Using Synthetic Biology to Generate Hyper-Stable Vaccines

Polypeptide vaccines effectively activate human T cells but suffer from poor biological stability, which confines both transport logistics and in vivo therapeutic activity. Synthetic biology has the potential to address these limitations through the generation of highly stable antigenic “mimics” using subunits that do not exist in the natural world. We developed a platform based on non-natural chemistry and used this platform to reverse engineer fully artificial T cell agonists that immunogenicity more than 5-fold of their natural blueprints. This non-natural chemistry is highly stable in human serum and gastric acid. In vitro, these synthetic agonists expanded antigen-specific responses against multiple epitopes across multiple viruses. In vivo, synthetic vaccinated mice were protected from lethal challenge. Moreover, the synthetic agonists were immunogenic after oral administration. We have since expanded this technology to other human viruses including SARS-CoV-2. These proof-of-concept studies highlights the power of synthetic biology to expand the horizons of vaccine design and therapeutic delivery.