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

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

Posted 31 Mar 2021
bioRxiv DOI: 10.1101/2021.03.30.437769

We recently described CC40.8 bnAb from a COVID-19 donor that exhibits broad reactivity with human {beta}-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 A resolution and found that the peptide adopts a mainly helical structure. Conserved residues in {beta}-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-{beta}-CoV vaccines.

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