Interview with Derric Nimmo, Head of Public Health Research at Oxitec

As a follow-up to last weeks post on genetic control of mosquitoes, I invited Derric Nimmo, the head of public health research at Oxitec, for a friendly chat about the experiences and potential of the Oxitec solution to control the mosquitoes transmitting Zika virus, dengue and chikungunya in Brazil.

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Derric Nimmo, head of public health research at Oxitec
Derric Nimmo, head of public health research at Oxitec

Derric, could you briefly summarise the potential of Oxitec Solutions in terms of controlling mosquito-borne pathogens such as the Zika virus?

Our technology is based around the genetic modification of insects. We put a gene into the mosquito which we call a self-limiting gene. What I mean by that is when we release the males they can do two things. One is that they can survive for a couple of days and then die, and the other is that they can mate with a female. If they do this in the wild, the female is impregnated with the self-limiting gene, she then lays eggs that carry the self-limiting gene. In the lab you can control the expression of the gene with an antidote, but this is not available in the wild and the offspring die. If you release enough of our males for a long enough time, you should be able to reduce the wild population. We have done this in field trials in Panama, Cayman Islands and Brazil. Every single trial, so far, has shown over 90% reduction in the mosquito population, relative to a control site. We can achieve a very good control using this technology.

Now, we have got regulatory approval in Brazil to start developing our technique in a larger capacity. We have treated about 5,000 people in Piracicaba, Brazil.

When you say treated people, you mean you released mosquitoes in an area that covers these people?

Yes, I should clarify that: we treated an area inhabited by 5,000 people with our Oxitec Solution. They have been very pleased with our results, we have interim results of over 80% reduction in the mosquito population, and hopefully soon they can sign up to treat an area of 35-60,000 people. We are in the process of building a factory which would eventually allow us to treat an area that covers 300,000 people. Of course, with the recent Zika outbreak that is linked to microcephaly, the government is looking to us to do further work out there.

So when you say 90% reduction in mosquitoes, is this something you can similarly achieve with going out and spraying insecticides and removing breeding sites? Or is that something that is really exceptional?

It is very exceptional. For example, in the Florida Keys, there is a mosquito control district down in Key West where they spend 1.1 million dollars just on Aedes aegypti control. They have three helicopters, 10 – 15 people, use Bti and they use all the latest insecticides. They can at best get somewhere between 30-50% reduction in the mosquito population. This is not enough. They would like to obviously get it down much more than that. And they are the best in the world.

There are a lot of other mosquito control agencies out there, they are very well funded, they do research, they have highly qualified people and they present their results in meetings, they cannot get this particular mosquito controlled very efficiently.

So how is it possible that the Oxitec mosquitoes can perform so much better?

We are using the natural ability of the males to find females. A. aegypti is an urban mosquito and is very closely associated with man, and that is because it almost exclusively feeds on humans. If you put a man in the middle of a cowshed, A aegypti will bite that man and none of the cows around him. They live in and around the house. They breed in small pools of water all around the house, for example, in the gutters. I have even seen them breeding in little bottle caps from Coca Cola bottles. Finding all these sites and treating all those sites with insecticides is extremely difficult. In addition, when you go around spraying, what do most people do? They close their windows and doors, so the mosquitoes sit there nice and happy inside the house and as soon as the sprays are gone, the doors are opened again and the mosquitoes are fine. There is also insecticide resistance, which is compounding the control efforts. Whereas, with our technology, we just have to go down the road with a pot of male mosquitoes, open the lid, release the males (about a 1000 at a time) every 50 meters or so down the road. The males will fly off and find the females whether they are inside the house, outside or resting. They are not held back by barriers or fences – for example, someone may not allow you onto their property, but that does not stop the mosquitoes. They are much more efficient at finding those females and that’s what makes our technology that much more efficient at controlling the population.

I know from reading your papers and of course from working at Oxitec for a year that the antidote you are talking about is tetracycline. Tetracycline is being used for other purposes, such as keeping cows healthy and things like that. I have heard that there has been a study looking at the effect of the levels of tetracycline found in the wild and whether that will be sufficient to sustain the mosquitoes that you are releasing, which could counteract the effect. Can you give more details about that study?

We published that study. We asked: what are the possible risks of mosquitoes finding or accessing tetracycline? One risk would be when a female bites a human that has been taking tetracycline. Would they be able to pass it on to the eggs? To find out, we fed female mosquitoes with blood containing tetracycline in much higher concentrations than you ever find in human blood, and we found that it was not passed onto the eggs.

We then considered the environment as a potential source of tetracycline. One example is that tetracycline is used in animal production to keep them healthy and also as a growth stimulant. Now, animal by-products such as faeces can have high concentrations of tetracycline, and these are found in farms. A. aegypti does not breed in those sites. If we look in towns and urban environments the most likely source of tetracycline is from human waste. When you take tetracycline as an antibiotic, you excrete 50 – 60% of it, so it is found in sewage systems. If you look at the concentration of tetracycline in sewage systems quoted in the literature, it is not high enough to rescue our mosquitoes. Plus, our mosquitoes don’t breed in sewers.

In his spare time, Derric is an artist, who makes models such as this giant Aedes aegypti. I keep a small version of the same that he made for me when I left Oxitec.
In his spare time, Derric is an artist, who makes models such as this giant Aedes aegypti. I keep a small version of the same that he made for me when I left Oxitec.

And there might be confusion because lots of other mosquitoes do breed in sewage systems, but not this species.

Other people have said ‘what about the study that shows cat food would increase the survival of the mosquitoes by 15%’, which we published. What if they breed in a bowl where there has been some food? Well, one thing is you need to replenish it every day to have the concentration of tetracycline that causes survival. But let’s say what if it did? What if they could survive? Well, what happens is that those insects that survive, they emerge and still carry the gene, and if they mate they still pass on that gene to the offspring and the offspring dies. Although you will have to remember that the original offspring will only carry one copy of the gene, so only half their offspring will die.

Another technological advantage is that we have a marker in all of our insects and that not only allows us to monitor them in the population almost in real time, we can bring eggs back to the lab and look at their fluorescence ratio. We normally look for greater than 50% of the eggs coming back to show fluorescence, and by this we know we are releasing enough insects.

We can also look at adults. If we get adults back either showing the fluorescence or we PCR them to see if they have the gene, we know they are from two sources: one is the 3-4% that survive or the other is tetracycline contamination. Mosquitoes don’t fly that far, so if we do find the latter, we know that somewhere in that area there is a problem – we can then treat it normally with insecticide. We have never said our technology is stand alone. It is always an integrated pest management solution, so you can use it in conjunction with larvicides, removal of breeding sites and even adulticides, as long as you spray at a different time to releasing the insects. Our technology has a big advantage in that it can be used not just on its own but in combination with other technologies.

So would you agree that this technology has now been tested and evaluated sufficiently that it would be ready for even larger scale operations or releases? Let’s say if the government of Brazil came to you and said we need help controlling the Zika outbreak, can you do this on a larger scale?

We have gone through the regulatory authorities in Brazil, Panama and the Cayman Islands, and each one of them have said ok, we have looked at the data, we have done the trials, this is effective, we have seen it to be environmentally friendly, it only targets A. aegypti, which is not a native species – I don’t think a lot of people realize it spread out of Northeastern Africa in the past few hundred years. We have also done predator studies to show that predators are not affected.

We call our technology ‘self-limiting’ technology because of the fact that the males die and the offspring die. And does this actually happen? Where we have stopped releasing after our trials, we use the fluorescent marker to detect our mosquitoes in the population. Within 2 months of stopping releasing, we found no evidence of the gene in the population, so we know the ‘self-limiting’ aspect works.

Yesterday (2/1/2016) the WHO declared a public health emergency of international concern about the Zika virus transmission in Brazil and South America in general, and so my hope is that there will be a push for an even larger scale operational use of this technology, which to me looks like the best option available. If the government of Brazil were to give you a call and say we need this today, what would it take to scale up to an even larger area, say treating the whole of Brazil. Is that feasible and what is the timeline it would take to do that?

Yes, of course it is feasible. We have the technology, we have the methods available so we can mass rear the insects in huge numbers, and we can treat area-wide, so what is the limitation? The limitation is really the expansion of the mosquito. Now, a single female lays 500 eggs in a lifetime in the wild. In the lab, we can get about 100-150 eggs on average from a female. That takes about a month, so if she produces 100-150 eggs, half of them will be female and they in turn will produce 100-150 eggs. Therefore, in 5-6 months you will have a billion mosquitoes just from that one female. So in terms of mosquito biology, you can expand very quickly and efficiently. Now, of course, to expand in Brazil, you need to build a factory and you need to supply it with people and get it up and running within months. From a biological point of view, within 6 months to a year, you can have enough mosquitoes to treat a very large area.

That sounds very quick, especially compared to vaccine production. Despite being a flavivirus, Zika is very closely related to West Nile virus, so we could start with a modified West Nile virus vaccine, but still going through the regulatory process and trials will take years. When compared to that, 5-6 months is a big deal. The summer is nearly over in Brazil, but then the problems will come back next summer.

Everyone is currently concerned about Zika, but this mosquito transmits dengue and chikungunya, both of which are very nasty diseases. Zika has been linked with microcephaly, which is of course worrying for pregnant women, so that is an added dimension to this, but it is not just Zika we are talking about. There are 100-400 million cases of dengue each year and 25-50,000 deaths. Chikungunya spread like wildfire through the Caribbean when it hit in 2013, and there were over a million cases in a year and it is still spreading. So I think, as bad as Zika is and as bad as people want the vaccine, you have to remember the mosquito spreads other diseases too: what’s next?

To combat Zika, you can control the vector and develop a vaccine against the virus itself. Both are viable and compatible solutions. Models show that combining the two approaches improves the control and rate of reduction in the disease.

Employees of Oxitec and FHP Health workers take to the streets and houses of the inhabitants of the neighborhood CECAP distribute brochures and educate residents about CECAP Aedes Project. Piracicaba / SP, March 28, 2015 . Fotos: Alexandre Carvalho
Employees of Oxitec and FHP Health workers take to the streets and houses of the inhabitants of the neighborhood CECAP distribute brochures and educate residents about CECAP Aedes Project. Piracicaba / SP, March 28, 2015 . Fotos: Alexandre Carvalho

My personal hope is that Zika virus will be the final push for the public and policy makers to say this is enough. We have had dengue for a century and we have had chikungunya for a couple of years, but now we have this Zika and it is about our children. We cannot delay anymore and we need a solution.

I agree and in Piracicaba, where we have been releasing the mosquitoes, we have been doing a lot of community engagement and a lot of surveys. About 96% of the people in Piracicaba are in favour of this technology. They have seen it working. That is why they have said it is ‘friendly’. It is something they have seen as a tool that can help them.

They see the effectiveness themselves?

Yes and we are very open in our community engagement. We tell them everything about the technology and how it works. We get people to put their hands in cages with males to show them these males do not bite. A lot of people don’t know what a mosquito is. They don’t know that males don’t bite and when you tell them they are initially sceptical. Our community engagement has been very successful and the local community is very supportive.

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Dr. P.K. Sumodan

I have a few points of disagreement. As far as I know male mosquitoes do not pursue their female counter parts. In fact, females are attracted to males. Second point- you need not spray larvicide in the breeding habitats to kill them. The best option is source reduction. Finally, you can’t be sure that only Aedes aegypti is the vector of Zika. There could be others like Aedes albopictus.

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