New P. vivax vulnerability could prevent liver-stage malaria infection

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.

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.”

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.”