Malaria is an infectious disease caused by infection with protozoan parasites belonging to the genus Plasmodium transmitted by female Anopheles species mosquitoes. Our understanding of these parasites begins in 1880 when Alphonse Laveran discovered the parasites in the blood of malaria patients. Laveran was later awarded a Nobel Prize for his discoveries. In 1898, Sir Ronald Ross demonstrated that mosquitoes transmit malaria, and he won the 1902 Nobel Prize for this work.

“Malaria was once endemic in the Nordic countries due to local Anopheles mosquitos and Plasmodium vivax that survived in cooler climates. The disease disappeared at the early 20th century due to improved drainage, sanitation, and medical advances,” explains Professor Billker, Director of the Laboratory for Molecular Infection Medicine Sweden (MIMS) at Umeå University.

“The Nordics have a long tradition of malaria research going back at least as far as Carl Linnaeus, who wrote his PhD thesis on an intermittent fever thought to be malaria,” he adds.

Oliver Billker, Professor, Umeå University Photo: Magnus Bergström

Billker’s research group focus on the basic biology of the parasite. “We study a model parasite infecting rodents to work out how the parasite interacts with its host and the mosquitoes that transmit them. We are interested in identifying new targets for interventions that could then be used to develop new drugs and vaccines or help us understand why some mosquito species transmit malaria while others do not,” he explains.

Billker and his team are studying hundreds of parasite and mosquito genes simultaneously using advanced genetic tools based on the gene editing technique CRISPR-Cas9, developed by Nobel Prize laureate Emmanuelle Charpentier. They are also breeding mosquitoes at a special facility where they can infect them with a mouse malarial parasite that is not infectious to humans.

A complex life cycle

The journey from the emergence of a disease to the development of a treatment is a lengthy process, especially for malaria vaccines that have been under development for nearly 60 years. Creating a vaccine against a parasite is more challenging than producing one for a virus or bacterium due to the parasite’s complex biology.

Plasmodium, the microorganism responsible for causing the disease, has a complex life cycle that involves multiple stages occurring in both humans and mosquitoes (its hosts). In humans, the parasite starts as sporozoites injected by a mosquito, which then travel to the liver and turn into merozoites. These merozoites enter red blood cells, multiply, and cause them to burst, leading to malaria symptoms such as fever and chills. This stage can escalate to severe complications, including anemia and organ failure.

Each stage presents distinct antigens that enable the microorganism to evade the immune system effectively, necessitating vaccines capable of targeting various parasite forms.

Each stage presents distinct antigens that enable the microorganism to evade the immune system effectively, necessitating vaccines capable of targeting various parasite forms. Additionally, the microorganism’s genetic diversity across geographic regions has complicated vaccine development, as a vaccine effective in one area does not work in another. Until recently, there were no successful vaccines for any parasitic disease in humans, leaving researchers without established templates for guidance.

Gametocytes (A) are taken by the mosquito when it bites. Inside the mosquito (in the gut), the gametocytes (A) form gametes that combine into a zygote (B), developing into ookinetes. These ookinetes pass through the intestinal wall and form oocysts (C) that release new sporozoites (D), which move to the mosquito’s salivary glands (they are near the head). The mosquito injects these sporozoites (D) when it bites humans while at the same time takes gametocytes (A). The sporozoites (D) released into the human travel to the liver and turn into merozoites. These merozoites enter red blood cells, multiply, and cause them to burst, forming new gametocytes (A), and leading to malaria symptoms such as fever and chills. The parasite needs both the mosquito and humans to complete its cycle. Illustration: Paula Pérez González-Anguiano

The first vaccine

So, developing an effective vaccine has been a huge challenge for medical science, and the world made great strides in beating the disease. And finally, in 2021, the World Health Organization (WHO) recommended the first malaria vaccine, RTS,S/AS01 for children living in sub-Saharan Africa in places with moderate to high transmission, and in 2023, the organization recommended R21/Matrix-MTM, the second vaccine for use in malaria-endemic countries.

An important step but no silver bullet

The first two vaccines, RTS,S and R21, were set for widespread use last year to significantly reduce childhood deaths. These vaccines, the first for any human parasitic disease, are effective but have limitations.

They will need to be deployed in conjunction with other interventions to be maximally effective, while research continues to be important to identify more efficient vaccines, complementary vaccination strategies, and new drugs.

“They target the parasite stage that gets delivered with the saliva of infected mosquitoes and prevent it from reaching our liver. They work because they target a population bottleneck and a parasite stage that is less adapted to evade immunity than the subsequent blood stage that causes disease,” says Billker.

“They are an important step but no silver bullet. They will need to be deployed in conjunction with other interventions to be maximally effective, while research continues to be important to identify more efficient vaccines, complementary vaccination strategies, and new drugs,” he adds.

2 x Danish malaria findings

Two findings from Denmark are among recent malaria vaccine progress in the Nordics. Scientists at the Statens Serum Institute in Copenhagen have developed a multifunctional vaccine for trials that targets parasite stages within the mosquito’s blood meal (Singh et al., npj Vaccines, 2021).

Normally, these stages do not trigger human antibody responses and have not evolved to evade them. By generating antibodies, the vaccine could disrupt parasite reproduction, exploiting its small and vulnerable population inside the mosquito.

The other finding was made by scientists at the University of Copenhagen (Reyes et al., Nature, 2024). The ideal malaria vaccine would target parasite stages inside red blood cells, which cause symptoms and mortality. However, these stages evade immunity by altering surface proteins. The Danish researchers have now shown that these proteins share features that antibodies can recognize, suggesting a vaccine against them may be possible despite the parasite’s immune-evasion tactics.

The path ahead

In 2013, global health organizations including the WHO developed a strategic plan to guide research toward highly effective malaria vaccines. The plan aims to achieve two key goals by 2030; develop vaccines with at least 75 percent efficacy against clinical malaria in areas with ongoing transmission, and create vaccines that reduce transmission and infection, supporting malaria elimination through mass vaccination campaigns.

The most recent data from the World Malaria Report 2024 shows that malaria caused around 600,000 deaths globally, of which 74 percent occur in children under five.

The most recent data from the World Malaria Report 2024 shows that malaria caused around 600,000 deaths globally, of which 74 percent occur in children under five. Continued research and efforts are essential to improving prevention and treatment, which will lead to healthier growth and development, ensuring children have better chances for education and overall well-being. The report also shows that climate change is one of many threats to the global response to malaria. Conflict and humanitarian crises, resource constraints, and biological challenges such as drug and insecticide resistance also continue to hamper progress.

Collaboration is key

In an interview with the Knut & Alice Wallenberg Foundation, Oliver Billker, who is a Wallenberg Scholar, emphasizes the importance of global collaboration for progress within malaria.

As an example, his team is working with researchers across the world, from laboratories in Europe to field studies in areas where Malaria is endemic, he says.

“It’s impressive to observe the skill of my colleagues in Africa, how they carry out field studies or conduct cutting edge molecular analysis, often under challenging circumstances. Working with researchers in endemic countries provides an invaluable perspective,” he said.

About the Author

Paula Pérez González-Anguiano, M.Sc. in Scientific, Medical and Environmental Communication, is a Science Journalist and Illustrator based in Barcelona, Spain.