Researchers found that individuals with acquired immunity to malaria have antibodies that prevent Plasmodium falciparum from attaching to their blood vessels, no matter how much the parasites mutate their adhesion proteins. These antibodies may aid in developing new vaccines that provide immunity against severe malaria.
Plasmodium falciparum parasites infect about 250 million people each year, resulting in 600,000 deaths, primarily in Africa.
For years, scientists have been trying to find ways to protect people from malaria, and they are now much closer to attaining this after a group of international researchers has identified antibodies in the blood of people who are immune to malaria.
The antibodies may be capable of protecting against all forms of severe malaria by targeting the very site on the virulence proteins of Plasmodium falciparum that the parasite cannot change. The researchers envision using these antibodies to develop new vaccines against malaria – either by designing a vaccine to produce similar antibodies or by administering the antibodies directly.
“We still have much work to do, but we discovered antibodies that act broadly against the parasites key virulence proteins and determined how they work. I envision these antibodies comprising part of a vaccine strategy, enabling vaccines to provide immunity against malaria in several ways,” explains a researcher behind the study, Thomas Lavstsen, Professor at Department of Immunology and Microbiology, University of Copenhagen, Denmark.
The research, which was carried out together with research groups in Tanzania, Uganda, the United States and Spain, has been published in Nature.
Virulence proteins: a key target for antibodies
Plasmodium falciparum has plagued humans for centuries, but people can acquire immunity against severe malaria.Plasmodium falciparum has its life cycle in both humans and mosquitoes, and it uses very specific proteins to penetrate people’s red blood cells and attach them to the inside of the blood vessels. To avoid being carried with the blood to the spleen, which removes spent and infected blood cells, Plasmodium falciparum uses a virulence protein to attach itself to the blood vessels. This protein constantly evolves through mutation, making it difficult for the immune system to develop effective defence. Antibodies targeting one variant of the protein often fail against others.
“We have spent many years studying what these virulence proteins do, what they look like and how they vary. The variation is so extreme that most researchers have assumed that the body cannot form antibodies that protect against all of them. However, some people develop immunity across many variants, and we aimed to understand this mechanism,” says Thomas Lavstsen.
Plasmodium falciparum cannot mutate to avoid these antibodies
The researchers examined the blood of two adults with acquired immunity to malaria to identify broadly inhibitory antibodies that target the virulence protein across variants.
The researchers tested the antibodies against many variants of the virulence protein and found that the antibodies from both of the immune individuals acted broadly against the virulence protein and prevented Plasmodium falciparum from attaching to the blood vessels.
The researchers then examined the molecular structure of these two antibodies and found that they functioned identically despite being very different.
Both antibodies bound to the same small sequence of three to four amino acids in the virulence proteins, a sequence critical for binding to the host receptor on blood vessel cells
“Plasmodium falciparum faces a problem: these three to four amino acids are essential for its adhesion proteins to function, so it cannot mutate them without losing its ability to attach to blood vessels. That is why the antibodies act against all investigated variants of the virulence protein,” adds Thomas Lavstsen.
The researchers also constructed 3D models of artificially produced blood vessels and showed that the antibodies very effectively prevent Plasmodium falciparum from attaching the infected red blood cells to the blood vessel.
A combination vaccine will be extra effective
Although the researchers only examined and identified broadly inhibitory antibodies against malaria from two immune people , Thomas Lavstsen suggests that most people immune to malaria have similar antibodies.
The next step is to study antibodies from more individuals to determine how the human body generates these broadly reactive antibodies to defend itself against malaria. The overall aim is to find the most simple and common broadly inhibitory antibodies that effectively block the ability of Plasmodium falciparum to attach to the blood vessels.
“Such antibodies will not prevent Plasmodium falciparum from infecting the body, but they will protect against severe illness,” explains Thomas Lavstsen, adding that the goal is to harness this new knowledge to develop a more effective vaccine strategy.
Such a strategy would aim to address all stages of the Plasmodium falciparum life cycle to create an effective vaccine. This means that a future vaccine must not only prevent people from becoming infected but also fight the parasites that might manage to infect the body – compared with current vaccines that currently only have limited protective efficacy.
“Vaccines that prevent severe illness while maintaining naturally acquired immunity without exposure to the disease would be transformative. Our research has now established that these broadly inhibiting antibodies exist and clarified how they work. Our ongoing research is directed towards achieving clinical development potential,” concludes Thomas Lavstsen.
