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Defending the liver: The liver is an important site of replication for Plasmodium parasites, and therefore a key goal in vaccination against malaria is to induce robust antiparasitic immunity in the liver. Using Plasmodium berghei as a model to study malaria in mice, Holz et al. have developed a glycolipid-peptide conjugate vaccine that induced robust T cell responses in the liver and was able to protect mice when challenged with P. berghei. Inclusion of the glycolipid adjuvant, α-galactosylceramide (α-GalCer) that activates natural killer T (NKT) cells was vital to promoting antiparasitic immunity in the liver. The authors propose that agonists that activate NKT cells could be useful in priming immune responses in the liver in the context of malaria and in other hepatotropic diseases. Liver resident-memory CD8+ T cells (TRM cells) can kill liver-stage Plasmodium-infected cells and prevent malaria, but simple vaccines for generating this important immune population are lacking. Here, we report the development of a fully synthetic self-adjuvanting glycolipid-peptide conjugate vaccine designed to efficiently induce liver TRM cells. Upon cleavage in vivo, the glycolipid-peptide conjugate vaccine releases an MHC I–restricted peptide epitope (to stimulate Plasmodium-specific CD8+ T cells) and an adjuvant component, the NKT cell agonist α-galactosylceramide (α-GalCer). A single dose of this vaccine in mice induced substantial numbers of intrahepatic malaria-specific CD8+ T cells expressing canonical markers of liver TRM cells (CD69, CXCR6, and CD101), and these cells could be further increased in number upon vaccine boosting. We show that modifications to the peptide, such as addition of proteasomal-cleavage sequences or epitope-flanking sequences, or the use of alternative conjugation methods to link the peptide to the glycolipid improved liver TRM cell generation and led to the development of a vaccine able to induce sterile protection in C57BL/6 mice against Plasmodium berghei sporozoite challenge after a single dose. Furthermore, this vaccine induced endogenous liver TRM cells that were long-lived (half-life of ~425 days) and were able to maintain >90% sterile protection to day 200. Our findings describe an ideal synthetic vaccine platform for generating large numbers of liver TRM cells for effective control of liver-stage malaria and, potentially, a variety of other hepatotropic infections. [ABSTRACT FROM AUTHOR]