Dengue vaccine pipeline: Are new approvals on the horizon?

As COVID-19 vaccines roll out across the world, researchers are hoping it could inject new momentum into the search for safe and effective vaccines against dengue fever. Could new vaccine technologies, including mRNA vaccine platforms, offer fresh hope?

It’s now five years since Sanofi Pasteur introduced the first dengue vaccine, Dengvaxia, to the world in 2015. In December 2018, the European Medicines Agency (EMA) approved Dengvaxia to prevent dengue in people aged between nine and 45 living in endemic areas with a documented prior infection. In May 2019, the US Food and Drug Administration (FDA) approved Dengvaxia to prevent dengue in children aged between nine and 16 living in endemic areas with a documented prior infection. Dengvaxia is also approved for use in several endemic countries in Latin America and Asia.

Other vaccines that could prevent dengue are advancing at pace. Amongst other things, Takeda recently announced that its TAK-003 vaccine is on track for regulatory filing very shortly. And Brazil’s Instituto Butantan is expected to announce the results of its phase III trial of TAV003 in the first half of 2021. Various other TV003/TV005 trials are in progress or have recently completed.

We last took a look at the dengue vaccine pipeline back in February 2018. Let’s see how it has progressed over the last three years.


Phase III trials


Takeda’s TAK-003 (also known as TDV) dengue vaccine is the most advanced vaccine candidate currently in the pipeline. Takeda recently told Reuters that TAK-003 “is on track for regulatory filing in Asia, Latin America, and the European Union by the end of fiscal 2020”.

TAK-003 is based on a live-attenuated DENV-2 (dengue serotype 2) virus, which provides the genetic ‘backbone’ for all four dengue serotypes. The tetravalent dengue vaccine candidate is given in two doses, three months apart.

Takeda began its phase III Tetravalent Immunization against Dengue Efficacy Study (TIDES) trial of TAK-003 back in September 2016. The on-going study, which is taking place in eight dengue-endemic countries in Latin America and Asia, completed enrolment of 20,100 children and adolescents ages 4 through 16 within seven months. The study aims to test how well the vaccine prevents dengue and the long-term side effects of the vaccine in children.

The primary results Takeda announced in November 2019 showed TAK-003 to be well-tolerated and to offer protection against dengue. The results revealed the vaccine’s efficacy (its ability to prevent dengue) 12-months after participants’ second dose, finding it to be 80% overall – 82% in participants who had not previously contracted dengue and 75% in participants who had previous contracted dengue. In other words, the vaccine protects whether or not a person has previously had dengue.

The Lancet published the trial’s secondary results – the results from an 18-month follow-up – in March 2020. These showed an overall efficacy of 73%. In its press release, Takeda announced a 70% vaccine efficacy for DENV-1, 95% for DENV-2 and 49% for DENV-3. It had insufficient data for DENV-4.


Developed by the US-government funded NIAID (National Institute of Allergy and Infectious Diseases, part of the US National Institutes of Health (US NIH)), TV003 and TV005 are variations of the same live-attenuated and recombinant vaccine, except that the former has ten times more of the DENV-2 component than the latter. Both are intended to be given as a single dose.

NIAID has licensed TV003/TV005 to several manufacturers for further development. These include Instituto Butantan in Brazil; VaBiotech in Vietnam; Panacea Biotec, Serum Institute of India and Indian Immunologicals in India; Medigen Biotech in Taiwan; and Merck in the US, Canada, China, Europe, and Japan. Its goal is to ensure market access through cheaper domestic production in key dengue-endemic regions.

While TV003/TV005 remains behind TAK-003 in development, progress is moving forward and looking positive. Brazil’s Instituto Butantan began a large phase III community-based trial of TAV003 in February 2016. The on-going trial includes almost 17,000 adults and children from a number of urban areas across Brazil that have dengue transmission. The institute expects to complete the trial to assess the vaccine’s safety and efficacy in the first half of 2021.

One significant advantage of the vaccine is that it is given in a single dose, making it especially attractive to travellers since this is more convenient and can be given at short notice.


Phase II trials


NIAID is also sponsoring a clinical trial of TV003/TV005 in countries such as Thailand and Bangladesh. The phase II trial of TV003 in Thailand was completed in October 2018, and the phase II trial of TV005 in Bangladesh was completed in February 2020. In parallel, a phase II trial in Brazil of TV003 that Butantan Institute is sponsoring is expected to complete in December 2020.

Elsewhere, the Medigen Biotech phase II trial of TV003 in healthy adults in Taiwan completed in May 2019. According to Medigen, the vaccine showed great safety and participants produced an immune response against all four dengue serotypes in participants whatever their age – from 20 to 70.

And the National Taiwan University Hospital is currently recruiting for a phase II trial of TV005 to determine the candidate vaccine’s safety and ability to elicit an immune response in people aged 50 to 70.


PIV emerged from a collaboration between GlaxoSmithKline (GSK), Walter Reed Army Institute of Research (WRAIR) and Fiocruz. TDENV-PIV is a purified inactivated vaccine, meaning it is made up of dead purified components of the dengue virus with an ‘adjuvant‘ (a substance that helps boost the body’s immune reaction). Like TDV, TDENV-PIV is given in two doses, in this case, four weeks apart.

The collaboration completed its phase II trial on 140 adults in the US in March 2018. The trial’s main objective was to evaluate and refine TDENV-PIV further. The trial results show participants tolerated the vaccinate well and that the vaccine is best given with a boost one month and six months after the initial vaccination.

While we mentioned in our last update that GSK might be developing a DPIV vaccine candidate from the knowledge gained from this collaboration, there is no mention of a dengue vaccine in its pipeline.


Phase I trials

Merck’s V180 is a recombinant subunit dengue vaccine, meaning it only contains essential antigens and not all the other molecules that make up the virus. It is intended to be administered in three doses, one month apart. Merck’s phase I trials in the US and Australia tested different doses of the vaccine candidate in combination with different ‘adjuvants’. Published results show that the vaccine formulations did induce a modest amount of antibodies against dengue serotype 1 in most participants that waned over time.

Also in phase, I, the US Naval Medical Research Center (NMRC) has evaluated its DNA vaccine (a technique using genetically engineered DNA to stimulate the body’s immune system) in combination with an adjuvant. While TVDV, as it is known, targets all four dengue serotypes, an earlier phase I trial evaluated its DENV-1 component, which is known as D1ME100.

KM Biologics (formerly Kaketsuken) completed a phase I trial of its KD-382 live attenuated tetravalent dengue vaccine in Australia in June 2020 after completing preclinical trials in Japan in 2018. The trial assessed the safety and tolerability of KD-382 in healthy adults aged between 18 and 65 who had not previously contracted dengue. It also evaluated the participants’ immune response over 57 days.

Meanwhile, the Serum Institute of India is currently recruiting in Australia for its phase I trial of its Dengusiil dengue vaccine candidate. This trial will assess the safety and tolerability of a single dose of Dengusiil in healthy adults aged between 18 to 45. It will assess participants’ immune response to Dengusiil over six months.

Other developments

Excitingly, an article published in Frontiers in Immunology in 2019 describes how an mRNA vaccine induced a potent immune response and protection against DENV-1 in mice. A more recent article published in Molecular Therapy describes an mRNA vaccine candidate that elicited a strong immune response and partial protection against DENV-2 in mice. “These results form the foundation for further development of a tetravalent DENV vaccine based on mRNA technology,” it concludes.

In addition to the mRNA vaccine candidates mentioned above, several other novel developments are progressing:

The dengue fever vaccine pipeline is continuing to make great steps forward, developing a variety of vaccines to help combat this terrible disease.

Additional sources:

Dengue in Africa: Are patients being treated for malaria by mistake?

Malaria and dengue can be difficult to distinguish. Symptoms are very similar. They typically include a high temperature, or feeling hot or shivery, a headache and feeling or being sick. And both diseases are vector-borne diseases spread by mosquitoes. But the two infections need different treatments. A recent study found dengue was going undiagnosed in children in Kenya. They were being treated with anti-malarial and anti-microbial drugs when, in reality, they didn’t need them. It also raised the question of whether the burden of dengue in Africa is actually far higher than thought.

The study into the high dengue burden and circulation of all dengue serotypes looked at more than 1,000 children. Each had visited an outpatient clinic in western and coastal Kenya with a fever between 2014 and 2017. The study tested blood samples from each of the children and found that 40% of them had evidence of the dengue virus in their bloodstream. Without those tests, it would have been hard to diagnose dengue. After all, their symptoms would have been similar whether they had dengue or not.

High levels of dengue in Kenya

The study noted that “the level of dengue we detected was surprisingly high” and “the number of concomitant (concurrent) serotype infections was also high and unexpected”. Moreover, the children with dengue had all four serotypes among their infections when the researchers hadn’t expected to find DENV-4, which is the dengue serotype least reported in Africa. 

Half of the children with dengue also had malaria. For some, their dengue was causing their fever; for others, it was their malaria. In each case, the other disease remained asymptomatic. 

Prescriptions for anti-malarial and anti-microbial drugs were much higher among children with dengue. This, the study suggests, indicates “severe disease in this group” and supports the idea that dengue was indeed the cause of their fever.

Understanding the distinction is essential, according to the study, because “asymptomatic dengue infections provide a major reservoir for human-to-mosquito dengue transmission”. 

Anti-malarials and anti-microbials overprescribed 

Of the 141 children found to have dengue but not malaria, doctors had prescribed an anti-malarial drug for 29 and an anti-microbial drug for 75 while only 12 didn’t receive either. This finding supports previous research, the study reveals, that shows malaria is over-diagnosed and anti-malarial drugs are over-prescribed. It also indicates that anti-microbial medications are commonly prescribed for fever in developing countries when the exact cause is unknown, which would explain the anti-microbial drugs being over-prescribed. 

Over-prescription of both anti-malarial and anti-microbial drugs can lead to drug resistance developing. Added to that, it can mean doctors need to sometimes treat patients for unwanted side effects. 

The study concludes by suggesting an enormous burden of dengue among children with a fever in Kenya. It finishes by saying “dedicated investments to develop a reliable dengue point-of-care diagnostic is urgently needed” along with “knowledge of the spatial-temporal dynamics of dengue circulation throughout Africa to inform a coordinated public health response in an increasingly interconnected world”.

Is dengue being under- or even over-diagnosed where you live? We’d love to hear your thoughts.

Dengue and COVID-19: Is there a link?

In March this year, an article published in the Lancet raised concerns that patients testing positive for dengue were later confirmed to have COVID-19. It describes two patients in Singapore with false-positive results from rapid serological testing for dengue who were later confirmed to be infected with SARS-CoV-2, the virus that causes COVID-19. Over the intervening months, other research has shown an intriguing, and also potentially crucial, link between the two seemingly unrelated viruses.

The first of two pieces of research we look at here examines what happened when researchers tested thirteen serum samples containing dengue antibodies for COVID-19. The second examines how dengue influenced the COVID-19 pandemic in Brazil.

What’s most interesting is the conclusions drawn by the researchers on each of the studies.

Dengue and COVID-19 false-positives confirmed

Noting that early symptoms of COVID-19 can be mistaken for dengue, researchers in India were concerned when both dengue and COVID-19 infections had started to rise simultaneously. Dengue numbers were rising as they do every year when the monsoon season hits. COVID-19 numbers were rising as the pandemic spread across the globe.

Worried that dengue antibodies might cross-react with COVID-19 rapid tests, the researchers tested thirteen serum samples for SARS-CoV-2. Of those thirteen samples, five showed a false-positive when tested for SARS-CoV-2 in two different rapid test kits. More importantly, the serum samples were dated 2017, long before the emergence of the COVID-19 epidemic.

So, in dengue-endemic countries, rapid testing kits may misdiagnose dengue patients as having COVID-19. And may misdiagnose COVID-19 patients as having dengue. The researchers concluded:

“It appears that both these viruses have some antigenic similarity that is resulting in the observed cross-reactivity.”

Potential cross-reactivity between dengue and SARS-CoV-2

The story gets even more intriguing when you examine a recent study exploring how dengue influenced the COVID-19 pandemic in Brazil this year. Our second study used mathematical modelling to understand what was behind the uneven geographic spread of COVID-19 cases and deaths in Brazil.

As COVID-19 spread across the country, researchers chanced about a link between the geographic distribution of dengue and COVID-19. Dengue had infected more than 3.5 million Brazilians between January 2019 and July 2020.

The researchers compared each of the country’s states. They looked at what fraction of the population had contracted dengue fever in 2019-2020 and the number of COVID-19 infections. They found that states in which a large proportion of the population had contracted dengue fever in 2019-2020 reported lower COVID-19 cases, infection rates and deaths.

When they looked for a similar link between SARS-CoV-2 and the chikungunya virus, they drew a blank. But when they looked for that link between COVID-19 and dengue in a sample of countries around Asia and Latin America, as well as in islands in the Pacific and Indian Oceans, it was clearly evident.

The researchers raised the possibility of ‘immunological cross-reactivity’ between dengue and SARS-CoV-2, concluding:

“Dengue infection or immunization with an efficacious and safe dengue vaccine could produce some level of immunological protection for SARS-CoV-2 before a vaccine for SARS-CoV-2 becomes available.”

We are still at the start of our journey to advancing our knowledge on the link between dengue and COVID-19. There’s a distinct possibility that uncovering potential new ways to fight either of these seemingly unrelated viruses might unlock the answer to combatting them both. But we have a lot more to learn.

Wolbachia-infected mosquito initiative is vital as COVID-19 bites

The number of dengue cases reported to the World Health Organization (WHO) has increased eight-fold since 2000, from 500,000 cases to 4.2 million in 2019. Wolbachia-infected Aedes mosquitoes are bringing hope; they reduced dengue case numbers by 77 per cent during a World Mosquito Program (WMP) trial in Indonesia. We spoke with Dr Katie Anders, Director of Impact Assessment at WMP.

The trial divided the city of Yogyakarta into 24 communities and randomly selected 12 to receive the Wolbachia-infected mosquitoes; the other 12 showed what would have happened in the absence of Wolbachia. “We’re excited about the results of our randomised controlled trial in Yogyakarta,” Dr Anders told us. “While the study supports what we see elsewhere, it is the first time we have generated solid evidence of the true impact of Wolbachia-infected Aedes mosquitoes on dengue.”

The study was specifically designed to stand up to scientific rigour. In addition to the control communities, the study confirmed dengue case numbers in laboratories, whereas previous trials had relied on health facilities notifying authorities of patients with the disease. Also, previous trials had struggled to exclude factors such as natural fluctuations in dengue dynamics.

The results are likely to be a conservative estimate of the Wolbachia effect. “The movement of people and mosquitoes across our randomly allocated communities may have diluted the result,” said Dr Anders.

Dr Anders goes on to explain how, equally importantly, the study showed that you don’t need to deploy Wolbachia-infected mosquitoes to every last square hundred metres of a city because “any holes left fill themselves in over time”.

Big cities targeted for Wolbachia-infected mosquitoes

WMP is currently prioritising big cities with a massive burden of disease, expanding interventions in Colombia, Brazil, Mexico and Indonesia. “The impact of Wolbachia might be even higher deploying across a whole city,” said Dr Anders. “In cities seeing tens of thousands of dengue cases, Wolbachia offers a huge potential benefit.” It aims to reach more than 75 million people over the next five years, from 5 million people to date.

The team plans to release mosquitoes for a second randomised controlled trial in Belo Horizonte in Brazil later this year. The trial is being run by a US-based academic group and funded by the US National Institutes of Health.

However, overall WMP is shifting focus from evidence generation to scaled implementation and cost-effectiveness. “We’re aiming operational deployments where we can achieve the biggest impact for the lowest cost,” Dr Anders explains.

Costs come down when regions manufacture their own mosquitoes at scale to supply countries within the region. With that in mind, Dr Anders shared WMP innovations since we last spoke in May of last year: “We are innovating for production at scale, quality assurance, a longer mosquito egg shelf-life, and to distribute eggs efficiently to cover larger areas faster and more cost-effectively.”

Its focus includes:

  • producing large quantities of high-quality mosquito eggs for cost-effective deployment over large cities
  • optimising the supply chain in distributing mosquito eggs from large regional manufacturing centres to partner countries
  • involving the community more directly, replacing the army of field officers it uses today
  • using drones to release measured numbers of mosquitoes, following a successful pilot in Fiji
  • finding new approaches to reaching big cities and complex environments

The impact of COVID-19

For WMP, the COVID-19 pandemic has affected operations. While WMP paused face-to-face interaction for distributing eggs, releases are now resuming. Sites have developed contact-free methods for setting mosquito containers and for receiving the mosquitoes collected to monitor Wolbachia establishment.

Data-gathering is being impacted too. Trials reliant on surveillance systems may be underestimating dengue case numbers as people are less likely to present at a health facility, and government are sometimes delaying data notifications.

On a global scale, community-based activities for mosquito control have paused. And people are spending more time at home, where the risk of dengue transmission is high. The pandemic may be fuelling dengue outbreaks. “Singapore is facing its largest dengue epidemic on record this year,” said Dr Anders. “Thailand and Malaysia have also had big years. And they’re also dealing with COVID-19. Dengue and COVID-19 combined could overwhelm health systems.”

What’s more, COVID-19 is diverting both attention and funding away from dengue and other diseases. Nevertheless, dengue-endemic countries are recognising how dengue has been a problem for decades, is a problem now and is going to continue being a problem. “WMP is still getting a lot of interest from communities and governments in dengue-endemic countries,” she says. “They see there’s still a massive need for effective control because dealing with COVID-19 and dengue is a double burden on their health systems.”

The exciting results from the Yogyakarta trial serve only to strengthen WMP as it engages prospective partners. We’re looking forward to seeing how WMP operations expand operations in the coming months and years.

How close are we to new treatments for dengue?

2020 is already turning out to be another terrible year for dengue. The Pan America Health Organization is reporting all four dengue serotypes circulating in Guatemala, Mexico, Columbia and Brazil, significantly increasing the risk of severe infections. We recently explored why the ideal dengue vaccine has to neutralise all four dengue serotypes. Equally, scientists need to design new drugs that can inhibit all four dengue serotypes. Let’s take a look at one recent breakthrough.

Industry experts say there is currently no specific treatment or vaccine available for fighting dengue: “The only existing means of fighting the disease are the control of mosquito vectors in the regions concerned and individual measures to protect against mosquito bites,” according to the Pasteur Institute.

Several compounds – some repurposed from other diseases and others designed specifically for dengue – have been identified as potential treatments. Some have even been tested in clinical trials. None, however, has worked well enough to advance. There are a number of reasons why, with their struggle to treat all four dengue serotypes one key challenge.

Nevertheless, the search for possible dengue treatments continues. One recent example comes from a team of researchers at the University of Texas Medical Branch. They have been learning about the structure of the interior of the virus.

Meet the dengue capsid

The research investigates something called the ‘dengue capsid’. The capsid is found in all viruses, and is essentially a shell made up of proteins that surrounds the virus’ genetic material. In some viruses, including the dengue virus, the capsid is coated by a membrane known as an ‘envelope’.

The capsid is responsible for releasing a virus’ genetic material during infection. But before the dengue capsid can do this, the envelope coating the capsid must first be removed – a process known as ‘uncoating’. And if you can stop the ‘uncoating’ from happening, that might stop dengue in its tracks. The research aimed to reveal how a specific chemical compound – an inhibitor – might do just that.

The researchers discovered that the inhibitor can attach itself to a dengue capsid in a way that then binds four capsids together into something called a ‘capsid tetramer’ – with tetra simply meaning ‘having four’. A dengue virus containing the capsid tetramer then struggles to uncoat. Unable to uncoat, it is then unable to infect new cells.

Advancing our knowledge on dengue

Understanding the structure of the interior of the virus has also helped researchers grasp one reason why resistance to therapeutics can emerge. If the dengue virus mutates, it can weaken the inhibitor’s ability to bind to the viral capsid protein. If the binding doesn’t happen, the tetramer is not formed. And if the tetramer is not formed, the virus can uncoat. And if the virus can uncoat, it can continue infecting cells.

Their work focuses on a compound that stops the DENV2 virus in its tracks but is unable to fight DENV1, DENV3 or DENV4 dengue serotypes. They also identified the amino acids (essential organic compounds present in all our bodies) that prevent the inhibitor from binding to the capsids of other dengue serotypes. This might help identify compounds that can combat all four dengue serotypes.

The findings of this research are published in the Proceedings of the National Academy of Sciences. It has advanced our knowledge on how the different dengue serotypes function, uncovering potential new ways of fighting the virus. And while this is great progress, there is more work to do.

Is dengue pre-vaccination screening the way forward?

Sanofi Pasteur’s Dengvaxia was the first dengue vaccine to be licensed. Originally licensed in Mexico in December 2015, it is now licenced in 20 countries, according to the World Health Organization (WHO), for use in people aged 9 and 45 living in dengue-endemic areas. While safe for people who had previously been infected with dengue, the vaccine appears to put people who have never been infected at higher risk of more severe dengue. So, what was behind the vaccine’s strange behaviour? And what does it mean for dengue vaccination programs?

Essentially it comes down to a phenomenon known as antibody-dependent enhancement (ADE). The dengue virus has four serotypes, all of which can cause disease. Anyone catching dengue for the first time will develop antibodies with long-lasting protection against the infection’s serotype. They also develop antibodies that protect against the other serotypes – but that protection only lasts a short time. Once it wanes, that person will only have protection against the first (or primary) serotype.

Dengue and ADE

Imagine they then catch the virus a second time. Their pre-existing dengue antibodies would only stop the virus if the second infection were of the same serotype as the first. If not, ADE occurs. With ADE, these antibodies – being of a different serotype to the infecting virus – don’t neutralise it. Scientists believe that they instead bind to the virus and help it enter and infect the person’s cells.

What would most likely have otherwise been a mild viral infection becomes severe. In other words, the impact of the dengue virus can be more severe if you contract one dengue serotype, then a different dengue serotype.

An ideal dengue vaccine has to provoke the body to produce antibodies for neutralising all four dengue serotypes to avoid ADE. But research seems to show that, in people who have never had dengue, Dengvaxia may predominantly provoke the production of antibodies that protect against once specific serotype: DENV-4.

Dengue pre-vaccination screening

The WHO currently recommends pre-vaccination screening for dengue so the vaccine is only given to people who have previously been infected. It notes that “Decisions about implementing a pre-vaccination screening strategy will require careful assessment” and “Vaccination should be considered as part of an integrated dengue prevention and control strategy.”

Laboratory-based tests would be the most likely approach for dengue pre-vaccination screening; but processes can be time-consuming and these tests require a fair amount of laboratory resources. Researchers believe there may be delays of several days between sampling and receiving the result. Patients unwilling or unable to attend the clinic more than once (initially, for sampling and, secondly, for vaccination) would not get the protection they need.

Despite not being as accurate as laboratory tests, rapid diagnostic tests (RDTs) could allow prompt screening in areas where dengue is endemic. These areas often have limited resources, and laboratories may have limited capabilities and capacity. RDTs may also be useful in areas where transmission rates are high, which would benefit from immediate vaccination.

But RDTs are typically used for detecting current rather than past dengue infections. And while they have shown reasonable performance compared with laboratory-based tests, more research is needed. Current RDTs may need to be modified or new RDTs may be needed before they can be used in earnest for dengue pre-vaccination screening.

If you have been involved in a dengue pre-screening program, tell us about your experience.

Dengue in the Americas: The worst epidemic in decades

In June, the US Centers for Disease Control and Prevention (CDC) shared the unwelcome news that countries listed in the Americas are currently reporting higher-than-usual numbers of dengue cases. Case numbers in Argentina, for instance, are fast-approaching the 80,000 reported throughout 2016 – itself a record year. What’s behind these numbers?

The Americas may still be feeling the impact of last year’s dengue outbreaks, which reached an all-time high. During 2019, case numbers across the region exceeded 3.1 million, with 1,500 fatalities, according to the most recent data from the Pan American Health Organization (PAHO). Dengue hit Brazil the hardest. The country reported more than 2.2 million cases and almost 800 fatalities.

Paraguay and Bolivia are seeing unprecedented case numbers. According to PAHO data, Paraguay reported almost 220,000 infections up until early June, which is 50 times the number reported during the same period in 2019 and 18 times the 2019 total. Bolivia reported almost 83,000 up until epidemiological week 22, which is nearly ten times the same period in 2019 and five times the 2019 total.

Argentina borders both Paraguay and Bolivia to its north. Here total dengue numbers had been continuing a gradual year-on-year rise: 3,220 in 2019, 1,829 in 2018, and 557 in 2017. The early months of 2020 were a different story; like Paraguay and Bolivia, numbers exploded: 72,701 dengue infections, including 24 fatalities – 29 times the number reported during the same period in 2019 and 24 times the 2019 total.

Numbers are also on the rise in Belize, Colombia, Costa Rica, Dominican Republic, El Salvador, Guadeloupe, Guatemala, Honduras, Mexico, Nicaragua, Peru and Saint Martin. Brazil, on the other hand, is seeing fewer cases in 2020. Until early June, the country had only reported two-thirds of the number reported during the same period in 2019: just under 1.1 million in 2020 versus just shy of 1.7 million in 2019.

Dengue has also reached North America. Miami-Dade in South Florida reported the state’s first locally-acquired dengue fever case of 2020 late in May, reports CBS Miami.

Is COVID-19 to blame?

The Americas are a major hotspot for COVID-19 outbreaks, reports Euractiv. While the larger US epidemics – in New York and New Jersey – are in decline, thousands of cases are reported daily in Brazil, Peru, Mexico and Chile. Although testing capacity in some countries is limited, Latin America appears to be the world’s worst-affected region, now that European outbreaks have abated. And many country’s health services are not sufficiently financed for this kind of emergency.

Could numbers, therefore, be down to dengue patients not receiving the treatment they need? Are they staying at home because they’re worried about COVID-19? Are overwhelmed hospitals having to turn them away?

Paraguayan lawyer Sonia Fernandez told Reuters that she had avoided seeking care when she and her two daughters got sick with dengue at the beginning of April. “All three of us had dengue, we had all the symptoms, the pain, the rash, but we didn’t go to a clinic or a health centre so as not to expose ourselves [to COVID-19],” Fernandez said. All three have since recovered, the report reveals.

People not seeking treatment may also lead to under-reporting, as Esteban Ortiz, a global health researcher at Quito’s University of the Americas in Ecuador, explained to Reuters: “Very clearly dengue is being under-reported. Cases haven’t decreased; the diagnosis of cases has decreased.” Ecuador has thus far reported 9,300 dengue cases in 2020, 1,100 more than 2019 totals.

COVID-19 may also be slowing the spread of dengue. Shut borders and flight restrictions are halting its march around the globe.

Are you currently in the Americas? Tell us how COVID-19 is impacting dengue infections and what could be done to limit that in your community.


Interview: Oxitec CEO on US field trials and the dengue fight in a new world

For any company developing new vector control tools, receiving an Experimental Use Permit (EUP) from the US Environmental Protection Agency (EPA) is a significant milestone. For Oxitec, it opens the way for field testing its genetically modified Aedes aegypti mosquitoes in Florida and Texas. Oxitec’s second-generation ‘Friendly mosquitoes’ have shown great promise for reducing mosquito populations and combatting the spread of mosquito-borne diseases such as dengue and Zika.

We spoke with Oxitec CEO Grey Frandsen about its implications, the impact of the current pandemic, why lockdowns could be fertile ground for dengue outbreaks – and why we need to view COVID-19 and dengue as interrelated.

Why is this EUP so important for Oxitec?

We’re thrilled that the EPA granted us this approval. The EUP will allow us to deploy pilot projects in the US to demonstrate the effectiveness of our new Friendly™ Aedes aegypti technology. Aedes aegypti continues to spread in the US, meaning the risk of dengue and other vector-borne diseases that this mosquito transmits continues to go up. With current tools like insecticides losing their effectiveness, and with a growing demand for safe technologies that do not have an impact on biodiversity, we think Friendly™ mosquitoes can play an important role in the US.

In addition, regulators around the world consider the US EPA a stringent regulatory authority. The amount of scientific effort that the EPA and other agencies such as the US Centers for Disease Control (CDC) put into reviewing our technology throughout the 18-month process was incredible. This adds to the body of scientific evidence and rationale for our technology, adding yet another layer of credibility as we engage with additional countries around the world.

What challenges did you face along the way?

Oxitec is developing first-in-class technology, and our EUP is the first time a genetically modified mosquito has been granted a EUP in the US. In most countries where we’ve operated, we’re the first technology of its kind for regulators, which means that our efforts are equal parts about Oxitec’s technology and the broader need for paths to market for a new generation of tools.

It can be difficult, but we have shown that when we focus on building a trusting and science-based working relationship with regulators and our stakeholders, we can shape a pathway to regulatory approval.

What next steps do you have planned?

Our field trials aim to demonstrate just how well our technology works. We’re going to be generating data in line with EPA requirements to ultimately gain full commercial approval.

In the case of Florida, we’re now seeking approval from Florida’s regulators, then will go to our local partners to seek their final approval of the trial. And once we have all of those lined up, we look forward to releasing our Friendly™ mosquitoes in a small field trial.

How is COVID-19 impacting dengue interventions?

Thankfully, Oxitec is relatively unaffected. All of our programs continue on track with only a few certain operational adjustments. We’re prioritising the safety of our staff and stakeholders, and our programs continue to advance.

As your readers know, COVID-19 is taking up most of the oxygen in the room on the global health front. But we can’t ignore the fact that COVID-19 is confounding already-challenging issues for those countries facing the challenges of dengue.

Aedes aegypti continues to expand its presence into new territories. Our warming climate, rapid urbanisation and limited vector control capacities in many countries remain major challenges to the dengue fight.

Dengue is a global epidemic, and it is making COVID-19 responses more difficult. Dengue patients – up to 200 million each year – are taking up precious hospital beds and medical resources that fragile public health systems need for COVID-19 patients. The reverse is true too, of course. COVID-19 is overwhelming public health systems, preventing the care that dengue patients need. In both cases, the result is more suffering.

Could the pandemic be a turning point in the fight against dengue?

So, from one vantage point, we have an opportunity now. We can slog through this and get back to what we were doing before: a relatively anaemic fight against dengue globally. Or we can re-think our approach entirely; learning from what we’ve seen is possible when the international community collaborates (or not in some instances) to respond to a pandemic.

How can we harness what is being done for COVID-19 into a renewed effort to eliminate dengue?

We need to view COVID-19 and dengue – and malaria and other vector-borne diseases and health challenges – as interrelated. Progress on one front helps us make progress on others. We have to use this as an opportunity to make the global fight against dengue stronger and smarter, because it relates directly to how our public health systems are capable of managing the next big shock.

And that’s where I believe technologies such as ours can play a significant role. We will accelerate efforts in what, no doubt, will be a very different era where we will have to fight harder for resources, energy and attention.

Are dengue outbreaks increasing with COVID-19?

We know that Aedes aegypti mosquitoes thrive in domestic environments. One could imagine that dengue rates could rise as a result of lockdowns, particularly in dense urban areas, but we have yet to see data. Many cities are struggling to sustain vector control operations, and in some, vector control operations aren’t a thing.

We know anecdotally from our partners in Brazil, for example, that COVID-19 is overburdening cities and they need to ensure dengue outbreaks do not tax the health system further. They are attempting to expand efforts to fight dengue and are eager for us to finalise our 2nd generation Friendly™ solution to deploy at scale. Stay tuned on that front!

How critical will new technologies be as we fight against dengue against the backdrop of COVID-19? We’d love to hear your thoughts.

New dengue-fighting technologies for 2020

Antibodies. Genes. Bacteria. Artificial Intelligence. Satellites. Drones. New technologies are being deployed in new ways in the fight against dengue. While some are halting the vector in its tracks, others are tackling the dengue virus. Some are already in use; others are experimental. Let’s look at the dengue-fighting technology we can expect to see as we take on this killer virus – and its vector – in 2020.

New approaches based on genes

Our first dengue-fighting technology stops Aedes aegypti mosquitoes infected with the dengue virus from transmitting the virus to humans. Researchers in UC San Diego have transferred genes from the human immune system to pass immunity to all four dengue serotypes to Aedes mosquitoes. Female Aedes are synthetically engineered to have the antibody, which is activated by feeding on blood. The antibody prevents the dengue virus replicating throughout her body, ensuring she can’t pass it on. A gene dissemination system could spread the antibody to wild mosquito populations.

Elsewhere, an article in Science Daily explores our second dengue-fighting technology: gene therapy that can prevent mosquitoes reaching maturity. The technique prevents a steroid hormone that insects require for sexual maturity from reaching the brain. The approach could limit mosquito maturity to somewhere between infancy and adulthood. They would die before they reproduce and remain in or on their food source rather than wander to feed.

The sterile insect technique bites back

Last September, the International Atomic Energy Agency (IAEA) announced a US$ 3.96 million grant from the US Government to overcome some of the challenges of sterile insect technique (SIT). SIT involves rearing, sterilising then releasing large numbers of a target pest into wild populations to suppress their number. It requires the females reared to be separated from the males, which is not easy. The IAEA is rearing Aedes mosquitoes and sterilising them using radiation; this short animation explains how it works. The grant will allow it to develop new ways of separating males from females.

Other projects are also using similar techniques to suppress mosquito populations – including Debug, a project backed by Verily, a subsidiary of Alphabet Inc, which is Google’s parent company. Debug is using the Wolbachia bacteria technique developed by the World Mosquito Program to prevent female Aedes mosquitoes transmitting dengue; it too must rear large numbers of female and release them into wild populations to propagate.

Verily’s dengue-fighting technology, according to the news pages of Harvard Chan, sorts the mosquitoes by sex and optimises releases. The project website describes how sensors, algorithms and innovative engineering sort males from females efficiently using unique aspects of mosquito biology. Verily, it says, is also “building software and monitoring tools to guide each release” and “developing new sensors, traps and software to determine better which areas need to be treated and re-treated”.

Artificial intelligence gets real

A not-for-profit called ‘the Program’ that has recently been awarded a Microsoft AI for Earth grant is also combining Wolbachia with software to optimise releases. An article on the Microsoft website describes how the global research consortium is combining Wolbachia with “data, machine learning, artificial intelligence (AI) and the computation power of the cloud” to create a predictive deep learning model that will determine the best release points “anywhere in the world”.

Another project has turned to AI – to develop real-time risk maps for public-health bodies. ZDNet describes how the Institute of Agrifood Research and Technology (IRTA) in Catalonia, Spain has combined AI, sensors and satellite communications for vector surveillance. Together these dengue-fighting technologies automatically classify mosquitoes – which are caught in traps – according to species, sex, age and their potential for causing infection. The Vectrack system, as it is known, is funded by the EU Horizon 2020 programme.

Flying high

Maps are not only being used to assess risk but also guide preventative measures, such as eliminating mosquito-breeding sites. Dengue MOsquito Simulation from Satellites (D-MOSS), reports Space for Development, issues alerts for dengue to mobilise local communities while assessing risk under future climate and land‑use change scenarios. Funded by the UK Space Agency’s International Partnership Programme, the project integrates and analyses Earth observation datasets, weather forecasts and a model of water flow to build its maps.

Scientists at Arthur C Clarke Institute for Modern Technologies (ACCIMT) in Sri Lanka are using drones to contain dengue outbreaks, according to local media. The dengue-fighting technology is helping the authorities observe, photograph and even fumigate sites where stagnant water could be found. The ACCIMT website describes a project at the Space Technologies & Applications Division using geographic information systems GIS for niche modelling of dengue fever.

Tackling dengue back down on Earth

Back down to Earth, a Malaysian start-up is tricking Aedes mosquitoes into eating their own eggs. Vulcan Post describes how MN Empire has developed a ‘solar-powered mosquito eliminator’. The dengue-fighting device attracts mosquitoes and encourages them to lay their eggs inside containers filled with a liquid that ensures they never hatch. The female mosquitoes then spread the “organic, odourless and completely safe” solution to other sources of stagnant water.

Meanwhile, EurekAlert! highlights a targeted biological approach that kills mosquito larvae using natural bacteria delivered by the male mosquito while mating. The ‘Trojan Mosquito’ is being developed by a team of undergraduate student researchers at Ben-Gurion University of the Negev in Israel. They tweaked the male mosquito’s gut microbiome to express BTI (Bacillus Thuringiensis Israelensis), which produces a toxin that only kills mosquito larvae. The males mate with females, who transfer the bacteria onto their eggs. The larvae die soon after birth.

In Australia, Bio-Gene Technology has developed an alternative insecticide. Based on a natural compound found in Australia’s eucalypt trees, Flavocide is rapidly toxic to adult mosquitoes. An article in Small Caps describes how Flavocide is a potential new product to address the diminishing effectiveness of current insecticides.

Our final dengue-fighting technology is a skin cream that could protect against dengue. Science Translational Medicine has published a paper on a topical treatment that, when tested on mice recently infected by dengue, elicited an immune reaction at the site of a mosquito bite that restricted the dengue virus’ ability to replicate.

We’d love to hear about your innovations and how they are helping in the fight against dengue. Whether you’re halting the virus in its tracks or eliminating Aedes populations, we’re interested to know more.

Ten top tips to stop dengue in its tracks

Globally, dengue kills around 100 people every day. While the world’s media focuses on combatting coronavirus, we must ensure the lack of attention doesn’t allow dengue to win through. If you live in one of the more than 125 at-risk countries, there are simple steps you can take to help protect your home and your family against the virus. Before we look at those, let’s start by quickly reminding ourselves how Aedes mosquitoes live and breed, and how the dengue virus spreads.   

Aedes aegypti mosquitoes – the primary dengue vector – live inside and outside the home. Their favourite breeding ground is containers with clear, stagnant water, such as old tyres, empty food cans, flower pots, plastic bottles or jars that collect rainwater. They lay their eggs in these. It then takes just eight days for the egg to hatch and the larvae to transform through the pupae stage to an adult mosquito.

You can catch dengue if an infected mosquito bites you. A mosquito becomes infected with dengue by biting an infected person. The parasite develops inside the mosquito during the next five to ten days. An infected mosquito can then pass the virus onto any person it bites. Aedes aegypti mosquitoes bite throughout the day, especially during early morning and late afternoon.

The most effective way to prevent dengue spreading is, therefore, to avoid mosquito bites and to stop mosquitoes breeding. These simple steps will help:

  1. Cover bare skin with loose clothing; mosquitoes can bite through tight-fitting clothes. Long sleeves, long pants, closed shoes and hats are ideal.
  2. Use insect repellants containing DEET, following the instructions on the label. Apply 30 minutes after sunscreen. Reapply after swimming or if you’re sweating a lot.
  3. Sleep under a mosquito net, ideally one that has been treated with insecticide.
  4. Fit fly screens on windows. And if you have an air-conditioner, use it instead of opening windows and doors.
  5. Use mosquito coils or electric insecticide vaporisers to kill any mosquitoes that do get inside. Always follow product instructions.
  6. Drain away standing water in containers such as buckets, tyres, bottles, jars and cans. Destroy and dispose of them if possible.
  7. Change the water in pet dishes, birdbaths, flowerpots and vases every day. Wash the containers out weekly with a brush or sponge to remove any mosquito eggs.
  8. Cover large cisterns and containers with a tight lid. If they don’t have a lid, cover with a mesh that has holes smaller than an adult mosquito.
  9. Put small fish, such as guppies, in large vessels with standing water that are difficult to drain; they like to eat mosquito larvae.
  10. If you get a fever, rest in a screened or air-conditioned room, or under a bed net. If you get bitten by a mosquito, you could pass your dengue on.

Do Aedes mosquitoes live in your neighbourhood? What are you doing to keep them at bay? How are you protecting yourself and your family from dengue?