USF Health researchers identify promising vaccine target in malaria parasite

USF Health researchers have discovered a previously unknown vulnerability in Plasmodium vivax (P. vivax), a malaria parasite that infects millions of people in Central and South America and Southeast Asia.

The discovery identifies a specific site on the parasite that antibodies can target to block P. vivax from invading liver cells - potentially preventing the parasite from establishing the dormant form that allows malaria to return months or even years later.

The findings, published in the journal Immunity, provide a new target for developing a vaccine against P. vivax, the most wide spread malaria parasite outside sub-Saharan Africa.

"Nobody has discovered a new way to target the major surface antigen, CSP, for vivax in over 40 years," said Noah Sather, PhD, a professor in the College of Public Health's Department of Global, Environmental and Genomic Health Sciences. "This is truly a game-changing, paradigm-shifting discovery."

Sather and John Adams, PhD, identified a previously uncharacterized epitope- a specific region of a malaria parasite antigen that can be recognized and targeted by antibodies- on the parasite's major surface protein, known as circumsporozoite protein, or CSP.

Their research shows that antibodies targeting this newly identified site can block the P. vivax parasite from infecting the liver.

That is particularly important for P. vivax because the parasite can establish dormant forms in the liver that remain long after the initial infection and later reactivate, causing repeated bouts of malaria. The new research demonstrates thatantibodies targeting the newly identified site of vulnerability can block infection before those dormant forms become established, potentially preventing both disease and 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," Sather explained. "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."

Until now, researchers had limited knowledge of protective sites on the CSP surface antigen that can be targeted by antibodies to prevent P. vivax infection. But the USF-led research identifies an inhibitory vaccine epitope that elicits antibodies capable of blocking the parasite from invading the host, providing researchers with a new target for vaccine design.

Sather likened it to finding the Achilles' heel of P. vivax.

"We identified a new kind of gap in the armor, 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 discovery came about in an unusual way, with two research teams initially working independently and approaching P. vivax from different scientific directions arriving at the same vulnerable region of the parasite, before joining forces.

A year ago, Adams and his USF research team identified the target through their studies of the parasite and human immune responses. Simultaneously, Sather - who joined USF in February - was still working as a professor at the University of Washington and principal investigator at Seattle Children's Research Institute, where he was examining the same region at the molecular level as a possible target for a malaria vaccine.

Neither knew about the other team's work, but that changed when Sather happened to be visiting USF while considering joining the USF College of Public Health malaria research program.

"Neither of us were aware of the other's progress on this," Sather recalled. "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!'"

The rare convergence of evidence from both human studies and vaccine development experiments gave them confidence that they had identified an important new target.

"Dr. Adams is a parasitologist and I'm a vaccine immunologist - and we were looking at this problem from completely opposite directions," said Sather. "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."

While the discovery marks a major step forward, Sather and Adams note that the eradication of malaria has a long journey ahead of it.

Another malaria parasite, known as Plasmodium falciparum, is responsible for the majority of cases in sub-Saharan Africa and can lead to severe illness or death if not treated within 24 hours. That type of malaria has received the majority of research attention.

P. vivax, meanwhile, affects a large portion of the world but has historically received less attention.

"Very little work had been done on trying to understand how to effectively target the major surface antigen when we started working on it," Sather said. "Yet there's this enormous section of the world that's dramatically affected by it."

One of the biggest challenges in controlling P. vivax is its ability to hide in the liver.

Unlike P. falciparum, P. vivax can remain dormant in the liver long after the initial infection and reactivate months or even years later.

"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."

While a vaccine based on the discovery remains several years away, Sather says the path forward is now much clearer and could ultimately save lives and provide a powerful new tool against an understudied form of malaria.

If successful, a vaccine built around the newly identified target could provide a new tool for preventing P. vivax malaria - particularly by stopping the parasite before it can establish the dormant liver forms that make the disease so difficult to control.

"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."