Authors

Discussion

Antigen selection is crucial for malaria vaccine discovery. Immunogenicity is regarded as one vital criterion for progression of candidate vaccines to clinical trials. We investigated this assumption in an infection and vaccination model for malaria pre-erythrocytic stages. We genetically engineered Plasmodium berghei parasites that harbour a well-characterised epitope for stimulation of CD8+ T cells, either as an antigen in the sporozoite surface-expressed circumsporozoite protein or the parasitophorous vacuole membrane associated protein upregulated in sporozoites 4 (UIS4) expressed in exo-erythrocytic forms (EEFs). We demonstrate that the antigen origin results in disparities in immunogenicity with a sporozoite antigen evoking robust, superior antigen-specific CD8+ T-cell responses, whilst an EEF antigen induces poor responses. Regardless of their differing immunogenic properties, both sporozoite and EEF antigens access antigen presentation pathways in hepatocytes, as recognition and targeting by vaccine-elicited effector CD8+ T cells results in high levels of protection when targeting either antigen. Our study is the first demonstration that poorly immunogenic EEF antigens do not exclude their vulnerability to antigen-specific CD8+ T-cell killing, which has important implications on antigen prioritisation for next-generation pre-erythrocytic malaria vaccines.