Results from a controlled human malaria infection (CHMI) trial show that a new type of vaccine for malaria protects healthy volunteers from infection. The researchers deleted three genes from the malaria-causing parasite Plasmodium falciparum, and then delivered the vaccine—the genetically attenuated parasite—to healthy volunteers through hundreds of mosquito bites. The vaccine elicited antibodies that blocked infection and was shown to be safe and protective for at least one month.

The study was led by Lisa Jackson, MD, senior investigator at Kaiser Permanente Washington Health Research Institute, and Stefan Kappe, PhD, principal investigator at Seattle Children’s Research Institute and the University of Washington, and was published in a Science Translational Medicine article entitled, “A genetically engineered Plasmodium falciparum parasite vaccine provides protection from controlled human malaria infection.”

Malaria is a leading cause of illness and death worldwide, especially in young children and pregnant women in sub-Saharan Africa. According to the World Health Organization, about 240 million people had malaria in 2020 and about 627,000 of them died.

Vaccines are critical for controlling and eradicating the disease. The recently approved RTS,S vaccine (Mosquirix), which is based on subunits of proteins that are expressed by the parasite during early infection, provides limited protection against naturally transmitted malaria.

Instead of protein subunits, the researchers in the current study used whole P. falciparum parasites that they had weakened by genetic engineering. These genetically attenuated parasites (GAPs) contain deletions in the P52, P36, and SAP1 genes, which are essential for establishing infections in humans.

The vaccine is named PfGAP3KO, which stands for Plasmodium falciparum GAP with three knockouts (deletions).

Human Malaria Infection
Sean Murphy, MD, PhD, associate professor at the University of Washington, demonstrates how study volunteers placed their forearms on mosquito-filled cups to undergo malaria human challenge. He and Ashley Vaughn, PhD, research assistant professor at the University of Washington and Seattle Children’s Research Institute, were first authors on the paper describing the work. [Sean Murphy, MD, PhD]

The researchers set out to evaluate the PfGAP3KO vaccine by CHMI in malaria-naïve subjects. They administered the vaccine through either three or five immunizations to 16 healthy volunteers, who received the vaccine through mosquitoes infected with PfGAP3KO. The vaccine was safe and well-tolerated, as the volunteers showed only localized rashes and general malaise likely related to the large number of mosquito bites required for vaccine administration.

One month after the last immunization, the volunteers were then exposed to bites from mosquitoes carrying fully infectious P. falciparum parasites. Half of the volunteers showed no evidence of infection in the blood after 28 days, and one of the protected participants remained completely protected against infection after a second exposure six months later.

“In conclusion, our study establishes a proof of concept for the safety, immunogenicity, and efficacy of PfGAP3KO,” the researchers wrote, indicating that it warrants further clinical trial investigation.

Because of the mosquito bite delivery method, the exact dose of PfGAP3KO administered in the current study was unknown. “Furthermore, the predominant AEs [adverse events] observed in our study were related to the mosquito bite administration and transition to DVI [direct venous injection] will reduce such AEs,” they wrote. “Thus, an aseptic, purified, cryopreserved, vialed, and DVI-administered formulation PfGAP3KO will allow for safe and precise dose-finding trials to achieve complete sterilizing protection with this candidate vaccine.”

Future studies also will help answer lingering questions about the vaccine’s mechanisms and effects on T cells, the authors noted.

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