Rationally Designed TLR2-QS-21 Liposomal Adjuvant Enhances Immunogenicity while Reducing Reactogenicity in Subunit Vaccines

Potent vaccine adjuvants often link strong adaptive immunity with excessive inflammation. Here, we developed BQS01, a liposomal adjuvant that replaces the TLR4 agonist monophosphoryl lipid A (MPL) with a synthetic TLR2 agonist (BXY-14) while retaining QS-21. BQS01 induced a TLR2-associated transcriptional profile, enhanced dendritic cell activation and T-cell priming, and was associated with increased IL-10 production. In ovalbumin and varicella-zoster virus mouse models, BQS01 generated antibody responses comparable to an AS01b-like MPL/QS-21 comparator and durable polyfunctional cellular immunity, while reducing systemic weight loss, local inflammation, and TNF-α accumulation. These findings suggest that innate signaling architecture, rather than inflammatory magnitude alone, contributes to adjuvant performance and may guide the design of next-generation vaccines with an improved immunogenicity−reactogenicity balance.