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

Area of Science:

• Biotechnology
• Immunology
• Nanomedicine

Background:

• Cancer and COVID-19 represent significant global health challenges requiring advanced vaccine strategies.
• Existing vaccine platforms may have limitations in inducing broad and durable immune responses.
• Targeting macrophages offers a promising approach for enhancing vaccine efficacy.

Purpose of the Study:

• To develop a universal vaccine design platform using novel ethoxy acetalated dextran nanoparticles (Ace-Dex-NPs).
• To functionalize Ace-Dex-NPs with a macrophage-targeting carbohydrate (^TCC Sia-LacNAc) for enhanced immunogenicity.
• To evaluate the efficacy of this platform in preclinical models for cancer and SARS-CoV-2 vaccines.

Main Methods:

• Synthesis of azide-containing oxidized Ace-Dex-NPs.
• Conjugation of nanoparticles with model antigens (ovalbumin) or viral antigens (SARS-CoV-2 RBD, N protein) and an adjuvant (resiquimod).
• Coupling of functionalized nanoparticles with ^TCC Sia-LacNAc-DBCO for macrophage targeting.
• Assessment of immune responses, including cytotoxic T-lymphocyte (CTL) activity and antibody production, in mouse models.

Main Results:

• ^TCC Sia-Ace-Dex-OVA-Rd induced potent, long-lasting OVA-specific CTL responses and high anti-OVA IgG, conferring superior tumor protection in mice.
• ^TCC Sia-Ace-Dex-RBD-Rd elicited potent RBD-neutralizing antibodies against live SARS-CoV-2.
• ^TCC Sia-Ace-Dex-N-Rd triggered strong N-specific CTL responses against SARS-CoV-2 and its variants, including Omicron.

Conclusions:

• The ^TCC Sia-Ace-Dex nanoparticle platform serves as a versatile and effective universal vaccine design strategy.
• This platform demonstrates significant potential for developing vaccines against both cancer and infectious diseases like COVID-19.
• The ability to elicit robust CTL responses and neutralizing antibodies highlights the platform's broad applicability.