Plasmodium knowlesi: Biomedical, environmental and social risk factors for infection

Plasmodium knowlesi: Biomedical, environmental and social risk factors for infection

In December, PaCCS Communications Officer Kate McNeil sat down with the London School of Hygiene & Tropical Medicine’s Professor Chris Drakeley, a Professor of Infection & Immunity who has spent the past 30 years working on malaria. Professor Drakeley’s work on the biomedical, environmental and social risk factors for human infection with Plasmodium knowlesi was designated as falling under the Global Uncertainties project umbrella. This conversation has been edited and condensed for clarity and concision.

Kate McNeil: Thank you so much for taking the time to speak to me today. I’m wondering if you could get started by telling me a bit about your research background, and how you ended up studying malaria in Malaysia?

Professor Chris Drakeley: I am a malariologist, and I am interested from a biological background in how malaria transmission is maintained in communities. Studies of transmission are typically very human-centric, but I am more interest in how malaria is transmitted to mosquitos, including zoonotic malaria.

Not surprisingly, many organisms have a type of malaria, including some primates. As humans are very biologically similar to primates, there is potential for movement between species. I became interested in and concerned by one of these forms of zoonotic malaria, plasmodium knowlesi. This form of malaria cycles through the blood much more rapidly than the forms of malaria typically found in humans. So, there is the potential for a very rapid increase in the number of parasites you have in your blood over a very short period of time, which could lead to hospitalization, severe disease, and in some cases, death.

The first known case of plasmodium knowlesi in humans was in an American CIA agent, who contracted it in Malaysia. Then, the CDC demonstrated that this disease could be passed between humans through mosquitoes, resulting in human-to-human transmission. Subsequently, it was discovered that 80% – 90% of all of the cases of malaria in Malaysia and northern Borneo were plasmodium knowlesi, which was associated with severe clinical manifestations and death. This is still relatively rare, and it is important to stress that the numbers are not huge, and this is not a massive problem. However, where this form of malaria was contracted, it had a very high case fatality rate. So, our project was to understand what drives the transmission of this form of malaria. We wanted to answer some really simple questions like ‘how does it work?’

What did this research project entail?

This project was conducted over the course of five years, and we were fortunate to have quite a lot of built-in flexibility to follow the results throughout the study. Our main signal was hospital clinical cases, and once we found cases, we would try to follow those cases back to the village. In the village, we wanted to understand who was getting infected, who was not getting infected, and what the differences were between those two groups. That could tell us where individuals might be getting infected. From there, we drew upon expertise from primatology, entomology, and sociology to try to unravel how the behaviors of mosquitos, macaques, and humans were contributing to the transmission cycle. Ours was the first study of this type to be published in the Lancet.

What we found is linked to broader issues of human-driven environmental change. Simply, human-driven environmental change, particularly deforestation which reduces the territory available to macaques, is bringing macaques, mosquitos, and humans into closer and more frequent contact. We were able to demonstrate this through drone work, which was truly eye-opening, in a sense, because you could capture the widespread destruction of forest and habitat from week to week. We put tracking collars on some macaques and were able to demonstrate that when their habitats are destroyed, they move, and range quite broadly during the period following their disruption. We then did a massive survey looking at associations for exposure and found that the majority of infections in clinical cases are in adult men who go into the forests.  Primates are very similar to us and host similar infectious diseases – mostly viral. Consequently, our study offers the building blocks to examine other vector-borne and zoonotic infections.

Have the findings of your research shone a light on any avenues for managing the challenges posed by plasmodium knowlesi?

While the Medical Research council gave us the funds to conduct this research, they did not subsequently fund a clinical trial of optimal drugs for treating plasmodium knowelsi. However, we were able to attract funds from another donor to do a clinical study demonstrating that the conventional treatment for malaria works in treating this form of malaria as well. This means there can be a unified treatment, which is huge, because it can reduce clinical morbidity, and that you do not have to worry about having lateral flow tests need to identify the type of malaria – though these lateral flow tests do still need to be improved.

With respect to forest management, we were able to provide our forest classification to the Malaysian government, so they could refine a map of where they think individuals might be at increased risk of contracting the disease. They now use that in their malaria guidelines. Often, it is difficult to prevent people from going into the forest to hunt or collect things, and beyond repellents there is not much in way of individual protection measures. What matters more is public awareness – so now, there is a series of posters which show that if you have a fever after being in the forest, you should go to a doctor to get checked because this is a malaria risk area.

We have also been approached by a number of other researchers interested in our samples and surveys to understand associations with other infections. So, there are infectious such as Nipah virus and filariasis which show distinct geographical patterns, and there are other zoonotic infections which show distinct patterns related to semi-domestic cats. From these understandings rise broader issues about how we deal with pandemic-potential viruses, and how we should manage bio-conservation.

What are you working on now?

I have been doing some work on covid-19 recently, but I am still working on malaria and malaria transmission. Our projects in Malaysia have finished, but we are still trying to support ongoing projects elsewhere. So, we have someone working on diagnostic tools in the Philippines (which has similar elements to Malaysia, but which has much lower rates of plasmodium knowlesi infections in humans, perhaps because the macaque population there is much more afraid of people). The Philippines does have quite a lot of malaria in general, and those cases are concentrated on a few of the archipelago’s islands, so we are working with indigenous communities in remote parts of the country to determine how we can protect them.

What do you want policymakers to be thinking more about?

I think policymakers need to think about interdisciplinarity in science. I am a biologist, but I have worked with primatologists, conservationists, geographers, and social scientists. Especially when you are trying to eradicate a disease, or study a disease that is quite rare, you need that interdisciplinarity. I also think it is worth mentioning the longevity of these things. We discovered all of the things we talked about today over the course of five years, but the research is still there, four years after the end of it. You invest a lot in collaborations, and you cannot be short-sighted. You need to monitor things even when they are fairly low risk at the time, longer term investments in surveillance and projects which are embedded in communities offer so much more value. I think we are learning that now with covid-19.