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

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 journal › Article › peer-review

43 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 language	English
Pages (from-to)	3486-3501.e21
Journal	Cell
Volume	184
Issue number	13
DOIs	https://doi.org/10.1016/j.cell.2021.05.001
State	Published - 24 Jun 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

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2021.05.001

Cite this

Fels, J. M., Maurer, D. P., Herbert, A. S., Wirchnianski, A. S., Vergnolle, O., Cross, R. W., Abelson, D. M., Moyer, C. L., Mishra, A. K., Aguilan, J. T., Kuehne, A. I., Pauli, N. T., Bakken, R. R., Nyakatura, E. K., Hellert, J., Quevedo, G., Lobel, L., Balinandi, S., Lutwama, J. J., ... Chandran, K. (2021). Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever. Cell, 184(13), 3486-3501.e21. https://doi.org/10.1016/j.cell.2021.05.001

@article{76ed13a6faca4ded9811712e22c27965,

title = "Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever",

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",

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

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = jun,

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doi = "10.1016/j.cell.2021.05.001",

language = "English",

volume = "184",

pages = "3486--3501.e21",

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Fels, JM, Maurer, DP, Herbert, AS, Wirchnianski, AS, Vergnolle, O, Cross, RW, Abelson, DM, Moyer, CL, Mishra, AK, Aguilan, JT, Kuehne, AI, Pauli, NT, Bakken, RR, Nyakatura, EK, Hellert, J, Quevedo, G, Lobel, L, Balinandi, S, Lutwama, JJ, Zeitlin, L, Geisbert, TW, Rey, FA, Sidoli, S, McLellan, JS, Lai, JR, Bornholdt, ZA, Dye, JM, Walker, LM & Chandran, K 2021, 'Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever', Cell, vol. 184, no. 13, pp. 3486-3501.e21. https://doi.org/10.1016/j.cell.2021.05.001

TY - JOUR

T1 - Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever

AU - Fels, J. Maximilian

AU - Maurer, Daniel P.

AU - Herbert, Andrew S.

AU - Wirchnianski, Ariel S.

AU - Vergnolle, Olivia

AU - Cross, Robert W.

AU - Abelson, Dafna M.

AU - Moyer, Crystal L.

AU - Mishra, Akaash K.

AU - Aguilan, Jennifer T.

AU - Kuehne, Ana I.

AU - Pauli, Noel T.

AU - Bakken, Russell R.

AU - Nyakatura, Elisabeth K.

AU - Hellert, Jan

AU - Quevedo, Gregory

AU - Lobel, Leslie

AU - Balinandi, Stephen

AU - Lutwama, Julius J.

AU - Zeitlin, Larry

AU - Geisbert, Thomas W.

AU - Rey, Felix A.

AU - Sidoli, Simone

AU - McLellan, Jason S.

AU - Lai, Jonathan R.

AU - Bornholdt, Zachary A.

AU - Dye, John M.

AU - Walker, Laura M.

AU - Chandran, Kartik

PY - 2021/6/24

Y1 - 2021/6/24

N2 - 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.

AB - 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.

KW - CCHFV

KW - Crimean-Congo hemorrhagic fever virus

KW - antibody therapeutic

KW - bunyavirus

KW - emerging virus

KW - human monoclonal antibody

KW - monoclonal antibody

KW - nairovirus

KW - tickborne

KW - viral glycoprotein

UR - http://www.scopus.com/inward/record.url?scp=85108370686&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.05.001

DO - 10.1016/j.cell.2021.05.001

M3 - Article

C2 - 34077751

AN - SCOPUS:85108370686

SN - 0092-8674

VL - 184

SP - 3486-3501.e21

JO - Cell

JF - Cell

IS - 13

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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