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.

► A recent experimental human challenge study established a new benchmark for malaria vaccine development.
► Polyfunctional effector memory T cells (TEM) were identified as correlates of protection against malaria.
► Proof-of-principle studies of ‘natural immunization’ by sporozoite exposure during antibiotic cover established potent and protracted protection against reinfection.
► Population genetics revealed a previously underestimated diversity of P. falciparum parasites in infected individuals.