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Malaria vaccines provide strong and lasting immunity

A microscopy image of malaria sporozoites, the infectious form of the malaria parasite that is injected into people by mosquitoesNIAID

Antimalarial drugs and measures to control mosquitoes have reduced the malaria burden worldwide. But this decline has stalled in recent years. Further progress against malaria will likely require vaccines, which have so far conferred only partial protection.

Malaria is caused by single-celled parasites from the genus Plasmodium. Infected mosquitoes transmit these parasites to people in a form called a sporozoite. Upon infection, sporozoites travel to the liver. There, they grow and replicate before they enter the blood and infect red blood cells. Only when the parasites infect red blood cells do they cause disease.

One potential vaccination strategy combines live sporozoites with an antimalarial drug. The sporozoites induce an immune response while the drugs kill the sporozoites before they can cause disease. This is called chemoprophylaxis vaccination, or CVac. Previous trials found that CVac conferred high immunity to malaria. But this immunity extended only to the specific parasite variant used in the vaccine.

A research team led by Dr. Patrick Duffy of NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and Dr. Stephen Hoffman of Sanaria Inc. further explored the CVac approach in Phase 1 clinical trials. Results were published in Nature on June 30, 2021.

Healthy volunteers were given three monthly doses of sporozoites and one of two drugs: pyrimethamine (PYR) or chloroquine (CQ). PYR kills liver-stage parasites before their release into blood, while CQ kills parasites at the blood stage. Three months after the last sporozoite dose, the researchers exposed the volunteers to malaria under carefully controlled conditions. In "homologous challenges," volunteers were exposed to the same African variant as that used for vaccination. "Heterologous" challenges exposed volunteers to a distantly related variant from Brazil.

The team first tested a low sporozoite dose used in previous studies. At this dose, only two of nine volunteers who received PYR were protected against homologous challenge. But a fourfold larger sporozoite dose, combined with PYR treatment, protected seven out of eight volunteers. This dose also protected seven out of nine PYR-treated volunteers against heterologous challenge. Combining the high sporozoite dose with CQ protected all six volunteers against heterologous challenge, an unprecedented level of efficacy.

Meanwhile, all 12 unvaccinated control participants developed infections, which were promptly treated. Immune protection correlated with a subset of T cells, called Vδ2 γδ T cells, and with antibodies against the malaria parasite.

“These findings suggest that CVac could protect people against diverse malaria strains in the field,” Duffy says. “This could benefit people living in malaria-endemic areas, as well as travelers and deployed military personnel.”

PYR has an excellent safety profile and is already widely used to prevent malaria in pregnant women and children in Africa. A Phase 2 clinical trial to assess the efficacy of CVac in real-world conditions is currently underway in Mali.

—by Brian Doctrow, Ph.D.