Multifunctional Lipidated Protein Carrier with a Built-In Adjuvant as a Universal Vaccine Platform Potently Elevates Immunogenicity of Weak Antigens

Abstract

Weak antigens represented by MUC1 are poorly immunogenic, which greatly constrains the development of relevant vaccines. Herein, we developed a multifunctional lipidated protein as a carrier, in which the TLR1/2 agonist Pam 3 CSK 4 was conjugated to the N-terminus of MUC1-loaded carrier protein BSA through pyridoxal 5′phosphate-mediated transamination reaction. The resulting Pam 3 CSK 4 − BSA-MUC1 conjugate was subsequently incorporated into liposomes, which biomimics the membrane structure of tumor cells. The results indicated that this lipidated protein carrier significantly enhanced antigen uptake by APCs and obviously augmented the retention of the vaccine at the injection site. Compared with the BSA-MUC1 and BSA-MUC1 + Pam 3 CSK 4 groups, Pam 3 CSK 4 −BSA-MUC1 evoked 22-and 11-fold increases in MUC1-specific IgG titers. Importantly, Pam 3 CSK 4 −BSA-MUC1 elicited robust cellular immunity and significantly inhibited tumor growth. This is the first time that lipidated protein was constructed to enhance antigen immunogenicity, and this universal carrier platform exhibits promise for utilization in various vaccines, holding the potential for further clinical application.

Rationally Designed Highly Potent NKT Cell Agonists with Different Cytokine Selectivity through Hydrogen-Bond Interaction

“…As the prototype NKT cell-activating ligand, α-galactosylceramide (αGalCer) has been extensively studied for applications in immunotherapy , and vaccine as adjuvant, − among which conjugating αGalCer to antigens has shown effective enhancement in vaccine efficacy as other conjugate vaccines. − On the other hand, scientists are still making efforts to pursue new αGalCer analogues, as structural alterations to αGalCer have been found to profoundly shape the balance between Th1 and Th2 responses. , However, the fundamental principles governing the preferential generation of either Th1 or Th2 cytokines still remain uncovered. Nonetheless, an intensified interaction between glycolipids and CD1d has been reported to promote Th1-skewed polarization. , In line with this premise, several representative Th1-biasing ligands have been designed regarding the structure–activity relationship (SAR) of glycolipid binding to CD1d, such as αGalCer analogues with aromatic groups introduced in the fatty acyl chain, − sphingosine chain, , or hydroxyl groups on the pyranose ring. − In addition, altering the stability of the CD1d/glycolipid binary or the association between the binary and T cell receptor (TCR) was also reported to favor the production of IFN-γ. − A collection of representative αGalCer analogues with Th1-biased modifications is shown in Table S1, most of which are designed to regulate the interaction between ligands and CD1d.…”