Breakthrough in developing a vaccine for placental malaria

Therapy Breakthroughs 22. aug 2021 4 min Professor Ali Salanti Written by Kristian Sjøgren

Placental malaria is the main cause of low birthweight among children in Africa. Researchers in Denmark have now discovered how to make a vaccine for pregnant women that specifically targets the malaria parasite.

The malaria parasite (Plasmodium falciparum) is an advanced killer that humanity has not eradicated despite enormous efforts.

One reason is that P. falciparum has developed many ways of protecting itself inside the human body. One involves hiding in a red blood cell, where it expresses a protein that mediates binding of the infected red blood cells to chondroitin sulfate in the placenta.

If the parasite is not freely circulating in the bloodstream, the immune system cannot find it and destroy it.

However, science may finally vanquish P. falciparum infections during pregnancy, now that researchers from Denmark and elsewhere have very accurately mapped the structure of the protein the parasite expresses to bind to the placenta.

This discovery paves the way for developing antimalarial vaccines, specifically when the parasite tries to infect a pregnant woman.

“Researchers have been trying to map the structure of this protein since 2003, a nearly impossible task, but we have succeeded now. With the modern vaccine development tools we have available, we are already developing and testing a vaccine candidate that attacks P. falciparum in the very place where it has been inaccessible so far,” explains an author behind the study, Ali Salanti, Professor, Centre for Medical Parasitology, University of Copenhagen.

The research has been published in Nature Communications.

Placental malaria is a huge problem in Africa

Today, malaria remains one of the greatest problems in Africa.

In addition to killing hundreds of thousands of children every year, P. falciparum also results in mothers with malaria giving birth to babies weighing up to 400 grams less than the babies born to uninfected women.

This has huge consequences because low birthweight is clearly associated with many cognitive and other health problems later in life.

P. falciparum hides from a pregnant woman’s immune system by expressing the VAR2CSA protein on the surface of the red blood cells. The woman’s immune response thus cannot attack the parasite, even though she has previously been infected and has therefore developed immunity.

“Pregnant women in Africa comprise a huge reservoir for malaria. Women who become pregnant for the first time have not encountered VAR2CSA before and have therefore not developed immunity to it,” says Ali Salanti.

This protein does not act like other proteins – and that is the problem

Ali Salanti discovered this notorious protein in 2003 and immediately recognised the great potential for developing a vaccine that specifically teaches the immune system to recognise VAR2CSA.

However, the problem was that VAR2CSA is hypervariable and constantly mutates, so it presents differently from infection to infection. As a result, researchers in the early 2000s did not have any tools to map the protein that could help them determine how to develop a vaccine against placental malaria.

“SARS-CoV-2 has maybe three mutations in the binding domain, whereas almost half the amino acids that make up P. falciparum VAR2CSA differ between parasites. Making a vaccine that broadly covers all the variants is therefore not easy without an exact structure of the protein to map where the conserved sites are. This required comprehensively mapping VAR2CSA, which was not possible until now,” explains Ali Salanti.

Cracking the code for the structure of VAR2CSA

Since 2003, many researchers have spent huge sums and resources on defining the fine structure of VAR2CSA. Now however, researchers in Denmark led by Ali Salanti have accomplished what many other researchers have been unable to do.

Ali Salanti and colleagues used a variety of scientific techniques and methods to achieve this breakthrough, including cryoelectron microscopy, plus a new generation of protein and structural chemists who approached the task in novel ways.

“Researchers from the National Institutes of Health in the United States cracked the code at the same time that we did. One month apart, two studies have been published that accurately map what VAR2CSA looks like and which amino acids interact with the chondroitin molecules in the placenta,” says Ali Salanti.

Developing a vaccine using a revolutionary platform

Although the discovery is a breakthrough for developing a vaccine against placental malaria, Ali Salanti explains that obstacles still need to be overcome before a vaccine can be produced.

The main market for an antimalarial vaccine is Africa. This means that the vaccine must be stable and capable of being stored at room temperature and not –80°C or –20°C.

In addition, the vaccine must provide a long-lasting response so that doctors can vaccinate women and girls before they become pregnant, so that they are protected against malaria throughout pregnancy.

If the vaccine is given to the woman when she is pregnant, she may already have malaria, and then it is too late. Further, it does not help if the vaccine only works for 6–12 months, because no woman really knows if or when she will get pregnant.

Specifically targets VAR2CSA

Since current vaccine platforms fail to induce strong and sustained immune responses, a research team under Ali Salanti has been working for more than 10 years to develop a new vaccine platform that is probably more ideal for delivering such an antimalarial vaccine. The research team has successfully developed a virus-like particle vaccine platform, which in theory is as effective as the successful human papillomavirus vaccine against cervical cancer.

The vaccine platform was developed at the University of Copenhagen and has formed the foundation for AdaptVac ApS, a spinout company. The platform is also being used to develop a very promising vaccine against COVID-19 in collaboration with Bavarian Nordic that is currently undergoing clinical trials in the Netherlands.

The development of a vaccine against COVID-19 with the AdaptVac platform has confirmed that it works as intended, and the researchers have already used this platform to develop a new vaccine that specifically targets VAR2CSA in placental malaria.

“COVID-19 has shown us that vaccines can be developed rapidly. We are doing the same thing with antimalarial vaccine. The problem with malaria, however, is that there are no good animal models for testing vaccines. We therefore face several years of work with preclinical studies before we know what the vaccine should be like before it can provide the optimal response to P. falciparum in people,” concludes Ali Salanti.

Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding” has been published in Nature Communications. In 2018, the Novo Nordisk Foundation awarded a grant for the project ROBUST: Resource for Biomolecular Simulations.

Translational science is the fuel for my passion for research. I was the first to define the antigen (VAR2CSA) responsible for malaria in pregnant wom...

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