Developing Next‐Generation Protein‐Based Vaccines Using High‐Affinity Glycan Ligand‐Decorated Glyconanoparticles

Abstract

Major diseases, such as cancer and COVID‐19, are frightening global health problems, and sustained action is necessary to develop vaccines. Here, for the first time, ethoxy acetalated dextran nanoparticles (Ace‐Dex‐NPs) are functionalized with 9‐N‐(4H‐thieno[3,2‐c]chromene‐2‐carbamoyl)‐Siaα2−3Galβ1−4GlcNAc (TCCSia‐LacNAc) targeting macrophages as a universal vaccine design platform. First, azide‐containing oxidized Ace‐Dex‐NPs are synthesized. After the NPs are conjugated with ovalbumin (OVA) and resiquimod (Rd), they are coupled to TCCSia‐LacNAc‐DBCO to produce TCCSia‐Ace‐Dex‐OVA‐Rd, which induce a potent, long‐lasting OVA‐specific cytotoxic T‐lymphocyte (CTL) response and high anti‐OVA IgG, providing mice with superior protection against tumors. Next, this strategy is exploited to develop vaccines against infection by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). The receptor‐binding domain (RBD) of the SARS‐CoV‐2 spike protein is the main target for neutralizing antibodies. The TCCSia‐Ace‐Dex platform is preferentially used for designing an RBD‐based vaccine. Strikingly, the synthetic TCCSia‐Ace‐Dex‐RBD‐Rd elicited potent RBD‐neutralizing antibodies against live SARS‐CoV‐2 infected Vero E6 cells. To develop a universal SARS‐CoV‐2 vaccine, the TCCSia‐Ace‐Dex‐N‐Rd vaccine carrying SARS‐CoV‐2 nucleocapsid protein (N) is also prepared, which is highly conserved among SARS‐CoV‐2 and its variants of concern (VOCs), including Omicron (BA.1 to BA.5); this vaccine can trigger strong N‐specific CTL responses against target cells infected with SARS‐CoV‐2 and its VOCs.

Overview of Nucleocapsid-Targeting Vaccines against COVID-19

“…Unique glyconanoparticles were created by Gao et al [ 56 ] by conjugation of whole recombinant N protein with a number of high-affinity dextran derivatives. The vaccines induced the production of anti-N antibodies in mice and rabbits and triggered potent and prolonged N-specific CTL responses against cells infected with different SARS-CoV-2 strains.…”

Glycopolymers for Antibacterial and Antiviral Applications

“…Another important future direction may be host−directed immunotherapy, as the disadvantages of pathogen−directed therapeutics include resistance selection and virus mutation. The effectiveness of cancer immunotherapy has aroused people’s great interest in applying these methods to treat bacterial and viral infections [ 74 , 75 , 76 , 77 , 78 ]. Glycopolymers have shown potential in cancer immunotherapy [ 79 , 80 ], which is believed to be a good candidate for bacterial and viral immunotherapy treatment with proper molecular design.…”

Biomaterial engineering strategies for B cell immunity modulations

“…[128][129][130][131][132] Gao et al recently designed TCC Neu5Ac-displaying acetylated dextran nanoparticles that carried both protein antigens and imiquimod, a TLR7/8 agonist, as adjuvant, to demonstrate the enhancing effect of TCC Neu5Ac ligand-mediated SSM-targeted delivery on B cell responses. 133 These nanoparticles showed a significant targeting effect toward CD169+ macrophages in vitro and elicited more potent antibody responses and CD8+ T cell responses as compared with the non-targeting control nanoparticles. Using SSM-targeting nanoparticles that carry SARS-CoV-2 RBD proteins showed a similar improvement in antibody responses in both mice and rabbits, as compared with either protein control or PEG nanoparticles.…”