Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base.

Summary

Single-domain antibodies (VHHs) targeting a conserved quaternary epitope at the HR2 base of spike broadly and potently neutralize SARS-CoV-1/2. A VHH-Fc prevented SARS-CoV-2 infection at low dose in two animal models, and escape variants were rare and poorly infectious.

Key Findings

• VHHs against the S2 HR2 base broadly neutralized SARS-CoV-1 and -2 with unusually high potency.
• A VHH clamps a conserved quaternary epitope in HR2, locking spike in prefusion state.
• Systemic low-dose VHH-Fc prevented SARS-CoV-2 infection in two animal models.
• Escape variants selected by pseudovirus were very rare and largely non-infectious.

Clinical Implications

While preclinical, these VHHs identify HR2 S2 base as a priority antiviral target and support development of pan-sarbecovirus prophylaxis/therapy less prone to escape, informing next-generation antibody designs.

Limitations

• Preclinical; no human safety or efficacy data yet
• Potential immunogenicity and manufacturability of VHH-Fc require evaluation

Future Directions

Advance to GLP toxicology and first-in-human trials; evaluate breadth against emerging sarbecoviruses; explore inhaled delivery for respiratory tract targeting.