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Immunization with a second-generation genetically attenuated parasite was safe and provided strong protection from malaria infection in young adults, a small clinical trial in the Netherlands suggested.

Protective efficacy against malaria infection occurred in eight of nine participants (89%) receiving a late-liver-stage attenuated malaria parasite (GA2), reported Meta Roestenberg, MD, PhD, of Leiden University Medical Center in the Netherlands, and co-authors in the .

As a comparator, the researchers assessed the effectiveness of a previously developed early-arresting parasite (GA1) and found that one of eight people (13%) was protected from infection. Three participants in the study received a placebo and all developed infection. Adverse events were similar across groups.

The proof-of-concept trial was among the first to test a new method of immunizing humans against malaria by genetically altering the Plasmodium falciparum parasite. The parasite spurred an immune response while replicating in the liver but died before it could leave and cause disease, said co-author Matthew McCall, MD, of Radboud University Medical Center, also in the Netherlands.

The GA2 parasite, which is missing one gene, died after 7 days, just before leaving the liver. The GA1 parasite, which is missing two genes, died within 24 to 48 hours of entering the liver.

"Having longer development of the parasites in the liver generates better immunity against malaria than having a short liver infection," McCall noted. "That's the main learning point of this study."

"This is a pretty pivotal study for the field because it's one of the first that has explored the potential of the late-liver-stage arresting GAP [genetically attenuated parasite] vaccine," said Debashree Goswami, PhD, a research scientist at Seattle Children's, who wasn't involved in the study. "It is also one of the first studies that shows us that late-stage arresting GAP is so much better than the early-stage arresting GAP."

Currently approved malaria subunit vaccines provide modest, short-lived protection against malaria, the researchers pointed out. "The progress in the eradication of malaria has slowed, creating a need for new tools," they wrote.

of young adults ages 19-35 was conducted from September 2021 to January 2022 in two phases. Stage A was an open-label, dose-escalation safety phase in which participants were exposed to the bites of either 15 or 50 mosquitoes infected with GA2.

Stage B was a double-blind, placebo-controlled phase that compared the protective efficacy of GA2 versus GA1 and placebo (bites from uninfected mosquitoes) after completing three immunization sessions, which were administered at 28-day intervals. In stage B, participants were exposed to the bites of 50 mosquitoes in each session.

There were no breakthrough blood infections in either stage. Adverse events reported included erythema, pruritus, myalgia, and headache.

Three weeks after receiving the last set of immunizations, all participants underwent controlled malaria infection by means of five bites from mosquitoes infected with wild-type P. falciparum. All were treated with a curative regimen of atovaquone-proguanil (Malarone) after their final exposure -- 28 days at the latest.

An immunogenicity analysis of participants showed that those exposed to GA2-infected mosquitoes developed a larger array of immune cells including helper T cells that produced multiple cytokines in response to the parasite, compared with those exposed to GA1-infected mosquitoes.

"The immune system responded in a more broad and diverse way with the GA2 vaccine, and we think that cellular response is important to understanding why the protection was so much stronger than with the GA1 vaccine," McCall said. "Now that we know that, we can do more to refine these vaccines."

Limitations included the trial's small sample size and the controlled environment of the experiment with participants who were malaria-naive, McCall acknowledged.

Larger studies are needed to better confirm the safety profile of the GA2 vaccine, the researchers noted. Studies with individuals who live in regions where malaria is endemic -- in particular, studies in children -- will be important to learn whether the vaccine is effective against natural exposure in populations most affected by malaria.

"For practicality purposes, further studies will also require the vaccines be delivered through a needle and syringe, rather than mosquito bites," McCall said.

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