Discussion

There is a pressing need for safe and highly effective Plasmodium falciparum (Pf) malaria vaccines. The circumsporozoite protein (CS), expressed on sporozoites and during early hepatic stages, is a leading target vaccine candidate and a crucial protective antigen in whole-sporozoite malaria vaccination. We describe a novel malaria vaccination platform using transgenic sporozoites of rodent P. berghei (Pb) parasites for expression and delivery of PfCS (PbVac). We show that both wild-type Pb and PbVac 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 to Pb hepatic but not blood infection, we show that PbVac elicits cross-species cellular immune responses and PfCS-specific antibodies that efficiently inhibit Pf sporozoite liver invasion in human hepatocytes and in mice with humanized livers. Thus, PbVac is safe and induces functional immune responses in preclinical studies. An extensive pre-clinical assessment of PbVac's safety was conducted, warranting the evaluation of this vaccine candidate in a first-in-human study. Early results from this ongoing Phase I/IIa clinical trial will also be presented.