In search of the “perfect protein” for the mRNA vaccine against malaria

After the success of mRNA vaccines against COVID-19, scientists are cautiously optimistic that the same technology can be used to fight other widespread diseases such as malaria. The technology is promising, vaccine developers say, but its success will depend on the results of the first tests now underway.

A vaccine against all types of malaria has so far been elusive, due to the complexity of the parasite that causes the disease. Malaria remains a neglected disease, meaning it has been neglected by the research community.

“Neglected diseases affect poor people,” Carlos Zarate-Bladés, an immunologist at Brazil’s Federal University of Santa Catarina, told SciDev.Net. “Any industry that is likely to generate a product will first look at the market. If the market is not promising in financial terms, it will not even be tested. »

Malaria is transmitted by the bites of Anopheles mosquitoes infected with Plasmodium parasites. In 2020, the disease caused around 627,000 deaths worldwide, among 241 million cases, according to the World Health Organization. In the same year, Africa recorded 96% of malaria deaths. Children under five are the most affected and account for around 80% of all malaria deaths in Africa.

Symptoms of malaria usually appear about 10 to 15 days after infection and include fever, headache and chills. If left untreated, the disease can become serious and lead to kidney failure, seizures, coma and death. Groups most at risk of developing serious illness include children under five, pregnant women and people living with HIV/AIDS. The WHO states that malaria is “both a consequence and a cause of poverty and inequality”.

First malaria vaccine

The first malaria vaccine was recommended by WHO in October 2021 for wide use in children, an event that has been hailed as a historic moment. GlaxoSmithKline’s Mosquirix, also known as RTS,S, provides protection against Plasmodium falciparum, the parasite responsible for malaria prevalent in Africa.

However, it is not effective against other types of Plasmodia, such as Plasmodium vivax, which is the dominant malaria parasite in most countries outside of sub-Saharan Africa.

In Brazil, scientists are testing a recombinant protein vaccine against P. vivax, responsible for 89% of malaria cases in the country. In this vaccine technology, a piece of DNA is taken from the pathogen and inserted into manufacturing cells which then become capable of producing a protein from the virus – or in the case of malaria, the parasite – which can be used in the vaccine.

For the past two decades, Irene Soares, a microbiologist at the University of São Paulo, has been researching this potential malaria vaccine. His team is focusing on a protein from P. vivax that has a similar function to that which was used in the vaccine approved for Africa. This protein attacks the parasite to prevent it from reaching the blood and causing serious illness.

Animal testing has shown that the vaccine is safe and provides protection. “We are now at the stage of preparing this formulation for the first phase of human trials,” Soares told SciDev.Net.

Global search

BioNTech, which developed a COVID-19 vaccine in partnership with Pfizer, plans to begin clinical trials with the first mRNA-based malaria vaccine by the end of 2022, the company has informed investors and the press. Last year. The German company also aims to set up mRNA manufacturing facilities in Africa.

The WHO recently announced a global mRNA technology transfer center, created to help manufacturers in low- and middle-income countries produce their own vaccines. A South African consortium was selected to manage the hub, and two regional “spokes” were established in Brazil and Argentina.

The Brazilian Institute of Immunobiological Technology (Bio-Manguinhos/Fiocruz) was selected in September by the WHO for the development and production of vaccines using mRNA. The primary focus will be the COVID-19 pandemic, but this initiative should allow for faster production and distribution of new vaccines, including one against malaria, in the future.

Fiocruz – a health research institute – is Latin America’s largest vaccine producer and was also developing a prototype coronavirus vaccine with a slightly different technology to mRNA, called auto-amplifying RNA.

Patrícia Neves, researcher at Bio-Manguinhos/Fiocruz, tells SciDev.Net: “In addition to continuing the development of our [COVID-19] vaccine, we are also preparing our production area, quality control and training of professionals. »

Searching for a target

Even with a promising platform like mRNA, the key to a malaria vaccine is finding the perfect target, the protein that will be presented to the human immune system.

The malaria parasite has a complex life cycle, with different forms and stages inside the host, which makes it difficult to select a good target for a vaccine. In the past, studies have tested several proteins at different stages of the parasite, and most of them have failed.

Additionally, the parasite genome is more complex: viruses typically have dozens of genes, while malaria parasites have around 5,000 genes.

“If, on the one hand, there are more possible targets, on the other hand, it becomes more difficult to discover which of them are the parasite’s greatest weaknesses”, explains Daniel Bargieri, immunologist and researcher at the University of Sao Paulo. SciDev.Net.

“And many gene collections perform the same function. So if you attack one, it doesn’t matter to the parasite, because it has other proteins that perform the same function. »

To make matters worse, parasites can mutate and have mechanisms to evade the immune system.

mRNA vs malaria

Bargieri and his team are looking for new antigens, or proteins, to identify a target among these 5,000 genes. They are exploring mRNA technology for a potential vaccine.

A protein can be a good target for a vaccine, but it is difficult to produce in the laboratory. The mRNA vaccine gets around this, because the mRNA itself, made in the lab, will teach human cells how to produce the protein – or part of it – that triggers an immune response.

“Even though it’s a newer technology, sometimes it’s easier to make mRNA than an antigen,” Bargieri says. His team has just started testing and the results aren’t expected for a few years yet, he says.

Scientists are eagerly awaiting the first data on mRNA vaccines against parasites, protozoa or bacteria, which have a very different biology from viruses. Bargieri says the malaria vaccines are one of the most advanced, but trial results will determine if and when they will be available.

If a new mRNA malaria vaccine is ultimately proven to be safe and effective, the challenge will be to deliver it to the regions most affected – developing countries in the South.

During the pandemic, some regions have been better prepared to meet this challenge. In some countries, including Brazil, scientific institutions have obtained the necessary funding and technology to produce vaccines against COVID-19. “All this infrastructure that has been put in place will certainly help the advancement of other vaccines,” says Soares.

For Zarate-Bladés, the only thing Brazilian research institutes need is better funding: “There is no shortage of knowledge or techniques in Brazil. What is missing is funding for product research and development.

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