Australian scientists have developed a new anti-malarial drug that targets the stage at which the disease reaches the stage of illness Plasmodium The parasite moves from the liver cells, where it initially grows, into the bloodstream. Blocking this process not only prevents symptoms of the disease and stops it spreading to other people, but incapacitating the parasite in this way has also been shown to trigger a very strong immune response against it, which can prevent subsequent infection, perhaps indefinitely. It also means that any other mosquito bites that occur in the meantime act almost like vaccine boosters, boosting the immune response and boosting protection. As Chris Smith hears, it’s a whole new way to stop malaria, and make people immune at the same time, and it’s the brainchild of Justin Boddy, a researcher at the Walter and Eliza Hall Institute in Melbourne…
Justine – We currently have anti-malaria measures in place. There are three lines of defence, really. Insecticide-treated mosquito nets, antimalarial drugs, and vaccines. The problem is that mosquitoes have acquired resistance to insecticides, and our two approved vaccines, which were already major breakthroughs, are incomplete because they do not provide broad, long-term protective immunity, so we need additional vaccines. And the parasites are constantly developing resistance to the antimalarials that we’ve developed, and we have some amazing antimalarials. So, we have a big problem on our hands, which is that while we continue to fight malaria, they continue to fight it.
Chris – And what do you do to try to take this fight to the parasite?
Justin – We are embarking on a drug development program. We were trying to develop drugs that would be effective not only against the parasite when it infects red blood cells, but when it moves through its life cycle between mosquitoes, human liver, human blood, and then back to mosquitoes again. And so when you’re developing new antimalarial drugs, what you really want to do is have activity at multiple stages of the parasite’s life cycle, because it gives you a number of different options. You may have heard the saying prevention is better than cure. And so what we set out to do here is the idea that we can actually use antimalarial drugs, not only to treat malaria, but also to prevent malaria before it takes hold. In doing so, we revealed that this drug can elicit a long-lasting immune response in preclinical models that we did not really expect.
Chris – Can you explain a little bit more, Justin, how this actually works in terms of how a drug that can prevent the parasite can also boost an immune response like this?
Justin – Sure. It all comes down to the way malaria is spread. So mosquitoes bite people and inject these little parasitic forms called sporozoites, and sporozoites are very small. They can come out of the mosquito’s proboscis, get into the skin and then into the liver, and they’ll actually invade the liver cells and grow inside them, and these people have no idea that they’re infected. It’s effectively silent. There are no symptoms, and there is no awareness that the person is infected. This continues for a week to 10 days, then the parasite emerges from the liver and infects red blood cells. This then leads to malaria, the disease, and all the pathophysiology associated with malaria. So what this drug does is it prevents the malaria parasite from moving from the liver into the blood. So remarkably, in fact, the drug allows these sporozoites to invade the liver, and allows these liver-stage parasites to grow and multiply in exponentially very large numbers, but it kills them at the end of the liver stage, before they can infect red blood cells. The late liver stage happens to be a good immune point for priming both CD8 T cells, but also antibody responses that together can provide multiple lines of defense.
Chris – And then supposedly, if a mosquito comes along and re-challenges someone with malaria again, while they’re on this agent, they’ll get a significant immune response to that liver stage, which is then allowed to go forward. But then it does not turn into clinical disease, because the parasite is prevented again at that stage. So they get all the benefits of immune priming, and none of the harms of the disease.
Justin – You hit the nail on the head, Chris. That’s why we’re so excited about it, and I think what this reveals is the possibility that unlike current vaccines, which are really important, where you need high enough input numbers of sporozoites to elicit a strong protective immune response, this anesthesia approach allows for the introduction of a small approach of sporozoites into still basic immunological education. And as you rightly identified, each subsequent mosquito bite will give up the same opportunity for immune education, but that’s in a boosted environment, and so we know that our immune systems really like to be boosted. This helps them maintain immunity, but it also helps expand immunity. So malaria can be a problem because there are different variants of it, like COVID-19, and so if there are areas where there is more than one variant that would be present in the population, this approach could also provide protection against those different variants through this booster approach every time a mosquito bites.
Chris – Tell us what evidence you have that this will work, because it sounds like a great approach. It might seem like an amazing theory if it works, but what evidence can this actually provide?
Justin: Yeah, that’s a really important question. And so I think it’s clear that we need to be conservative about this, but we need to present the evidence that we have very carefully. So the evidence is twofold. Our study is in pre-clinical models using different strains of mice. So there’s malaria that infects mice, and mice can predict perfectly. Sometimes these results are not predictive, but the mice can be predictive of malaria vaccination. And in our mouse models, what we’ve observed is that just one encounter with a sporozoite that’s been given to an animal in the presence of this new drug that we’re developing with our pharmaceutical partners, that’s enough to not only protect them from disease, but to protect those animals for the rest of their lives, so we have lifelong immunity from a small encounter. We tested this across a range of different mouse strains that themselves have different immune arms. So, in some mice, you get strong antibody responses, but not as strong T-cell responses, and in other strains of mice, the opposite is true. And so what we can show is that we get strong, long-lasting antibody responses, but also long-lasting, what we call tissue-resident memory T cells that are primed and boosted, and will remain there, particularly in the liver, waiting for the infected liver cells to be recognized by a variety of different parasite antigens.
Chris – Does this require the individual to stay on the medication though? So is this drug only effective while you continue to take it, like all the other antimalarials we have at the moment?
Justin – This is where we would like to investigate this further in humans. So, for future mice, the drug no longer exists. The half-life of the drug is about two and a half hours in mice. And when we challenged those mice even two years later with mosquito bites, they were still completely protected against malaria infection. So, there’s this long-term protection that this specific mechanism provides. And so what we would like to understand is whether or not this is true in humans, because if so, this has the potential to be a complete game-changer in terms of how the drug can be used to prevent malaria in vulnerable communities.
