Eliminate Dengue

Scott O’Neill shares his passion for developing novel approaches to controlling mosquito transmitted viruses by introducing Wolbachia infections in mosquitos. Scott describes the troubling rise in mosquito-borne viruses, and offers the promising results of his work with Eliminate Dengue.

Script

Scott O'Neill:

Thank you very much. Like others, I'd like to thank NEB for this award. For me, an award is a little bit like a reference letter. It has two components. One is the content of the letter, and then the other thing is the person who signs the letter is sometimes more important than the actual content. For me, getting this award from NEB is important, and something that I'm very grateful for, because NEB is a cool company in an ocean of very uncool companies. Thank you.

 

Let me tell you a little bit about what we're doing. I'm working in a program called Eliminate Dengue. We've been working for around 10 years now. We work with a lot of different people in different countries. Currently, our operations are sitting five countries: Australia at the top, and then Brazil, Colombia, Indonesia, and Vietnam.

 

What we're doing is trying to focus on a problem that is a hideously large problem. We're focused on the viral diseases that are transmitted by the mosquito Aedes aegypti. The first of these is dengue. For dengue, it's a huge problem around the world that many people may not appreciate.

 

This viral disease is costing close to $9 billion every year in direct costs to governments, but not only that, it's really creating a huge social and economic burden on families, where around 40% of the health costs are borne by the family, and these costs can be up to three months of the income of that family. It's a major burden.

 

It's not a small problem. We have around half of the world's population is at risk of acquiring dengue in any given year, and it's estimated that around 390 million people are infected each year. It's a huge problem, and no current solution for it.

 

Then we just heard, I think, in some previous talks, mention of this thing called Zika. Zika is a virus quite similar to dengue. It's transmitted by the same mosquito. It was originally isolated in Uganda, from the Zika Forest. A research forest where a lot of virology has been done over the years.

 

Then it had ... as we heard in the previous talk, there was scattered transmission going on, until there was a huge outbreak of Zika in South America in the last year. Most people would have been aware of what's been happening in Brazil.

 

One of the real terrible things around Zika are the deformities that it's causing in newborn babies. We were seeing problems in brain development in these babies with microcephaly. In Brazil, normally, we would see around 163 cases nationwide of microcephaly reported. Babies with small heads. In the last year, almost 2,000.

 

These are children, or babies, that will, if they do survive, are going to have life-long caring needs, placing huge burdens on families that really can't afford the disaster of it. Also, other syndromes are now being recognized, as well. Guillain-Barré syndrome, for example, and I think a greater appreciation of the breadth of the neurological syndromes associated with Zika virus.

 

It's been roaring through South America in the last year, as everybody, I imagine, knows here. It's on your doorstep. Certainly, transmission's occurring in Florida at the moment. In the work we're doing in Southeast Asia, we're now seeing it spill into Southeast Asia, with microcephaly being reported just in the last month in Thailand and Vietnam. Singapore's reporting hundreds of cases, and KL, as well. I think we can expect, in the next month or so, governments declaring the actual extent of the Zika problem in Southeast Asia, which is a direct flow-on from what's happening in South America.

 

We think we have a solution to this problem. I'd like to try to walk you through, very quickly, what it is. It involves a microorganism called Wolbachia, which some of the people at NEB know about. This is a slightly different Wolbachia. This is a Wolbachia that lives in insects.

 

It's estimated that around 60% of all insect species carry Wolbachia naturally, but not the mosquito that transmits these viruses, Aedes aegypti. Just some key features of it. It's naturally occurring. It's vertically transmitted, so this is a strange microorganism, in that it lives in insects and gets passed from one generation to the next in the eggs of the insect. It's quite safe for humans, and animals, and the environment. It occurs naturally, but is not in this one species of mosquito.

 

The key point here is that, when we introduce it, and change the microbiome of this insect species, what we find is that the mosquito is no longer able to support the replication of any of these viruses. If a virus can't replicate in the mosquito, then it can't be transmitted. That's the key point of what the work here is we're doing.

 

This bacteria has some other key features, which make it really interesting in a public health intervention space. This is something called cytoplasmic incompatibility. If you're a male insect, and you have Wolbachia ... These little green dots ... and you mate with a female insect that doesn't, then all of the eggs that that female lays will die. They won't develop properly. I won't go into the scientific details behind that. Just take my word for it.

 

But if the female insect has Wolbachia, then her eggs will hatch, and all of her children will have Wolbachia. Similarly, if a female has it, but a male doesn't, we get the same effect. This agent, without being ... It doesn't need to be infectious to be successful. It's able just to be vertically transmitted.

 

Through this thing here ... manipulate the reproduction, and it can both spread into an insect population and maintain itself, even if it puts a genetic load on that population. This is the key to the success of this bacterial agent, and why it's so common in the environment.

 

It also makes for a fantastic public health intervention, because once this bacterium has been released into a mosquito population, because of this action, it will maintain itself in that population. It will be sustainable, and so it won't need reapplication. Makes a really lousy business model. There's nothing really here to sell. But it makes a great public health intervention. As a result, we're structured as a not-for-profit.

 

Just to show you a little bit of some modeling that's being done at Imperial College ... not by us, but by others ... showing the likely impact on dengue, which can be extrapolated to Zika, as well. This is just based on real-world data where we've been feeding patients in Ho Chi Minh City, in Vietnam, on mosquitos with and without Wolbachia, and then estimating the reduction in transmission, and from that, the reduction in disease, through simulation models.

 

This is showing that for Dengue One, compared to Dengue Two, Three, and Four, that we see within a very short period of time almost 100% reduction in virus transmission. Then that reduction is then sustained.

 

These are in different R naught settings, which is a measure of the intensity of the force of transmission of the infectious disease. Most dengue R naughts usually would sit between 1.5 and 3.5. We see some little rebound occurring around 50 years after introduction for Dengue One under extreme R naught conditions, but we think these models are fairly conservative. The bottom line is, this intervention, at least on the modeling that's being done, suggests very quick and very large impact on these diseases.

 

What's involved in doing this ... because this is an intracellular bacterial agent, and it's vertically transmitted, we actually have to release mosquitoes in the environment to seed them with Wolbachia. Then those mosquitoes will mate with wild mosquitoes, and Wolbachia will then take care of the rest of the business, if you like and spread itself into the mosquito population.

 

You can imagine a situation here, where we've got a wild mosquito population with no Wolbachia. We then undertake a series of releases to deploy Wolbachia, to a certain period where have a frequency above a key threshold frequency, which I won't go into. Then Wolbachia will take care of the rest itself, spread itself into all of the mosquitoes in that area, and then sustain itself going forward.

 

We release mosquitoes in a different way. Here is one of our people working for us in Colombia, releasing adult mosquitoes that have been grown in the laboratory. Here is one of the people working with us in Brazil, with a bucket where they'll be putting the mosquito eggs into that water, and letting them grow up natural in the environment. Here is a child in Australia, where we're doing deployments of this method in a citizen science approach, using schoolchildren to actually do the work with a piece of science curriculum structured around the intervention. Different ways that we can put it out.

 

Here's some data from the very first work we did in Australia, nearly six years ago now, where we first released mosquitoes. This was a period of time, this little green shading, when the actual releases took place. We released mosquitoes for 10 weeks. One day each week, we would release the equivalent of 10 mosquitoes per house in an area. We did that 10 times.

 

This is, looking at these two locations, the Wolbachia frequency in the mosquitoes. You can see that it climbs during the release period, then continues to climb, and then has maintained itself at above 90% for however long that is now, and appears to be continuing in an ongoing way.

 

We can take these mosquitoes from the field and bring them back to the lab, and we show that they're not competent to transmit dengue. Not only that, is that we can measure dengue in the surrounding communities, and we can see that there is no dengue transmission has occurred in this site during the last six years.

 

This is just some more observational data on efficacy. This is showing the city of Townsville, where we've now deployed Wolbachia, in Northern Australia. It's a small regional city in Australia of around 250,000 people. In the process of deploying from late 2014, this is showing you locally ...

 

Well, before I explain it, just to give context to this graph, there is not endemic transmission of dengue in Northern Australia. It's brought in by travelers each year, and then we get local transmission occurring from imported cases. That's usually people going to Bali for holidays, or something like that, and they bring it back.

 

We have a background of imported cases. Small numbers of imported cases trickling in to our Northern Australian cities. You can actually see that this is getting worse over time, and this just reflects the growing problem of dengue as a disease. That the disease burden is increasing across the world, as we don't really have any effective means to control it.

 

This is then local transmission that's triggered from these imported cases. There hasn't been a 12 month period ... These are over one month intervals ... There hasn't been a 12 month period in the last 10 years where there hasn't been local transmission of cases.

 

Then we released Wolbachia here. We've had no cases here, except for these three, but each of these three cases occurred in areas outside the deployment area, as we were putting the deployment in place. So effectively no transmission in this city since Wolbachia's been deployed. We see that in all of the places where we're working. A complete knockdown in transmission.

 

Currently, we're working in these different locations. I'm based here, with 60 other people in Melbourne. We've been working for six years in the field in Northern Australia. We're just about to complete our deployments.

 

We're running a large randomized controlled clinical trial in Indonesia, to get the gold-standard evidence, if you like, on the impact. These clinical trials take a long ... They're complex, they're expensive, and they take a long time to complete, so it's still got around two-and-a-half to three years before it's completed. We're doing a similar study with a sightly different design in Central Vietnam, that again, will take a number of years.

 

But Zika and dengue are not waiting for clinical trials to be completed. The World Health Organization has declared a global emergency for Zika, and we desperately need new interventions, or something that has a prospect for working, when apparently nothing is working at all. The World Health Organization has recommended scaled-up deployments of Wolbachia while we wait for the clinical trial data to come through, based on both the modeling that's been done, and also the observational data that's coming out from existing deployments.

 

As a result, we've been working in Colombia, in the City of Medellín, and also in Rio de Janeiro, with doing small pilot deployments. Last week, in London, I was able to announce that we're going to do expanded deployments over the next two years in both of these cities, where we hope to be able to cover around two-and-a-half million people in each city. As well as, we hope, provide a very powerful protective effect, we'll be able to get a type of evidence data that we can't ... which will complement what's coming out of our more traditional clinical trials, but being done on a larger scale.

 

That's where we're sitting at the moment. We have a plan that, if everything keeps going well, what we would like to see happen over the next 10 years or so, where we hope to be able to deploy Wolbachia globally in all of the major countries where these diseases are a problem. Thank you.

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