Novel Malaria Vaccine Candidate Triggers Pathogen to Self-Destruct

A malaria vaccine candidate that uses antibodies to trigger self-destruction in the Plasmodium falciparum pathogen has shown promise in animal tests, according to a new study.

For the study, published in Nature, investigators took a novel approach to fighting malaria that triggers a “kill switch” in the pathogen during a different stage of infection than other vaccines have targeted.

“What’s exciting is that this is a vaccination strategy that attacks malaria in a way that it has never been attacked before — one in which the parasite becomes complicit in its own demise,” study senior author Jonathan Kurtis, MD, PhD, a professor at the Warren Alpert Medical School of Brown University and laboratory director of the Center for International Health Research at Rhode Island Hospital said in a news release. “We are hopeful that this vaccine, perhaps combined with other malarial antigens, will translate into a strategy that can help prevent severe malaria in people.”

Investigators identified the antibody to a malaria protein -- P falciparum glutamic-acid-rich protein (PfGARP) -- in children with a natural immunity to malaria and developed two types of vaccine that have been tested in 2 independent studies in primates. Beginning in 2001, Children in Tanzania were followed from birth to determine who among them developed malaria resistance. Blood samples taken from resistant and susceptible children at age 2 were analyzed, with malaria proteins introduced one by one until antibodies to PfGARP were identified in resistant samples but not in susceptible samples.

Children without antibodies to PfGARP were 2.5 times more likely to develop severe malaria infections.

In vitro studies found that the antibodies killed 98% to 99% of malarial trophozoites, which live in red blood cells, by binding to the PfGARP protein and sending a signal to the cells to die.

“It’s not necessarily in a parasite’s best interest to kill its host,” Kurtis said in the news release. “Keeping the host infected but alive means more chances for the parasite to reproduce. So what this might be is a means of sensing a host in distress and then reducing parasite load accordingly.”

When a mosquito carrying malaria bites a person, it injects malarial sporozoites, which travel to the liver before transforming into merozoites, which travel to red blood cells and transform into trophozoites. Previous vaccines have targeted the parasite during the sporozoite stage. The new vaccine approach targets the parasite in the final of these 3 stages in the infection cycle, when PfGARP is expressed on the surface of erythrocytes.

This new approach presents a longer window of time to target the parasite — up to 24 hours compared with about 5 minutes that the pathogen is in the sporozoite stage.

Human trials likely are still years away, but investigators are hopeful the anti-PfGARP antibody could be effective in both prophylactic and therapeutic treatments for malaria.

Malaria is the leading single-agent cause of childhood mortality, according to the World Health Organization. Previous attempt to develop a vaccine against the disease have had limited success.

Ongoing research includes a phase 1 trial of a monoclonal antibody CIS43LS to prevent malaria, sponsored by the National Institute of Allergy and Infectious Diseases.

Pilot introduction of a vaccine, known as RTS,S, began last year among children in Kenya, Ghana and Malawi.

A phase 1 trial of a placental malaria vaccine candidate, PRIMVAC, demonstrated safety and immunogenicity but hasn’t yet been tested in pregnant women.