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Scientists are Vaccinating Mosquitoes to Fight Dengue

Would you let scientists release bacteria-infected mosquitoes in your backyard?

Photo by Drew Hays on Unsplash.

Nine years ago, the Portuguese Island of Madeira suffered the first outbreak of dengue with sustained transmission in the European Union since 1927. Between September of 2012 and March of 2013, the Atlantic Island reported over two thousand probable cases of dengue fever — half of which were confirmed by laboratory diagnosis. Fortunately, no deaths resulted from the outbreak, however it raised a dire warning of things to come.

Dengue fever is an infectious disease caused by the dengue virus. Its most common symptom, as the name implies, is high fever with body temperatures spiking up to 40ºC (104ºF). This is typically accompanied by skin rashes and flu-like symptoms (muscle and joint pains, headaches, nausea and vomiting), which normally last between two days and a full week. Dengue fever not only presents with a myriad of symptoms, but their severity is also highly variable. For the majority of people, infection with dengue virus is either asymptomatic or causes mild sub-clinical symptoms, which can be self-managed. However, one in twenty people develop severe dengue — a life-threatening condition.

Warning signs of severe dengue may manifest three to seven days after symptoms onset, when the patient’s fever begins to drop (defervescence). These include severe abdominal pain along with persistent vomiting, rapid breathing and bleeding gums. Doctors call this period the critical phase of infection, because although the majority of people survive the infection without displaying any of these signs, those who do will require close hospital monitoring within the next twenty-four to forty-eight hours.

Patients who develop severe dengue experience an increase in vascular permeability which causes plasma leakage. This is when plasma — the liquid component of blood — leaks from the blood vessels. As a consequence, there is a loss of volume in circulation (hypovolemia) and the heart cannot pump enough blood to the body, much like a leaky pipe causes a faucet to lose water pressure. In the worst-case scenario, the patient can go into hypovolemic shock, called in this case dengue shock syndrome. On the other hand, there is also liquid accumulation outside the circulation where it should not be, for example in the lung pleura, where it causes difficulty breathing.

In places where the vascular permeability is most aggravated patients will suffer internal bleeding. In other words, not only plasma is leaking from the circulatory system but also blood cells — which is why severe dengue is also known as dengue hemorrhagic fever. Internal bleeding in dengue patients is most common in the gastrointestinal track, which is why bleeding gums and blood in vomit are important warning signs of deteriorating conditions.

Unfortunately, there is no specific anti-viral treatment against dengue as of today. Symptoms are tackled with paracetamol, which acts as a pain killer and lowers the patient’s fever. Non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or aspirin often used to treat flu symptoms, are avoided in dengue patients because they also act as blood thinners, which can aggravate internal bleeding.

Since symptom relief does not address the vascular leakage, fluid therapy is extremely important. In patients with mild symptoms, this means drinking lots and lots of water but for those in critical conditions it means intravenous administration of saline or even blood transfusions, to replace what is being lost. These measures can reduce the mortality rate of severe dengue from one in five people (20%) to one in one hundred (1%).

Aedes aegypti mosquito — the primary dengue virus vector. Photo by James Gathany from the CDC (US).

In the last two decades, the incidence of dengue around the world has increased over eight-fold, with the largest number of cases ever being reported in 2019. This led the World Health Organization to consider dengue one of the Top Ten Global Health Threats that year. It is estimated that currently between fifty to one hundred million symptomatic cases occur worldwide every year. The increase in cases is partially explained by an improvement in reporting but is largely driven by explosive outbreaks and the spread of the disease to new areas including Europe.

Dengue viruses are transmitted to humans by female mosquitoes primarily of the species Aedes aegypti, which is widespread throughout the tropics. As such, most cases of dengue cases detected in Europe are imported from tropical countries by recent travelers. The 2012 outbreak in Madeira was no exception; the viral strain of dengue observed in the island was imported from South America. However, sustained transmission of the virus was only possible due to the presence of a stable A. aegypti population, which had been detected in the island for the first time in 2005.

Mosquito populations continue to be monitored in Madeira today as the threat of a second outbreak lingers in the air, but that is not limited to the subtropical island. In fact, there is now active vector surveillance all over Europe. The main difference being that mainland European countries are mostly worried about the secondary vector of dengue virus — A. albopictus. This species spread from Asia to Europe and North America largely due to international trade and is becoming a major cause of concern because it has a higher tolerance to cold weather than its tropical cousins. For theses reasons, the threat of an outbreak of dengue within the continent is increasingly becoming a reality.

Sadly, vector-control measures against Aedes mosquitoes have been largely unsuccessful against dengue in the tropics for several reasons. These mosquitoes are day-time feeders and have become well adapted to urban environments, which renders classic approaches used for malaria, such as bed-side mosquito nets and swamp draining, unproductive. Insecticides have also been counterproductive due to the development of resistance by mosquitoes and to environmental pollution, which led governments to impose limitations on effective chemicals such as DDT. But most importantly perhaps is the complacency towards preventing dengue fever, which was not considered a major public health threat until recently, due to its low mortality rate and intermittent outbreaks.

The gold-standard for infectious disease prevention continues to be vaccination, but even that has mostly failed in the face of dengue. When a patient develops dengue fever, it may be infected with one of the four different dengue virus serotypes (DENV 1 through 4), all of which target a specific subset of white blood cells (i.e. macrophages, monocytes and dendritic cells). As in many infectious diseases, the infected person will build long-term immunity against the pathogen, however it will be tailored towards the specific virus serotype which has infected that person. Upon a secondary infection with a different serotype, there is limited cross-immunity. This makes vaccination particularly challenging. To make matters worse, the immune system will recognize dengue viral particles and rely on its immune memory against the serotype it was familiar with. This will be the wrong serotype and patients will have a higher risk of developing severe dengue. Unfortunately, the same mechanism was observed when people were given the first dengue vaccine approved in 2015 — Dengvaxia®. The vaccine is safe and efficacious in patient who had previously been infected with dengue. However, for those who had never been infected before, the vaccine increases their risk of developing severe dengue upon vaccination.

Going into 2020, the prospects of reducing the spread of dengue were slim. Especially, once the COVID-19 pandemic began to cripple health care systems around the world. However, a new method of disease prevention was unraveling behind the scenes.

In 2017, a team of scientist lead by the non-profit World Mosquito Program (WMP) in collaboration with the Gadjah Mada University, began releasing bacteria-infected A. aegypti mosquitoes at different sites in the city of Yogyakarta, Indonesia. These mosquitoes were infected with a bacterium called Wolbachia.

Wolbachia is a common insect parasite, which captured the attention of the scientific community when it was shown that bacteria-infected laboratory fruit flies (Drosophila melanogaster) became more resistance to viral infections. More specifically, RNA virus — the family to which dengue viruses belongs to. The reason behind this anti-viral protection remains a subject of research, but it is considered that Wolbachia triggers the insect’s immune system to fight off viruses while also competing for resources. This meant that scientist now had a way to prevent insects from carrying viruses around.

Although Aedes mosquitoes are not natural Wolbachia hosts, once they were infected with a bacteria strain derived from fruit flies, they too became more resistant to infection with viruses — most importantly, dengue viruses.

As science journalist Doctor Alan Dove put it on the podcast This Week in Virology (TWIV):

“In essence [it is] like a dengue vaccine for mosquitoes.”

The purpose of the study in Indonesia, was to assess whether releasing Wolbachia-infected mosquitoes could lead to a reduction in the incidence of dengue fever in the region. Similar field studies of a smaller scale had been performed in Australia and Malaysia, but these made it hard to infer the actual impact of the Wolbachia intervention. The Yogyakarta project was the first cluster-randomized control trial using the Wolbachia method to date, with mosquito egg-filled containers deployed in twelve randomly assigned locations while another twelve sites acted as control — no deployment.

There were several challenges to the trial, beginning with community approval. It takes a lot of convincing before people living in dengue endemic areas agree to having live mosquitoes be released in their backyards. The Indonesian branch of WMP spent several years gaining local support by setting up community meetings and WhatsApp hotlines. Doctor Adi Utarini, one of the leading researchers on the trial, told reporter Ed Yong from The Atlantic that they went as far as opening up their laboratory to the public, so people could see the technology for themselves. When the trial began, the team had the support of 88% of the public and approval from thirty-seven urban villages.

The second challenge to the trial was whether or not Wolbachia bacteria, initially present in the laboratory mosquitoes, would spread to the local mosquito population. Each of the twelve clusters had received between nine to fourteen rounds of deployment but, in this case, the team relied on the natural survival strategies of the bacteria. Wolbachia is a very interesting parasite because it gives a reproductive advantage to infected-female insects. Infected males cannot reproduce with non-infected females because the resulting embryos do not survive — this occurs through a mechanism called cytoplasm incompatibility between egg and sperm cells. Theoretically, non-infected females will have less and less males with which they can successfully mate over time. It did not take long until scientists knew whether or not their theory was correct. By the end of the first year, over 70% of the local mosquito populations was infected with Wolbachia bacteria in each of the twelve intervention sites. When the trial was over, Wolbachia was established beyond any doubt.

From January 2018 to March 2020, researchers were actively testing for dengue virus in people who showed up at primary care clinics with fever. They enrolled more than eight thousand participants in the trial — roughly half from the intervention clusters and half from control clusters. The final results of the trial were announced in a press release in August 2020, and finally published in June of this year in the New England Journal of Medicine. The intervention was shown to be a tremendous success. The incidence of dengue cases within the intervention clusters was reduced by 77% when compared to control clusters. This protective efficacy was similar against all virus serotypes. Furthermore, there was an 86% reduction in dengue hospitalization in the Wolbachia-treated communities. This means that for every one hundred people hospitalized in the control sites only less that fourteen people were hospitalized in the areas of intervention.

Since Wolbachia does not carry a major fitness cost to the mosquitoes, neither the insects nor the bacteria will have any pressure to mutate. This makes their symbiotic relationship very stable in the long-term. The greatest threat to its stability will be the virus itself, which has a strong incentive to evolve resistance mechanism against the bacteria. The WMP is never-the-less optimistic given the incredible outcome of the trial. It now has on-going projects in eleven countries including Vietnam, Colombia and Brazil — with encouraging preliminary results in all three. Altogether, the projects cover short of seven million people — a number which is likely to increase in the upcoming years as the organization aims to protect seventy-five million people by 2025.

Thanks to the work of the people behind the World Mosquito Program, dengue may soon become a disease of the past. However, their ambitions do not stop there. With evidence suggesting that the Wolbachia method may also work against other illnesses such as Zika, chikungunya, and yellow fever, the organization is striving for a future free from mosquito-borne diseases.

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Gil Pires

Gil Pires

Junior Consultant | MSc in Biotechnology

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