Self-Adjuvanting Vaccine Candidates for Cancer and Tuberculosis

Abstract

Each year, cancer and tuberculosis cause approximately 10 million deaths. The only approved tuberculosis vaccine, BCG, has highly variable efficacy. For the majority of cancers, no efficacious vaccines currently exist. The difficulty of designing vaccines for cancer lies in the fact that most of the biomolecules produced by cancer cells are the same as those produced by healthy cells. Thus, tumour‑associated antigens are typically poorly immunogenic. There is an urgent need for new vaccine candidates with improved safety and efficacy for both cancer and tuberculosis. To improve the immunogenicity of such antigens, we and others have investigated self‑adjuvanting vaccine candidates, in which an antigen is covalently attached to a lipopeptide adjuvant. Such vaccines have an advantage over traditional subunit vaccines in that they have improved uptake by antigen‑presenting cells (APCs), while ensuring that the APCs are activated by the adjuvant are the same cells exposed to antigen. To date, however, there has been a dearth of synthetic techniques for the rapid, efficient synthesis of self‑adjuvanting vaccines. This thesis details the design, synthesis and immunological evaluation of novel self‑adjuvanting vaccine candidates for cancer and tuberculosis. Chapter 2 describes the immunological evaluation of a series of glycolipopeptide self‑adjuvanting cancer vaccine candidates. When injected into mice, these candidates induced high titres of tumour‑specific antibodies, but not cytotoxic T cell responses. In order to accelerate the synthesis of rationally designed self‑adjuvanting vaccine candidates, a new synthetic method to access them needed to be developed. Chapter 3 describes the development of a novel strategy for the synthesis of long lipopeptide vaccine candidates through native chemical ligation. This strategy was successfully applied to the synthesis of a self‑adjuvanting TB vaccine candidate, which demonstrated protective efficacy in a mouse model of M. tuberculosisinfection. In Chapter 4, this synthetic strategy was applied to the synthesis of a self‑adjuvanting cancer vaccine candidate that had been re‑designed with the goal of inducing cytotoxic T cell responses while maintaining strong humoral responses. Chapter 5 describes the synthesis and immunological evaluation of the signal peptide of the cancer antigen mucin 1 (MUC1) and a more soluble analogue, K4-MUC1SP. Through the investigation of K4‑MUC1SP as a potential antigen for cancer vaccines, we uncovered a novel role for the MUC1 signal peptide as a potent immunosuppressant.