Protective immunity against malaria by 'natural immunization': a question of dose, parasite diversity, or both?

Plasmodium undergoes an obligate liver phase before the onset of malaria, which is caused exclusively by cyclic propagation of the parasite inside erythrocytes. The diagnostically inaccessible and clinically silent pre-erythrocytic expansion phase is a promising target for inducing sterilizing immunity against reinfections. Recent studies in rodent and human malaria models called attention to the induction of potent protective immunity by administration of anti-malarial drugs during sporozoite exposure. Here, we review the concept of drug-mediated pathogen arrest as a natural immunization strategy. This previously unrecognized immunological benefit might also open new opportunities for population-wide presumptive drug administration as an adjunct malaria control tool.