A plasmodium falciparum sporozoite's journey: through organs and across CD8+ T-cell challenges

Schuijlenburg, R. van

doi:doi:10.60602/1887-4296576

Malaria causes approximately 600,000 deaths annually, mainly in sub-Saharan Africa, with Plasmodium falciparum responsible for most fatalities. Although two WHO-approved vaccines provide partial protection, their efficacy is limited and wanes over time, underscoring the need for more effective approaches. Whole sporozoite (SPZ) vaccines targeting the liver stage show the greatest promise. Genetically attenuated parasites such as GA2, which arrest late in the liver stage, induce substantially higher protection than early-arresting strains, highlighting the importance of late liver-stage development for optimal immunity.

CD8⁺ T cells are central to protection by recognizing and eliminating infected hepatocytes. We established a functional model to determine which SPZ-derived epitopes are recognized by memory CD8⁺ T cells and to dissect liver-stage immune mechanisms. Using this system, we demonstrated that circumsporozoite protein (CSP)–specific CD8⁺ T cells, including those...Show moreMalaria causes approximately 600,000 deaths annually, mainly in sub-Saharan Africa, with Plasmodium falciparum responsible for most fatalities. Although two WHO-approved vaccines provide partial protection, their efficacy is limited and wanes over time, underscoring the need for more effective approaches. Whole sporozoite (SPZ) vaccines targeting the liver stage show the greatest promise. Genetically attenuated parasites such as GA2, which arrest late in the liver stage, induce substantially higher protection than early-arresting strains, highlighting the importance of late liver-stage development for optimal immunity.

CD8⁺ T cells are central to protection by recognizing and eliminating infected hepatocytes. We established a functional model to determine which SPZ-derived epitopes are recognized by memory CD8⁺ T cells and to dissect liver-stage immune mechanisms. Using this system, we demonstrated that circumsporozoite protein (CSP)–specific CD8⁺ T cells, including those targeting a defined CSP epitope, directly recognize and kill P. falciparum–infected hepatocytes. We further showed that CD8⁺ T-cell priming can occur in the lungs, expanding insight into how protective immunity is generated and distributed across tissues.

Vaccine efficacy depends on SPZ biology and administration strategy. Older SPZ induce stronger CD8⁺ T-cell responses than younger SPZ, and intravenous immunization elicits more robust tissue-resident memory T cells than intradermal delivery. Notably, a single GA2 SPZ immunization achieved up to 90% protection in humans. Together, these findings inform rational optimization of durable, highly protective malaria vaccines.
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A plasmodium falciparum sporozoite's journey: through organs and across CD8+ T-cell challenges