Design and Synthesis of a Bifunctional Linker for generating Haptenated Flagellin Bioconjugates for Improving Vaccine Reach and Lifespan (360G-Wellcome-211829_Z_18_Z)

The protein, flagellin, has been shown to enhance vaccine responses in systemic and mucosal sites, and bolster long-lived Ab responses. The ability of flagellin to migrate to mucosa opens up a strategy for delivering other antigens to the gut mucosa to elicit a more robust immune response, which is desirable for a vaccine to maximise its potential to protect. Activated iNKT-cells elicit potent systemic IgG responses but their ability to modulate mucosal antibody responses, including IgA, is less clear. If we could administer iNKT-cell agonists systemically in a way that ensures they reach mucosal sites, we would be able to examine this in depth. We now propose to use flagellin–iNKT-cell agonist conjugates to do just this, by employing flagellin as a carrier to deliver iNKT-cell antigens to the mucosa and in so doing, hopefully induce a robust mucosal antibody response. This Summer research project will focus on the synthesis of a bifunctional molecule which we will use to attach a potent iNKT-cell glycolipid agonist, which we have previously assembled, and then use the second functionality to conjugate the iNKT-cell agonist to the flagellin molecule selectively through surface-exposed Tyr residues that are concentrated in the hypervariable region of the flagellin molecule.