Semi-synthetic terpenoids with differential adjuvant properties as sustainable replacements for shark squalene in vaccine emulsions

Synthetic biology has allowed for the industrial production of supply-limited sesquiterpenoids such as the antimalarial drug artemisinin and beta-farnesene. One of the only unmodified animal products used in medicine is squalene, a triterpenoid derived from shark liver oil, which when formulated into an emulsion is used as a vaccine adjuvant to enhance immune responses in licensed vaccines. However, overfishing is depleting deep-sea shark populations, leading to potential supply problems for squalene. We chemically generated over 20 squalene analogues from fermentation-derived beta-farnesene and evaluated adjuvant activity of the emulsified compounds compared to shark squalene emulsion. By employing a desirability function approach that incorporated multiple immune readouts, we identified analogues with enhanced, equivalent, or decreased adjuvant activity compared to shark squalene emulsion. Availability of a library of structurally related analogues allowed elucidation of structure-function relationships. Thus, combining industrial synthetic biology with chemistry and immunology enabled generation of sustainable terpenoid-based vaccine adjuvants comparable to current shark squalene-based adjuvants while illuminating structural properties important for adjuvant activity.

Automated summary

Synthetic biology has been used to produce supply-limited sesquiterpenoids, such as artemisinin and beta-farnesene. As the overfishing of deep-sea sharks has led to potential supply problems for squalene, a triterpenoid derived from shark liver oil, researchers have chemically generated squalene analogues from fermentation-derived beta-farnesene to serve as sustainable vaccine adjuvants. By evaluating the adjuvant activity of these analogues, they have identified compounds with enhanced, equivalent, or decreased activity compared to shark squalene emulsion, shedding light on the structural properties important for adjuvant activity.