Researchers at the University of South Florida have characterised a previously unknown vulnerability on the surface of Plasmodium vivax, demonstrating that antibodies targeting a novel epitope on the circumsporozoite protein can block liver cell invasion.
Researchers at the University of South Florida have identified a previously unknown vulnerability in Plasmodium vivax that could lead to a new vaccine strategy capable of stopping the parasite before it establishes its dormant form in the liver.
The discovery targets a previously uncharacterised site on circumsporozoite protein, or CSP, a major surface protein of the parasite. The researchers found that antibodies targeting this site can block P. vivax from invading liver cells.
Preventing the parasite from reaching the liver could be particularly important for P. vivax, which can remain dormant for months or even years before reactivating and causing another episode of malaria. These relapses can also contribute substantially to further transmission.
Around three-quarters of vivax transmissions actually come from relapse infections, not from the first mosquito bite and the infection somebody gets from it. Our vaccine and our antibodies can prevent the formation of the dormant form, so this could actually tackle the major source of both transmission and disease.”
Noah Sather, Professor, the USF College of Public Health Department of Global, Environmental and Genomic Health Sciences.
The findings could provide a new target for vaccine development against P. vivax, the most widespread malaria parasite outside sub-Saharan Africa.
Why target the liver stage?
Following an infected mosquito bite, Plasmodium parasites travel through the bloodstream to the liver, where they invade cells and develop. In P. vivax, some parasites become dormant forms called hypnozoites, which can reactivate long after the initial infection.
These relapses make the disease difficult to eliminate. Treatments that clear parasites from the blood do not necessarily remove dormant liver forms, while drugs that target hypnozoites require careful consideration of safety risks, including haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
A vaccine that blocks liver-cell invasion could prevent hypnozoites from forming in the first place. The USF findings identify a potential point of intervention before the parasite establishes this persistent reservoir, although protection in humans has not yet been demonstrated.
Finding a weakness in the parasite
The USF-led team identified an epitope, a specific region of an antigen that can be recognised and targeted by antibodies, that had not previously been characterised as a potential target for blocking P. vivax infection.
Laboratory experiments showed that antibodies directed against the site could prevent the parasite from invading liver cells.
Sather likened the discovery to finding an Achilles’ heel in the parasite.
“We identified a new kind of gap in the armour, so to speak, that nobody knew about,” Sather said. “We found that we can exploit that to prevent the bug from infecting. It’s a completely new weakness that was never known before or defined.”
The researchers say the finding is particularly significant because protective sites on the CSP protein of P. vivax have been poorly understood. Identifying a site that can generate antibodies capable of blocking infection provides a potential new route for vaccine design.
Two teams uncover the same target
The discovery came from an unusual convergence between two research teams working independently.
John Adams and his USF research group had identified the target through research into the parasite and human immune responses. At the same time, Sather, who has since joined USF, was studying the same region at the University of Washington and Seattle Children’s Research Institute as a potential target for a malaria vaccine.
The researchers discovered their overlapping work when Sather visited USF while considering joining its malaria research programme.
“Neither of us were aware of the other’s progress on this,” Sather said. “We were actually sitting in the same conference room and Dr Adams and his group started to talk about it. I immediately knew what they were talking about. I was like, ‘Oh my God, they’re talking about this epitope!’”
Sather said the two approaches provided complementary evidence for the importance of the site.
“Dr Adams is a parasitologist and I’m a vaccine immunologist – and we were looking at this problem from completely opposite directions,” Sather said. “I was breaking it down atom by atom and molecule by molecule, and Dr Adams was taking a large-scale, natural immunity associative approach. Together, our data fit together like puzzle pieces to complete a very complicated picture.”
Why this matters for drug discovery
The findings provide a starting point for developing vaccine candidates that present the CSP epitope to the immune system and stimulate protective antibody responses. Researchers will need to determine which antigen formulations generate sufficiently potent and durable immunity.
The site could also inform antibody-based prevention strategies, including monoclonal antibodies designed to bind CSP and block infection. Further studies could assess binding strength, protective activity and effectiveness against genetically diverse parasite strains.
Structural characterisation may help establish which molecular interactions are essential for antibody recognition, supporting the optimisation of vaccine antigens and antibody candidates. Whether the site could support small-molecule drug discovery remains speculative and would require additional evidence.
A key consideration will be whether the epitope is conserved across parasite populations. Genetic variation or limited accessibility could reduce the effectiveness of an intervention, making studies of sequence diversity and immune escape important next steps.
Ultimately, preventing liver infection could complement existing treatments by reducing the formation of dormant parasites rather than attempting to eliminate them after infection. The potential impact on relapse rates and transmission will depend on the efficacy, durability and coverage of any resulting vaccine.
A potential new route to prevention
Unlike Plasmodium falciparum, which causes most malaria cases in sub-Saharan Africa, P. vivax can remain dormant in the liver and reactivate months or even years after the initial infection.
“Somewhere from six months to 30 years later, you can get random reactivations in the liver,” Sather said. “You get full-blown fever and malaria complications, and most importantly, you can transmit it through mosquito bites. It’s an unusual transmission pattern that’s been difficult to understand and to fight.”
A vaccine based on the discovery remains several years away from potential use in humans. However, the researchers say the findings establish a clear direction for further development.
“We’re a few developmental steps away from being able to advance this into humans, but the feasibility is already established,” Sather said. “Our next step is to translate this discovery into effective vaccine formulations.”
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