by Justin Jackson , Medical Xpress

Credit: Pixabay/CC0 Public Domain

Researchers at Leiden University Medical Center and Radboud University Medical Center in the Netherlands have demonstrated promising safety and efficacy of a late-liver-stage attenuated malaria parasite vaccine in a small clinical trial.

The study found that immunization with a genetically modified Plasmodium falciparum parasite, known as GA2, induced a favorable immune response and provided protective efficacy against malaria infection.

Globally, malaria continues to pose a significant health challenge, with over 200 million cases reported annually and nearly half a million deaths, predominantly in sub-Saharan Africa and parts of Asia and Latin America. The disease disproportionately affects young children and pregnant women, underscoring the urgent need for more effective and durable vaccination strategies.

Malaria eradication efforts have stalled and new strategies are urgently needed. Current malaria vaccines offer modest short-term protection. Whole-sporozoite vaccination with live-attenuated parasites presents an alternative approach that may enhance immunity by exposing the immune system to a broader array of antigens.

In the study, “Safety and Efficacy of Immunization with a Late-Liver-Stage Attenuated Malaria Parasite,” published in the New England Journal of Medicine, researchers conducted a double-blind, controlled clinical trial to assess the safety, side-effect profile, and efficacy of immunization via mosquito bites with a genetically modified P. falciparum parasite (GA2) designed to continue developing longer in the liver.

GA2 allows the parasite to develop further within liver cells, which exposes the immune system to a broader range of parasite antigens. This prolonged exposure is hypothesized to enhance the immune system’s ability to recognize and combat the parasite by activating more complete immune responses.

Healthy adult volunteers with no prior malaria exposure were randomly assigned to receive immunization with GA2, exposure to another parasite known as GA1 or to a placebo of uninfected mosquito bites. A total of 25 participants were enrolled in the trial, with 10 assigned to the GA2 group, 10 to the GA1 group, and five to the placebo group. Each group consisted of both male and female volunteers.

Participants underwent three immunization sessions at 28-day intervals, each involving exposure to 50 mosquitoes infected with the respective parasites or uninfected in the case of the placebo group. Three weeks after the final immunization, all participants were exposed to controlled human malaria infection to evaluate protective efficacy.

The primary endpoints were the number and severity of adverse events and the occurrence of blood-stage parasitemia (presence of parasites in the blood) exceeding 100 P. falciparum parasites per milliliter. Adverse events were similar across all groups, primarily involving mild local reactions such as erythema and pruritus at the mosquito bite sites.

Efficacy results were striking. Protective efficacy was observed in eight of nine participants (89%) in the GA2 group, compared to one of eight participants (13%) in the GA1 group and none in the placebo group. No breakthrough infections occurred after exposure to GA2, indicating a strong safety profile. The median time to parasitemia after controlled human malaria infection was 12 days for the placebo group and 11 days for those who received GA1.

Immunological analyses revealed that participants receiving GA2 had a significantly higher frequency of P. falciparum-specific polyfunctional CD4+ T cells than those receiving GA1. These cells exhibited a strong proinflammatory response characterized by the production of interferon-γ, tumor necrosis factor α, and interleukin-2.

Both GA2 and GA1 induced similar antibody titers against the P. falciparum circumsporozoite protein, suggesting enhanced protection with GA2 is associated with cellular immune responses rather than antibody levels alone.

The study concludes that GA2 testing found favorable immune profiles and substantial protective efficacy against malaria infection, enough to warrant further evaluation in larger and more diverse populations.

More information: Olivia A.C. Lamers et al, Safety and Efficacy of Immunization with a Late-Liver-Stage Attenuated Malaria Parasite, New England Journal of Medicine (2024). DOI: 10.1056/NEJMoa2313892

Journal information:New England Journal of Medicine

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