Safety and Efficacy of Immunization with a Late-Liver-Stage Attenuated Malaria Parasite

   This double-blind, controlled clinical trial evaluated the safety and efficacy of immunization with a genetically attenuated Plasmodium falciparum parasite (GA2), which arrests late in the liver stage, compared to an early-arresting parasite (GA1) and placebo. Healthy malaria-naive adults were exposed to bites from infected mosquitoes across two trial stages. In stage B, 89% of participants immunized with GA2 were protected against homologous controlled human malaria infection (CHMI), versus 13% with GA1 and 0% with placebo. GA2 induced significantly higher frequencies of polyfunctional CD4+ and Vγ2+ γδ T cells with proinflammatory cytokine profiles, while antibody titers against PfCSP were similar across groups. No breakthrough blood-stage infections occurred, and adverse events were mild. The findings suggest that extended liver-stage antigen exposure via GA2 enhances cellular immunity and protective efficacy, supporting further development of late-arresting whole-parasite malaria vaccines.

   This double-blind, controlled clinical trial evaluated the safety and efficacy of immunization with a genetically attenuated Plasmodium falciparum parasite (GA2), which arrests late in the liver stage, compared to an early-arresting parasite (GA1) and placebo. Healthy malaria-naive adults were exposed to bites from infected mosquitoes across two trial stages. In stage B, 89% of participants immunized with GA2 were protected against homologous controlled human malaria infection (CHMI), versus 13% with GA1 and 0% with placebo. GA2 induced significantly higher frequencies of polyfunctional CD4+ and Vγ2+ γδ T cells with proinflammatory cytokine profiles, while antibody titers against PfCSP were similar across groups. No breakthrough blood-stage infections occurred, and adverse events were mild. The findings suggest that extended liver-stage antigen exposure via GA2 enhances cellular immunity and protective efficacy, supporting further development of late-arresting whole-parasite malaria vaccines.