May 31, 2019 — Each year, more than 200 million people around the world are infected with malaria and more than 400,000 die. For the past two decades, the most successful method of malaria prevention has involved treating bed nets with long-lasting insecticides that kill mosquitoes. But that progress is being threatened as mosquitoes increasingly grow resistant to the most commonly used insecticides.
Now, new Harvard T.H. Chan School of Public Health research offers a potential fresh approach to fighting malaria: directly target the parasite responsible for the disease. A recent study showed that mosquitoes that landed on surfaces coated with the antimalarial compound atovaquone were completely blocked from developing Plasmodium falciparum, the parasite that causes malaria. The study was led by Flaminia Catteruccia, professor of immunology and infectious diseases and Doug Paton , a research fellow at the Harvard Chan School. In this week’s episode we sit down with Paton to discuss the findings—and how they could be used to make progress in the fight against malaria.
Sex, Drugs & Mosquitoes (Harvard Public Health magazine)
photo: Doug Paton
NOAH LEAVITT: Coming up on Harvard Chan This Week in Health…A new approach to fighting malaria.
DOUG PATON: We allowed the mosquitoes to land on surfaces. And then, immediately after that, we’d provide them with an infectious blood meal. And so, after infecting those mosquitoes, I would leave them for a week. And what we found is that, in our untreated control groups, we would find very good infection, lots of parasites growing on the guts. And then, in the atovaquone treated group, we would find zero infection at all.
NOAH LEAVITT: Progress against malaria has stalled as mosquitoes grow resistant to commonly used insecticides. So, scientists are exploring a new approach: directly targeting the parasite that causes malaria.
NOAH LEAVITT: Hello and welcome to Harvard Chan: This Week in Health, I’m Noah Leavitt.
Each year, more than 200 million people around the world are infected with malaria—and more than 400,000 die.
For the past two decades, the most successful method of malaria prevention has involved treating bed nets with long-lasting insecticides that kill mosquitoes.
It’s estimated that such bed nets are responsible for 68% of all malaria cases averted since 2000.
But that progress is being threatened as mosquitoes increasingly grow resistant to the most commonly used insecticides.
Now, new Harvard Chan School research offers a potential fresh approach to combating malaria: directly target the parasite responsible for the disease.
A recent study showed that mosquitoes that landed on surfaces coated with the antimalarial compound atovaquone were completely blocked from developing Plasmodium falciparum, the parasite that causes malaria.
The study was led by Flaminia Catteruccia, professor of immunology and infectious diseases and Doug Paton a research fellow at the School.
I recently had the chance to sit down with Paton to discuss the findings—and how they could be used to make progress in the fight against malaria. Take a listen.
NOAH LEAVITT: Where did this idea of targeting the malaria parasite itself come from? Is this something that any researchers had looked at before?
DOUG PATON: I’ve been working on some compounds that we’d discovered had sterilizing effects on the mosquito in our original plan. And we’ve always been a reproductive lab. We work on mosquito reproduction primarily. And I’ve been working on ways to sterilize mosquitoes through contact with a surface, in the same way that the insecticides work.
And, as a kind of aside to that, we do infectious experiments here. We’re able to infect mosquitoes with malaria, and because we have those facilities, I tested these compounds against a malaria infection, and found that it actually reduced malaria infection as well, which was a really unexpected result. And that got Flaminia, my PI, and I thinking about that effect on its own. So we had all these different effects with sterilizing and the reduction in infection, and we were working with the modelers that came out and showed that both of those effects would be effective at controlling mosquito populations and malaria transmission.
And we got thinking about this sort of single effect of curing mosquitoes or preventing infections in mosquitoes. And we thought about this for some time, and I did some digging in the literature just to see what was going on there, and picked a couple of compounds and just tried, tried to see what would happen there. And it turned out actually what we– just as a proof of concept it worked extraordinarily well. And then we just kind of ran with it from there.
NOAH LEAVITT: And so, for this study– and I might pronounce this wrong, so feel free to correct me– you coded a service in this antimalarial called atovaquone, which is an active ingredient in medication that’s commonly used in humans to prevent and treat malaria. So was there a particular reason that you chose to use atovaquone? Was there something about this that stuck out?
DOUG PATON: So when I was doing this kind of literature search really what stuck out about atovaquone is a couple of things. One is it’s actually really not a very good drug. It’s very, very lipid bound. It’s extraordinarily insoluble in water and very soluble in lipid. So when you take Malarone, which is the atovaquone containing antimalarial medication, you have to take it with a fatty meal or it doesn’t work. Because your body is so bad at absorbing it.
Now, mosquitoes are coated in a exterior layer of lipids, basic waxes, basically, which protects them from water loss. And so we really thought that maybe those qualities that make atovaquone a bad human therapeutic– although it’s extraordinarily effective– would sort of facilitate its traversal of the insect cuticle, and then allow it to concentrate within the internal compartments of the mosquito. And as it happened that turned out to be a correct assumption.
NOAH LEAVITT: What makes it bad for humans makes it really good for mosquitoes?
DOUG PATON: That seems to be the case, yes. So we’re hoping to kind of follow up on that and start looking for more compounds that have those kind of qualities. And see if they also work.
NOAH LEAVITT: Interesting. And so what happened in your research when mosquitoes did land on these coated surfaces?
DOUG PATON: So what we were doing, we did– we allowed the mosquitoes to land on surfaces. And then, immediately after that, we’d provide them with an infectious blood meal. So this is human blood that contains malaria parasites. They’re infectious to mosquitoes. And they typically take anywhere from 10 days to two weeks to develop within the mosquito and become– and then the mosquito becomes infectious and we’ll transfer that to another human being.
And so, after infecting those mosquitoes, I would leave them for a week, and then come back to them and dissect out their guts to look for the presence of growing parasites on the external surface of the midgut. And what we found is that, in our untreated control groups, we would find very good infection, lots of parasites growing on the guts. And then, in the atovaquone treated group, we would find zero infection at all.
So we were using fairly low doses of a atovaquone and only very short periods of contact– six minutes of contact. And that seemed to be sufficient to completely obliterate any kind of infection in those mosquitoes after really only a short period of contact. That was very exciting.
NOAH LEAVITT: So that’s interesting. So they didn’t necessarily have to be exposed to this compound for a long time.
DOUG PATON: It was very transient contact. So we– the exposure itself is a small glass Petri dish with a lid on top basically, and the mosquitoes are placed in there. And they’re bouncing around, they’re flying, they don’t– they’re very rarely immobile. They really do move around a lot. So the real contact time is very, very brief indeed. Some are probably in the seconds to minutes, rather than the full six minutes. So the contact is very, very short.
But it was still sufficient to get enough atovaquone into their internal compartments. And that’s partly because the atovaquone is good at penetrating the cuticle, and partly because it’s effective at extremely low doses as well. So those two qualities make it kind of ideal for this approach.
NOAH LEAVITT: And so I think what’s interesting here, too, is– so the mosquito lands on it. It can essentially block the development of this parasite, but it doesn’t it doesn’t kill the mosquito itself. And so what’s the benefit of that, of not killing the mosquito?
DOUG PATON: Killing mosquitoes is actually quite difficult. There are many hundreds of insecticides out there with different modes of action and different potencies, but there are only two or three that are safe enough to be used on a bed net.
Now, bed nets are the primary delivery method for insecticides for antimalarial purposes, and the people that sleep under bed nets are almost always children under the age of five and pregnant women. And these are very vulnerable members of the population. And so the compounds that they come into contact with have to be extraordinarily safe. And so almost all insecticides are neurotoxic, and they have some effects on humans. And so finding compounds that are good at killing mosquitoes that are not harmful to humans is actually very, very challenging. It isn’t a very effective approach for controlling malaria transmission.
And so, in this case, we were looking for– this is more of an alternative approach in the absence of an effective insecticide approach. And so, if we are– if the primary goal of the compound is not to– is to kill the parasite, not the mosquito, it makes more sense for there to be no insecticidal effect, because, if there is, then the mosquito will develop resistance to that effect as well. And, in this case, to maintain efficacy over a longer period, you want to avoid that. Possibly using those compounds, in combination with an insecticide as well, with two different modes of action for increased efficacy.
NOAH LEAVITT: And so you touched on resistance there, and part of this challenge of, like you said, it is so difficult to kill mosquitoes. I mean, is that– I mean, malaria has kind of proven to be this really kind of like lingering, difficult to address global health problem. So, I mean, what are some of the biggest barriers for addressing malaria? Is resistance kind of number one?
DOUG PATON: Yeah, I would say resistance in the mosquito is probably the– arguably the largest public health challenge when it comes to malaria at the moment. So, since 2000, when nets treated with insecticides were really began to start being distributed, they’ve contributed to something like a 68% reduction in malaria over that period. But also, at that time, you start seeing very potent and widespread resistance spreading through all of the major human malaria vectors within– particularly in Africa, but also in the other tropical ranges, Southeast Asia and South America.
And, over that time, not only– so you initially start seeing some resistance, a little reduced potency, and now, in certain areas of West Africa, in particular, these mosquitoes are completely resistant to insecticides, even at five times the doses that are commonly used on nets. They’re incredibly resistant. And that’s partly because the insecticides themselves, there’s a single monotherapy, so there’s no combinationary effect, and it’s actually relatively– resistance can evolve relatively rapidly.
But, also, these compounds are used in agriculture in the same areas. And so you get this kind of total environmental challenge throughout their whole period– life stage. All of their life stages, sorry, which will then massively increase the amount of resistance that’s present in the population.
And so what we see now, I was in I was in Burkina Faso in September working with mosquitoes that we were bringing in from rice paddies and villages out there, and they’re insanely resistant to insecticides, and it’s a massive problem.
NOAH LEAVITT: And so because atovaquone targets the parasite essentially, like is there any danger of resistance there, or is it because that’s a different kind of mechanism that it’s not as big of a risk?
DOUG PATON: I mean, it’s definitely an issue, and it’s certainly one that we can’t ignore. But there are a couple of encouraging factors to do with targeting them at the malaria parasite in mosquitoes. Particularly when– in humans, there’s typically something like 10 to the 14 parasites in an infected human being. So an enormous number of parasites. And so the– just through sheer stochastic effects, and just population size, the likelihood of resistance arising in a single human that’s being treated with a single drug is much, much higher than in a mosquito, where typically you’re– particularly where we’re targeting the parasite, which is in the early stages of infection, there’s anywhere between 1 and 100 parasites.
And so the probability of resistance arising at random, or selecting for a particular resistance parasite– resistance mutation, sorry– is much, much lower. Although, the number of mosquitoes is much, much larger.
So there’s models– we’re actually working with some modelers at the moment to try and work out– because we do get this question a lot, and, at the moment, obviously, we– the initial paper was more of a proof of concept, and we are going to be working a lot more on resistance.
But really the– it’s definitely a problem. And particularly because our initial findings were with a human therapeutic, there are some concerns about resistance arising to that compound, because it is used in prophylaxis, particularly for travelers. So two of our ongoing goals are to find alternative compounds. And I think, if we were going to deploy this in a field, like on a net, for example, then we would probably use combinations in the same way that most drugs are now applied as combinations, just to prevent– to reduce the probability of resistance arising.
NOAH LEAVITT: So you just touched on there about like actually putting this out in the field. Like you said, this was kind of like an initial proof of concept step. Like, if the down the line you wanted to test a atovaquone like on a bed net, how would that work? Would the bed nets basically be shipped with this compound on it? Would like a field worker have to go and slather this compound on? How would that work?
DOUG PATON: Well, it’s a good question. So we actually– we’ve started– since the paper came out, we’ve been approached by a couple of different bed net manufacturers about prototyping. And so, typically, there are kind of two kinds of bed net available at the moment. One is an insecticide treated net, which is basically a normal polyester or polyethylene net that’s been dipped in a solution and allowed to dry. So it’s coated. And those are those are effective. They’re kind of first generation nets, and that was the kind of nets you saw up till 2010, and they don’t last very long, and they lose their efficacy over time very quickly.
And, since 2010, the WHO has been rolling out a new kind of net, which is a long lasting insecticide impregnated net, which is where the– I actually believe these are proprietary methods. Most of this is done in industry. The active compounds are combined with the plastic pellets, and then extruded into the net. So it’s actually impregnated directly into the net. And those nets lost anywhere up to five or six years and can resist washing up to 20 times. And so I think, typically, for– and that’s really the kind of direction that public health is going in, in terms of net design.
And so for this kind of approach and maybe in the initial prototyping stages, we’ll be dipping, because it’s going to be low scale and we’ll probably be doing– if we were to take this to field initially, we would be doing experimental huts, which are like fake houses, where– in a kind of grid pattern, where we treat some and we don’t treat others, and then we have various outputs for our trialing. So that would probably be the dip nets.
But if we’re going to scale this up to effectively a clinical trial, then we’d need to partner with industry and really start developing this on a large scale– hundreds of nets. And so that would almost certainly be in impregnated fashion. So whether that’s with the atovaquone or not is still a matter of– it’s actually currently being– we’re working on that with various stakeholders. But we’re also looking for new compounds and the hope would be we’ll find one or two and we’ll be able to really push this forward.
NOAH LEAVITT: And you mentioned that you kind of done some modeling of this approach. So like, what do you– what is the potential impact here? Like, if you get to this point where you’re prototyping, it becomes maybe more widespread, what could the potential impact of this approach be?
DOUG PATON: So when we did model this, and this was with some collaborators we have here at the School of Public Health, Caroline Buckee, and a long term collaborator of ours that’s now at Virginia Tech, Lauren Charles, what we found was this kind of intervention– and we always– we modeled it in a hypothetical intervention where we had an insecticide treated net combining– and also combining an atovaquone-like compound. And so this is a net that will kill an insecticide susceptible mosquito, but cure any mosquito that is not killed by that net.
And so what we saw was, in areas where there is 100% susceptibility to insecticides, the addition of atovaquone had no effect, which is what we’d expect. And, in fact, it’s not really the case anywhere in Africa now. I don’t believe there are any really susceptible populations left in Africa– completely susceptible.
And then what was really exciting, during the modeling, is what we saw, as insecticide resistance increased, the relative contribution of atovaquone or an atovaquone-like compound to reducing malaria transmission became more– much more of the– became more prominent. And so what that really looks like, and this is in much more detail in the model– sorry, in the paper– is that you almost disassociate the effectiveness of your net from insecticide resistance.
So, in a normal circumstance, you see insecticide resistance, completely removing the efficacy of nets for killing mosquitoes, very, very low levels of insecticide resistance. And with the addition of something like atovaquone you see those nets remaining effective, even in extreme cases of insecticide resistance. And so that’s where we think this is going to be the most useful. In those very hotspot areas of malaria transmission where there’s very high resistance and very intense malaria transmission, this may really just put us back on the front foot.
And then this would be combined with mass drug administration, or other human targeting therapies. And we feel like it would really fit into that kind of multi-modal, antimalarial approach that’s really the kind of thing that’s being increasingly proposed to interrupt transmission in these very intense malaria transmission areas.
NOAH LEAVITT: So yeah, I was going to ask, because it sounds like what you’re saying is that this needs to be kind of– it’s not just a broad use kind of the net alone is the solution, but the net in conjunction with these other things in the right area. So my guess is that part of that also kind of figuring out which areas this should be most effective, and most areas maybe it will be less effective?
DOUG PATON: Yeah. And that’s absolutely why we wanted to get involved with the sort of epidemiology side of things early on. Because this kind of integrated approach is– it can be really very potent. I mean, one of the major issues with tropical malaria transmission is it’s year round, and it’s very difficult to interrupt. And so you really need this kind of integrated approach.
And there’s all sorts of sort of slight complexities, where, if we’re using antimalarial compounds on the net, we could also combine that with human treatments that are antagonistic to any resistance that might develop there. And so you have this kind of almost holistic approach, where you’re targeting the parasite in humans as a reactive treatment, and then preventing the parasite in transmission in mosquitoes as a kind of proactive treatment, using different targeting, different compounds, different targets that are complementary in some way. And so kind of amplifying our current efforts.
And most of the things we have at the moment worked very, very well. It’s just that they are– we only have one or two interventions at the moment, and they’re at risk of resistance. So the more tools we can bring to bear, the better. You really have to throw the kitchen sink at malaria to get it to go away, unfortunately.
NOAH LEAVITT: And so, talking about that, I mean, kitchen sink, I mean, what else are you and Flaminia, in your lab, working on? I mean, are there other kind of approaches that you’re examining in terms of that area of targeting the parasite itself?
DOUG PATON: So we have– yeah. I mean that’s– we are. So we’re a mosquito lab, and we do have the ability to give infections, so a lot of our research sort of runs around that kind of access. And so some of the other things that we’re doing in the lab, we’re working on Wolbachia, which is a mosquito endosymbiont It’s a bacterium that lives in the mosquito that we’ve actually– some of my colleagues, Rob Shaw and Perrine Marcenac, recently showed, a couple of years ago, that the infection of Wolbachia in Anopheles gambiae, principal vector of malaria in Africa, prevents or reduces malaria within those individual mosquitoes. And it’s present in wild populations at a low level. And so those individuals are rarely infected with malaria.
And we’re working on ways, at the moment, with some other colleagues in my lab to– in Flaminia’s lab– to try and, one, work out what the– how that works, and whether we can increase the amount of Wolbachia in those populations, and try and make mosquitoes more refractory to malaria transmission.
And then another thing that another colleague of mine, Andie Smidler, is working on is a gene drive approach, which is this kind of transgenic or genetically modified mosquito that’s either carrying a sterilizing cassette, which will suppress malaria– mosquito populations, or carrying some kind of transgene that prevents them transmitting malaria in some way.
So there’s a couple of sort of multi-modal approaches there. And, obviously, my work is only a small part of what we do in the labs. So there’s a lot of different and potentially complementary approaches that are coming through the pipeline at the moment that are kind of trying to move away from insecticides, because they’re so difficult. It’s difficult to find new ones and they have this potential environmental and human toxicity issues as well.
NOAH LEAVITT: Yeah, so it’s interesting you mentioned that, because my thought, as you were describing some of the other work, was it seems like a lot of this work kind of is based on understanding the biology of the mosquito, and then either finding a vulnerability, so you’re not as relying as much on insecticides. So is that kind of– would you say that’s accurate, that a lot of your lab kind of works on targeting the biology of the mosquito and using that instead?
DOUG PATON: I mean, we’ve always kind of– we really– Flaminia really started off as a kind of– very much investigating basic biology, and a lot of our more applied research is just coming from our basic research, which is really– it gives us some advantages. And that means we kind of throw off some fairly interesting ideas fairly regularly. So there’s always a lot of work to do.
But really, yeah, one thing that I think has been clear for a long time within our field is that the more tools we have, the better. I mean, they’re not all going to be useful all the time, and obviously it’s very expensive to get these things ready for the field, but the more potential ideas we have coming through, the better that is for everybody. And that’s, I think, something we’re really focused on, is, as you say, that kind of basic biology of the mosquito, and really trying to describe how they function, and then finding ways– of novel ways of interdicting malaria transmission from that.
And then, also, that has potential effects. We can potentially translate some of this to other mosquito borne diseases, like dengue or Zika as well. And so this is really kind of almost a crucible of new data that then will hopefully potentially inform disease control in a lot of different spheres. So it’s really exciting work.
NOAH LEAVITT: And so just to kind of end back at the beginning, what are some of your next steps here? Is one of the next steps, really, OK, let’s see if we can find other compounds that work similarly to atovaquone, or the next step, B, kind of doing more of like this prototyping and putting it on a bed net? So where do you and Flaminia head next?
DOUG PATON: Probably all of those directions. Honestly, this is a lot. So things are really expanding. We’re trying to bring in funding, so we can really build this up. And there’s sort of three major goals we have. One is– atovaquone works so well. I mean I’m still trying to describe– I haven’t really reached the limits of it. This is my major– what I’m doing right now is trying to find out where it stops working. So we tried to do– the initial results that we published recently were all exposure around blood feeding, so the point of infection.
And one of the things I’m trying now, because the length of time the parasite spends in the mosquito is so long, there’s this opportunity for not only preventing infection, but actually removing infection from mosquitoes. And that would make the whole approach a lot more potent, in terms of– just in terms of the probability of whether a mosquito is infected before or after it comes into contact with the intervention.
And so some of the work I’m doing at the moment is trying to find out what happens when you expose mosquitoes that were already infected to atovaquone, and that took a lot of time to get sorted out, just simply because it’s a lot more dangerous. Because we’re working with infected mosquitoes, so we have to be very careful. And it took a while to get the protocol sorted out for that. So that’s my main focus at the moment.
But, over the next six months, we’re going to be doing a lot more screening. We have some partnerships with some– with an NGO called the Medicines for Malaria Venture, who will be supplying us with a library of compounds that we can– antimalarial drugs– that we’re going to test in our current setup, and see if we can find more compounds, and particularly more modes of action that work. And then, we do partner with– regularly with– some colleagues of ours in Burkina Faso, so we have a really strong collaboration with some field based colleagues out there. And I think, within the next year or two, we’re hoping to do some very limited field trials.
The other thing is that we’re– in the lab, we tend to work with insecticide susceptible mosquitoes. And one of the things we can do in Africa, if we go to Burkina, for example, is work with the actual mosquitoes that we want to target initially. And so I’ve done a little bit of work there. And what’s exciting is atovaquone appears to continue working against very, very insecticide resistant mosquitoes. And that’s something that we need to continue, and think about how resistance affects the kind of pharmacokinetics of the compound within the mosquito.
So there’s a lot of very descriptive work to do, as well as more sort of discovery as well. So it’s– and, at the moment, it’s just me. So I’m mostly– the primary focus is to pull in a few more staff members and build a team, and really start working on it. Because this thing has really kind of blossomed into a very large research project, and I can’t do all of it.
NOAH LEAVITT: Well, hopefully you’ll build that team out.
DOUG PATON: Yeah, I hope so. Yeah.