Stopping malaria in its tracks

Developing a better vaccine in malaria with the help of Amnesty International, which can save hundreds of thousands of lives every year

When Biochemistry Matthew Higgins created his research group in 2006, he was firmly malaria in his eyes. The disease transmitted by mosquitoes is second after tuberculosis in terms of its devastating global effect. Malaria killed an estimated 627,000 people in 2020, most of them children under the age of five, and half of the world’s population are on hand, although Africa is more difficult. Symptoms of infection can begin with fever and headache, which makes it miss or diagnose it incorrectly – and thus leave without treatment.

Thus, preventing malaria is a priority, which is why Higgins, a professor of molecular parasites at Oxford University, works tirelessly with his team to understand how malaria parasite interacts with the human host proteins. Their goal is to use these ideas to design improved treatments, including the vaccine that will be much more effective than currently available.

When a person is bitten by mosquitoes, one of the five types of parasites of malaria parasites may enter the bloodstream. These single -cell parasites are usually transferred to the liver, where they are ripened and doubled, and more in the bloodstream. Symptoms such as fever, cold, fatigue and disease may not appear up to 10 days to four weeks after the infection, however the speed of diagnosis is very important. Among the five parasitic species that cause malaria in humans, two are particularly serious. For example, the Plasmodium Falciparum infection can escalate, if not treated, to severe illness and death within one day.

The main challenge of Tagins is the strict nature of malaria. Their ability to constantly change its appearance as well as those of its host cells (red blood) allows them to evade the human immune system. He says: “In terms of drugs, vaccine, discovery, it makes it difficult to determine and determine what it targets.” It seems that the possibility of a vaccine is completely effective – the only way to stop malaria in its paths – far.

The race is confirmed to develop an effective vaccine through the number of teams that work for this goal. Currently, RTS, S, is widely known as its Mosquirix brand, is the only approved vaccination. Higgins says in October 2021. His arrival was “great progress” and “very good news”. Since RTS, S targets only the first step of infection, as the malaria parasite is performed into the liver, but only about 30 % of the effectiveness. “30 % is big. This means that many lives have been rescued,” he says. “But it is far from 100 % we want.”

Recently, another team at the University of Oxford – the Jenner Institute – has reported promising results for another similar vaccine. Her approach, which consists of three doses, followed by one year after one year, is an average effectiveness of 77 %. However, like mosquirix, this vaccine in the first stage, before the liver of the life cycle of malaria.

On the contrary, HighGins – along with his collaborators residing in Oxford, Simon Draper and Sumi Biswas – develops vaccine immunity for a multi -stage vaccine can work simultaneously at each stage of the infection cycle. In addition to entering the initial parasite into the cells of the human liver, the final goal of the laboratory is a vaccine that cannot be aimed at invading the blood cells that follow the infection, but also the final reproductive stage of the parasite cycle, which involves the merging of its forms of males and females. It is important to treat this stage, because the injured people can transfer the parasite to the previously unprecedented mosquitoes if they are bitten, and continue the course.

The progress was hard and slow. To explain the reason, consider the Covid-19 virus. This type of Coronavirus virus contains only one spike protein on its surface that the vaccine needs to target. Malaria parasites, on the other hand, have hundreds or even thousands of surface proteins, according to Chigns. It is a slippery shape.

It is important, that the development of a vaccine that contains an embarrassing infection component requires knowledge of the molecular composition of the Gamete-PFS48/45–It is necessary to develop the parasite in the middle of mosquitoes. This is the place where Higgins and his team went out of his path. For years they tried to decode the form of protein, with limited success. Even by using two of the best experimental techniques available to distinguish the protein-crystallization of X-ray and the electron microscope by cooling-researchers can only have mysterious low-resolution images. As a result, its structural models of PFS48/45 were incomplete and not necessarily complete.

It was, until Alfafold arrived.

“We were fighting with this problem for years, trying to get the details we need,” says Higgins. “Then we added Alphafold to the mixture. When we collected our model with the expected Alphafold structure, we can suddenly see how the entire system works.” Higgins remembers the exciting moment by the KUANG-to-Ping Ko- “who was trying all kinds of different things to improve experimental images”-storm the office with the news.

“It was a great relief,” says Higgins, and a turning point for the project. The combination of hard experimental work and the prediction of artificial intelligence rapidly led to a severe width of PFS48/45. “We have enabled the decisive alphafold information to identify the protein parts that we want to put in a vaccine and how we want to organize these proteins,” says Higgins. “Alphafold allowed us to move our project to the next level, from the basic science stage to the pre -clinical and clinical development stage.”

Alphafold is not without faults, of course. Higgins noted that although the artificial intelligence system works well in predicting how each unit is built inside the protein its structure, there were cases when his three -dimensional perceptions were slightly. For more accurate and confident results, it is better to use Alphafold along with more traditional tools such as electron microscope, he says. “I am sure that alphafold predictions will improve and better. But for the moment, the combination of experimental knowledge and Alphafold models is the best approach, because we allow us to collect everything together. This is the approach we follow for many of our projects.”

The Higgins collaborators, Professor Sumi Bisas, will conduct a human clinical experience for PFS48/45 groups in early 2023. Now that the PFS48/45/4 structure has been understood, this will allow Biswas and Higgins groups to work together to understand the immune response generated in these vaccination experiments. In the pursuit of a vaccine that operates at each stage of the life cycle of malaria, the highgins also take steps in understanding another goal, which is a large complicated protein key in malaria where parasites affect red blood cells, causing symptoms to appear. Using a mixture of Alphafold and Cryo-Em, the team works hard to understand how this complex is fit together.

Higgeins looking, higgins looking up to the top of the road, Alphafold as a critical technique to create new beneficial proteins from the zero point, is a process known as De Novo Protein Design. “The future of Alphafold may not be much in predicting the molecules already in the cells, but rather in predicting the structures of the molecules that people design for specific applications, such as vaccines,” he says. “If we can design proteins and then use Alphafold to predict whether it will fold the way we need, it will be very strong.”