A protective broadly cross-reactive human antibody defines a conserved site of vulnerability on beta-coronavirus spikes

Zhou, Panpan; Yuan, Meng; Song, Ge; Beutler, Nathan; Shaabani, Namir; Huang, Deli; He, Wan-ting; Zhu, Xueyong; Callaghan, Sean; Yong, Peter; Anzanello, Fabio; Peng, Linghang; Ricketts, James; Parren, Mara; Garcia, Elijah; Rawlings, Stephen A.; Smith, Davey M.; Nemazee, David; Teijaro, John R.; Rogers, Thomas F.; Wilson, Ian A.; Burton, Dennis R.; Andrabi, Raiees

We recently described CC40.8 bnAb from a COVID-19 donor that exhibits broad reactivity with human β-CoVs. Here, we show that CC40.8 targets the conserved S2 stem-helix region of the coronavirus spike fusion machinery. We determined a crystal structure of CC40.8 Fab with a SARS-CoV-2 S2 stem-peptide at 1.6 Å resolution and found that the peptide adopts a mainly helical structure. Conserved residues in β-CoVs interact with the antibody, thereby providing a molecular basis for its broad reactivity. CC40.8 exhibits in vivo protective efficacy against SARS-CoV-2 challenge in a hamster model with reduction in weight loss and lung viral titers. Furthermore, we noted CC40.8-like bnAbs are relatively rare in human COVID-19 infection and therefore their elicitation may require rational vaccine strategies. Overall, our study describes a new target on CoV spikes for protective antibodies that may facilitate the development of pan-β-CoV vaccines. SUMMARY A human mAb isolated from a COVID-19 donor defines a protective cross-neutralizing epitope promising for pan-β-CoV vaccine strategies