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 Zeitlin; Thomas W Geisbert; Felix A Rey; Simone Sidoli; Jason S McLellan; Jonathan R Lai; Zachary A Bornholdt; John M Dye; Laura M Walker; Kartik Chandran

doi:10.1016/j.cell.2021.05.001

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

Cell. 2021 Jun 24;184(13):3486-3501.e21. doi: 10.1016/j.cell.2021.05.001. Epub 2021 Jun 1.

Authors

J Maximilian Fels¹, Daniel P Maurer², Andrew S Herbert³, Ariel S Wirchnianski⁴, Olivia Vergnolle⁵, Robert W Cross⁶, Dafna M Abelson⁷, Crystal L Moyer⁷, Akaash K Mishra⁸, Jennifer T Aguilan⁹, Ana I Kuehne¹⁰, Noel T Pauli², Russell R Bakken¹⁰, Elisabeth K Nyakatura⁵, Jan Hellert¹¹, Gregory Quevedo⁵, Leslie Lobel¹², Stephen Balinandi¹³, Julius J Lutwama¹³, Larry Zeitlin⁷, Thomas W Geisbert⁶, Felix A Rey¹¹, Simone Sidoli⁵, Jason S McLellan⁸, Jonathan R Lai⁵, Zachary A Bornholdt¹⁴, John M Dye¹⁵, Laura M Walker¹⁶, Kartik Chandran¹⁷

Affiliations

¹ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
² Adimab, LLC, Lebanon, NH 03766, USA.
³ U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA; The Geneva Foundation, Tacoma, WA 98402, USA.
⁴ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Deparment of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁵ Deparment of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁶ Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77550, USA.
⁷ Mapp Biopharmaceutical, Inc., San Diego, CA 92121, USA.
⁸ Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
⁹ Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
¹⁰ U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA.
¹¹ Structural Virology Unit, Department of Virology, CNRS UMR 3569, Institut Pasteur, Paris 75724, France.
¹² Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
¹³ Uganda Virus Research Institute, Entebbe, Uganda.
¹⁴ Mapp Biopharmaceutical, Inc., San Diego, CA 92121, USA. Electronic address: [email protected].
¹⁵ U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA. Electronic address: [email protected].
¹⁶ Adimab, LLC, Lebanon, NH 03766, USA; Adagio Therapeutics, Inc., Waltham, MA 02451, USA. Electronic address: [email protected].
¹⁷ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: [email protected].

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.

Keywords: CCHFV; Crimean-Congo hemorrhagic fever virus; antibody therapeutic; bunyavirus; emerging virus; human monoclonal antibody; monoclonal antibody; nairovirus; tickborne; viral glycoprotein.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Antibodies, Monoclonal / immunology
Antibodies, Neutralizing / immunology*
Antigens, Viral / metabolism
Biophysical Phenomena
Chlorocebus aethiops
Epitope Mapping
Epitopes / metabolism
Female
Hemorrhagic Fever Virus, Crimean-Congo / immunology
Hemorrhagic Fever, Crimean / immunology*
Hemorrhagic Fever, Crimean / prevention & control
Humans
Immunoglobulin G / metabolism
Male
Mice
Neutralization Tests
Protein Binding
Protein Engineering
Recombinant Proteins / immunology
Survivors*
Vero Cells
Viral Proteins / chemistry

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antigens, Viral
Epitopes
Immunoglobulin G
Recombinant Proteins
Viral Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding