Isolation and escape mapping of broadly neutralizing antibodies against emerging delta-coronaviruses

Megi Rexhepaj; Daniel Asarnow; Lisa Perruzza; Young-Jun Park; Barbara Guarino; Mathew Mccallum; Katja Culap; Christian Saliba; Giada Leoni; Alessio Balmelli; Courtney N Yoshiyama; Miles S Dickinson; Joel Quispe; Jack T Brown; M Alejandra Tortorici; Kaitlin R Sprouse; Ashley L Taylor; Davide Corti; Tyler N Starr; Fabio Benigni; David Veesler

doi:10.1016/j.immuni.2024.10.001

Isolation and escape mapping of broadly neutralizing antibodies against emerging delta-coronaviruses

Immunity. 2024 Oct 30:S1074-7613(24)00481-3. doi: 10.1016/j.immuni.2024.10.001. Online ahead of print.

Authors

Megi Rexhepaj¹, Daniel Asarnow¹, Lisa Perruzza², Young-Jun Park³, Barbara Guarino², Mathew Mccallum¹, Katja Culap², Christian Saliba², Giada Leoni², Alessio Balmelli², Courtney N Yoshiyama¹, Miles S Dickinson¹, Joel Quispe¹, Jack T Brown¹, M Alejandra Tortorici³, Kaitlin R Sprouse³, Ashley L Taylor⁴, Davide Corti², Tyler N Starr⁵, Fabio Benigni⁶, David Veesler⁷

Affiliations

¹ Department of Biochemistry, University of Washington, Seattle, WA, USA.
² Humabs Biomed SA, a Subsidiary of Vir. Biotechnology, 6500 Bellinzona, Switzerland.
³ Department of Biochemistry, University of Washington, Seattle, WA, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
⁴ Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
⁵ Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Electronic address: tyler.starr@biochem.utah.edu.
⁶ Humabs Biomed SA, a Subsidiary of Vir. Biotechnology, 6500 Bellinzona, Switzerland. Electronic address: fbenigni@vir.bio.
⁷ Department of Biochemistry, University of Washington, Seattle, WA, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA. Electronic address: dveesler@uw.edu.

PMID: 39488210
DOI: 10.1016/j.immuni.2024.10.001

Abstract

Porcine delta-coronavirus (PDCoV) spillovers were recently detected in febrile children, underscoring the recurrent zoonoses of divergent CoVs. To date, no vaccines or specific therapeutics are approved for use in humans against PDCoV. To prepare for possible future PDCoV epidemics, we isolated PDCoV spike (S)-directed monoclonal antibodies (mAbs) from humanized mice and found that two, designated PD33 and PD41, broadly neutralized a panel of PDCoV variants. Cryoelectron microscopy (cryo-EM) structures of PD33 and PD41 in complex with the S receptor-binding domain (RBD) and ectodomain trimer revealed the epitopes recognized by these mAbs, rationalizing their broad inhibitory activity. We show that both mAbs competitively interfere with host aminopeptidase N binding to neutralize PDCoV and used deep-mutational scanning epitope mapping to associate RBD antigenic sites with mAb-mediated neutralization potency. Our results indicate a PD33-PD41 mAb cocktail may heighten the barrier to escape. PD33 and PD41 are candidates for clinical advancement against future PDCoV outbreaks.

Keywords: PDCoV; cryo-EM structures; deep mutational scanning; neutralizing antibodies; porcine deltacoronavirus; spike glycoprotein; zoonosis.