NEW YORK (Reuters Health) - The Plasmodium falciparum glutamic-acid-rich protein (PfGARP) antigen partially protects against malaria in non-human primates, researchers report.
“I would expect a PfGARP-based vaccine to confer protection against severe malaria and likely uncomplicated malaria,” said Dr. Jonathan D. Kurtis of Brown University Medical School, in Providence, Rhode Island.
“We are currently combining PfGARP with our other vaccine candidate (PfSEA-1), which blocks parasite escape from infected red blood cells. I expect the combination to be more effective than either individual component,” he told Reuters Health by email.
Dr. Kurtis and colleagues identified 11 parasite genes whose protein products were uniquely recognized by antibodies in plasma from individuals who are resistant to malaria but not in susceptible individuals. They focused their attention on PfGARP, which they expressed and purified in E. coli as the recombinant protein PfGARP-A.
Anti-PfGARP-A antiserum generated in mice inhibited parasite growth by 94% to 99% compared with controls in three P. falciparum strains and four freshly isolated parasite lines, the team report in Nature.
Similarly, human anti-PfGARP-A antiserum isolated from plasma pooled from adults living in a Tanzanian field site also significantly inhibited parasite growth by 94% to 99% compared with controls in three parasite strains.
Anti-PfGARP-A antibodies completely disrupted food vacuole integrity in parasites and caused substantial DNA fragmentation, evidence that the parasites were killed through activation of programmed cell death.
In studies of Tanzanian children and Kenyan male volunteers, higher anti-PfGARP IgG levels were associated with a significantly decreased risk of severe malaria and with significantly decreased parasite density, respectively, compared with individuals lacking anti-PfGARP antibodies.
Monkeys immunized with nucleoside-modified mRNA encoding PfGARP-A encapsulated in lipid nanoparticles generated antibody responses and, after intravenous challenge with red blood cells infected with blood-stage P. falciparum, demonstrated substantially lower levels of parasitemia compared with control monkeys.
“Together, our data support PfGARP as a vaccine candidate against malaria that is caused by P. falciparum,” the authors conclude. “By killing trophozoite-infected RBCs, immunization with PfGARP could synergize with other vaccines that target the parasite invasion of hepatocytes or the invasion of and egress from erythrocytes.”
“Malaria continues to kill over 10,000 children under the age of 5 every week, and it has been doing this for tens of thousands of years,” Dr. Kurtis said. “We desperately need investments for research on malaria vaccines.”
Dr. Matthew Laurens of the University of Maryland School of Medicine’s Malaria Research Group, in Baltimore, told Reuters Health by email, “The expression of PfGARP at the early trophozoite stage makes it an ideal candidate for a blood-stage vaccine against Plasmodium falciparum.”
“Early expression of the protein,” he added, “facilitates early recognition by the human immune system that serves two important purposes: 1) it permits killing infected red blood cells before the parasite multiplies, decreasing the total parasite burden in a human host and thus the severity of malaria illness, and 2) it can kill infected red blood cells before they reach target end organs, including brain and kidney, thus preventing the most severe forms of P. falciparum malaria.”
“The pleasant surprise for malaria researchers is that the gene encoding PfGARP shows little genetic variation, a problem that has plagued malariavaccine development since its inception and caused many malaria vaccine development projects to fail,” he said.
“Characterization of a novel candidate malaria-vaccine antigen PfGARP in persons in endemic areas, in preclinical studies, and in genomic analyses provide strong support for subsequent testing in human clinical trials either as a standalone vaccine or combined with other pre-erythrocytic antigens,” said Dr. Laurens, who was not involved in the new research. “This is a welcome finding for malaria vaccine research for P. falciparum, as most promising efforts to date have been directed toward a single antigen, the circumsporozoite protein.”
The study had no commercial funding, but several authors are named inventors on a patent on the use of PfGARP as a vaccine.
SOURCE: go.nature.com/2S9FM8V Nature, online April 22, 2020.
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