Fighting 'the deadliest animal on Earth' with a tiny bacteria

Those who work on mosquito-borne illnesses often refer to mosquitos as "the deadliest animal on Earth." They certainly cause more human suffering than any other organism – mosquito-borne diseases infect up to 700 million people per year and kill well over a million people annually.

With rising global temperatures expanding the areas where mosquitoes thrive, those number are set to rise. Already endemic across sub-Saharan Africa, Southeast Asia, and Latin America, mosquito-borne diseases are spreading to other regions. One study from 2019 suggested that one billion more people could be exposed to mosquito-borne disease by 2080 as temperatures continue to rise.

One of the main threats to people is the Aedes aegypti mosquito, a tropical mosquito that carries dengue, yellow fever, Zika, and other viruses. Dengue alone infects more than 400 million people and kills some 20,000 people each year. People have traditionally resorted to insecticides, bed nets, and traps to stem the spread of these diseases. But all these are only partial solutions and can't address the sheer scale of the problem.

Scott O'Neill of the World Mosquito Program has been working on this problem for the past two decades and has developed a radically new solution: infecting the mosquitoes with the Wolbachia bacteria, which severely limits the mosquito's ability to transmit disease. Better yet, as these lab-raised mosquitoes breed with wild mosquitoes, the bacteria spreads through the mosquito population and prevents their offspring from spreading diseases as well.

We spoke with O'Neill about the program, which is in the process of releasing Wolbachia mosquitoes in countries around the world, including Brazil, Colombia, Mexico, Indonesia, Sri Lanka, Vietnam, Australia, Fiji, Kiribati, New Caledonia, and Vanuatu.

How did the The World Mosquito Program get started? Tell us about the problem you're addressing and why it's so important.

O'Neill: The World Mosquito Program evolved out of my research program. The core research my group was working on was: how could we utilize Wolbachia bacteria to control insect-transmitted diseases. The reason that it evolved is that we were able to find a solution to a big problem – people getting sick from being bitten by a mosquito that's transmitting a range of viruses to humans. Probably the best known of these viruses is dengue.

We found we could put a naturally occurring bacteria from insects into the mosquito. When the mosquito had this bacteria, the viruses that make people sick couldn't grow in the mosquito's body. And if they couldn't grow they couldn't be transmitted. This pointed towards a whole new approach to thinking about controlling mosquito-transmitted virus diseases.

The problem we're trying to address is huge – around half the world's population is at risk of being bitten by a mosquito carrying one of these viruses each year, so huge numbers of people are at risk. We don't actually know in many parts of the world how big the disease burden is, but it's significant. It's a big problem without a solution. We've been able to find a solution we want to scale up and provide to countries around the world.

How was the Wolbachia method developed and how does it work?

O'Neill: Wolbachia is this bacteria that only grows in insects and was discovered in the 1920s, but its significance wasn't really understood until many years later. It does a couple of very interesting things.

One, which is very unusual, is that it can affect the reproduction of insects to enhance its own spread into an insect population. It actually manipulates the reproduction of the insects so that females that transmit it to their eggs are given a reproductive advantage in the population and they leave behind more offspring. Wolbachia spreads because it lives inside these insects.

The other key property of Wolbachia is something we discovered many years later, which is that, when insects carry Wolbachia, certain viruses are unable to replicate in their cells as effectively. That's very significant from a human disease point of view because these viruses get carried by mosquitoes and transmitted by them. If they can't replicate inside the cells, then you've effectively stopped transmission.

This solution is sustainable and actually cost-saving in most geographies. It's also very effective and safe. It doesn't involve the spraying of toxins or insecticides into the environment. It looks like a solution that's going to have a very large impact and our interest in the moment is how to scale it up.

I also think that one of the key aspects of this technology that makes it really different from other technologies is that it's self-sustaining. For example, in Northern Australia, we released [Wolbachia] mosquitoes over 10 years ago for 10 weeks and then we didn't release any more. We're still measuring Wolbachia in those mosquitoes now 10 years later and close to 100 percent of the mosquitoes carry it. Guess what? We don't see any transmission of dengue anymore in Northern Australia. It's gone.

Why this is unusual is that with most public health interventions, whether it's a vaccine or a drug, you have to keep giving it to people on a regular basis. It's an ongoing expenditure. This is more like infrastructure. It's more like building a bridge or putting in piped water into a community. You do it once, it has an upfront cost but then it just keeps returning health benefits for years.

What evidence have you gathered about the effectiveness of the Wolbachia method?

O'Neill: We did a very large randomized controlled trial in the city of Yogyakarta in Indonesia across a population of around 400,000 people. Of those 400,000 people, we divided them into 12 clusters that received Wolbachia mosquitoes and 12 that didn't. We then looked at what the disease progression was in people who lived in those different areas. We found a very significant reduction – 77 percent – in virologically confirmed dengue and an 86 percent reduction in hospitalizations. We've done a number of non randomized studies as well. We're now working in 12 countries with multiple deployments [of the mosquitoes]. All of our deployments are showing significant disease reductions, whether they're in a clinical trial format or just observational data.

A lot has been written about the effectiveness of the Wolbachia method against dengue – how effective is it for other mosquito-borne illnesses such as chikungunya, Zika, and yellow fever?

O'Neill: We have data from the laboratory measuring how effectively Wolbachia prevents transmission of viruses such as Zika and chikungunya, as well as dengue. Field studies are obviously much more powerful, but are much more difficult to conduct. You have to put in place your intervention and then measure disease in areas that received the intervention and areas that didn't. The problem with some of these diseases is that they can have roaring outbreaks in a given geography, like Zika did in South America a number of years ago, and then go very quiet with very little disease for a number of years – and then it comes back again.

The natural history of these diseases makes it very hard to set up a trial in the right place at the right time to catch the disease so that you have [the necessary sample] to do the study. We've focused mainly on dengue because dengue is so prevalent it's quite easy to research. But other diseases like chikungunya and Zika are a bit more patchy in their distribution. It's harder to predict where they're going be and therefore harder to do the actual trial to measure the effectiveness against those diseases.

In one location, however, Rio de Janeiro, we're getting a measurable number of not only dengue, but also Zika and chikungunya cases so we're able to make some estimates from the field. Those estimates look very similar to what we see for dengue, and in the laboratory. The blocking we see in mosquitoes in the laboratory is almost identical for Zika, chikungunya, yellow fever as it is for dengue. It's just a lot easier to work with dengue in the field, so most of our measurements occur with dengue.

How is climate change increasing the spread of mosquito-borne illnesses? Do we have any data on how quickly the habitable zone of the Aedes aegypti mosquito is spreading and where?

O'Neill: We know that the Aedes aegypti, the mosquito that transmits all these viruses, is spreading its geographic range as we're seeing temperatures warm. But there's more to the climate story than just temperature. You hear a lot about mosquito-transmitted diseases and temperature. As temperature goes up, we have more diseases. Well, that's all very straightforward, but there's something about climate people don't spend as much time thinking about it, and that's water.

Mosquitoes live in aquatic environments. They need water to live. This is maybe a little counterintuitive, but if you're in an area that's becoming drier due to your climate changing, there's usually a response to that drying and that's to store water. If you need water for your garden, if your water supply becomes less predictable from rainfall, then you start storing water. Stored water is where the mosquitoes which transmit these viruses like to live and grow. There's also a very big story around mosquitoes and water storage and how water gets handled in a changing climatic scenario. I think that's potentially an even bigger problem than the temperature problem.

What measures would you recommend countries facing new risks from Aedes aegypti-borne illnesses take before outbreaks start to happen?

O'Neill: We're seeing a range expansion of Aedes aegypti, but we don't have very good information on disease following that range expansion. We know that dengue is occurring in countries in Africa, for example, but disease burden in Africa is very poorly understood. In coastal countries in Western and Eastern Africa where outbreaks are occurring, we don't know just how important those outbreaks are at the moment, we don't really know the extent of them. If dengue is not a problem in a tropical country, it's a problem that's about to start. It's spreading that quickly and cases are rising dramatically.

One of the first things I think governments need to be doing is putting at least basic surveillance in place to be able to measure these diseases. The first thing that needs to be done is to have a good understanding if the disease is present. I think one of the things we really need to be thinking about globally is surveillance for viral diseases and mosquito-transmitted diseases that could cause the illness. I think it's quite clear in the data that countries should be preparing themselves for crippling outbreaks. When you have a massive outbreak of a disease like dengue, it has some similarities to COVID. We were all very worried about COVID, because of what it might do to our health systems. That they could collapse and our hospitals would be overrun with patients. That was the big underlying fear of COVID for governments. It wasn't being talked about that much, but it was clearly very evident.

You notice exactly the same thing for dengue. When you had a massive dengue outbreak, the hospitals have two patients to a bed and patients in the corridors. Things become overloaded quickly. Being prepared for dengue, from the health system perspective, from a diagnosis point of view, and from a disease surveillance point of view, are all very important.

We can help govenments implement the Wolbachia method. One way we can work with you is to give you the technology free of charge, and mosquito strains and let you use your existing capacity and the mosquito experts in your country to implement the method, if you wish. The second level is that we'll not only give you the technology, but we'll provide you with data tools, with ways to design, implement, and measure the effectiveness of a program. That's the way we're collaborating closely with countries like Brazil, for example. The third way is working more closely with countries to jointly design and operate rearing facilities to grow the mosquitoes that need to be released carrying Wolbachia to implement the method. We are working with governments from very light touched to quite heavy involvement in giving them access to the technology and helping to implement it.