Fighting Malaria Resistance

With the widespread introduction of disease-tackling tools we’ve seen big reductions in malaria cases and deaths over the last 10 years. But half the global population still remains at risk and in 2016, the World Health Organization reported a worrying reversal in progress with 216 million malaria cases reported that year, a 5 million increase over the previous one.

Malaria is fighting back against our current interventions, with the parasite and mosquitoes developing resistance to antimalarials and insecticides respectively. In April 2018, global leaders from government, business, science and global health met in London for the Malaria Summit to reinvigorate efforts to eliminate malaria, urging Commonwealth leaders to make a commitment to halve malaria in the next five years.

The renewed action aims to combat resistance focusing on three important areas, increased funding and political leadership, better data driven solutions and finally, by accelerating innovation to produce alternative weapons to join the fight, from new antimalarial drugs to malaria vaccines.

On World Malaria Day, we spoke with NIBSC scientist Dr Paul Bowyer about the development of new vaccines and how his group’s work aims to better understand parasite resistance to support the development of innovative solutions to malaria.

“Antimalarials can be a very effective measure to clear up infections, but with 200-300 million cases of malaria each year and a need for repeated dosing, huge numbers of drugs are required.”

“Lessons from mass administration of drugs like chloroquine teach us that when it comes to malaria elimination, strategies that involve flooding an antimalarial into a population can have localised benefits, reducing and sometimes removing malaria. But these activities increase the risk of the parasite adapting to the drug and becoming resistant.”

“There’s also an additional complication with counterfeit malaria medicines. Not only do these ‘fake’ medicines mean people aren’t receiving the treatment they need to protect against malaria, but if the drugs have some but not the necessary dose of the active ingredient, they can also contribute to resistance.”

Today’s malaria fighting tools have been made possible through vital investments in research. World Health Organization infographic for World Malaria Day 2018.

Anti-malarial therapy alone isn’t enough to combat malaria, and we’re increasingly seeing resistance develop to even the most recent classes of anti-malarial drugs. Eliminating malaria needs a combination of effective methods including interventions to limit mosquito bites such as bednets and insecticides, novel drug therapies to treat disease and effective vaccines to boost malaria immunity in whole populations.

“The most cost-effective way of tackling infectious disease is through vaccination. For malaria elimination, a vaccine offers great advantages as it should provide longer-term protection from the parasite”

“Most malaria deaths occur in Sub-Saharan Africa, in children under the age of 5, before they’ve been able to build up their natural immunity to the parasite. A malaria vaccine could accelerate the development of this immunity and ideally achieve this process nice and early in someone’s life before they’ve even been infected.”

So where are we with malaria vaccines?

Mosquirix™ is the most advanced malaria candidate vaccine. Phase III clinical trials in infants were successfully completed in 2012 and it has since received a positive scientific opinion from the European Medicines Agency (2015). But there are more in the pipeline.

Developing a malaria vaccine is challenging, so manufacturers are adopting a number of approaches. One of the first things vaccine scientists need to consider is when to target the parasite.

The parasite’s life cycle is complex as it develops both within the mosquito and human host. It first enters the human host via a mosquito bite, then travels to the liver, where it replicates, before emerging and infecting red blood cells. Once the parasite is in the red blood cell, it undergoes cycles of replication, egress and re-invasion, infecting more and more red blood cells. Some parasites also undergo a transformation, remaining in the red blood cells for far longer and developing into the sexual stages of the parasite ready to be taken up by the mosquito during its next blood meal.

“Vaccines like Mosquirix™ protect against the early stages of the disease before the parasite begins to replicate in the blood. The idea is that by targeting this stage, you raise response against the parasite before it ever establishes and starts multiplying.”

“Another option is to target the parasite later, when it’s living within the patient’s red blood cells. As most clinical signs start to appear at this point, targeting this stage could stop the most dangerous symptoms of the condition from developing. Although targeting this stage wouldn’t block all infection, as the parasite would have already invaded the patient’s liver cells.”

“Transmission-blocking vaccines instead focus on preventing infection of the mosquito from humans and thus stop the parasite from being passed on from one person to the next. These vaccines present a really interesting dilemma as the vaccinated individual wouldn’t get any direct benefit from the vaccine, but they could prevent the spread of malaria through a population.”

As it progresses through its life cycle the parasite is continually changing, expressing different molecules on its surface. So once the stage has been selected, developers need to think carefully about the specific molecules on the parasite surface that could be vaccine targets. And this is where the issue of resistance again comes into play.

“At the moment the one vaccine we have targets a single malaria protein, sort of akin to a single malaria drug. Lots of different molecules on the parasite surface that have been identified as potential vaccine candidates have, over time, evolved to escape the human immune system and show huge amounts of genetic variation. So for any given protein that’s selected, there may be many different antigenic forms out there that are capable of causing an immune response.”

“By selecting only one antigenic form of a protein for a vaccine, there’s a risk that the vaccine form of the protein might disappear from the malaria population and the vaccine will eventually become ineffective”

With the emergence and spread of antimalarial resistance, current drug approaches look to combination therapies where more than one therapy is given to the patient at the same time to try and prevent resistance. Should a similar approach be adopted for vaccine development?

“Ultimately there’s all sorts of ways to approach vaccine design with respect to the life-stage targeted, numbers and genetic forms of proteins, or even whole parasites, and lots of different people are taking different routes.”

“Vaccines are being developed to cover all these bases, but the outstanding question is which ones are going to be the best? Should we target several antigens from one life stage, or one antigen from multiple life stages?”

“There might be a degree of overelaboration for some vaccine candidates that are targeting many different proteins from different parasite stages, but there are also potential concerns regarding resistance if all angles haven’t been covered at once. As it stands we don’t know enough about how they work to predict if they’ll prevent malaria, let alone if evasion is going to be a problem.”

Where we fit in

The team here at NIBSC are trying to design a number of tests that will help us to see how the parasite might evade pressure from the human immune system and give us an understanding of the protection each vaccine might offer.

“Currently, it’s very difficult to understand how effective vaccine candidates are outside of clinical trials in humans as we can’t recreate the immune system in the lab. So, in general, it’s hard to know how the current vaccine candidates are working.”

“In drug discovery, scientists will test the parasite’s ability to generate resistance to the drug of interest, by putting varying amounts of drug on the parasite and seeing what parasites survive to understand the basis of this resistance. It’s inconceivable that you’d go ahead with a drug without some sort of knowledge of potential resistance.”

“For biologics, we don’t have the same portfolio of things to test, or the range of assays to test them in. There’s several tests we can do in the lab to build up parts of the picture of the human immune response and my group is assessing and developing these to understand if they can be used to tell us how effective a vaccine might be and, also, how easily the parasite could change to evade it.”

Cryoscanning Electron Microscopy (CryoSEM) image of a red blood cell (red) with a malaria parasite (cyan) within its parasitophorous vacuole (orange). Image courtesy of the Biological Imaging Group, NIBSC.