Vaccine-elicited murine antibody WS6 neutralizes diverse beta-coronaviruses by recognizing a helical stem supersite of vulnerability

  1. Wei Shi
  2. Lingshu Wang
  3. Tongqing Zhou
  4. Mallika Sastry
  5. Eun Sung Yang
  6. Yi Zhang
  7. Man Chen
  8. Xuejun Chen
  9. Misook Choe
  10. Adrian Creanga
  11. Kwan Leung
  12. Adam S. Olia
  13. Amarendra Pegu
  14. Reda Rawi
  15. Chen-Hsiang Shen
  16. Erik-Stephane D. Stancofski
  17. Chloe Adrienna Talana
  18. I-Ting Teng
  19. Shuishu Wang
  20. Kizzmekia S. Corbett
  21. Yaroslav Tsybovsky
  22. John R. Mascola
  23. Peter D. Kwong
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Abstract

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.

Highlights

  • SARS-CoV-2 spike mRNA-immunized mouse elicited an antibody, WS6, that cross reacts with spikes of diverse human and bat beta-coronaviruses

  • WS6 neutralizes SARS-CoV-2 variants, SARS-CoV, and related viruses

  • Crystal structure at 2-Å resolution of WS6 in complex with a conserved S2 peptide reveals recognition of a helical epitope

  • WS6 neutralizes by inhibition of fusion, post-viral attachment

  • WS6 recognizes a supersite of vulnerability also recognized by other recently identified antibodies

  • Helical supersite of vulnerability comprises a hydrophobic cluster spanning three helical turns, with acid residues framing the center turn

  • Genetic and structural analysis indicate supersite recognition to be compatible with diverse antibody ontogenies

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