Although there is currently no highly effective vaccine for malaria, a concept based on radiation attenuated sporozoites (RAS) and a ‘prime and trap’ protocol have highlighted the potential for vaccination to provide protection by targeting the generation of liver tissue-resident memory CD8+ T cells (Trm).¹ In addition to T cell priming, expression of antigen and inflammation in the liver were likely drivers of liver Trm cell generation and immunity against malaria. Here, we present the development of a fully synthetic glycolipid-peptide version of the vaccine that comprises MHC class I-restricted peptide epitopes conjugated to a prodrug form of the NKT cell agonist, α-galactosylceramide (α-GalCer). In this design we modified the α-GalCer structure by N-O acyl migration of the hexacosanoyl moiety to form the inactive α-GalCer prodrug² and installed a cathepsin-sensitive immolative linker to the revealed amine. Peptides were conjugated to the linker via chemoselective methodologies to form vaccine candidates. A single dose of the vaccine induced substantial numbers of Trm cells which could be further increased upon boosting resulting in complete protection against sporozoite challenge. Admixed components were ineffective in generating liver Trm cells and were unable to protect against challenge. Furthermore, we have shown that minor chemical modifications, peptide design and changes in synthetic methodology were able to further increase the potency of the vaccine. The relatively cheap manufacturing cost, stability and the ability to simply alter the peptide within the vaccine to target specific populations highlight the promising nature of this vaccine concept.