Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever

J. Maximilian Fels, Daniel P. Maurer, Andrew S. Herbert, Ariel S. Wirchnianski, Olivia Vergnolle, Robert W. Cross, Dafna M. Abelson, Crystal L. Moyer, Akaash K. Mishra, Jennifer T. Aguilan, Ana I. Kuehne, Noel T. Pauli, Russell R. Bakken, Elisabeth K. Nyakatura, Jan Hellert, Gregory Quevedo, Leslie Lobel, Stephen Balinandi, Julius J. Lutwama, Larry ZeitlinThomas W. Geisbert, Felix A. Rey, Simone Sidoli, Jason S. McLellan, Jonathan R. Lai, Zachary A. Bornholdt, John M. Dye, Laura M. Walker, Kartik Chandran

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Crimean-Congo hemorrhagic fever virus (CCHFV) is a World Health Organization priority pathogen. CCHFV infections cause a highly lethal hemorrhagic fever for which specific treatments and vaccines are urgently needed. Here, we characterize the human immune response to natural CCHFV infection to identify potent neutralizing monoclonal antibodies (nAbs) targeting the viral glycoprotein. Competition experiments showed that these nAbs bind six distinct antigenic sites in the Gc subunit. These sites were further delineated through mutagenesis and mapped onto a prefusion model of Gc. Pairwise screening identified combinations of non-competing nAbs that afford synergistic neutralization. Further enhancements in neutralization breadth and potency were attained by physically linking variable domains of synergistic nAb pairs through bispecific antibody (bsAb) engineering. Although multiple nAbs protected mice from lethal CCHFV challenge in pre- or post-exposure prophylactic settings, only a single bsAb, DVD-121-801, afforded therapeutic protection. DVD-121-801 is a promising candidate suitable for clinical development as a CCHFV therapeutic.

Original languageEnglish (US)
Pages (from-to)3486-3501.e21
JournalCell
Volume184
Issue number13
DOIs
StatePublished - Jun 24 2021

Keywords

  • CCHFV
  • Crimean-Congo hemorrhagic fever virus
  • antibody therapeutic
  • bunyavirus
  • emerging virus
  • human monoclonal antibody
  • monoclonal antibody
  • nairovirus
  • tickborne
  • viral glycoprotein

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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