Eukaryotic pathogens typically follow a complex life cycle, including host switch and morphologically distinct forms. Parasite stage conversion offers exceptional opportunities for whole organism vaccine development. In case of Plasmodium, the causative agent of malaria, disease is exclusively caused by asexual blood stages that invade and replicate within erythrocytes. Pathogenic blood stage infections are preceded by a silent parasite growth phase inside the liver. Two alternative experimental whole organisms vaccine strategies that lead to arrested Plasmodium liver stages elicit potent, lasting immunity against re-infection. Live irradiation- or genetically arrested parasites are metabolically active and correspond to classical attenuated vaccines. Specific antimalarial treatment during experimental natural sporozoite infections prevents a febrile malaria episode and, simultaneously, induces effective anti-liver stage immunity. Translation of these strategies into a safe, affordable, and accessible pediatric anti-malaria vaccine requires major bioengineering and pharmaceutical improvements, respectively, but holds promise for a truly effective immunization scheme against the most prevalent and fatal vector-borne disease.
