ACE2 engagement exposes the fusion peptide to pan-coronavirus neutralizing antibodies

Low, J. S.; Jerak, J.; Tortorici, M. A.; McCallum, M.; Pinto, D.; Cassotta, A.; Foglierini, M.; Mele, F.; Abdelnabi, R.; Weynand, B.; Noack, J.; Montiel-Ruiz, M.; Bianchi, S.; Benigni, F.; Sprugasci, N.; Joshi, A.; Bowen, J. E.; Walls, A. C.; Jarrossay, D.; Morone, D.; Paparoditis, P.; Garzoni, C.; Ferrari, P.; Ceschi, A.; Neyts, J.; Purcell, L. A.; Snell, G.; Corti, D.; Lanzavecchia, A.; Veesler, D.; Sallusto, F.

doi:10.1101/2022.03.30.486377

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bioRxiv · 10.1101/2022.03.30.486377

ACE2 engagement exposes the fusion peptide to pan-coronavirus neutralizing antibodies

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Abstract

Coronaviruses use diverse Spike (S) glycoproteins to attach to host receptors and fuse with target cells. Using a broad screening approach, we isolated from SARS-CoV-2 immune donors seven monoclonal antibodies (mAbs) that bind to all human alpha and beta coronavirus S proteins. These mAbs recognize the fusion peptide and acquire high affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha and beta coronaviruses, including Omicron BA.1 variant and bat WIV-1, and reduce viral titers and pathology in vivo. Structural and functional analyses show that the fusion peptide-specific mAbs bind with different modalities to a cryptic epitope which is concealed by prefusion-stabilizing 2P mutations and becomes exposed upon binding of ACE2 or ACE2-mimicking mAbs. This study identifies a new class of pan-coronavirus neutralizing mAbs and reveals a receptor-induced conformational change in the S protein that exposes the fusion peptide region.

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Low, J. S., Jerak, J., Tortorici, M. A., McCallum, M., Pinto, D., Cassotta, A., Foglierini, M., Mele, F., Abdelnabi, R., Weynand, B., Noack, J., Montiel-Ruiz, M., Bianchi, S., Benigni, F., Sprugasci, N., Joshi, A., Bowen, J. E., Walls, A. C., Jarrossay, D., Morone, D., Paparoditis, P., Garzoni, C., Ferrari, P., Ceschi, A., Neyts, J., Purcell, L. A., Snell, G., Corti, D., Lanzavecchia, A., Veesler, D., Sallusto, F.. 2022-03-30. ACE2 engagement exposes the fusion peptide to pan-coronavirus neutralizing antibodies. https://doi.org/10.1101/2022.03.30.486377

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