Cross-neutralizing antibodies bind a SARS-CoV-2 cryptic site and resist circulating variants

The emergence of numerous SARS-CoV-2 variants challenges pandemic control. The authors obtained two cross-neutralizing antibodies (7D6 and 6D6) targeting sarbecovirus RBD with very high affinities and potent neutralization of authentic SARS‑CoV‑2. Crystal structures show both bind a cryptic, highly conserved site distinct from epitopes recognized by many existing antibodies. Binding of these antibodies clashes with the adjacent N‑terminal domain and disrupts the spike trimer. Both antibodies resist mutations present in circulating variants. These findings support their potential as passive therapeutics/prophylactics and inform pan‑sarbecovirus vaccine design.