Protective Efficacy Induced by Genetically Attenuated Mid-to-Late Liver-Stage Arresting Plasmodium berghei[Delta]mrp2 Parasites

Whole parasite immunization strategies employing genetically attenuated parasites (GAP), which arrest during liver-stage development, have been applied successfully for induction of sterile malaria protection in rodents. Recently, we generated a Plasmodium berghei GAP-lacking expression of multidrug resistance-associated protein (MRP2) (Pb[Delta]mrp2) that was capable of partial schizogony in hepatocytes but showed complete growth arrest. Here, we investigated the protective efficacy after intravenous (IV) immunization of BALB/c and C57BL/6J mice with Pb[Delta]mrp2 sporozoites. Low-dose immunization using 400 Pb[Delta]mrp2 sporozoites induced 100% sterile protection in BALB/c mice after IV challenge with 10,000 wild-type sporozoites. In addition, almost full protection (90%) was obtained after three immunizations with 10,000 sporozoites in C57BL/6J mice. Parasite liver loads in nonprotected Pb[Delta]mrp2-challenged C57BL/6J mice were reduced by 86% + or - 5% on average compared with naive control mice. The mid-to-late arresting Pb[Delta]mrp2 GAP was equipotent in induction of protective immunity to the early arresting Pb[Delta]b9[Delta]slarp GAP. The combined data support a clear basis for further exploration of Plasmodium falciparum parasites lacking mrp2 as a suitable GAP vaccine candidate.