Polypeptide vaccines effectively activate human T cells but suffer from poor biological stability, which confines both transport logistics and in vivo therapeutic efficacy. Synthetic biology has the potential to address these limitations through the generation of hyper-stable antigenic “mimics” that do not exist in the natural world. We have developed a platform based around non-natural chemistry and have used this platform to reverse engineer fully artificial T cell agonists that are that up to 6-fold more immunogenic than natural counterparts, including blueprints from influenza A, EBV, CMV and SARS-CoV-2. These non-natural vaccines are highly stable in human serum and gastric acid. In vivo, vaccinated mice were protected from lethal challenge. Moreover, the synthetic agonists were immunogenic after oral administration without adjuvant. These proof-of-concept studies highlight the power of synthetic biology to expand the horizons of vaccine design and delivery.