TY - JOUR T1 - Vaccine-elicited murine antibody WS6 neutralizes diverse beta-coronaviruses by recognizing a helical stem supersite of vulnerability JF - bioRxiv DO - 10.1101/2022.01.25.477770 SP - 2022.01.25.477770 AU - Wei Shi AU - Lingshu Wang AU - Tongqing Zhou AU - Mallika Sastry AU - Eun Sung Yang AU - Yi Zhang AU - Man Chen AU - Xuejun Chen AU - Misook Choe AU - Adrian Creanga AU - Kwan Leung AU - Adam S. Olia AU - Amarendra Pegu AU - Reda Rawi AU - Chen-Hsiang Shen AU - Erik-Stephane D. Stancofski AU - Chloe Adrienna Talana AU - I-Ting Teng AU - Shuishu Wang AU - Kizzmekia S. Corbett AU - Yaroslav Tsybovsky AU - John R. Mascola AU - Peter D. Kwong Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/01/26/2022.01.25.477770.abstract N2 - Immunization with SARS-CoV-2 spike elicits diverse antibodies, but can any of these neutralize broadly? Here, we report the isolation and characterization of antibody WS6, from a mouse immunized with mRNA encoding the SARS-CoV-2 spike. WS6 bound diverse beta-coronavirus spikes and neutralized SARS-CoV-2 variants, SARS-CoV, and related sarbecoviruses. Epitope mapping revealed WS6 to target a region in the S2 subunit, which was conserved among SARS-CoV-2, MERS-CoV, and hCoV-OC43. The crystal structure at 2-Å resolution of WS6 with its S2 epitope revealed recognition to center on a conserved helix, which was occluded in both prefusion and post-fusion spike conformations. Structural and neutralization analyses indicated WS6 to neutralize by inhibiting fusion, post-viral attachment. Comparison of WS6 to other antibodies recently identified from convalescent donors or mice immunized with diverse spikes indicated a stem-helical supersite – centered on hydrophobic residues Phe1148, Leu1152, Tyr1155, and Phe1156 – to be a promising target for vaccine design.HighlightsSARS-CoV-2 spike mRNA-immunized mouse elicited an antibody, WS6, that cross reacts with spikes of diverse human and bat beta-coronavirusesWS6 neutralizes SARS-CoV-2 variants, SARS-CoV, and related virusesCrystal structure at 2-Å resolution of WS6 in complex with a conserved S2 peptide reveals recognition of a helical epitopeWS6 neutralizes by inhibition of fusion, post-viral attachmentWS6 recognizes a supersite of vulnerability also recognized by other recently identified antibodiesHelical supersite of vulnerability comprises a hydrophobic cluster spanning three helical turns, with acid residues framing the center turnGenetic and structural analysis indicate supersite recognition to be compatible with diverse antibody ontogeniesCompeting Interest StatementThe authors have declared no competing interest. ER -