Extended intrahepatic development of Plasmodium parasites overcomes age-associated loss of malaria vaccine efficacy in mice

Abstract Vaccine efficacy can be markedly affected by age, highlighting the need for strategies that sustain protective immunity across adulthood. Malaria whole-sporozoite vaccines employ attenuated sporozoites, the liver-infective forms of Plasmodium parasites, to induce high levels of protection, but how adult age influences their efficacy remains poorly understood. Here, we show that radiation-attenuated sporozoite (RAS) immunization confers robust sterile protection in young mice but fails to protect older adult mice. This age-associated loss of efficacy is associated with a blunted hepatic transcriptional response and with limited expansion of local CD8⁺ T cell populations, including liver-resident memory CD8⁺ T cells. Importantly, immunization with late-arresting genetically attenuated parasites (LA-GAP), which prolong and broaden exposure to liver-stage antigens, restores vaccine efficacy in older mice and confers durable sterile immunity. LA-GAP-mediated protection is associated with preferential accumulation of 60S ribosomal protein L6 (RPL6)-specific memory CD8⁺ T cells with preserved cytokine-producing capacity. These findings show that age can reshape the tissue-specific immune programs required for effective vaccination, but that these constraints can be overcome by modifying vaccine design to elicit appropriate immune responses.