VSA-2-, a novel plant-derived adjuvant for SARS-CoV-2 subunit vaccine.

QS-21, a key component of several licensed vaccines is facing limited supply, dose-limiting toxicity and other drawbacks which together limit its broader usage. Development of saponin alternatives to QS-21 that retain its desirable adjuvant activity without its drawbacks is in high need. Incorporating an amide side chain into the more sustainable Momordica saponins (MS) I and II led to the recent discovery of two semisynthetic immunostimulatory adjuvants VSA-1 and VSA-2. Here, we showed that SARS-CoV-2 receptor-binding protein (RBD) adjuvanted with VSA-2 induced high titers of SARS-CoV-2 specific humoral and T helper-1 prone immune responses in mice comparable to that triggered by QS-21-RBD vaccination. Vaccination with VSA-2-RBD provided strong protection against SARS-CoV-2 and variants infection and the virus-induced lung inflammation and pathology similarly as QS-21-RBD vaccination. Overall, our results suggest that VSA-2 adjuvant can potentially complement the clinically proven saponin adjuvant QS-21 in vaccines against infectious diseases.