Malaria trial to deliberately infect people with parasite

Learning more about the vivax species could lead to new treatments...
24 January 2025

Interview with 

Andrew Duncan, University of Oxford

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MOSQUITO

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A group of volunteers are about to be deliberately infected with a form of malaria at the hands of researchers at the University of Oxford’s Vaccine Group who want to understand more about Plasmodium vivax - which is one common form of human malaria that can remain dormant in the liver, and then reappear even years later. To explain what they’re trying to do, and how, here’s Andrew Duncan, the doctor who’s leading the trial…

Andrew - We are planning a research study where we're taking five healthy volunteers from the United Kingdom. We are deliberately going to infect them with a species of malaria called vivax malaria to find out more about it.

Chris - Lots and lots of people, particularly people in Southeast Asia, catch this naturally, don't they? So why do you need to infect even more people with it?

Andrew - That's a very good question. You're absolutely right. It's a mosquito-borne infection, particularly common in Southeast Asia, as you say, and South America as well. The particular problem is that it causes a relapsing illness. What that means is when you get the mosquito bite that introduces the infection, it can come back months or even years later. So in Southeast Asia, where this is found, you can't really tell whether this is a new infection or a relapse—an infection that's come back. We want to develop a very controlled scenario where we can study these relapse infections closely and find out more about them.

Chris - Is it as simple as you put someone in a room with some mosquitoes that you know have got this particular form of malaria and you let the people get bitten?

Andrew - In a nutshell, yes. It has to be slightly more controlled than that. It's not a room with lots of mosquitoes whizzing around. We actually contain them in a box that's got netting on it and ask the volunteers to place their arm on the netting so that we can see the mosquitoes biting the surface of the skin. But yes, in essence, it is a mosquito bite-administered infection.

Chris - And how will you know who's got it and who hasn't?

Andrew - Once the mosquito bite has happened, we'll do daily blood tests, tracking the infection as it appears over the next week or two. What's great is that with our fancy blood test called a qPCR test, we can often detect the infection before people even develop some of the malaria symptoms you might be familiar with, like fever, muscle aches, or headache. We can treat people with a tablet to get rid of the active infection but deliberately leave the dormant form of the parasites that stay hidden in their liver. That's the bit where these sleeping parasites can reawaken in the months following to cause a relapse infection—one that comes back.

Chris - Is that the follow-up aspect of the study then? So, having made sure that people are not going to get acute, really severe malaria, you nevertheless let them develop the dormant phase and then follow that up because that's the one you're interested in. How does that happen? Why does it happen? When does it happen?

Andrew - Yeah, brilliant question. We give tablets to get rid of the active infection, leave these dormant sleeping parasites alone, and monitor people very closely for a six-month period. We're going to see them in our clinic every two weeks, and there's going to be a doctor on call 24 hours a day. If they did develop any of the symptoms such as fever or headache, they would give me a ring, and I would come to see them, take a blood test, and check to see whether they had this active reawakened infection.

Chris - And is the aim then to learn what the triggers are when this thing comes out of its dormant state in this way? Why is it doing that, and are there any markers we can look for that might give us a clue? I presume that's what you're doing this for.

Andrew - Yeah, that's the big unknown, really. In the natural world, in these countries in Southeast Asia, it's really tricky to tell the difference between a new infection from a mosquito bite and one that's coming back. They look exactly the same. So we're hoping we'll get really good insight into why these come back when they do, how the body responds when it comes back, and what the molecular processes are that happen to reawaken the parasite. It's all a big unknown. The relapse infections, we think, are responsible for the bulk of all the infections with vivax malaria that occur in the world. Understanding them to develop novel drugs, treatments, or vaccines is really key. I should say that if this study works, we will have the perfect platform to test new vaccines and new tablets. So there are two goals: one, to find out more, and two, to develop a method of testing new vaccines and drugs.

Chris - And presumably, once you're done with these people, you have got a way of clearing the dormant stage as well, so they're not destined to be wandering around with this—just like a ticking time bomb for the rest of their life.

Andrew - Yeah, thankfully, there is an additional antimalarial tablet called Primaquine that can clear the dormant parasites. What's interesting, and in keeping with all this, is no one really knows how it works. You have to take a tablet once a day for two weeks, but it is effective and will clear away the sleeping parasites that can reawaken.

Chris - Does this translate then into almost like an archive sequence of blood samples charting the infection, possibly the reactivation from the dormant state, and its retreat when you start to treat each of these phases, so that people in the future, not just you even, but other researchers, can then look at those samples and probe through them, looking for triggers and possible markers of what is going on when and possibly why?

Andrew - Absolutely. And that's what I find really exciting about this study. It's about gathering new information and new insights into something that's not particularly well understood. So we will have a series of blood samples, as you say, taken over a period when the infection's completely asleep, when they've got no symptoms, no detectable signs, during early reawakening, and then fully awake. We'll treat this reawakened infection. We'll have this whole time series. We've already got lots of advanced tests and analysis planned. But you're right—there might be things in the future that we think of, and we'll have this wonderful resource of blood samples to explore further things that may not even be invented yet. It's really exciting.

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