A broadly neutralizing antibody recognizing a unique epitope with signature motif common across coronaviral families

Cross-reactive antibodies that bind to diverse epitopes have been identified in Sarbecoviruses, but the precise molecular mechanisms remain poorly understood. This study describes the isolation of a broadly neutralizing monoclonal antibody, 3D1, derived from a fully human combinatorial antibody library that targets the highly conserved HR1 domain of Sarbecoviruses. 3D1 uniquely recognizes a type 1 β-turn fold consisting of a 6-mer epitopic peptide, pepDVVNQN/Q, which forms during a pre-hairpin transition state—a conformation that occurs exclusively before membrane fusion during viral infection. It effectively neutralizes a wide range of live SARS-CoV-2 wild-type strains and variants of concern (VOCs), with the exception of Omicron, which evades neutralization due to a detrimental point mutation (Q954H). Notably, this cryptic epitope reveals a signature binding motif that appears to extend throughout the core region of the glycoprotein of coronaviruses and is also present in various RNA virus orthologs, including those of HIV and Marburgvirus. 3D1 functions as a natural or background antibody capable of binding to a diverse array of non-self antigens. Its cross-reactivity toward a wide variety of antigens underscores the effectiveness of the combinatorial antibody library approach, which encompasses the entire antibody repertoire.