DNA-Engineered Modular Nanovaccines Featuring Precise Topology for Enhanced Immunogenicity.

Area of Science:

• Vaccinology
• Immunology
• Structural Biology

Background:

• Multivalent antigen display is crucial for enhancing subunit vaccine immunogenicity.
• Controlling the topology of multivalent antigens is challenging, limiting understanding of its immunomodulatory effects.

Purpose of the Study:

• To investigate the impact of antigen topology on immunogenicity using SARS-CoV-2 receptor-binding domains (RBDs).
• To develop a modular platform for precise assembly of multivalent antigens for vaccine development.

Main Methods:

• Utilized DNA-mediated modular precision assembly to create SARS-CoV-2 RBDs with distinct topological connections (linear vs. branching).
• Preserved native epitopes during assembly to ensure antigen recognition.

Main Results:

• Branching-connected RBDs elicited significantly higher IgG titers than linear-connected RBDs at higher antigen valencies (≥4).
• Increased IgG response correlated with enhanced B cell proliferation, suggesting improved B cell receptor signaling.
• Branching-connected RBDs demonstrated superior humoral immunity in mice and enhanced protection in SARS-CoV-2-infected hamsters compared to adjuvanted RBD.

Conclusions:

• Antigen topology plays a critical role in determining vaccine immunogenicity.
• A universal modular platform for precision assembly of multivalent antigens can lead to more effective subunit vaccines.