A weapon against malaria

What is malaria?

Malaria is a life-threatening disease found in tropical and sub-tropical areas of Africa, South America and Asia. It is caused by tiny Plasmodium parasites that are carried from one human to another by mosquitoes. Malaria is responsible for hundreds of thousands of deaths each year. Sadly, the majority of these are children under five years old.

Plasmodium falciparum has evolved cunning ways to shrug off the effects of many drugs.

Malaria has been a feature of human life for thousands of years. In the past few decades, team”s of scientists, doctors and charity-workers around the world have joined forces to come up with strategies to prevent and treat malaria – distributing hundreds of millions of mosquito nets, carrying out insecticide spraying to kill the mosquitos and developing antimalarial drugs. Although there are five species of Plasmodium parasite that cause malaria in humans, Plasmodium falciparum causes the most serious, life threatening infection and is therefore the focus for much of these efforts.

Since 2000, funding for malaria control has increased and huge progress has been made, with death rates falling globally by 47%. However, Plasmodium falciparum has evolved cunning ways to shrug off the effects of many drugs that were once very effective. Drug resistance has become one of the largest challenges in the fight against malaria.

Scientists and charities around the world are working together to take on the challenge, but the fight against drug-resistant parasites would be greatly aided by the development of a vaccine.

What is a vaccine?

Vaccination is one of the most effective ways to control infectious diseases.

A vaccine is given to an individual to help ‘train’ their immune system to recognise a particular pathogen in the future. A vaccine usually contains a small amount of the pathogen, which the body will recognise as foreign and start producing antibodies against. This means that when the body is later exposed to the pathogen itself, the body already has an army of antibodies ready to launch a direct attack against it.

Vaccination is considered one of the most effective ways to control infectious diseases because, unlike a drug, it uses the body’s natural defence system. Vaccines can provide protection against a particular disease for a much longer period of time, and can sometimes prevent infection from happening at all.

Why haven’t we got a malaria vaccine already?

Plasmodium parasites were first identified as the cause of malaria in 1880 and the role of mosquitos as vectors for the parasite was revealed in 1898. So why are we still without an effective vaccine against malaria?

Complex organism

The Plasmodium species are protozoan parasites. This means that they are eukaryotic cells, just like those in our body. Plasmodium parasites have a similar structure to our cells, with a nucleus, and have much more complex cellular structures and life cycles than bacteria and viruses. This complexity makes developing a vaccine against Plasmodium parasites much more of a challenge. Although vaccines have been developed against several viruses (for example, smallpox) and bacteria (for example, tetanus), there is currently no vaccine against any eukaryotic parasite.

Cunning life cycle

By definition, a parasite is an organism that lives in or on another organism (its host) and benefits from them at their expense. However, to survive and thrive inside the host the parasite has to avoid being detected by the immune system. To do this, the cunning Plasmodium parasite has evolved so that a large chunk of its life cycle takes place hidden inside the cells of its host. As soon as it enters the bloodstream Plasmodium heads straight for the liver and burrows into the cells there. Here it matures and multiplies before bursting out of the liver into the blood and invading red blood cells, where it multiplies repeatedly, causing the disease we know as malaria. This strategy of multiplying inside the host’s cells means that the malaria parasite is hidden and protected from the immune system for much of its life cycle.

Variability

A complex life cycle is not the only trick Plasmodium has up its sleeve to evade the host’s immune system. When the malaria parasite enters the host’s cells, protein signals appear on the cells’ surface. A vaccine could be based on these signals but the malaria parasite has developed a complex method to frequently change the specific protein signal that it displays. So, while a vaccine could be developed to train the immune system to recognise one protein signal, it wouldn’t necessarily help it to recognise any others.

Why do we believe a vaccine against malaria could work?

If people repeatedly get infected with Plasmodium falciparum, they eventually develop a level of natural protection, also known as immunity. This suggests that if the human body experiences the P. falciparum parasite enough times it becomes able to recognise when it is present and launch an effective attack against it. A vaccine would simply be a way to speed up a process that already happens naturally.

The scientists then stuck their arms into the cage of mosquitoes and voluntarily got bitten…

There is also direct experimental evidence that it is possible to vaccinate people against malaria. In one example, scientists took a number of mosquitos infected with malaria and exposed them to gamma radiation strong enough to hinder the parasite’s function but not to kill them altogether. The scientists then stuck their arms into the cage of mosquitoes and voluntarily got bitten around 100 times to infect themselves with the malaria parasites. Because the parasites had been exposed to radiation, they did not cause malaria, but they did stimulate the volunteer’s immune systems enough to protect them against future exposure to live parasites.

This experiment demonstrated the effectiveness of an ‘attenuated’ vaccine where the virulence of the pathogen is reduced so it is harmless and doesn’t cause disease. However, this particular approach would be difficult to perform on hundreds of millions of patients. Much research has therefore focussed on finding easier ways to develop a malaria vaccine.

How close are we to finding a vaccine?

In the history of malaria vaccine development, scientists have usually steered towards targeting just one specific stage of the parasite’s life cycle at a time, such as when the parasite leaves one red blood cell and tries to invade another one. To date, the most advanced vaccine candidate has been RTS,S.

RTS,S

RTS,S has been under development for over 20 years and several studies in the lab and in children in Africa have shown that it may help protect young children and infants against malaria caused by Plasmodium falciparum.

RTS,S is based on a protein called circumsporozoite protein (CSP) that forms a coat around the sporozoite stage of the parasite. These are the thin, slender malaria parasites that are first transferred to a human host when a mosquito bites someone.

CSP appears to act like GPS helping the parasite get to the liver.

CSP is therefore one of the first proteins that the host’s immune system encounters after the parasite is injected. The protein appears to act a bit like GPS helping the parasite get to its first destination, the liver. The RTS,S vaccine was developed to train the immune system to recognise CSP and trigger an immune response that would kill the parasite before it reaches the liver.

Vaccine trials

Initially the RTS,S vaccine was trialled as part of the U.S. Military Force Malaria Programmes. The armed forces are at great risk of developing malaria while deployed in malaria-endemic regions and have consequently been heavily involved in investigating methods to control the parasite. The vaccine was then picked up by the British pharmaceutical company GlaxoSmithKline (GSK) in the 1990s. In the last few years, GSK has put the vaccine through to Phase III clinical trials, the furthest a malaria vaccine has ever got, meaning the vaccine was tested in over 10,000 people.

Vaccine given green light

In 2015, after 30 years of research, the European Medicines Agency gave RTS,S (marketed as Mosquirix) the green light for safety and effectiveness. This is one of the last hurdles before final approval and was considered a significant scientific achievement. The vaccine is intended for use against malaria infection in children in Africa rather than for travellers.

While the vaccine has been shown to be safe with few side effects it is unclear how long its protection will last in the long term. The best level of protection was found when children aged five to 17 months were given three doses of the vaccine, each a month apart, in conjunction with a crucial booster dose after 20 months. So far it has been seen to protect patients for up to five years but no longer, so it is likely that it will need to be used in conjunction with other preventatives.

So what’s happening now?

Scientists are currently looking for a vaccine that will target the blood-stage of malaria and could work together with RTS,S. So far the furthest a blood-stage vaccine has progressed in clinical trials is to Phase II. This is when the vaccine is given to one or two hundred people who are then monitored to see if they are protected from malaria.

One of the big challenges in developing a blood stage vaccine is choosing which of the large number of potential target proteins is the best one. In 2014, scientists at the Wellcome Trust Sanger Institute and the Kenya Medical Research Institute collaborated to come up with a new malaria vaccine. They started by selecting a library of proteins from Plasmodium falciparum that were considered promising candidates for a malaria vaccine. All of the proteins selected are expressed by the parasite late in the blood stage, when it leaves one red blood cell and tries to enter another.

In the study, a group of children infected with malaria were studied for six months by scientists at the Kenya Medical Research Institute. Some of the children became sick while others were protected naturally by antibodies that stopped the malaria parasite from entering their red blood cells. Blood samples were taken from the protected children and studied to find the combinations of antibodies in their blood that protected them against the malaria parasite.

The team” then screened the antibodies against their library of proteins from Plasmodium falciparum to see which proteins they bound to. It was found that protection was associated with having antibodies against lots of the proteins at once rather than just one ‘magic bullet’. This supported previous theories that a successful blood-stage vaccine will need to include multiple different targets to be truly effective.

Looking forward, what are the challenges?

Transmission-blocking vaccine

There is also a lot of interest in developing a vaccine that prevents transmission of the malaria parasite from one human to another, for example by blocking development of the sexual stages of the parasite in the mosquito’s gut. One interesting aspect of a transmission-blocking vaccine is that they wouldn’t directly benefit the person being vaccinated. However, in areas of the world where the burden of malaria is very high, people can get bitten by malaria-infected mosquitos a couple of times a day. Although not directly treating an existing malaria infection, this type of vaccine would significantly reduce parasite transmission and protect entire communities against future episodes of this deadly disease.

‘Super’ vaccines

Ideally, a vaccine should offer long-lasting (preferably life-long) protection, be relatively cheap and easy to administer. Although it is the blood stage of malaria that causes the clinical disease, scientists have realised that to develop a really effective vaccine against malaria, it will probably have to focus on multiple stages of the parasite life cycle. This means combining the best transmission-blocking vaccine, with the best blood-stage vaccine and the best liver stage vaccine to produce one ‘super’ malaria-fighting vaccine.

However, developing a super vaccine like this will be an expensive and complicated process so a balance will have to be found between effectiveness and cost.

Resistance

Developing an antimalarial vaccine carries with it some of the same problems as developing a new antimalarial drug. Malaria parasites are very adaptable, and could change and become resistant to the vaccine. By developing any antimalarial vaccination or drug you are encouraging the parasite to evolve and develop resistance in order to survive exposure and maintain the species. This is important to consider when working on a long-term vaccine.

Realistically, the fight against malaria is going to be a long one…

Realistically, the fight against malaria – whether with insecticides, drugs or vaccines – is going to be a long one and will probably need many approaches at the same time. The Red Queen hypothesis is sometimes used to describe our battle against malaria. It is an evolutionary hypothesis that proposes that organisms must constantly adapt, evolve and multiply in order to survive against their ever-evolving opposition.

While scientists are working to develop the next generation of antimalarial drug or vaccine, the malaria parasite is already planning its next move.