Uncovering new approaches to prevent malaria

Malaria has plagued humanity for millennia. Historical and genetic data suggest that humans first encountered the parasites that cause malaria — and the mosquitoes that carry them — around the time they discovered fire (1). But despite decades of research and drug development, the disease continues to pose a major public health threat. According to the latest World Health Organization (WHO) report, malaria caused an estimated 263 million cases and nearly 600,000 deaths worldwide in 2023 — an increase from the previous year.

One major obstacle in the fight against malaria is the causative parasite’s ability to evolve. “The parasite is very good at developing resistance to these drugs,” said George Dimopoulos, a molecular microbiologist at Johns Hopkins University. “The same is true for insecticides: Mosquitoes are very good at developing resistance to chemical insecticides. And in fact, in all malaria endemic regions today, you do find insecticide-resistant mosquitoes.”

Since 1991, molecular microbiologist George Dimopoulos has been studying the biology of mosquitoes to identify vulnerabilities to target to help stop malaria transmission.

Johns Hopkins University, Bloomberg Schol of Public Health

Malaria spreads through a complex cycle involving humans, mosquitoes, and the highly adaptable Plasmodium parasite. It begins when a female Anopheles mosquito bites an infected person and ingests Plasmodium gametes — sexual forms of the parasite found in the blood. Inside the mosquito’s gut, the parasite reproduces and transforms into sporozoites, an infectious form that can be passed to a person. When the mosquito feeds again, it injects the sporozoites into another human through its saliva, continuing the transmission cycle.

Once inside the human body, the sporozoites travel to the liver, where they mature and replicate. After one to two weeks, they re-enter the bloodstream, this time by invading red blood cells and multiplying further. At this stage, symptoms such as fever, chills, and fatigue begin to emerge in the infected individual. In severe cases, malaria can lead to organ failure, and it can cause serious complications during pregnancy.

With increased mosquito resistance to insecticides along with the complexity of Plasmodium’s multiple life stages, single approaches to preventing malaria have consistently fallen short. “We need to target malaria using multiple approaches simultaneously,” said Dimopoulos. “In some areas, vaccines and drugs might work better; while in other areas and settings, insecticides and insecticide-treated bed nets may work better.”

In search of better malaria prevention strategies, scientists have developed innovative approaches, including a novel parasite-based vaccine, a way to block infected mosquitoes from transmitting the parasites, and a monoclonal antibody approach to work alongside existing malaria vaccines. However, recent funding cuts to malaria research by the United States and other global partners now threaten to halt or derail progress on these promising innovations.

A parasite as a vaccine

For decades, scientists have worked to create an effective vaccine against malaria, but the parasite’s complex and constantly changing life cycle has made these efforts particularly challenging.

“The parasite has figured out how to evade and use different proteins to escape from immune responses,” explained Stephen Hoffman, a tropical medicine specialist and Chief Executive Officer and Chief Scientific Officer of Sanaria, a biotechnology company focused on developing malaria vaccines. Consequently, researchers must decide whether to focus on targeting a single stage of the parasite’s life cycle or combining strategies that could target multiple stages at once.

As the Chief Executive Officer of Sanaria, Stephen Hoffman led his company’s efforts to develop a single-dose vaccine against malaria with up to 90 percent efficacy at preventing P. falciparum infection.

Sanaria

A breakthrough came in 2021, when the WHO recommended the first malaria vaccine, RTS,S, for widespread use in at-risk children in sub-Saharan Africa — marking the first approval of a vaccine targeting a human parasite. Two years later, the WHO approved a second vaccine, R21/Matrix-M, which began rolling out for malaria prevention in late 2023.

Both RTS,S and R21/Matrix-M work by triggering the human immune system to produce antibodies against a specific protein subunit of Plasmodium falciparum sporozoites — the species responsible for the most severe malaria cases worldwide. While both vaccines are considered safe and generally well tolerated, their efficacy may be limited by the speed of the parasite’s infection process (2).

After a mosquito bite, sporozoites travel from the skin to the liver in less than an hour, giving the immune system only a brief window to eliminate them. “If you don’t knock out all of those sporozoites, a week later, from one sporozoite … 50,000 parasites emerge into the bloodstream,” said Hoffman. “The antibodies that you made against the sporozoites don’t recognize the blood-stage parasites that actually cause disease and transmission.” Indeed, while both vaccines significantly reduce the risk of malaria, they fall short of reaching the WHO’s target of at least 90 percent protection against P. falciparum infection (3).

In response, Hoffman and his team at Sanaria set out to develop a more effective vaccine. In February, they announced the development of PfSPZ-LARC2, a new antimalarial, whole-parasite vaccine designed to provide high-level protection — up to 90 percent — against P. falciparum infection with just one dose.

To create the vaccine, the researchers began by genetically modifying whole P. falciparum sporozoites. Partnering with Stefan Kappe at the Seattle Children’s Hospital, they used CRISPR-Cas9 editing to delete two critical genes — Mei2 and LINUP — which are essential for the parasite’s development after it enters liver cells.

Without these genes, the parasite can still enter the liver and replicate there for up to one week, but it cannot develop any further. That’s because the gene deletions cause P. falciparum to self-destruct before the parasite exits the liver.

This delayed self-destruction is key to how the PfSPZ-LARC2 vaccine works: By allowing the weakened parasite to survive in the body for several days, the vaccine gives the immune system more time to respond to the pathogen. During this window, the body produces a broader repertoire of antibodies that target antigens from both the early blood stages and the later liver stages of the parasite’s life cycle, which also strengthens the immune system’s response to future infections. “There, we have a week to work, not just five to 30 minutes,” said Hoffman. “This is the most elegant vaccine ever made.”

Sanaria plans to begin clinical trials for the PfSPZ-LARC2 vaccine later this year across three countries — the US, Germany, and Burkina Faso. The team will focus first on evaluating the vaccine’s safety and efficacy in diverse populations and settings. “We’re working with our African colleagues to do this, because they’re the ones who need it,” Hoffman said. “No one, including us, has ever managed to do this before.”

Dissecting the mosquito’s secrets

Rather than developing a conventional vaccine that protects humans after they’re bitten by an infected mosquito, researchers in Dimopoulos’ laboratory are taking a different approach. “The efficacy of malaria vaccines is not that great yet,” Dimopoulos explained. “But even if you would have an effective vaccine, the logistics of vaccinating large populations in some of the poorest parts of the world becomes a complicated task.”

To overcome this challenge, Dimopoulos set out to develop new ways to control malaria transmission by targeting the mosquito itself. “The main objective is to understand how the parasite interacts with a mosquito at the molecular level in order to identify weak points that can be manipulated, either genetically or through inhibitory agents, to block the parasite’s infection within the mosquito,” he said.

In a recent study published in Nature Microbiology, Dimopoulos and his team identified one such weak point in the mosquito: the prefoldin chaperonin complex, a conserved molecular system essential for folding cytoskeletal proteins in the mosquito gut epithelium (4).

They had identified this complex in a genetic screen for genes expressed by Anopheles mosquitoes that affect Plasmodium survival and transmission. Also, earlier studies had shown that Plasmodium infection alters the integrity of the mosquito gut epithelial lining (5).

The researchers fed female Anopheles mosquitoes a blood meal infected with both P. falciparum parasites and antibodies targeting the mosquito’s prefoldin chaperonin complex. As the mosquitoes consumed the blood, the team observed that the insects developed a “leaky gut syndrome,” where the gut became hyperpermeable. This allowed Plasmodium microbes to spill into the mosquito’s open circulatory system, exposing the parasite to the insect’s immune system.

“The malaria parasite cannot protect itself effectively against the mosquito’s innate immune system,” said Dimopoulos. As a result, when Plasmodium leaks outside of the mosquito gut, “the parasite loses its ability to evade the [mosquito’s] immune system that can then target it and kill it,” he added. The antibody treatment led to reduced parasite transmission and increased mosquito mortality.

This discovery opens the door to a new kind of vaccine — one that works indirectly by turning humans into vectors of mosquito control. “The significance of being able to do this with an antibody is that we could now envision the development of vaccines by which humans would carry such antibodies in their blood,” Dimopoulos said. “When a mosquito would feed on these humans, then these mosquitoes would suffer death.”

However, this type of vaccine wouldn’t offer direct protection to vaccinated individuals. Because the antibody acts only within the mosquito, the vaccine’s success would depend on widespread immunization to reduce community-level transmission. “It protects the population since an infected individual would not be able to transmit the parasite further,” Dimopoulos explained.

Despite these complexities, Dimopoulos is hopeful about the potential impact of the team’s findings. “My hope is that this discovery could lead to the development of an additional weapon against malaria and contribute to the fight against this disease that is affecting a very large number of people and killing a very large number of children each year,” he said. “I don’t view this discovery leading to a silver bullet for malaria control, but it can be effectively combined with other control methods.”

Toward a new kind of therapy

No region has borne a heavier burden from malaria than Africa. As global attention concentrates on developing better vaccines, some researchers on the continent are pursuing alternative strategies that they believe may be better suited to local needs.

Among them is Kassoum Kayentao, a physician and epidemiologist at the University of Science, Technique and Technologies of Bamako (USTTB). For the past two decades, he has worked to develop new antimalarial therapies aimed at protecting high-risk groups — infants, young children, and pregnant individuals — in his home country of Mali, where malaria remains widespread. “Here, our main diseases are malaria, pneumonia, and viral diseases,” he said. “But the leading cause of death, in Mali as in many sub-Saharan countries, is really malaria.”

For the past two decades, physician and epidemiologist Kassoum Kayentao has focused on developing new antimalarial therapies aimed at protecting high-risk groups in his home country of Mali, where malaria remains widespread.

Ibrahim Dia

Since 2020, Kayentao has turned his attention to monoclonal antibodies as a potential tool for preventing malaria infections. In a recent Phase 2 clinical trial, published in The New England Journal of Medicine, he and his team tested the safety and efficacy of a new monoclonal antibody — called L9LS — in protecting children from P. falciparum infection and clinical malaria (6).

L9LS targets a key surface protein that P. falciparum sporozoites use to invade liver cells. In the clinical trial, the researchers showed that a single subcutaneous dose of L9LS provided up to 70 percent protection against P. falciparum infection and up to 77 percent protection against clinical malaria over a six-month malaria season in children aged six to 10. The treatment also led to no major safety concerns, highlighting its potential as an effective preventative option against malaria for vulnerable populations.

One of L9LS’s most promising advantages is its long-lasting protection. Because a single dose remains effective for up to six months, it could reduce the number of healthcare visits required for children in malaria endemic regions. “In seasonal settings, like in Mali … malaria season lasts only like six months,” Kayentao explained. “The remaining six months of the year are almost free of malaria.”

He noted that administering L9LS at the beginning of the rainy season — when malaria transmission peaks — may be enough to protect children throughout the highest-risk period. “You can renew the dose maybe [in the] next year at the beginning of the season,” he said.

By comparison, the RTS,S and R21/Matrix-M vaccines require a more intensive treatment schedule: three initial doses administered one month apart from each other, followed by a booster dose at 12 months. Even with all four doses, RTS,S has shown only 36 percent efficacy over four years in infants aged five to 17 months, and R21/Matrix-M has delivered similar results (3,7). Such limitations, Kayentao believes, make L9LS a potentially more practical and effective option for preventing infection in young children living in malaria-endemic regions. “I really think that the monoclonal antibody is more valuable now than the vaccine,” he said.

Multiple people are in Kassoum Kayentao’s clinic in Mali. — Kassoum Kayentao (far right, in a white coat) consults with patients at a clinic in Mali where he researches new strategies to prevent malaria.
brahim Dia

L9LS could also significantly reduce how often at-risk children need to visit health facilities. Currently, children receiving seasonal malaria prevention must undergo four monthly treatments each year, leading to more than 20 healthcare visits by age five. In contrast, an annual L9LS dose given at the start of the malaria season would require only five visits during the same period.

However, Kayentao acknowledged one major challenge to deploying L9LS in malaria-endemic regions: the high cost associated with producing monoclonal antibodies like L9LS at scale.

Nonetheless, Kayentao remains committed to advancing L9LS research. The research team plans to test the monoclonal antibody therapy in a larger group of vulnerable individuals in malaria-endemic areas to explore how it might work alongside existing vaccines. “That's one potential question that we're trying to address.”

A worsening investment landscape

Over the past two decades, global efforts to eliminate malaria have prevented over two billion cases and nearly 13 million deaths, according to the WHO. However, recent US funding cuts to such programs now threaten to reverse these gains and put millions of lives at risk.

From 2010 to 2023, the US contributed an average of 37 percent of the global malaria funding, supporting essential prevention measures such as bed net distribution, insecticide spraying, and the delivery of antimalarial medicines. When funding was suspended earlier this year, many implementing organizations were forced to lay off thousands of staff and halt critical services. The WHO has warned that these cuts could severely undermine decades of hard-won gains in malaria research and control.

“We have a situation in which one of the most successful public health programs in history, which is the President’s Malaria Initiative, which funds a huge portion of malaria control efforts in Africa, has been terminated,” said Hoffman. “That’s already having an impact, and the impact that that could have on the number of cases and number of deaths from malaria, on transmission from malaria, is huge.”

Although the US has since reinstated some of the global health programs previously halted, the WHO cautions that the initial disruptions may have already left critical gaps in care and research. “There are several knowledge gaps that need to be filled,” said Dimopoulos. “For that, we need funding and investment and commitment from governments and various agencies.”

Hoffman echoed this concern. “There’s two major issues in developing a malaria vaccine,” he said. “One is the complex biology of the parasite that's learned over millennia to evade host immune responses. And the second is that it primarily afflicts the most disadvantaged people in the world, and therefore investment is not forthcoming in the same way it might be for something quite different.”