Identification of a conserved neutralizing epitope present on spike proteins from highly pathogenic coronaviruses

Huang, Y.; Nguyen, A. W.; Hsieh, C.-L.; Silva, R.; Olaluwoye, O. S.; Wilen, R.; Kaoud, T. S.; Azouz, L. R.; Qerqez, A. N.; Le, K. C.; Bohanon, a. L.; DiVenere, A. M.; Liu, Y.; Amengor, D.; Dalby, K.; D'Arcy, S.; McLellan, J. S.; Maynard, J. A.

doi:10.1101/2021.01.31.428824

bioRxiv · 10.1101/2021.01.31.428824

Identification of a conserved neutralizing epitope present on spike proteins from highly pathogenic coronaviruses

Huang, Y.·Nguyen, A. W.·Hsieh, C.-L.·Silva, R.·Olaluwoye, O. S.·Wilen, R.·Kaoud, T. S.·Azouz, L. R.·Qerqez, A. N.·Le, K. C.·Bohanon, a. L.·DiVenere, A. M.·Liu, Y.·Amengor, D.·Dalby, K.·D'Arcy, S.·McLellan, J. S.·Maynard, J. A.

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Abstract

Three pathogenic human coronaviruses have emerged within the last 20 years, with SARS-CoV-2 causing a global pandemic. Although therapeutic antibodies targeting the SARS-CoV-2 spike currently focus on the poorly conserved receptor-binding domain, targeting essential neutralizing epitopes on the more conserved S2 domain may provide broader protection. We report an antibody binding an epitope conserved in the pre-fusion core of MERS-CoV, SARS-CoV and SARS-CoV-2 spike S2 domains. Antibody 3A3 binds a conformational epitope with ~2.5 nM affinity and neutralizes spike from SARS-CoV, SARS-CoV-2 and variants of concern in in vitro pseudovirus assays. Hydrogen-deuterium exchange mass spectrometry identified residues 980-1006 in the flexible hinge region at the S2 apex as the 3A3 epitope, suggesting 3A3 prevents the S2 conformational rearrangements required for conversion to the spike post-fusion state and virus-host cell fusion. This work defines a conserved vulnerable site on the SARS-CoV-2 S2 domain and guides the design of pan-protective spike immunogens.

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Huang, Y., Nguyen, A. W., Hsieh, C.-L., Silva, R., Olaluwoye, O. S., Wilen, R., Kaoud, T. S., Azouz, L. R., Qerqez, A. N., Le, K. C., Bohanon, a. L., DiVenere, A. M., Liu, Y., Amengor, D., Dalby, K., D'Arcy, S., McLellan, J. S., Maynard, J. A.. 2021-02-01. Identification of a conserved neutralizing epitope present on spike proteins from highly pathogenic coronaviruses. https://doi.org/10.1101/2021.01.31.428824

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