More time to kill: A longer liver stage increases T cell-mediated protection against pre-erythrocytic malaria

Abstract

Liver stage (LS) Plasmodia mature in 2-2.5days in rodents compared to 5-6days in humans. Plasmodium-specific CD8+ Tcell expansion differs across these varied timespans. To mimic the kinetics of CD8+ Tcells of human Plasmodium infection, a two-dose challenge mouse model that achieved 4-5days of LS antigen exposure was developed. In this model, mice were inoculated with a non-protective, low dose of late-arresting, genetically attenuated sporozoites to initiate Tcell activation and then re-inoculated 2-3days later with wild-type sporozoites. Vaccines that partially protected against traditional challenge completely protected against two-dose challenge. During the challenge period, CD8+ Tcell frequencies increased in the livers of two-dose challenged mice but not in traditionally challenged mice, further suggesting that this model better recapitulates kinetics of CD8+ Tcell expansion in humans during the P.falciparum LS. Vaccine development and antigen discovery efforts may be aided by using the two-dose challenge strategy.