6″-Modifed α-GalCer-peptide conjugate vaccine candidates protect against liver-stage malaria.

Abstract

Self-adjuvanting vaccines consisting of peptide epitopes conjugated to immune adjuvants are a powerful way of generating antigen-specific immune responses. We previously showed that a Plasmodium-derived peptide conjugated to a rearranged form of α-galactosylceramide (α-GalCer) could stimulate liver-resident memory T (TRM) cells that were effective killers of liver-stage Plasmodium berghei ANKA (Pba)-infected cells. To investigate if similar or even superior TRM responses can be induced by modifying the α-GalCer adjuvant, we created new conjugate vaccine cadidates by attaching an immunogenic Plasmodium-derived peptide antigen to 6″-substituted α-GalCer analogues. Vaccine synthesis involved developing an efficient route to α-galactosylphytosphingosine (α-GalPhs), from which the prototypical iNKT cell agonist, α-GalCer, and its 6″-deoxy-6″-thio and -amino analogues were derived. Attaching a cathepsin B-cleavable linker to the 6″-modified α-GalCer created pro-adjuvants bearing a pendant ketone group available for peptide conjugation. Optimized reaction conditions were developed that allow for the efficient conjugation of peptide antigens to the pro-adjuvants via oxime ligation to create new glycolipid-peptide (GLP) conjugate vaccines. A single dose of the vaccine candidates induced acute NKT and Plasmodium-specific CD8+ T cell responses that generated potent hepatic TRM responses in mice. Our findings demonstrate that attaching antigenic peptides to 6″-modifed α-GalCer generates powerful self-adjuvanting conjugate vaccine candidates that could potentially control hepatotropic infections such as liver-stage malaria.

• Authors: Michael A Meijlink, Yu Cheng Chua, Susanna T S Chan, Regan J Anderson, Matthew W Rosenberg, Anton Cozijnsen, Vanessa Mollard, Geoffrey I McFadden, Sarah L Draper, Lauren E Holz, Ian F Hermans, William R Heath, Gavin F Painter, Benjamin J Compton
• Journal: RSC chemical biology (RSC Chem Biol) Vol. 3 Issue 5 Pg. 551-560 (May 11 2022) ISSN: 2633-0679 [Electronic] England
• PMID: 35656478 (Publication Type: Journal Article)
• Copyright: This journal is © The Royal Society of Chemistry.