Intranasal DC-targeting vaccine booster elicits durable and cross-clade protective immunity against sarbecoviruses in mice.

Summary

In Comirnaty-primed mice, an intranasal Clec9A-targeted dual-RBD booster (Clec9AOMNI) elicited stronger and more sustained cross-clade neutralizing antibodies and T-cell responses than a bivalent mRNA booster, with durable mucosal immunity and undetectable respiratory viral titers upon challenge. Sustained Tfh, germinal center B cells, and long-lived plasma cells supported affinity maturation and triple cross-reactive B cells.

Key Findings

• Clec9A-targeted dual-RBD nasal booster induced stronger, sustained cross-clade nAbs and T-cell responses than bivalent mRNA booster in Comirnaty-primed mice.
• Persistence of RBD-specific Tfh, germinal center B cells, and long-lived plasma cells with triple cross-reactive B cells to ancestral, XBB.1.5, and SARS-CoV-1 RBDs.
• Intranasal boosting yielded robust mucosal immunity and undetectable respiratory viral titers after SARS-CoV-2 challenge.

Clinical Implications

Supports development of intranasal DC-targeted boosters as complementary to systemic mRNA vaccines to enhance mucosal sterilizing immunity and breadth; informs antigen design and delivery routes for next-gen coronavirus vaccines.

Limitations

• Preclinical murine model; human safety and immunogenicity unknown
• Manufacturing and scalability of DC-targeting antibody-fusion constructs require validation

Future Directions

Evaluate safety, dosing, and durability in nonhuman primates and phase 1 studies; assess transmission-blocking potential and breadth against emerging sarbecoviruses; optimize intranasal delivery platforms.