.

The famous Brazilian city of São Paulo has an incidence rate of just below 0.9 per cent, with nearly 400,000 suspected cases in 2019 – a 40-fold increase on the 10,000 suspected cases in the first six months of 2018. The city has also seen a significant increase in cases of severe dengue, from nine in 2018 to 245 in 2019, and fatalities, from seven to 167.

Across the country, cases of severe dengue are up three-fold, from 246 in the first half of 2018 to 800 in 2019; fatalities are similarly up from 129 to 414. The elderly are most at risk with more than half of deaths in the 60+ age group. Fatality rates among people aged 80+ have reached 0.69 per cent.

The dengue fatality rate among the general population, however, has been dropping steadily over the years, from 0.069 per cent in 2014 to 0.032 per cent in 2019.

What’s behind Brazil’s latest dengue epidemic?

An article in the Financial Times raises concerns that global warming is allowing dengue fever to circulate longer in the region. Ester Sabino, a professor at the Institute of Tropical Medicine at the University of São Paulo, is quoted as saying: “We have had more days with high temperatures, so mosquitoes continue to multiply.”

The article also highlights the potential impact of recent outbreaks of Zika, particularly in São Paulo: “Some scientists have argued that the current outbreak of dengue […] can be attributed to the spread of Zika, which they say left Brazilians more susceptible to the tropical illness.”

Other scientists, the FT reports, don’t agree; instead of pointing to “increasingly extreme weather patterns, including soaring temperatures and high volumes of rain, as well as the emergence of a new strain of dengue from the Caribbean.”

Meanwhile, a HuffPost article highlighting the ‘dramatic dengue epidemic’ quotes infectiologist Kléber Luz, director of the Brazilian Society of Infectious Diseases (SBI), as saying the epidemic is “mainly due to lack of control of the mosquito”.

With the country similarly facing a sharp rise in cases of chikungunya and Zika, it’s clear that the Aedes mosquito continues to be a problem. The cause, however, is not so easy to pinpoint.

Are you currently in Brazil? Tell us what you feel needs to be done to combat dengue in your community this year.

Oxitec’s new Friendly mosquitoes: could they unlock new possibilities in the fight against dengue?

In the 18 months since we last met with Oxitec, the ‘Friendly™ Mosquito’ biotech company has a new CEO and has been busy advancing new technologies, new partnerships and new initiatives. By releasing self-limiting mosquitoes, they are able to control populations of the Aedes aegypti, the main vector of dengue fever and other diseases. The company has recently announced that the total number of Friendly Aedes aegypti released globally has passed the 1 billion mark. We spoke with Grey Frandsen, Oxitec’s CEO, and his staff. In this first of our two-part series, Frandsen reveals Oxitec’s 2nd generation Friendly mosquito technology.

 

“This has been an incredibly exciting period for the team at Oxitec. Over the last 18 months, we’ve launched our new 2nd generation technology platform for mosquitoes, entered into new partnerships in both the public health and agricultural spaces, and expanded our technology into the fight against malaria,” says Frandsen.

 

Oxitec has recently announced a new partnership with the Bill & Melinda Gates Foundation to develop new malaria-focused Friendly mosquito technology and the expansion of its agricultural program with two new crop pest initiatives.

 

Self-limiting insect technology

 

A UK company and wholly owned subsidiary of Intrexon, Oxitec Ltd was founded in 2002 as a spinout from the University of Oxford. The company positions itself as a pioneer in utilising genetics to develop solutions to insect pests that spread disease and damage crops. Oxitec’s mission is to “save lives and improve livelihoods by developing safe, highly-effective biologically-engineered solutions to control disease-transmitting and crop-destroying insects globally.”

 

Oxitec has developed a novel solution to control harmful insect populations, including the Aedes aegypti mosquito species that spreads dengue fever, Zika, chikungunya and yellow fever. This ‘self-limiting’ platform utilises proprietary and precision genetics to embed self-limiting properties in mosquitoes, agricultural pests and other insects.

 

Oxitec’s transition to its 2nd generation technology represents the next phase of its mission to target Aedes aegypti. “Our most recent announcements include the complete transition to our new 2nd generation platform and successful field trial results of our 2nd generation Aedes aegypti technology,” says Frandsen. “We’ve been busy!”

 

So, how does Oxitec’s 2nd generation Friendly mosquito technology work?

 

The Friendly mosquitoes technology

 

Oxitec’s 1st generation approach involved releasing genetically engineered male mosquitoes that, like their male counterparts in the wild, do not bite or transmit disease. After the adult males mate with wild female mosquitoes of the same species, their offspring die before reaching maturity.

 

“Following sequential releases in several countries over the last decade, we have shown that Aedes aegypti can be reduced by more than 90% in urban environments using our 1st generation genetically engineered strain,” says Frandsen.

 

Oxitec has now transitioned to a new strain of self-limiting Aedes aegypti mosquito that uses its 2nd generation ‘Friendly’ technology. The 2nd generation males mate with wild females after being released into the wild. However, only female offspring die before reaching adulthood, providing what Frandsen describes as “near-term suppression effects”.

 

Multi-generational but self-limiting suppression effects

 

The male offspring inherit the self-limiting gene and can survive to adulthood. They seek out and mate with wild females, eliminating the next generation of females while passing the self-limiting trait to the next generation of males. This is different from the 1st generation technology, which could not provide suppression effects over multiple generations from a single release as both male and female offspring died.

 

“As the self-limiting gene is passed on through males, its occurrence gradually declines in each successive generation, ultimately to disappear eventually,” says Frandsen. “In the meantime, it also prevents any female carriers of the gene from surviving to reproduce. These major technical advancements unlock a range of performance and operational benefits.”

 

Oxitec anticipates a potentially greater impact per released insect with its 2nd generation insect. Designed to provide a multi-generational but self-limiting suppression effect, it expects improvements in pest suppression and cost-effectiveness.

 

Reversing insecticide resistance

 

The new technology has other benefits too: it also introduces the potential for countering the growing spread of insecticide resistance in target insect pest populations.

 

“Our 2nd generation technology will be ideal for use within integrated pest management programs because it has the potential to reverse the resistance that mosquitoes are developing to traditional pesticides,” says Frandsen. “So, this means that end-users may be able to simultaneously extend the life of existing chemical control tools while reducing the amount of insecticides necessary for effective suppression.”

 

Unlocking operational benefits

 

Frandsen also highlighted other new benefits: “Our new 2nd generation technology has the potential to be a highly scalable intervention tool that is more easily deployable by non-specialist staff without large rearing facilities or equipment. Our continued investment in new deployment modes for our new 2nd generation Aedes aegypti mosquito will provide alternatives to costly adult mosquito rearing facilities that other technologies must use.”

 

The technology, Frandsen tells us, also solves one of the most significant cost-drivers and operationally challenging requirements for insect release technologies: “By preventing females surviving, our technology eliminates the possibility of releasing the female insects (which bite and transmit disease), and therefore also the need for sex-sorting in the manufacturing process.”

 

Oxitec is now accelerating product development for scalable commercial solutions for use by anyone. These “big advancements expand what is possible within our broader public health and vector control community,” says Frandsen.

 

“We’re looking forward to a busy year as we ready our 2nd generation technology for large-scale deployments,” he continues. “Once fully developed, we believe this will be the first technology capable of giving governments and commercial end-users the power to deliver safe, effective Aedes aegypti control with an easy-to-deploy, cost-effective and still self-limiting solution.”

 

In the second of our two-part series, Frandsen shares news on developments in Brazil, explains why public engagement is so important and reveals two new strains of Oxitec’s 2nd generation Friendly mosquitoes technology.

A unique approach to predicting the future spread of Aedes

Aedes aegypti and Aedes albopictus are spreading across the globe, increasing the number of people at risk from mosquito-borne diseases, including dengue. Their expansion is largely due to human movement and climate change. Scientists are using statistical modelling techniques to show how Aedes is spreading. We asked them which regions the dengue vectors have populated today, where their model anticipates the mosquitoes will spread to next and how their predictions are helping slow – or even halt – the spread of Aedes.

 

“Aedes aegypti and Aedes albopictus are found in all continents except Antarctica,” revealed Dr Moritz Kraemer from the Department of Zoology at the University of Oxford. “Aedes aegypti is distributed around the tropics and subtropics. Aedes albopictus can also be found in temperate regions, especially in China, the US and Europe.”

 

Aedes spreading across Europe and the US

 

Despite the spread of Aedes expanding over the last 40 years, a lack of data means it’s often difficult to pinpoint their distribution during that period. That said, authorities in Europe and the US have been monitoring Aedes closely.

 

Dr Kraemer confirmed our own analysis of Europe’s emerging dengue threat by saying, “Over the past 10 to 15 years, Europe has seen a rapid expansion of Aedes albopictus northward towards more temperate regions, from Albania into Italy and from Italy towards France and over the Alps into Switzerland and Germany.” His viewpoint also aligns with the European Centre for Disease Prevention and Control (ECDC), which reports “Aedes albopictus is currently considered a serious biting nuisance for humans in Italy, southern France and Spain.”

 

The US is the only place where Aedes aegypti has been monitored well enough at a continental level, according to Dr Kraemer. Data from the late 1980s onwards shows how the primary dengue vector has spread along the highway network “coming from the southeastern US into more northern and western parts,” he says.

 

Predicting the spread of Aedes

 

The researchers are using mathematical modelling to predict how both Aedes species might spread in response to accelerating urbanisation, human movement and climate change. It is unique in that, unlike previous models, it takes the impact of human movement into account. “We are interested in how Aedes spreads to new places, looking at both the environment and who might import the vector,” says Dr Kraemer.

 

The mosquitoes can only fly around 100 metres (and on occasion a bit further), so they need to be transported to new regions. While anecdotal evidence shows they have arrived on cars or by laying their eggs in ships, this movement had not previously been quantified or used to predict future spread.

 

The model also predicts and takes into account future urbanisation processes, specifically focused around Asia and sub-Saharan Africa where vast areas will become urbanised. Dr Kraemer adds, “The movement of people into urban areas is very important when you’re looking specifically at Aedes aegypti. People are travelling from areas where there are mosquitoes and importing eggs or even adults into new locations.”

 

Urbanisation behind the spread of Aedes aegypti

 

Indeed, the model showed Aedes aegypti moving into urban areas because they are climactically suitable. “These mosquitoes breed in artificial containers near houses where humans live,” said Dr Kraemer. Urban areas potentially at risk include the high population centres in the coastal areas of China and the US, where we have already seen importations of the species.

 

In regions where the mosquito is already a problem – Brazil, Asia or sub-Saharan Africa in particular – the model doesn’t see such rapid expansion in mosquito populations or invasion to new areas. Rather, the model showed mosquitoes might be able to transmit disease for longer. “The current six months when the mosquito can transmit disease may extend to eight or nine months as temperatures increase,” says Dr Kraemer. That can have devastating impacts on disease transmission, he adds.

 

The model has also predicted that some areas of the US, such as the centre mid-west, are becoming too dry for the mosquito.

 

Aedes albopictus spreads opportunistically

 

The model predicts Aedes albopictus to expand along the fringes of its current population in a “wave-like” fashion. “We anticipate the niche Aedes albopictus can occupy today will be filled over the next ten to fifteen years,” says Dr Kraemer. “We expect it to spread to habitats where it can survive but isn’t present today, then to new habitats where increasing temperatures or increasing precipitation make the environment suitable for these mosquitoes to establish new populations.”

 

Targetted surveillance and control

 

Global surveillance and control efforts that aim to mitigate the spread of vector-borne diseases such as dengue need to understand how Aedes is spreading. Experts in the ECDC in Europe and US Centre for Disease Control (CDC) can use the model’s maps and predictions to identify locations most at risk of Aedes invasion so they can target surveillance and control programmes more effectively.

 

“We’re not just thinking about where the mosquito might arrive but where Aedes might spread and become established,” says Dr Kraemer. “If we can prevent it from establishing its population in a new place, that would help slow down its spread.”

 

The model’s European maps show regions in northern France, Belgium, the Netherlands and northern parts of Germany at risk. Dr Kraemer explains how having pinpointed those locations; “collaborators set mosquito traps along highways or in other places where the mosquitoes are likely to arrive. If they find mosquitoes, they can start preventing those populations from growing and establishing themselves in those places.”

 

Improving predictions

The team feeds the information from the local surveys in Europe back into their model to update their model predictions to become more relevant to the local context. They do the same with the information gleaned from their surveys in the US, Indonesia and Brazil. The model’s massive dataset of up to 40,000 records for both species also collates data from literature and government agencies.

 

Going forward, the team would also like to include data from social media and citizen science approaches. “We are looking at ways of validating data from people on the ground who could feed information back to us in a more real-time fashion,” says Dr Kraemer. “People who have been bitten by a mosquito might send a picture of the mosquito so an expert can identify it. That would be a very great opportunity to advance the quality and reliability of our model.”

 

Following their interest in monitoring where new introductions are coming from, the team are also looking at using mosquitoes’ genetic code to relate Aedes populations within their model. “It would be interesting to see whether new Aedes populations coming into California originate from central America or the eastern US,” says Dr Kraemer.

 

“Genetic sequencing has already been used for tracing Zika virus from the Americas, yellow fever throughout Brazil, and the importation of chikungunya into the Americas from Angola. It helps us to stratify the geographic landscape of disease. If we could do that for mosquitoes, that would improve the accuracy of our methodologies,” he concludes.

 

We can’t wait to see the model evolve in the coming months and years. Get in contact with us if you are working on your own models to predict the spread of Aedes.