New insecticides & new formulations of current insecticides

SARAH REES: Hello. I’m Sarah Rees, and I work for IVCC, the Innovative Vector Control Consortium, and my role is as R&D portfolio manager. So I look over all of the projects that we sponsor around product development. So today I’m going to talk about the problems of insecticide resistance and why that’s important in vector control, and how we might overcome that. And this slide here shows how the incidence of malaria deaths has fallen globally since the millennium by half, essentially. And most of those cases that we see today are in Africa, mostly affecting children under the age of five.

So malaria is decreasing as we’ve seen, and when we’ve done some analysis to look at the key factors that have been responsible for reducing malaria cases, and these slides show that the interventions for vector control have had a significant impact. So we can see that nearly 70% of cases of malaria that have been averted have been due to the use of bed nets, specifically those treated with insecticides. The use of indoor residual spray, spraying insecticides inside people’s houses, has also had a significant effect. And then the third factor that has also had some effect is the use of anti-malarial drugs.

So that significant decrease in the number of cases of malaria is under threat right now because we know that insecticide resistance to the products that have been used to reduce that number of deaths is increasing. So this map here shows the incidence of insecticide resistance that has been detected in different countries across Africa to different classes of insecticide. So up until now, there’ve been four main classes of insecticide that have been used either as indoor residual sprays or on bed nets in Africa, and this graph here shows the incidence of resistance that’s been noted or detected to those insecticides. And we can see that, actually, there is resistance detected to all four major classes of insecticide that have been used.

So pyrethroids, organic chlorines, carbametes, and organic phosphates. So the question is, does insecticide resistance really have an impact, and what impact does that have on the levels of disease? So here we see the results of a study in Ghana where the indoor residual spray has been used traditionally for many years. And an up until a time of 2012 in this study, pyrethroids were in use. And we can see that there were quite high levels of parasitemia in children up to 50%, and also in terms of detecting the presence of the parasite with rapid diagnostic testing, we can see even higher levels at 70%.

And because of the concern about insecticide resistance to pyrethroids, in 2012 a switch was made and organic phosphates were introduced as the insecticide of choice for use in indoor residual sprays. And we can see here the dramatic effect that that had over the space of one or two years where the levels of parasitemia fell to 20% and the levels of the detection of the parasite in RDTs was down to 30%. So I think that really demonstrates very clearly the impact that insecticides have on the ability to control the incidence of disease in children and the unfortunate consequence when you have insecticide resistance, and that is preventing the control of the vector.

So what this really means is that if we have insecticide resistance is detected to all the major classes of insecticide that are currently in use or have been until recent times in use for vector control, then we have a real challenge on our hands, and the challenge is to find new insecticides that are not susceptible to those mechanisms that the insects have that allow them to survive insecticide treatment. So the way we can do this is to– well, we can do two things.

We can look for other examples of insecticides that already exist that, for example, have been developed for use in agriculture, and we can see whether those fit the profile of a good vector control agent, and we can formulate those specifically for use in vector control market. So for use as an indoor residual spray or to be incorporated in or coated on a bed net. Or we can actually see if it’s possible to discover brand new chemistry as well that will be new to both agriculture and to vector control and be able to develop those insecticides as well. So this is the major work, actually, that IVCC does in collaboration with various manufacturing partners.

And you know, this is a significant challenge. So for example, when we’re looking for the utility of existing insecticides and whether they would be useful for vector control, if we’re wanting them to be useful as an indoor residual spray agent or a use with bed net, then the requirement is that when the insect lands on those surfaces that are treated with insecticide, they have to be able to take up the insecticide through their legs at a sufficient dose that will kill them. And if you think about how tiny those legs are and how difficult, you know, the strong the cuticle is, that’s really quite a challenge.

So it really isn’t a very easy task at all, and there are various other factors that we have to consider when we’re looking for a good insecticide to develop for the vector control. And this slide here is quite complicated, but it does show all the different sort of aspects that are important in product development, whether we’re looking for a brand new insecticide or whether we’re looking to repurpose an existing insecticide from the world of agriculture.

So one of the first things we look at when we’re looking for insecticides that are not susceptible to the resistance mechanisms that are already out there is we look for chemistry that’s got a different mode of action to the insecticides, like pyrethroids, and carbonates, and so on. And we use a framework to do that which is set up by a body called IRAC, which stands for the Insecticide Resistance Action Committee. And that group classifies insecticides based on their mode of action.

So one of the things that we do in IVCC is we look to test a wider range of possible of those different classes of insecticides so then we’ve got different alternative types of chemistry that are going to be effective. We also look to see whether those potential new insecticides are metabolised by the enzymes that the insects will produce to detoxify chemicals. So we know that a lot of pyrethroids resistance is due to enzymes called P450S, and so we look to make sure that the chemistry is not susceptible to P450 breakdown. So having identified some chemistry that we think is potentially useful, it has to be potent.

You know, tiny amounts can be taken up by the insect through the tarsi and then go on to kill the insect, and that they will also kill mosquitoes that are resistant to pyrethoirds. We then also need to think about the other characteristics of that compound to see whether it’s suitable for use as vector control. So something else that is very important is formulation. So we know that when we’re trying to develop an indoor residual spray it needs to stick on the walls the houses are made out of, and they’re made out of all sorts of different substrates, so mud and cement and wood.

So we need to have a formulation that will work on those different services, and some of them are quite difficult and might be quite, sort of, might break down the formulation. They might break down the insecticide. So we need to optimise our formulation to work in that way. When we’re looking for an insecticide, for example, to work on a bed net, one of the requirements is that the bed net has to be able to go through 20 cycles of washing during the three years of that net life. And therefore, insecticide can’t be too water soluble. It can’t wash out when the householder does the normal sort of household washing.

So all of these things are quite challenging but a key to success of developing a successful product. Of course, it’s very important that insecticides which are toxic to insects are not toxic to humans and particularly small humans, babies who will be sleeping under bed nets, for example. So we have to go through very extensive toxicology testing. So for a brand new chemical, brand new insecticide, that requires three years of long term toxicology studies, checking that the compound doesn’t have any toxicological effects, certainly at the rates at which it would be used in the in these sorts of products.

So that’s a very expensive process, and to avoid falling at that hurdle, we would do a lot of scoping and profiling the toxicological profile of a chemical before we put it into those very expensive long term studies. Of course, we have to be able to manufacture the product and to manufacture that economically as well. So there will be work done on optimising the process for manufacturing and being sure that we can scale that up and that we can still continue to make the product at a cost effective rate. So that’s very important.

And then finally, we need to be able to make sure that there what we would call freedom to operate, which means that the manufacturer has the appropriate intellectual property that allows them to be able to sell their innovation in the market and be able to manufacture it as well. So all of these things have to come together, you know, all in the right way in order for us to reach a successful product. And I’m pleased to say that, you know, we are beginning to see those products coming into the market just now, and that’s fantastic news because it means that we have some brand new chemistry that is now going to enable us to practise good insecticide resistance management.

So a couple of a couple of examples of that would be a product from Sumitomo which is for indoor residual spraying called SumiShield, and this uses a brand new chemistry called clothianidin, and this is not belonging to any of the classes that have been used for vector control up until now. And so clothianidin is very effective at controlling pyrethroid resistant mosquitoes. So we’re really looking forward to that coming into the programme and to be able to alternate that with existing chemical products in the indoor residual spray programmes, and then there’s good news on the bed net front as well.

So it’s really been a very difficult situation with bed nets up until now because the only class of chemistry that was really suitable for developing bed nets were pyrethroids, and we know that we have widespread pyrethroid resistance. So really all insecticide treated bed nets suffer the problem of being less effective because of insecticide resistance. And BSF with whom IVCC has been collaborating have developed an insecticide treated bed net with a brand new chemistry for vector control, and this one’s called chlorfenapyr, and that’s different from the Sumitomo clothianidin in product.

So we’ve got yet another class of chemistry that’s coming into the vector control space, and that bed net is just being made available in the market in 2019, and so we’re very excited that that’s really going to help the fight against insecticide resistance. So, I mean, historically, we only had the pyrethroids as an insecticide that had the right physical properties to be able to use with bed nets, and so we had no choice. And one of the problems therefore was that pyrethroids were always out there and insects were exposed to pyrethroids the whole time, 365 nights a year for as long as you can imagine. And of course, that gives tremendous pressure on the insects to develop resistance.

So I think what we can really learn from that is that when you do have long periods of continuous exposure to insecticides without a break, it’s inevitable that resistance will arise. And so what we can learn from that is we can start to alternate different products or put them together in mixtures, and that will really alleviate that pressure or make it much more difficult for mosquitoes in this case or insects in general to develop resistance mechanisms. So I think it’s very important that we do map where insecticide resistance is occurring because– and that might be at the very local level. It may occur in one place and not be a problem, you know, relatively close by.

But once resistance starts to arise, because of the rapid generation time of mosquitoes, then it can really quickly explode in a population, and that’s, really, you want to take preventative measures to avoid that happening because, you know, once it’s out there, you’ve lost control.