Read why some of us are more attractive to mosquitoes than others

Always getting bitten? Here’s why some of us are more attractive to mosquitoes…

Why do mosquitoes love me so much?

Ever thought you are more attractive to mosquitoes than your companions? Are you always the one covered in bites? There is a scientific reason why. Researchers in Kenya have been investigating what makes victims attractive to mosquitoes. Their studies identified four groups of chemical compounds in body odor that could be used to develop more effective bait traps for controlling dengue and chikungunya.

Female mosquitoes need to feed on human blood; it provides the protein and iron she needs for her eggs. Studies have shown mosquitoes are attracted to the CO2 in our breath, and to physical cues such as heat and moisture, along with visual stimuli such as light, color, and form.

While other studies have shown body odor also has a role to play, Dr. Eunice Anyango Owino, Medical Entomologist at the School of Biological Sciences, University of Nairobi, wanted to find out more: “We wanted to test the entire body odor, not just the breath.”

Mosquitoes love our body odor

In their first study, Dr. Owino and her team compared commercially available bait traps with bait traps made from natural body odors. They used samples of body odor trapped in used socks and worn t-shirts.

“When we compared the body odor traps to the commercial versions, we found the mosquitoes were more attracted to the body odor traps,” said Dr. Owino. “Once we established this, we then analyzed the body odor and identified the most potent chemical compounds.”

To extract the body odor from the clothing, volunteers working with the team wore the socks and t-shirts for 18 hours before placing them in tightly sealed collection jars. The odors were then absorbed into special fibers using suction provided by a vacuum.

Chemicals identified

An analytical method known as gas chromatography-mass spectrometry (GC-MS) identified the chemical components in body odor. Another method, known as gas chromatography-electroantennographic detection (GC-EAD), identified which specific chemicals mosquitoes can pick up using their antenna.

“We found the mosquitoes are attracted to four groups of compounds: aldehydes, fatty acids, ketones, and alcohols,” said Dr. Owino. “These four major groups of compounds are also the main chemical compounds that make a human odor. It’s an evolutionary relationship between mosquitoes and their human hosts.”

While our body odor mainly comes from aldehydes and fatty acids, the exact mix of these chemical compounds varies between individuals – which is why some people are more attractive to mosquitoes than others.

Read about Dengue and ethnicity and learn who is most at risk.

The mix also changes across different points of our bodies. “Certain parts of the body are more or less attractive to the mosquito,” said Dr. Owino.

Building better bait traps

For their second study, the team studied the effectiveness of these compounds by placing them into baited traps. They found combining the compounds with carbon dioxide sharpened mosquitoes’ ability to pick up body odors.

“Our results suggest there are additional chemical compounds that could potentially be commercialized to attract mosquitoes, particularly Aedes aegypti,” said Dr. Owino. “This could lead to a technology being made from compounds from human body odors to lure and kill mosquitoes that spread the dengue and chikungunya viruses.”

With chemical compound mix and release rate critical to how mosquitoes react, future work will focus on optimizing these. The team will also try to identify other compounds in body odor that could also attract mosquitoes. Once the team has identified these, they will need to test them to see if they are also capable of being used as bait for mosquitoes.

“We aim to come up with a super bait for mosquitoes to control transmission of the dengue and chikungunya viruses,” said Dr. Owino. “I believe in a good bait that we can produce at a low price.”

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Dengue and ethnicity: who is most at risk?

Dengue is now endemic in more than 100 countries across Africa, the Americas, the Eastern Mediterranean, South-East Asia, and the Western Pacific. Countries in the Americas, South-East Asia, and Western Pacific are most seriously affected, as the Dengue Health Map shows. Cases across these regions grew from 1.2 million in 2008 to more than 3.2 million in 2015, according to the World Health Organization. Could there be a link between dengue and ethnicity? Do people of African – or even European – descent have better natural protection against the virus?

The idea that skin color might influence dengue risk is nothing new. It’s more than a century since dark-skinned Cubans were first reported to be significantly less prone to catching the virus than their light-skinned counterparts. Decades later, during the Cuban dengue epidemics of 1981 and 2001, dengue and ethnicity were again seen as being linked.

“Cubans with darker skin most probably have African heritage and Cubans with lighter skin most probably have a European background,” says Dr. Luisa Pereira, Population Geneticist at IPATIMUP (Instituto de Patologia e Imunologia Molecular da Universidade do Porto). “Studies looking at genetic markers have confirmed that Cubans with African ancestry are less susceptible to severe dengue.”

Natural protection from severe dengue

Dr. Pereira is part of a team of scientists investigating whether our genes increase our risk of catching dengue and, if we do, make us more likely to develop the severe form of the disease. “Genetics is important in infections,” said Dr. Pereira. “Human genetics are important, along with virus genetics and mosquito genetics. Human genetics can affect how susceptible a population is to a virus; they can predispose some populations to dengue.”

With that in mind, Dr. Pereira collaborated with Cuban colleagues to study a population with two clear ancestral lines: African and European. Their research aimed to identify the genes involved. They found two: OSBPL10 and RXRA.

What’s more, they found that OSBPL10 and RXRA impact how lipids behave in our bodies. More importantly, these genes affect lipids differently in different dengue patients depending on whether they are of African or European heritage.

Knowing that lipids play an important part in infections in humans, they delved deeper. Dr. Pereira explains: “The dengue virus needs lipids to enter and multiply in the cell. Cubans of African ancestry have a natural adaption of the OSBPL10 and RXRA genes that limit the virus’ ability to enter and replicate inside cells, protecting them from developing severe dengue.”

Who’s most at risk from dengue?

The team next took their research to Thailand where Chinese, Indian and Southeast Asian ancestries are all represented within the population. “In Thailand, we found there were different genes associated with different forms of dengue,” said Dr. Pereira.

They found four genes (CHST10, AHRR, PPP2R5E, and GRIP1) associated with dengue fever. These genes affect how cells in our body signal others to seek out and destroy foreign bodies such as viruses (the ‘xenobiotic metabolism signaling pathway’ in technical terms). “These four genes probably also help the dengue virus to enter the cells,” says Dr. Pereira.

They found another two genes (the newly discovered PLCB4 and the previously known PLCE1) associated with the inflammation in blood vessels experienced with severe dengue. “These two genes cause the blood vessels to become more permeable, causing the hemorrhages you get with dengue shock syndrome,” says Dr. Pereira.

Dengue and ethnicity: genes influence susceptibility

Looking into the link between these genes and the risk of catching dengue and developing severe dengue, the research team determined:

People of Southeast and Northeast Asian ancestry are highly susceptible to both dengue and severe dengue.
People of African ancestry are intermediately protected against dengue fever and best protected against severe dengue.
People of European ancestry are the best protected against dengue fever but the most susceptible to severe dengue.

Prioritising dengue campaigns

With no dengue treatment available and dengue in Europe likely in the near future, organizations need to know where they need to vaccinate populations or educate populations about dengue prevention and control. “By understanding which populations are most at risk from dengue, organizations such as the World Health Organization can decide where campaigns are needed the most,” says Dr. Pereira.

The team is currently working in the lab, running tests to prove that the genes they have identified are the human genes involved in dengue. They are also running tests to understand the mechanisms involved. Understanding how our bodies naturally protect us from dengue and severe dengue is an important first stage in identifying new treatments for dengue, and new drugs to treat this disease.

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Dengue in Europe: the threat is real

Before 1970, only nine countries had experienced severe dengue epidemics. The disease is now endemic in more than 100 countries, as The World Health Organization (WHO) confirms. It can be found in the Americas, South-East Asia and Western Pacific, Africa and the Eastern Mediterranean, with the first three of those regions most seriously affected. But what about dengue in Europe?

Europe is no stranger to dengue; Greece suffered a major outbreak in 1927. The first reports of local transmission of dengue in Europe in recent times came in 2010, from France and Croatia. That year, three other European countries detected imported cases of the virus.

Did Cristiano Ronaldo start a dengue outbreak?

Just two years later, in 2012, the Madeira islands of Portugal found themselves in the midst the first outbreak of dengue in Europe since 1927. Mainland Portugal, along with ten other European countries, also detected imported cases of dengue in 2012.

Dengue is a vector-borne disease, primarily spread by Aedes aegypti mosquitoes. The dengue outbreaks in France and Croatia in 2010, however, were caused by its secondary and less potent vector, Aedes albopictus (commonly known as the Asian tiger mosquito).

Dengue in Europe: understanding vectorial capacity

As with all vector-borne diseases, the dynamics of dengue transmission are extremely complex. Many of the factors that affect it are linked to the mosquitoes’ ability to survive, thrive and spread the virus in a particular territory.

“For a dengue outbreak to occur in Europe, there must be sufficient Aedes vectors, and the dengue virus must be present,” says Dr. Jing Helmersson, an epidemiologist at Umea University in Sweden. “There also needs to be enough susceptible humans and a suitable environment, with climate the main factor.”

Dr. Jing Helmersson is interested in the link between climate and the potential for dengue transmission. She drew on her mathematical background to develop mathematical models that predict ‘temperature-dependant vectorial capacity’ and estimate the likelihood of dengue epidemics.

In other words, she built a model to explore whether the temperature in parts of Europe would be sufficient for Aedes aegypti mosquitoes to become established and then if the dengue virus was introduced, spread by both Aedes aegypti and Aedes albopictus.

Aedes making itself at home

Until recently, Aedes aegypti could only be found in three regions of Europe: small coastal areas of the Black Sea in Georgia and southwestern portions of Russia, in addition to the Madeira Islands of Portugal. However, the European Centre for Disease Prevention and Control (ECDC) reports new settlements of Aedes aegypti on the island of Fuerteventura in the Canary Islands. It adds “The species is now spreading to the west along the Black Sea coast of Turkey.”

Map from ECDC showing dengue in Europe in 2018

Image via ECDC

And we should also not forget Aedes albopictus. ECDC reports sightings of this secondary dengue vector across more than 25 European countries, primarily around the Mediterranean.

map showing the distribution on dengue in Europe.

Image via the ECDC

The Paris Agreement

Dr. Helmersson has linked her research into the likelihood of dengue outbreaks in Europe to the Paris Agreement, a treaty on greenhouse gas emission reductions agreed at the 2015 Paris Climate Conference. The agreement sets out a global action plan to limit global warming to well below 2°C to avoid dangerous climate change. She looks at different scenarios, each with a different level of greenhouse gas emissions and different level of global warming.

Her best-case scenario assumes we will achieve the greenhouse gas levels set in the Paris Agreement. In it, annual greenhouse gas emission peaks during 2010-2020 and declines substantially after that, limiting global warming to below 2°C relative to the pre-industrial level. This scenario predicts Aedes aegypti could potentially cause a dengue outbreak in Nice and Paris, in addition to Málaga, Athens, and Rome, where Aedes aegypti could cause a dengue outbreak today if the mosquito is abundant. In this scenario, the region where Aedes albopictus could potentially cause an outbreak of dengue (if all the necessary conditions coincide and the dengue virus circulates over a period of time) is unlikely to spread further afield from where it is today: Málaga, Athens, and Rome.

Her worst-case scenario would occur if we don’t do anything to address greenhouse gas emissions and they – along with temperatures – continue to rise throughout this century. In this scenario, alarmingly the region where mosquitoes could potentially cause a dengue outbreak (if both mosquitoes are abundant and the virus is introduced) spreads as far north as Stockholm for Aedes aegypti and as far north as Berlin for Aedes albopictus.

Healthier lifestyles

In a nutshell, Dr. Henlmersson’s research clearly shows there is a substantial risk for dengue in Europe by the end of the century if we don’t do something to reduce greenhouse gases.

With a longstanding interest in health, Dr. Helmersson says adopting a healthier lifestyle is key to reducing greenhouse gas emissions and avoiding dangerous climate change: “We can all contribute to climate change. We can eat less meat and walk or cycle instead of taking the gasoline car.”

In terms of what Europe needs to do as the threat of dengue rises, Dr. Helmersson advocates dengue surveillance combined with chemical-free vector control, such as reducing mosquito breeding sites – with governments, local authorities and individuals all playing their part.

If you’ve been unfortunate enough to experience dengue while traveling in Europe, we’d love to hear your story.

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Our priorities: set by experts

The Break Dengue Advisory Board met in Brussels in February to set our priorities for 2018. This diverse group of experts, drawn from academia and industry, joined our senior executive team to review progress on our various projects and chart the way forward.

Among the highlights for the year will be initiatives to advance awareness of our Dengue Track platform, increase share of voice in online dengue discussion, foster an online global community of dengue experts, and create web content that pulls together original information from across the dengue community.

As a four-year-old start-up, Break Dengue is enormously grateful to the external advisors and partners who share their insights and expertise as we continue to advance this exciting project.

Growing our share of voice in the Philippines

Recent challenges in dengue prevention programs in the Philippines have provided an opportunity to demonstrate the power of partnerships in public debate about health. The online space can be a particularly noising place to have meaningful conversations – especially in times of crisis.

For Break Dengue, crises can be opportunities. We used our networking power and social media tools to analyse the dengue-related topics the public is searching for online. Taking the Philippines as a case study, we found that public discussion on dengue is unique: the search terms trending there are different to those dominating online debate globally. In some countries the public tends to search for facts about dengue, there has been a rise in negative search terms in the Philippines where queries about the vaccine have arisen.

In response, we can craft web content and social media messages that will resonate. Rather than simply telling people what we want them to know, we can begin by producing material that chimes with the topics close to their heart. This provides opportunities to bring clarity and credibility, by bringing the voices of experts to the fore.

The beauty of online media is that results are measurable. Our campaign reached 450,000 people and we observed a shift in negative sentiment during the first three weeks of our initiative. We also recorded almost 20,000 engagements sparked by our online activities.

The next step is to take what we learned from this case study and develop a preventive approach for other regions at risk of outbreaks of negative sentiment. Talk to us if you would like to try this approach in your region.

Science meets art at ISNTD Fest

Innovative approaches to communicating scientific information were in the spotlight at this year’s ISNTD Fest in London. Hosted at the Wellcome Trust by the International Society for Neglected Tropical Diseases (ISNTD), long-standing partners of Break Dengue, it was an opportunity to bring together an eclectic and diverse group of researchers, artists, data experts, and musicians. Participants use data, art, and humor to communicate around some of the biggest problems in global health.

#ISNTDfestival Magic Glasses helps to fight parasite infections in school children pic.twitter.com/RR7RSGVl25

— KasiaHP (@Kasia_HP) March 27, 2018

Break Dengue Program Manager, Aaron Hoyles, was on hand showcase some of the innovations we have been pioneering with partners recently. In addition to the Dengue Prize for community action, the AIESEC exchange partnership in Brazil, and the Dengue Lab expert network, Aaron explained the eBarometer tool which uses big data to crowdsource disease surveillance.

How do you build strong communities in global health? Aaron Hoyles from @BreakDengue gives us insights from digital tools, and speaks about the eBarometer at #ISNTDFestival. Find out more here https://t.co/DQ0jD4pIUK pic.twitter.com/i7RkBxkK2z

— ISNTD (@ISNTD_Press) March 27, 2018

Developed in collaboration with researchers at Harvard University and Boston Children’s Hospital, the system turns big data and analytics into an innovative, actionable, vector-borne disease surveillance and alert system.

For Aaron, the March festival was a chance to meet current partners, engage with new contacts, and learn about some ground-breaking approaches to problem-solving in health. “The breadth of projects shared at ISTND Fest, and the variety of backgrounds from which it draws participants, make it a real one-off,” he says. “I was delighted to take the opportunity to share our work and to get such a positive response.”

Mosquito gut fungi: How a common fungus could help us beat the dengue virus

We recently looked at how environmental factors such as climate change can affect how the dengue virus thrives in the Aedes aegypti mosquito and the mosquito’s ability to transmit the disease. Researchers at Johns Hopkins University Bloomberg School of Public Health in Maryland in the U.S. have found another environmental factor that can influence the virus within the mosquito: a common species of fungus. We spoke with Professor George Dimopoulos about the Talaromyces fungus that lives in the Aedes aegypti mosquitoes’ gut. He explained how it makes the insects more susceptible to dengue infection – and could potentially improve their ability to transmit the disease.

“This common fungus makes the mosquito more susceptible to infection by the dengue virus and could, potentially, also influence the mosquito’s ability to transmit the disease,” says George Dimopoulos, Ph.D., Professor in the Bloomberg School’s Department of Molecular Microbiology and Immunology.

Fungi living in mosquitoes

Professor Dimopoulos and his team have known for some time that mosquito microbiota – the bacteria and fungi that live in mosquitoes – influence how susceptible the mosquito is to infection from a pathogen such as the dengue virus. Laboratory studies had also led them to suspect that microbiota could influence how well a mosquito could transmit that pathogen.

Image of the top of the Talaromyces fungus.

The Talaromyces fungus (top) growing in the lab. Image courtesy of Johns Hopkins University Bloomberg School of Public Health

“We needed to go out in the field and see what kind of bacteria and fungi are found naturally in wild mosquitoes and whether they influence mosquito’s ability to get infected with, for example, the malaria parasite or the dengue virus,” says Professor Dimopoulos.

Read the latest update on the dengue fever vaccine pipeline

The team set out on a field trip to bring wild mosquitoes back to the lab: Anopheles mosquitoes that transmit malaria along with Aedes aegypti. They fed fungi to the wild mosquitoes. “We noticed that certain fungi, when fed to a mosquito, would make it more susceptible to malaria or dengue fever infection,” says Professor Dimopoulos. “A penicillium fungus made it more susceptible to malaria while a Talaromyces fungus made it more susceptible to dengue.”

So, what was going on?

The team wanted to find out whether the mosquito’s gut needed the whole Talaromyces fungus or something the fungus was producing and secreting to make it more susceptible. They made a culture of the fungus and filtered it to leave the molecules secreted by the fungus. “When we fed the mosquitoes on this filtrate, they still became more susceptible to the dengue virus infection,” says Professor Dimopoulos.

They ran another experiment. It proved that the fungus was changing something in the mosquito. “The fungus wasn’t making the virus replicate quicker or anything like that, it was just making the mosquito more susceptible to infection,” says Professor Dimopoulos.

Digesting the virus?

By comparing gene expression (the process by that converts DNA instructions into something the body uses) between mosquitoes exposed to this fungus filtrate with those not, the team found that many of the digestive enzymes in the mosquito’s gut were produced in smaller quantities when this filtrate was present.

“The fungus seemed to be influencing the mosquitoes’ digestive system in some way,” says Professor Dimopoulos. “It was slightly impairing the mosquito’s ability to digest the blood. We also noticed that the mosquitoes fed on the filtrate did not produce as many eggs. Egg production is highly dependent on blood digestion.”

The team then turned their focus to trypsins, enzymes that digest proteins. When they removed some trypsins from a mosquito’s gut and then infected the mosquito with the dengue virus, the mosquito becomes more susceptible to dengue virus infection.

Image of the bottom of the Talaromyces fungus.

The Talaromyces fungus (bottom) growing in the lab. Image courtesy of Johns Hopkins University Bloomberg School of Public Health

“We think that these particular trypsins are, in some way, impairing the virus’ ability to infect the gut,” says Professor Dimopoulos. “They could be digesting something on the surface of the virus, or there could be some other mechanism. It’s not entirely clear.”

More studies needed

While all these experiments took place in the lab, the Talaromyces fungus occurs naturally – and indeed is commonly found – in rural areas in most South-Eastern Asian countries.

“We know these fungi are common in nature and wild mosquitoes are exposed to them,” says Professor Dimopoulos, “but it is very difficult to determine whether that natural exposure to the fungi in the field influences mosquitoes’ susceptibility to the dengue virus and their ability to transmit the virus.”

Read how Wolbachia-infected mosquitoes are reducing dengue outbreaks

Understanding that influence may one day part of a larger study to explore the impact of various microbiota on mosquitoes in the wild. If a correlation could be proven, it would suggest that these fungi do play a role in regulating Aedes aegypti mosquitoes’ susceptibility to the dengue virus and perhaps also transmission.

If a link could one day be proven, the knowledge gained could be used to develop a new tool to fight the dengue virus, something that would prevent dengue from spreading. If it could be shown that removing the fungi in the field would have an impact on dengue transmission, for instance, we could one day be using a fungicide to kill off Talaromyces as well as – or even instead of – spraying insecticide to kill mosquitoes.

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Dengue fever vaccine pipeline update: the latest progress on protection against the virus

The dengue fever vaccine pipeline is advancing and as candidates approach clinical trials, we decided to take a closer look at the vaccines that could ease the burden of this disease.

The world’s first dengue vaccine, Dengvaxia, was licensed by Sanofi Pasteur in 2015. It is available in more than a dozen countries and can prevent all four serotypes of dengue fever. (See the World Health Organisation’s Q&A on the dengue vaccine.)

While Dengvaxia was the first vaccine against dengue fever, there are several others at various stages of development. We last looked at the dengue vaccine pipeline back in April of 2017.

Since that time, progress has continued to develop at a steady pace. Amongst other things, Takeda and the WRAIR, GSK & Fiocruz collaboration have recently published data; Takeda has also initiated a second phase III trial, and Panacea Biotec is expecting to start a clinical trial sometime later this year.

Let’s examine the status of the dengue vaccine candidates currently in or approaching clinical trials – all of which, incidentally, target all four dengue serotypes:

Phase III trials

TDV

Takeda’s TDV dengue vaccine is a good place to start. Arguably the most advanced vaccine candidate currently in the pipeline, TDV is a live-attenuated and recombinant vaccine, meaning it is made up of a weakened live dengue virus and produced through recombinant DNA technology. It is intended to be given in two doses, 90 days apart.

Takeda began its phase III trials of TDV began back in September 2016. The first of these trials, a large 5-year study in Asia and Latin America, aims to test both how well the vaccine prevents dengue fever and the long-term side effects of the vaccine in children. It began a second phase III trial in December 2017. This 12-month study is testing TDV on 400 healthy adolescents in non-endemic areas in Mexico.

In addition, Takeda recently published the interim data from its ongoing phase II trial of TDV on children in Asia and Latin America.

According to the published results, TDV is safe and produces an immune response in children aged 2-17 years, irrespective of previous exposure to dengue – validating the initiation of its phase III trials.

TV003/TV005

Developed by the US-government funded NIAID (part of the United States National Institutes of Health (US NIH)), TV005 and TV003 are variations of the same live-attenuated and recombinant vaccine, except that the former has ten times more dengue serotype 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 February 2016, Instituto Butantan began a large phase III community-based trial on both children and adults in urban areas with dengue transmission across Brazil.

Phase II trials

TV003/TV005

NIAID is also sponsoring a clinical trial of TV003/TV005 in countries such as Thailand and Bangladesh. The on-going phase II trial of TV003 in Thailand is expected to complete in August, while the phase II trial of TV005 in Bangladesh is not expected to complete until 2020.

According to First World Pharma, Panacea Biotec has secured permission to conduct phase I/II trials in India, with trials expected to start in 2018. Other manufacturers are still in the preclinical phase.

TDENV-PIV

The vaccine candidate TDENV-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.

Its on-going phase II trial on 140 adults in the U.S. is helping it further evaluate and refine TDENV-PIV. The collaboration recently published results from its phase I trial of TDENV-PIV in the U.S. but has not yet published results from its phase I trial of the vaccine in Puerto Rico

GSK is developing its DPIV vaccine candidate, from the knowledge gained from this collaboration. DPIV has not yet reached clinical trials.

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’.

Also in phase, I, the U.S. 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.

Dengue fever vaccine pipeline: other evaluations

In addition to the clinical trials mentioned above, other trials are testing vaccines in combination to glean more information on how our bodies respond to dengue infection and vaccines, along with how the vaccines complement each other.

First, WRAIR is combining two dengue vaccines using a ‘prime-boost strategy’ that primes the body’s immune system with a first vaccine before boosting its immune response with a second. Its trial to test TDENV-PIV with an adjuvant in combination with TDENV-LAV was withdrawn in April 2017 because it wasn’t moving forward. TDENV-PIV is a purified inactivated vaccine while TDENV-LAV is a live attenuated vaccine. WRAIR is, however, currently recruiting for a new phase I study to test TDENV-PIV as a prime vaccine in combination with a TDENV-LAV booster. The study will compare different dosing schedules, where the booster is given 90 or 180 days after the main vaccine.

Second, a collaboration between NIAID and Merck has tested a combination of dengue vaccine candidates TV005 and V180 in a phase I trial using a prime-boost strategy.

Third, Takeda is expected to begin a phase III trial in February, testing TDV alongside a Yellow Fever vaccine known as YF-17D.

Pre-clinical developments

One final development worth mentioning, The Hindu has reported that a collaboration between The International Centre for Genetic Biotechnology (ICGEB) and Sun Pharma is also developing a dengue vaccine. DSV4, as it is known, is intended to be administered at in three doses, each a month apart. The collaboration is expected to begin phase I trials in 2020.

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:

http://www.who.int/research-observatory/monitoring/processes/health_products/en/

http://www.who.int/immunization/research/vaccine_pipeline_tracker_spreadsheet/en/

https://www.sciencedirect.com/science/article/pii/S0264410X17311647

Dengue in Acre: how the virus took hold in a rural Brazilian state

Once the only state in Brazil to be free from dengue, investments aimed at developing rural Acre have, unfortunately, allowed Aedes aegypti to move in and thrive. Together, the movement of people, development projects, and unplanned urbanization have created the conditions for the dengue vector to spread and, establish breeding sites in the Amazonian region. Dengue in Acre has now reached epidemic proportions.

Turn the clock back 20 years to the mid-1990s. The Aedes aegypti mosquito is well-established across Brazil, having reinvaded the country since the 1970s. Dengue epidemics are commonplace across many Brazilian states and have been since the 1980s.

Increasing movement of people between growing Brazilian cities had helped the mosquito to spread. Immature and adult mosquitoes simply hitched a ride on lorries, trains, cars, buses and even planes. The virus hitched a ride too – on both infected mosquitoes and humans.

Meanwhile, fast-growing cities were providing the habitat for mosquito populations to grow. “An increased flow of people into Brazilian cities started in the 1970s,” says Raquel Martins Lana, Ph.D. in Epidemiology, Oswaldo Cruz Foundation. “The cities were not able to guarantee the infrastructure this influx needed, which led to poor infrastructure, low sanitation rates, water supply and garbage collection – and an increasing number of breeding sites for the mosquito.”

Acre, Brazil Photo courtesy of Raquel Martins Lana

Raquel M. Lana together with Marcelo F. C. Gomes (Oswaldo Cruz Foundation) were the primary researchers on a study exploring how “The introduction of dengue follows transportation infrastructure changes in the state of Acre, Brazil”. The project was led by Cláudia T. Codeço (Oswaldo Cruz Foundation), with the collaboration of Nildimar A. Honório (Oswaldo Cruz Foundation) and Tiago F. M. Lima (Federal University of Ouro Preto).

Acre: the final frontier

Development programs had yet to reach Acre. Lying relatively close to the Pacific Ocean and bordering Peru and Bolivia, this Amazon rainforest state was one of the last frontiers of development in Brazil.

Acre has great cultural diversity, with several indigenous peoples. In 1991 it boasted a population of just over 400,000 – a figure that has now almost doubled. Today, Acre has 18,240 indigenous people who inhabit 210 villages distributed across the state. Their indigenous lands make up 2,390,112 ha of 7,523,699 ha of protected natural areas – around 45% of the state.

“In the 1990s the state still had a relatively small population along with low urbanization and low industrialization up to the end of the last century,” says Raquel.

But Acre has seen significant investment and development since the turn of the century. Settlements and agriculture have emerged in previously unoccupied lands. “The population of some of Acre’s municipalities doubled between 2000 and 2010,” says Raquel. “And the percentage of people living in urban areas increased in 20 of Acre’s 22 municipalities during that time.”

In addition to allowing the change of land use, investment also allowed Acre to develop its major roads. The relatively recently completed Transoceanic Highway, for instance, channels Brazilian agricultural production via Ocean Pacific while the much-improved BR-364 highway links Acre to the neighboring state of Rondônia.

The arrival of dengue in Acre

It was during this period that the dengue virus was introduced into and spread across the state, almost 20 years after its introduction and establishment in Brazil.

While the first Aedes aegypti mosquito reached Acre in 1995, most probably arriving by road, Acre didn’t report its first cases of dengue until four years later, in 1999. “Acre’s first three cases of dengue are considered imported cases, which is also indicative of the importance of human travel to the introduction of the virus,” says Raquel.

Acre reported its first autochthonous dengue case in Rio Branco, the state’s capital city and the main destination for travelers to the state, in 2000. Cases of dengue in Acre have grown rapidly since 2000. Today, incidence rates follow a similar pattern to the neighboring states of Amazonas and Rondônia and are consistent with endemic regions:

“The first dengue epidemic occurred in Rio Branco,” says Raquel. “Municipalities connected to the capital city registering epidemics sooner than more distant municipalities, many of which do not register autochthonous (local) dengue cases until the end of our study, in 2015.”

Dengue in Acre

Findings from the new study, published in PLOS Neglected Tropical Diseases, suggest that the movement of people, development projects, and unplanned urbanization have combined to create the conditions needed for Aedes aegypti to establish itself in Acre. Raquel explains: “The mosquito had the means of transportation and favorable environmental conditions for introduction and fixation.

“The Aedes aegypti mosquito has a limited flight range, something between 50 to 200 meters. Therefore, it probably arrived in the state by road and then spread to the municipalities in a passive way, such as in cargo vehicles, passenger cars, aircraft, and containers.”

After all, Acre had improved its major roads, along with airborne access to the state; this had increased the number of trucks, containers and other vehicles moving around the state. Mosquitoes simply hop aboard as stowaways, taking advantage of the free ride from an infested area to an uninfected one.

Brazil port chief struck down by dengue in Paranaguá

Meanwhile, Acre’s many construction sites, unplanned urbanization (urbanization without improving the coverage of general services, such as garbage collection, water supply, and sanitary sewage) and population growth, not only provided ideal breeding sites for mosquitoes but also obstructed mosquito control.

Image: mosquito breeding grounds, Acre, Brazil.

Photo courtesy of Raquel Martins Lana

Despite the development programs, most of the municipalities in Acre are more rural than urban. These also have the conditions Aedes aegypti needs to establish itself once it reaches a village.

A stark warning

The study reconstructed how dengue most likely arrived and took hold into Acre, focusing on changes in infrastructure that improved access to cities, increasing the flow of people and urbanization. In essence, the study’s findings suggest that the development programs played a central role in the spread and establishment of the Aedes aegypti mosquito and dengue in Acre.

“Nevertheless, we should not stand in the way of development or view those projects as ultimately bad for the state,” says Raquel. “It is a strong warning against unplanned side-effects of such endeavors. These should be taken into account in the future to prevent them from happening.”

Image showing breeding grounds for Aedes mosquitoes in Acre, Brazil.

Photo courtesy of Raquel Martins Lana

“Our findings highlight the importance of establishing protocols within development projects that take into account the possible impacts on the ecosystem, so contractors take action to prevent the invasion of new vectors and their associated diseases.”

Do you have any stories about how you stopped dengue from invading your community? We’d love to hear what action you took.

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Dengue Track

Spotlight on new treatments for dengue

We’ve talked a lot recently about the dengue vaccine, but treatments for dengue have also been making significant progress over recent years. Let’s take a brief look at three treatments for dengue, each at a different stage of development.

NGI-1: inhibiting access to resources

Researchers at the Stanford University School of Medicine are in the midst of developing a novel treatment for dengue that could potentially also work against other flaviviruses – a family of viruses that includes the West Nile virus, yellow fever, and Zika as well as dengue.

According to a report published on the school’s website, “The approach, rather than killing the viruses directly, is akin to cutting off a crime family’s bank accounts. It revolves around inhibiting access to a complex of proteins in mammalian cells on which the viruses rely when they invade.”

So, how does it do that?

Simply put, the treatment stops the body’s cells feeding sugars to the proteins that the virus relies on to multiply and invade the body. When researchers grew cells that didn’t have this mechanism, they found the virus was unable to multiply in those cells.

After this discovery, the Stanford team teamed up with another group of researchers, this time from Yale School of Medicine. The Yale team had developed a drug, NGI-1, that blocks this mechanism in human cells.

The researchers saw a 99 percent decrease in infection when they treated dengue-infected cells with NGI-1 immediately after initial infection and an 80 percent decrease when they administered the treatment after 24 hours, according to an article in Medical Xpress. The article also reveals that the researchers have shown that the treatment could potentially treat “all four dengue types and multiple strains of Zika, as well as against West Nile and yellow fever virus.”

The newsfeed on Yale’s website reports, “The research team found that while NGI-1 restricted viral activity, it did not affect other cell functions, which suggests a low risk of toxicity or side effects.”

Next steps focus on improving the treatment further and extending testing.

VIS513: lowering viremia levels

US-based Visterra has identified an antibody that can neutralize all four dengue serotypes. The company hopes VIS513, as this treatment for dengue is known, will not only reduce the levels of virus in circulation but also prevent severe dengue and reduce platelet loss.

VIS513 is a monoclonal antibody, which means it can recognize and find a specific protein on the virus. Simplifying an explanation in Science Direct, Visterra believes the antibody will reduce the amount of virus circulating in the blood – or levels of viremia if you want to get technical – by binding to one of the virus’ proteins.

Researchers have found that people with severe dengue have high levels of the virus circulating in their blood in the early stages of the illness than those with uncomplicated dengue. Visterra, therefore, believes “lowering viremia in the early phase of illness could reduce the risk of severe dengue”, and pre-clinical trials have shown the candidate drug does protect animals against the virus.

Visterra is developing VIS513 further in collaboration with the Serum Institute of India Private Limited. SIIPL is expected to initiate clinical trials later this year and then manufacture, obtain regulatory approval for and commercialize VIS513 around the world, except for in North America and the EU.

If all goes well, we could potentially see this treatment for dengue entering clinics in 2018.

GBV006: combining therapies

Globavir Biosciences, Inc. has created a proprietary compound by combining two oral drugs that are already approved. A Globavir corporate presentation reveals that GBV006 combines GBV001 and GV002, two drugs that have been shown to be very effective in treating Chikungunya. Like NGI-1, GBV006 targets processes in the body’s cells.

According to PR Newswire, the compound is “based on research carried out at Stanford University School of Medicine.”

While there is little information on how the compound works or its components work, the corporate presentation does show that early clinical trials planned for Q2 2018 will test how safe and how tolerable the drug is, while taking an early look at how well it works. Trials planned for Q2 2019 will establish how well it works; a blind trial will compare the drug against a placebo. The next step, after these evaluations, will be gaining approval in Singapore.

We hope you found this taster of the many treatments for dengue currently under development around the world today interesting. We’d love to hear about any novel treatments for dengue you might be aware of.