Superimmunity by pan-sarbecovirus nanobodies

Yufei Xiang, Wei Huang, Hejun Liu, Zhe Sang, Sham Nambulli, Jérôme Tubiana, Kevin L. Williams, W. Paul Duprex, Dina Schneidman-Duhovny, Ian A. Wilson, Derek J. Taylor, Yi Shi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Vaccine boosters and infection can facilitate the development of SARS-CoV-2 antibodies with improved potency and breadth. Here, we observe superimmunity in a camelid extensively immunized with the SARS-CoV-2 receptor-binding domain (RBD). We rapidly isolate a large repertoire of specific ultra-high-affinity nanobodies that bind strongly to all known sarbecovirus clades using integrative proteomics. These pan-sarbecovirus nanobodies (psNbs) are highly effective against SARS-CoV and SARS-CoV-2 variants, including Omicron, with the best median neutralization potency at single-digit nanograms per milliliter. A highly potent, inhalable, and bispecific psNb (PiN-31) is also developed. Structural determinations of 13 psNbs with the SARS-CoV-2 spike or RBD reveal five epitope classes, providing insights into the mechanisms and evolution of their broad activities. The highly evolved psNbs target small, flat, and flexible epitopes that contain over 75% of conserved RBD surface residues. Their potencies are strongly and negatively correlated with the distance of the epitopes from the receptor binding sites.

Original languageAmerican English
Article number111004
JournalCell Reports
Volume39
Issue number13
DOIs
StatePublished - 28 Jun 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)

Keywords

  • CP: Immunology
  • SARS-CoV-2
  • VH antibody
  • broadly neutralizing nanobody
  • inhalable bispecific nanobody PiN-31
  • pan-sarbecovirus neutralization
  • super immunity

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