Plasmodium berghei sporozoite-based vaccination platform against human malaria

AbstractThere is a pressing need for safe and highly effectivePlasmodium falciparum(Pf) malaria vaccines. The circumsporozoite protein (CS), expressed on sporozoites and during early hepatic stages, is a leading target vaccine candidate, but clinical efficacy has been modest so far. Conversely, whole-sporozoite (WSp) vaccines have consistently shown high levels of sterilizing immunity and constitute a promising approach to effective immunization against malaria. Here, we describe a novel WSp malaria vaccine that employs transgenic sporozoites of rodentP. berghei(Pb) parasites as cross-species immunizing agents and as platforms for expression and delivery ofPfCS (PbVac). We show that both wild-typePbandPbVac sporozoites unabatedly infect and develop in human hepatocytes while unable to establish an infection in human red blood cells. In a rabbit model, similarly susceptible toPbhepatic but not blood infection, we show thatPbVac elicits cross-species cellular immune responses, as well asPfCS-specific antibodies that efficiently inhibitPfsporozoite liver invasion in human hepatocytes and in mice with humanized livers. Thus,PbVac is safe and induces functional immune responses in preclinical studies, warranting clinical testing and development.