Abstract
The ability to generate long-lasting antibodies that target small molecule haptens has far-reaching implications in the ongoing development of effective immunotherapies. In general, small molecule haptens often require conjugation to macromolecules such as carrier proteins to facilitate immunorecognition and stimulate durable anti-hapten antibody responses. Unfortunately, carrier vaccines are often difficult to manufacture and have been reported to exhibit decreased effectiveness over time. Self-adjuvanting vaccine conjugates offer a promising alternative to carrier vaccines whereby a hapten is conjugated to chemically tractable immunomodulator that can stimulate a robust anti-hapten response in the absence of a macrocarrier. The prototypical iNKT cell agonist α-galactosylceramide (α-GalCer) is a potent glycolipid adjuvant that has been previously demonstrated to enhance hapten-specific antibody responses in vivo. While several α-GalCer-hapten conjugates have shown great promise in generating high titers of primary IgG anti-hapten antibodies, many fail to induce long-lasting memory responses. To remediate this issue, we expect that ‘tricomponent’ conjugate vaccines comprising α-GalCer, hapten and a T helper epitope will elicit long-lasting humoral immunity against the selected hapten via complimentary activation of both classical CD4+ T and iNKT cells. To achieve this, a series of stereoselective glycosylation methods were investigated for the synthesis of α-GalCer and other C-6 modified derivatives thereof. Additionally, a series of novel mercaptan- containing α-GalCer N-acyl analogues were synthesised for the purpose of binding covalently to CD1d via disulfide exchange and to facilitate immobilisation of vaccine conjugates onto AuNPs.